Helicobacter pylori - Portal Neonatal

Textbook of 

Pediatric Gastroenterology 

and Nutrition

Edited by 

Textbook of 

Pediatric Gastroenterology 

and Nutrition 

Stefano Guandalini MD 

Professor of Pediatrics 

Chief, Section of Gastroenterology 

University of Chicago Children’s Hospital 

Director, University of Chicago Celiac Disease Program 

Chicago, IL 

USA

© 2004 Taylor & Francis, an imprint of the Taylor & Francis Group 

First published in the United Kingdom in 2004 

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Contents 

Contributors vii 

Preface xi 

I Congenital Disorders 

1 Microvillus inclusion disease and 1 

epithelial dysplasia 

Olivier Goulet, Nelly Youssef and 

Frank M Ruemmele 

2 Congenital problems of the 13 

gastrointestinal tract 

Nigel Hall and Agostino Pierro 

II Diseases of the Esophagus and Stomach 

3 Infectious esophagitis 29 

Salvatore Cucchiara and 

Osvaldo Borrelli 

4 Gastroesophageal reflux disease 39 

Yvan Vandenplas, Silvia Salvatore 

and Bruno Hauser 

5 Achalasia 61 

Carl-Christian A Jackson and 

Donald C Liu 

6 Helicobacter pylori gastritis and 73 

peptic ulcer disease 

Costantino De Giacomo 

7 Other gastritides 95 



III Infectious Diseases of the Gastrointestinal 

Tract 

8 HIV and the intestine 113 

Nigel C Rollins 

9 Viral diarrhea 127 

Alfredo Guarino and Fabio Albano 

10 Bacterial infections 145 

Alessio Fasano 

11 Intestinal parasites 161 

David Brewster 

12 Post-infectious persistent 193 

diarrhea in developing countries 

Zulfiqar A Bhutta 

13 Small-bowel bacterial overgrowth 201 

Mauro Batista de Morais and 

Ulysses Fagundes-Neto 

IV Functional Disorders and 

Neurogastroenterology 

14 Functional abdominal pain and 213 

other functional bowel disorders 

Miguel Saps and Carlo Di Lorenzo 

15 Disorders of sucking and swallowing 233 

Erasmo Miele and Annamaria Staiano 

16 Constipation and encopresis in 247 

childhood 

Jan Taminiau and Marc Benninga 

17 Hirschsprung’s disease and 259 

intestinal neuronal dysplasias 

Annamaria Staiano, Lucia Quaglietta 

and Renata Auricchio 

18 Chronic intestinal pseudo- 269 

obstruction in childhood 

Peter J Milla 

19 Gastrointestinal and nutritional 283 

problems in the neurologically 

handicapped child 


20 Cyclic vomiting syndrome 289 

Bhanu Sunku and B UK Li 

V Inflammatory and Immune-mediated 

Disorders of the Gastrointestinal Tract 

21 Acute and chronic pancreatitis 303 

Michelle M Pietzak 

22 Food allergies 319 

Simon Murch 

23 Crohn’s disease 347 

Qian Yuan and Harland S Winter

vi 

Contents 

24 Indeterminate colitis 379 

Barbara S Kirschner 

25 Ulcerative colitis 385 

Leslie M Higuchi and Athos Bousvaros 

26 Vasculitides 419 



27 Celiac disease 435 

Stefano Guandalini 

28 Protein-losing enteropathy 451 

Jorge Amil Dias and Eunice Trindade 

29 Short-bowel syndrome 461 

Olivier Goulet 

30 Lymphonodular hyperplasia 479 

Jorma Kokkonen 

VI Nutritional Problems 

31 Malnutrition 489 

Michael H N Golden 

32 Biotherapeutic and 525 

nutraceutical agents 

Kirsi Laiho and Erika Isolauri 

33 Enteral nutrition 539 

Olivier Goulet and Virginie Colomb 

34 Parenteral nutrition in infants 555 

and children 


VII Gastrointestinal Disorders and Nutrition 

in the Neonatal Age 

35 Gastrointestinal problems of 579 

the newborn 

Moti M Chowdhury and 

Agostino Pierro 

36 Enteral nutrition in 599 

preterm infants 

Mario De Curtis and Jacques Rigo 

37 Parenteral nutrition in 619 

premature infants 

Jacques Rigo and Mario De Curtis 

VIII Approach to Selected Gastrointestinal 

Disorders 

38 Approach to gastrointestinal 639 

bleeding 

Samy Cadranel and 

Michèle Scaillon 

39 Approach to the child with 655 

acute diarrhea 

Hania Szajewska and 

Jacek Z Mrukowicz 

40 Approach to the child with 677 

acute abdomen 

Luigi Dall’Oglio, Paola De Angelis and 

Giovanni Federici di Abriola 

41 Management of ingested 691 

foreign bodies 

Yvan Vandenplas, Said Hachimi-Idrissi 

and Bruno Hauser 

42 Medical aspects of intestinal 701 

transplantation 


IX ‘Surgical’ and Neoplastic Disorders of the 

Gastrointestinal Tract 

43 Intussusception 719 

Adolfo Bautista Casasnovas 

44 Meckel’s diverticulum 729 

Richard G Azizkhan 

45 Acute appendicitis 739 


46 Vascular lesions of the 751 

gastrointestinal tract in childhood 

Steven R Allen and Richard G Azizkhan 

47 The role of minimally invasive 761 

surgery in pediatric 

gastrointestinal disease 

Stig Somme and Donald C Liu 

48 Polyps and other tumors of the 771 


Warren Hyer and John Fell 

Index 787

Contributors 

Fabio Albano 

Department of Pediatrics 

University of Naples ‘Federico II’ 

Via S. Pansini 5 

80131 Naples, Italy 

Steven R Allen 

University of Cincinnati College of Medicine 

Cincinnati, OH 45229, USA 

Jorge Amil Dias 

Pediatric Gastroenterology Unit 

Hospital S. João 

4200 Porto, Portugal 

Renata Auricchio 






Cincinnati Children’s Hospital Medical Center 

Division of Pediatric Surgery 

3333 Burnet Avenue 

Cincinnati, OH 45229, USA 

Mauro Batista de Morais 

Division of Pediatric Gastroenterology 

Escola Paulista de Medicina 

Universidade Federal de São Paulo 

São Paulo, Brazil 


Section of Pediatric Surgery 

Clinical University Hospital of Santiago de 

Compostela 

Choupana s/n 

15706 Santiago, Spain 

Marc Benninga 

Emma Kinderziekenhuis AMC 


Postbus 22660 

NL-1100 DD 

Amsterdam, The Netherlands 


Department of Paediatrics 

The Aga Khan University 

Stadium Road 

Karachi 74800, Pakistan 



Gastroenterology Service 

University of Rome ‘La Sapienza’ 

Viale Regina Elena 324 

00161 Rome, Italy 

Athos Bousvaros 

Division of Gastroenterology and Nutrition 

Children’s Hospital 

Boston, MA 02115, USA 


Northern Territory Clinical School 

Flinders University 

Casuarina NT0811, Australia 

Samy Cadranel 

Queen Fabiola Children’s Hospital 

Department of Gastroenterology and Nutrition 

Avenue J J Crocq 15 

B-1020 Brussels, Belgium

viii 

Contributors 

Moti M Chowdhury 

Department of Paediatric Surgery 

Surgery Unit 

Institute of Child Health 

30 Guilford Street 

London WC1N 1EH, UK 

Virginie Colomb 

Service de Gastroentérologie et Nutrition 

Pédiatriques 

Hôpital Necker – Enfants Malades 

149 Rue de Sèvres 

75743 Paris, France 

Salvatore Cucchiara 


Gastroenterology Service 

University of Rome ‘La Sapienza’ 

Viale Regina Elena 324 


Luigi Dall’Oglio 

Digestive Surgical and Endoscopic Unit 

Ospedale Pediatrico Bambino Gesù-IRCCS 

Viale S. Onofrio 


Paola De Angelis 





Mario De Curtis 

Dipartimento Materno-Infantile 

University of Palermo 

90142 Palermo, Italy 


Unità Operativa di Pediatria 

Ospedale Niguarda Cà Granda 

Piazza Ospedale Maggiore 3 

20162 Milano, Italy 

Carlo Di Lorenzo 


Children’s Hospital of Pittsburgh 

University of Pittsburgh Medical Center 

3705 5th Avenue 

Pittsburgh, PA 15213, USA 

Ulysses Fagundes-Neto 


Escola Paulista de Medicina 

Universidade Federal de São Paulo 

São Paulo, Brazil 


Mucosal Biology Research Center 

University of Maryland School of Medicine 

22 S. Greene Street 

Baltimore, MD 21201, USA 

Giovanni Federici di Abriola 





John Fell 

Chelsea and Westminster Hospital 

London, UK 


Department of Medicine and Therapeutics 

University of Aberdeen 

Scotland, UK 



Pédiatriques 





Section of Gastroenterology, Hepatology and 

Nutrition 

University of Chicago 

5839 S. Maryland Avenue 

Chicago, IL 60637, USA 

Alfredo Guarino 





Said Hachimi-Idrissi 

Academische Ziekenhuis Kinderen 

Vrije Universiteit Brussel 

Laarbeeklaan 101 

B-1090 Brussels, Belgium 

Nigel Hall 




London WC1N 1EH, UK

Bruno Hauser 





Leslie M Higuchi 


Children’s Hospital 


Warren Hyer 

Northwick Park and St Mark’s Hospital 

Middlesex, UK 

Erika Isolauri 


University of Turku 

Kiinamyllynk. 4-8 

FIN-20520 Turku, Finland 

Carl-Christian A Jackson 

University of Chicago Pritzker School of Medicine 




University of Chicago Pritzker School of Medicine 





University Hospital of Oulu 

Oulu 

FIN-90029, Finland 

Kirsi Laiho 


University of Turku 

Kiinamyllynk. 4-8 

FIN-20520 Turku, Finland 

B UK Li 


Northwestern University McGraw School of 

Medicine 

Children’s Memorial Hospital 


Donald C Liu 

Pediatric Surgery 

University of Chicago Comer Children’s Hospital 



Erasmo Miele 





Peter J Milla 

Gastroenterology Unit 



London, WC1N 1EH, UK 

Contributors ix 

Jacek Z Mrukowicz 

Polish Institute for Evidence Based Medicine 

Cracow, Poland 

Simon Murch 

Centre for Paediatric Gastroenterology 

Royal Free Hospital and University College 

Medical School 

Royal Free Campus 

Rowland Hill Street 

London, NW3 2PF, UK 

Agostino Pierro 




London WC1N 1EH, UK 



Children’s Hospital of Los Angeles 

4650 Sunset Boulevard 

Los Angeles, CA 90027, USA 

Lucia Quaglietta 





Jacques Rigo 


Division of Neonatology 

University of Liège 

CHR Citadelle 

4000 Liège, Belgium 


Department of Paediatrics and Child Health 

Nelson R Mandela School of Medicine 

719 Umbilo Road 

Congella 4013 

Durban, South Africa

x 

Contributors 

Frank M Ruemmele 


Pédiatriques 




Silvia Salvatore 





Miguel Saps 


Children’s Hospital of Pittsburgh 

University of Pittsburgh Medical Center 

3705 5th Avenue 

Pittsburgh, PA 15213, USA 

Michèle Scaillon 

Queen Fabiola Children’s Hospital 

Department of Gastroenterology and Nutrition 

Avenue J J Crocq 15 


Stig Somme 

Louisiana State University School of Medicine 

1542 Tulane Avenue 

New Orleans, LA 70112, USA 

Annamaria Staiano 





Bhanu Sunku 


Northwestern University McGraw School of 

Medicine 

Children’s Memorial Hospital 


Hania Szajewska 

Department of Pediatric Gastroenterology and 

Nutrition 

The Medical University of Warsaw 

Dzialdowska 1 

01-184 Warsaw, Poland 

Jan Taminiau 

Emma Kinderziekenhuis AMC 


Postbus 22660 

NL-1100 DD 

Amsterdam, The Netherlands 

Eunice Trindade 

Pediatric Gastroenterology Unit 

Hospital S. João 

4200 Porto, Portugal 

Yvan Vandenplas 





Harland S Winter 

Pediatric IBD Center 


Massachusetts General Hospital for Children 

55 Fruit Street 


Nelly Youssef 


Pédiatriques 


149 Rue de Sèvres Paris 


Qian Yuan 

Pediatric IBD Center 


Massachusetts General Hospital for Children 

55 Fruit Street 

Boston, MA 02114, USA

Preface 

Our discipline is young. When I began focusing on 

pediatric gastroenterology, in the early 1970s, 

there were no textbooks available. My training was 

based on the teaching of outstanding mentors 

(such as Salvatore Auricchio and Armido Rubino, 

to whom I will always be indebted), on eager clinical 

work and on tireless research; and reading of 

adult gastrointestinal textbooks that were regarded 

as the necessary theoretical fundaments of knowledge. 

Then the Silvermann, Roy and Cozzetto 

book (Pediatric Clinical Gastroenterology. St Louis, 

MO: Mosby, 1971) came along, somewhat officially 

identifying our field as a free-standing subspecialty 

and heralding a new exciting era of 

educational tools directed at our discipline. 

The knowledge then seems to have almost 

exploded, with technology rapidly introducing 

new investigative, diagnostic and therapeutic 

modalities; new acquisitions making old approaches 

quickly obsolete; and the sheer body of 

new information forcing us to become sub-subspecialists. 

Hepatologists (now rightly even transplant 

hepatologists), endoscopists, neurogastroenterologists 

and more ‘ologists’ have emerged and 

have gained or are gaining their cultural and 

operative independence. 

In this scenario of ever-changing evolution, and in 

the Internet era, why another pediatric gastroenterology 

and nutrition book? I believe the 

answer lies in the progressive globalization that 

the Internet has certainly catalyzed and that we 

see occurring before our eyes. We are living more 

and more in a true global village, where educational 

resources need not only to be scientifically 

correct and updated, but also able to offer, in 

a comprehensive, cohesive package, information 

that is also reflective of the different realities that 

gastroenterological and nutritional problems take 

on in different parts of the world. Intentionally, 

this book does not cover any liver-related disorder. 

Hepatology has become a discipline in its own 

right, and authoritative, specific books addressing 

only pediatric hepatology have already appeared 

and are available. We felt that focusing on the two 

intertwined areas of gastroenterology and nutrition 

would serve better the needs of the pediatric 

gastroenterologist. However, the book has a rather 

ambitious goal: that of having a global ‘flavor’. It is 

in fact born out of a new vision of worldwide cooperation 

among pediatric gastroenterologists, 

which is embodied by the recently created 

Federation of the International Societies of Pediatric 

Gastroenterology, Hepatology and Nutrition 

(FISPGHAN). I can only hope that its goal will be 

reached; certainly all the authors and I tried very 

hard. Happy Reading! 

Stefano Guandalini, MD 

Professor of Pediatrics 

President of FISPGHAN

1 

Introduction 

Microvillus inclusion disease 

and epithelial dysplasia 

Olivier Goulet, Nelly Youssef and Frank M Ruemmele 

The definition, presentation and outcome of 

intractable diarrhea of infancy (IDI) have changed 

considerably over the past three decades, owing to 

major improvements in nutritional management, 

and a better understanding of the pathology of the 

small bowel mucosa. 

Definition of protracted and 

intractable diarrhea of infancy 

Originally, the syndrome of IDI was described by 

Avery et al in 1968, based on the following 

features: diarrhea occurring in a newborn younger 

than 3 months of age, lasting more than 2 weeks, 

with three or more negative stool cultures for 

bacterial pathogens. 1 Most cases were managed in 

hospital, using intravenous fluids while the diarrhea 

was persistent and intractable, with a high 

mortality rate from infection or malnutrition. 2 

Recently, the term ‘severe diarrhea requiring 

parenteral nutrition’ was proposed. 3,4 Within this 

group of pathologies, two major subtypes can be 

differentiated. The first group is made up of 

patients with ‘protracted diarrhea of infancy’ (PDI), 

which subsides despite its initial severity. PDI can 

result from a specific immune deficiency, a sensitization 

to a common food protein (e.g. cow’s milk 

or gluten), or it can be secondary to a severe 

infection of the digestive tract (post-enteritis 

syndrome). The second group is characterized by 

an ‘intractable diarrhea of infancy’, with onset 

within the first 2 years of life. In this second group, 

diarrhea persists sometimes for years, despite 

prolonged bowel resting and various therapeutic 

trials. In most cases, such as constitutive enterocyte 

disorders 5 or autoimmune enteropathy, 6 the 

situation becomes rapidly life threatening, and 

these patients depend on long-term parenteral 

nutrition (PN). Some of them are candidates for 

intestinal transplantation. Table 1.1 shows the 

diagnostic heterogeneity of 65 cases with severe 

diarrhea requiring PN for more than 1 month, as 

recently analyzed by a French multicenter study. 7 

The so-called ‘intractable ulcerating enterocolitis’ 

of early onset is difficult to classify. 8 It is very 

important to distinguish between IDI and PDI, 

since children with PDI always recover, sometimes 

after only several weeks or months of parenteral 

and/or enteral nutrition. In contrast, patients with 

IDI never recover, and are dependent on life-long 

parenteral nutrition or – in the case of autoimmune 

enteropathy – life-long massive immunosuppressive 

medication. 

Current classification 

An attempt to classify intractable diarrhea according 

to villus atrophy was proposed, on the basis of 

immunohistological criteria emphasizing the role 

of activated T cells in the intestinal mucosa. 9 A 

multicenter survey from the European Society for 

Paediatric Gastroenterology, Hepatology and 

Nutrition (ESPGHAN) collected different cases of 

IDI and villus atrophy with precisely defined light 

microscopic characteristics, categorizing several 

types of IDI. 10 On histological analysis, two clearly 

different groups of IDI can be separated. The first 

one is characterized by a mononuclear cell infiltration 

of the lamina propria, and is considered to 

be associated with activated T cells. Within this 

group, two different clinical presentations can be 

distinguished. Patients presenting with additional 

extradigestive autoimmune symptoms (such as 

diabetes, arthritis, thyroiditis, dermatitis and 

nephrotic syndrome) tended to have a later onset 

1

2 

Microvillus inclusion disease and epithelial dysplasia 

Table 1.1 Causes and outcomes of protracted and intractable 

diarrhea of infancy 

Cause Patients (n) Deceased (n) 

Protracted diarrhea 39 1 

Multiple food intolerance 15 0 

Infectious enteritis 14 0 

Colitis (including two with CMV) 6 1 

CDG syndrome 1 0 

Ganglioneuroblastoma 1 0 

Unknown 2 0 

Intractable diarrhea 

Abnormalities of the enterocyte 

21 4 

intestinal epithelial dysplasia 6 1 

microvillus atrophy 3 0 

Autoimmune enteropathy 5 3 

Phenotypic diarrhea 3 0 

Undefined 4 0 

CMV, cytomegalovirus; CDG, congenital disorders of glycosylation 

of diarrhea, which was more abundant and more 

severe than in patients with isolated gastrointestinal 

symptoms and gut autoantibodies. The second 

histological pattern includes the early onset of 

severe intractable diarrhea with villus atrophy, 

without mononuclear cell infiltration of the 

lamina propria but specific histological abnormalities 

involving the epithelium. To date, several 

types of primary epithelial abnormality inducing 

IDI have been identified. The first described was 

microvillus atrophy or microvillus inclusion 

disease (MVID) and, more recently, tufting 

enteropathy or epithelial dysplasia. 11 Some 

patients are small for gestational age and present 

with phenotypic abnormalities corresponding to 

the previously described syndromatic diarrhea. 12 

Microvillus inclusion disease 

In 1978, Davidson et al reported five infants with 

severe, persistent diarrhea beginning in the 

newborn period, in whom light microscopy 

revealed crypt hypoplastic villus atrophy. 13 

Electron microscopic examination of small intestinal 

biopsies from three of the patients showed 

severe brush-border abnormalities and increased 

liposome-like bodies and, in one, intracytoplasmic 

cysts made up of brush border. Further children 

were reported with these characteristic cytoplasmic 

inclusions of the brush-border membrane. 5,14 

From these first clinical and histological descriptions, 

MVID has been established as a distinct 

disease within the syndrome of IDI, based on the 

characteristic morphological features. MVID in its 

typical form is a congenital disorder of intestinal 

epithelial cells, presenting as intractable secretory 

diarrhea within the first days of life. 15 

Clinical expression 

In general, infants develop severe secretory diarrhea 

within the first days after birth. Stool volumes 

reach 250–300ml/kg body weight per day, with

electrolyte concentrations similar to those seen in 

small-intestinal fluid. This disorder is life threatening, 

since massive diarrhea leads to rapid dehydration 

and electrolyte imbalance, with subsequent 

metabolic decompensation within a few 

hours. 13–15 Severe watery diarrhea persists despite 

bowel rest. The differential diagnosis may include 

congenital chloride diarrhea or sodium malabsorption 

diarrhea, which can be easily distinguished 

from MVID by blood and stool electrolyte assessment. 

16,17 In contrast, clinical presentation of 

MVID may sometimes be atypical, in the form of a 

predominantly pseudo-occlusive syndrome, with 

full and distended small bowel and colon. Some 

newborns have been thought to present intestinal 

pseudo-obstruction syndrome, and unfortunately 

in some of them an ileostomy was created. The 

most common time of onset of diarrhea in MVID is 

within the first few days (early-onset or congenital 

form). However, in a few patients the onset of diarrhea 

is delayed (first month) and less severe (lateonset 

form). 

Histological examination 

Histological analysis of small bowel biopsies 

shows a variable degree of villus atrophy without 

any inflammatory infiltrate. Highly characteristic 

for this disorder is the accumulation of periodic 

acid Schiff (PAS)-positive secretory granules 

within the apical cytoplasm of enterocytes. 18–20 On 

(a) (b) 

Microvillus inclusion disease 3 

the ultrastructural level, rare or absent microvilli 

on intestinal epithelial cells along with inclusions 

of microvilli in the cytoplasm of enterocytes are 

seen, which define this entity. 21 

Diagnosis may be easily performed from light 

microscopic examination of a duodenal or jejunal 

biopsy specimen. On hematoxylin–eosin staining, 

the mucosa appears flattened with hypoplastic 

villus atrophy. PAS staining reveals an abnormal 

brush-border pattern with positive-staining material 

within the apical cytoplasm of enterocytes 

(Figure 1.1). A valuable new tool for the light 

microscopic diagnosis of MVID was recently 

proposed. 22,23 CD-10 is a membrane-associated 

neutral peptidase, shown to have a linear brushborder 

staining pattern in normal small intestine. 

In contrast to this surface staining in different 

controls (normal intestine, celiac disease, autoimmune 

enteropathy, allergy), all MVID cases 

revealed prominent intracytoplasmic CD-10 

immunoreactivity in surface enterocytes 22,23 

(Figure 1.2). Similar results were obtained with 

PAS, polyclonal carcinoembryonic antigen and 

alkaline phosphatase, three stains known to show 

cytoplasmic staining of surface enterocytes in 

MVID. 23 On electron microscopy, surface epithelial 

cells show absent or grossly abnormal 

microvilli, as well as numerous vesicular bodies of 

various sizes, and the characteristic microvillus 

inclusions (Figure 1.3). Crypt cells are morphologically 

almost normal, but do not contain increased 

Figure 1.1 Microvillus inclusion disease: periodic acid-Schiff (PAS) staining. (a) Normal mucosa, normal PAS, brushborder 

staining; (b) abnormal accumulation of PAS, positive material in the apical cytoplasm of epithelial cells in microvillus 

inclusion disease.

4 


(a) (b) 

Figure 1.2 Microvillus inclusion disease: CD-10 immunostaining. (a) Normal mucosa, normal CD-10, brush-border 

immunostaining; (b) abnormal accumulation of positive material in the apical cytoplasm of epithelial cells in microvillus 

inclusion disease. 

Figure 1.3 Microvillus inclusion disease. Electron 

microscopy of jejunal biopsy specimen. The brush border 

is almost absent. The cytoplasm contains a microvillus 

inclusion. 

Figure 1.4 Microvillus inclusion disease. Electron 

microscopy of colonic biopsy specimen. 

numbers of apical vesicles and vesicular bodies. 

Microvillus inclusions, as well as increased secretory 

granules, are also present in the large bowel, 

more easily accessible for biopsy, especially in 

early infancy (Figure 1.4). 

Pathophysiology and mode of transmission 

A defect in the membrane trafficking of immature 

and/or differentiating enterocytes has been 

discussed as an etiopathogenic mechanism in 

MVID. 20,21 This membrane defect results, as a

direct functional consequence, in complete intestinal 

failure. It has been speculated that the disease 

is associated with a disorder of the enterocyte 

cytoskeleton, which produces an abnormal assembly 

of microvilli. Intestinal microvillus dystrophy 

was reported as being a hypothetic variant of 

MVID. 24 The underlying pathogenesis of MVID is 

still unclear, although a cytoskeletal myosin deficiency 

has been found. 25 When analyzing the 

turnover of sucrase-isomaltase, as a representative 

brush-border protein, there is clear evidence that 

the direct and indirect constitutive pathways are 

intact in MVID. 21 Therefore, a defect in endocytosis 

is rather unlikely. More recently, by investigating 

the glycobiological nature of the epithelial 

accumulation of PAS, Phillips et al 26 suggested 

that MVID involves a defect in exocytosis of the 

glycocalyx. 26 The absence of glycocalyx might 

impair normal cell functions. 

Considering the number of cases with affected 

siblings, and the frequency of consanguinity 

among patients in families of affected infants, this 

disease appears to be transmitted as an autosomal 

recessive trait. 13,15,27 No candidate gene has been 

identified to date. MVID has been reported in a girl 

with autosomal dominant hypochondroplasia. 28 

The gene defect of this disease was recently localized 

on the chromosome region 4p16.3, which 

might help in elucidating the genetic basis of MVID. 

Long-term outcome 

MVID is a congenital constitutive intestinal epithelial 

cell disorder leading, in its typical early-onset 

form, to permanent intestinal failure. The largest 

multicenter survey, of 23 MVID patients, 15 

revealed an extremely reduced life expectancy 

with a 1-year survival rate of less than 25%. Most 

children died of septic complications, liver failure, 

or metabolic decompensation. Few cases of MVID, 

especially with the late-onset form, may survive 

with limited stool output and may require only 

partial PN. 29 Treatment with corticosteroids, 

colostrum or epidermal growth factor has not been 

successful, but octreotide has been used with 

partial success in one patient. 15 In contrast to the 

initial outcomes before the 1980s, PN now allows 

most infants and children to survive. However, 

complications related to inadequate PN do limit 

long-term survival. These include recurrent 

Microvillus inclusion disease 5 

catheter-related sepsis, extensive thrombosis, fat 

overload syndrome and cholestasis. In addition, 

without evidence of an associated renal disease, 

some of these infants and children present chronic 

hydro-electrolytic imbalance and acidosis, with 

subsequent impaired length growth. Others, 

because of repeated dehydration episodes associated 

with unadapted phosphocalcic intakes, 

present with nephrocalcinosis. Finally, even with 

adequate long-term PN and normal growth, most 

children remain with high and uncomfortable 

stool output. This requires daily fluid replacement 

with the high risk of severe dehydration. Intestinal 

transplantation therefore became the only definitive 

treatment of this rare intestinal disease. 30–33 

Definitive treatment 

Since the introduction of tacrolimus (originally 

FK506) as an immunosuppressive drug after organ 

transplantation in the early 1990s, the outcome of 

intestinal transplantation markedly improved. 

Several cases of successful transplantation for 

MVID have been reported. 30–35 Transplantation 

involved isolated intestine, 30–33 or intestine 

combined with the liver. 31,32 Following the report 

of these cases, there has been an ongoing discussion 

on whether or not the colon should be transplanted 

together with the small bowel. 

We recently evaluated the possibility and outcome 

of intestinal transplantation in ten consecutive 

patients with early-onset congenital MVID at 

Necker-Enfants Malades Hospital (Paris) (Ruemmele 

et al, submitted for publication). Two 

patients died before they could be put on a waiting 

list for small-bowel transplantation; one patient is 

still waiting. We performed cadaveric intestinal 

transplantation in seven patients aged between 3 

and 11 years by using tacrolimus, steroids and 

interleukin (IL-2) blockers. Three transplantations 

were performed with isolated intestine, and four 

with intestine associated with the liver. Right 

colon transplantation was performed in five cases 

(two with isolated intestine). One patient died 

during transplantation surgery from acute liver 

failure and hemodynamic shock, probably due to 

re-perfusion shock. The six others (86%) survived, 

with a median follow-up of 3 years (range 1–8 

years). Graft rejections occurred in two patients 

(one with isolated intestinal transplantation, and

6 


one with intestine and liver), who responded 

favorably to methylprednisolone pulses. Complete 

weaning from PN was achieved in all patients: the 

five patients with an additional colon graft were 

off PN after a median of 36 days after surgery, as 

opposed to those without colonic transplant who 

obtained full intestinal autonomy several months 

after transplantation. Thus, intestinal transplantation 

alone or in combination with liver, offered 

MVID children for the first time a long-term 

perspective. In this series at Necker-Enfants 

Malades Hospital, additional colon grafting 

markedly improved outcome and quality of life 

after transplantation in MVID. These preliminary 

results of intestinal transplantation in this rare 

disease are very encouraging, and demonstrate 

that the prognosis of MVID has changed dramatically 

during the past decade. 

Finally, in a child suspected of having MVID, a 

precise classification into one of three different 

subtypes (congenital–early-onset, late-onset or 

atypical) should be obtained as early as possible 

and confirmed by an experienced pathologist, 

according to clearly defined morphological criteria. 

Recently, Croft et al 34 reported a 5-year-old girl 

with a late-onset form of MVID who was weaned 

from total PN and is thriving on a normal unrestricted 

diet. This rare form of MVID probably has 

a better prognosis than the most frequent form of 

early-onset MVID, with a high mortality rate. 15 

Given the high success rate of intestinal transplantation 

in MVID, we recommend transplantation, 

once the definitive diagnosis of early-onset MVID 

is made. In addition, the potential candidate for 

transplantation has to be in a eutrophic phase 

under total PN. This policy should allow avoidance 

of liver impairment. Conversely, patients 

with a late-onset or atypical form of MVID should 

not be automatically scheduled for small-bowel 

transplantation. The individual course of the 

disease will help in deciding whether or not a 

child with MVID is a candidate for intestinal transplantation. 

Intestinal epithelial dysplasia (or 

tufting enteropathy) 

In 1994, three cases of neonatal severe diarrhea 

with abnormal epithelial pictures were reported by 

Reifen et al under the name of ‘tufting enteropa- 

thy’. 36 In our own series at Necker-Enfants 

Malades, we identified nine cases of severe neonatal 

diarrhea that were clearly different from 

MVID. 12 Further studies in these patients 

confirmed that intestinal epithelial dysplasia (IED) 

is a constitutive epithelial disorder involving both 

small intestine and colon. 37 In our experience, IED 

seems to be frequent in patients of Arabic origin, 

from the Middle-East or North Africa. Main characteristics 

of this disease are its clinical and histological 

heterogeneity and its association with 

malformations or other epithelial diseases. 


Typically, the patients present during the first 

weeks of life with severe diarrhea. Most have 

affected consanguineous parents and/or siblings, 

some of whom died during the first months of life 

with severe diarrhea of unknown origin. Most of 

the time, diarrhea persists despite bowel rest, but 

at a lower level when compared to MVID. 

Therefore, attempts at continuous enteral feeding 

with protein hydrolysates or amino acid-based 

formulas were performed in some patients. 

Unfortunately, most often the continuous enteral 

feeding exacerbated the diarrhea, and particularly 

the newborns with IED did not grow adequately. 

They rapidly developed failure to thrive, with 

severe protein energy malnutrition. Because of the 

early onset of diarrhea, MVID is often suspected in 

these children. However, morphological analysis 

of small- and large-bowel biopsies easily distinguishes 

these entities (see above). A major problem 

in the diagnosis of IED is its clinical and histological 

heterogeneity. 

Histological features 

Villus atrophy of variable severity is present. In the 

typical form, abnormalities are localized mainly in 

the epithelium and include a disorganization of 

surface enterocytes with focal crowding, resembling 

tufts (Figure 1.5). These characteristic ‘tufts’ 

of extruding epithelium first described by Reifen et 

al 36 are seen towards the villus tip, and may affect 

up to 70% of villi. The tufting process is not 

limited to the small intestine but also involves the 

colonic mucosa. 11 This picture can also be 

observed in crypt epithelium and, in addition,

Figure 1.5 Epithelial dysplasia. Disorganization of 

surface epithelium showing tufts with apical rounding 

epithelial cells. 

crypts often have an abnormal aspect with dilatations 

such as pseudocysts and abnormal regeneration 

with branching 11 (Figure 1.6). The study of 

basement membrane components demonstrated 

an abnormal laminin and heparan sulfate proteoglycan 

deposition at that level, compared to biopsy 

specimens from patients with celiac disease or 

autoimmune enteropathy. 11 Relative to the 

controls, there was faint and irregular laminin 

deposition at the epithelial–lamina propria interface, 

while heparan sulfate proteoglycan depositions 

were large and lamellar, suggestive of abnormal 

development of basement membrane at the 

origin of the epithelial abnormalities. On the other 

hand, we observed an increased immunohistochemical 

expression of desmoglein in IED, and 

ultrastructural changes of desmosomes, which 

were increased in length and number (Figure 

1.7). 37 

Diagnosis 

Diagnosis of IED is sometimes difficult for several 

reasons. The early onset of severe and permanent 

diarrhea and the lack of features diagnostic of 

microvillus inclusion disease are important diagnostic 

elements. However, the characteristic tufts 

of extruding epithelium may not be obvious, especially 

early on. At the onset of the clinical course, 

IED is most often suspected after elimination of 

MVID, and the final diagnosis is made rather late, 

by performing repeated intestinal biopsies which 

Intestinal epithelial disease 7 

Figure 1.6 Epithelial dysplasia. Partial villus atrophy with 

crypt hyperplasia and/or pseudocystic crypt appearance, 

branching and disorganization of surface epithelium. 

Figure 1.7 Desmoglein staining. Increased expression of 

desmoglein in the tight junctions. 

change from normal in early life (only non-specific 

villus atrophy with or without mononuclear cell 

infiltration of the lamina propria) to the characteristic 

tufts. In addition, it is difficult to show the 

rare, specific abnormalities of basement 

membrane components, integrins or desmosomes 

in part of the mucosa, in the absence of tufts. 

Another difficulty is related to the infiltration of 

the lamina propria by T cells, a finding that would 

support the hypothesis of an immune-related 

enteropathy, especially when tufts are missing. 

One might speculate that defective cell adhesion 

increases intestinal permeability, with a subse-

8 


quent inflammatory reaction. In a mouse model of 

dysfunctional E-cadherin, this primary disorder of 

epithelial integrity was responsible for secondary 

T-cell-mediated mucosal damage. 38 Murch et al 39 

described this type of lesion in infants with epithelial 

dysplasia. They showed that inhibition of 

secondary T-cell activation significantly improved 

enteral absorption and decreased crypt cell proliferation, 

without, however, permanent resolution 

of the severe diarrhea. 

Associated disorders 

Several cases of IED have been reported as being 

associated with phenotypic abnormalities (e.g. 

Dubowitz syndrome or malformation syndromes). 

40,41 An association between congenital 

IDI and choanal atresia was recently reported in 

four children. 40 In our experience, we have 

observed malformations including rectal atresia, 

choanal atresia or esophageal atresia. We recently 

reported the association with a non-specific punctiform 

keratitis in more than 50% of patients with 

clinically and histologically recognized IED. 42 

Therefore, the diagnostic work-up should include 

a systematic ophthalmological examination by an 

experienced specialist. The latter association is 

intriguing, since punctiform keratitis is also an 

epithelial disease; thus, studying this condition 

might help to elucidate the molecular mechanisms 

of the intestinal epithelial disease. The fact that 

some children have no ophthalmological symptoms 

confirms the heterogeneity of the disease. 

Interestingly, Lachaux et al have reported a case of 

a newborn presenting with pyloric atresia and 

intractable diarrhea. 43 Light microscopic examination 

showed extensive desquamation from fundus 

to rectum, with only a few epithelial cells remaining 

at the base of the crypts. Electron microscopy 

of the gut revealed normal desmosomes, but a 

cleavage located between the lamina propria and 

the basal pole of the enterocytes. This firstdescribed 

disease is supposed to be related to 

congenital deficiency of α6β4 integrin. This integrin 

is known to be defective in epidermolysis 

bullosa, in which gross epidermal shedding 

occurs, although the cutaneous expression of α6β4 

integrin appeared normal in this case of IDI. This 

is consistent with a mutation within an intestinal 

isoform of the α6β4 integrin, or a deficiency of a 

related and immunohistochemically cross-reactive 

intestinal integrin. 44,45 Rather like epidermolysis 

bullosa, which shares several similarities with 

deficiency of α6β4 integrin at the ultrastructural 

and possibly molecular level, there are likely to be 

several distinct mutations that can cause this 

phenotype. 

Pathophysiology and mode of transmission 

In infants with epithelial dysplasia with characteristic 

tufts, we have reported abnormal laminin 

and heparan sulfate proteoglycan deposition on 

the basement membrane, compared to biopsy 

specimens from patients with celiac disease or 

autoimmune enteropathy. 11 Basement membrane 

molecules are involved in epithelial–mesenchymal 

cell interactions, which are instrumental in 

intestinal development and differentiation. 46–49 

Alterations suggestive of abnormal cell–cell and 

cell–matrix interactions were seen in patients 

with epithelial dysplasia without any evidence of 

abnormalities in epithelial cell polarization and 

proliferation. 37 Alterations included abnormal 

distribution of adhesion molecules α2β1 integrin 

along the crypt–villus axis. The α2β1 integrin is 

involved in the interaction of epithelial cells to 

various basement membrane components, such as 

laminin and collagen. To date, the pathophysiological 

mechanisms resulting in an increased 

immunohistochemical expression of desmoglein, 

and the ultrastructural changes of desmosomes 

remain unclear (Figure 1.7). 37 Tufts correspond to 

non-apoptotic epithelial cells at the villous tips 

that are no longer in contact with the basement 

membrane. It can be speculated that a defect of 

normal enterocyte apoptosis at the end of their 

lifespan, or an altered cell–cell contact, is responsible 

for this effect. The primary or secondary 

nature of the formation of tufts remains, however, 

to be determined. 

To date, the genetic origin of this disorder is 

suspected from the clear association of parental 

consanguinity and/or affected siblings. These 

features suggest an autosomal recessive transmission. 

The gene involved in this congenital inherited 

autosomal recessive disease is not yet 

identified. This enteropathy appears more 

common than MVID, especially within the 

Middle-Eastern population.

Outcome 

This neonatal diarrhea, which resists all treatments, 

requires permanent PN. However, it seems 

that some infants have a rather milder phenotype 

than others. 50 Thus, because of partial intestinal 

function and limited amount of stool output, some 

patients only need partial long-term PN, with three 

to four weekly infusions. Careful monitoring 

should be performed, in order to avoid progressive 

growth retardation. In most patients, the severity 

of intestinal malabsorption and diarrhea make 

them totally dependent on daily long-term PN 

with subsequent risk of complications. This is 

therefore another indication for intestinal transplantation. 

51–53 

Other diseases of the intestinal 

epithelium 

The classification of IDI is probably incomplete, 

since other forms with abnormal small-bowel 

mucosa have been described. These include mitochondrial 

DNA rearrangements; congenital enterocyte 

heparan sulfate deficiency, phosphomannose 

isomerase deficiency; and a 

carbohydrate-deficient glycoprotein syndrome 

with hepatic-intestinal presentation. 54–59 Rare 

diseases involving the immune system and smallbowel 

mucosa, 60 or severe intractable enterocolitis 

of infancy, 6 seem clearly different from the 

above-described diseases. The so-called ‘phenotypic 

diarrhea’ that is an IDI syndrome associated 

with phenotypic abnormalities and immune deficiency 

is one of these rare diseases recently 

reported. The patients present with diarrhea starting 

within the first 6 months of life (

10 


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2 

Introduction 

Congenital problems of the 


Nigel Hall and Agostino Pierro 

Congenital abnormalities of the gastrointestinal 

(GI) tract are relatively common. Owing to their 

nature, they frequently require surgical correction. 

On occasion this must be undertaken as a matter of 

emergency in order to avoid catastrophic intestinal 

ischemia and necrosis, resulting in loss of bowel or 

damage to a secondary organ system. It is not 

possible in the realms of one chapter to describe in 

detail all of the variants of congenital GI tract 

abnormalities that may be encountered and the 

precise nature of the treatment options available. 

Therefore, what follows is an overview of the most 

common conditions encountered and those which 

require intervention as a matter of urgency. For 

ease of understanding we commence with the 

upper GI tract and continue in a caudal direction. 

Conditions affecting the upper 


Disorders of the mouth and oral cavity 

Cleft lip and palate is one of the more common 

congenital anomalies with an incidence of about 1 

in 600 live births. 1,2 The etiology is probably 

multifactorial: a genetic component is implicated 

as are a wide variety of exogenous factors and up 

to 50% of infants may have other associated anomalies. 

3 The presentation may be during routine 

antenatal scans, although some cases do not 

become apparent until birth. Whilst the esthetic 

appearance may be the most obvious, respiratory 

and feeding difficulties associated with clefts carry 

greater medical significance and in some cases 

may require early intervention. The long-term 

management of these disorders is best in the 

setting of a specialist multidisciplinary team in 

order to achieve a satisfactory functional and 

cosmetic repair. 

Esophageal atresia and tracheoesophageal 

fistula 

This complex group of anomalies, with an incidence 

of 1 in 2440–4500 live births, 4,5 results from 

failure of correct division of the tracheal 

primordium from the esophagus during early 

embryonic development. The precise etiology is 

unknown with a number of embryological theories 

proposed to explain the different variants of this 

anomaly. There is a high incidence of co-existing 

abnormalities including the VACTERL syndrome, 

CHARGE association and isolated cardiovascular 

anomalies. 6 

Classification 

A number of classification systems have been 

proposed over the years. The abbreviated list in 

Table 2.1 describes the most commonly encountered 

anatomical variants (Figure 2.1). The 

Table 2.1 Classification of esophageal 

atresia (EA)/tracheoesophageal fistula (TEF) 

anomalies and frequency 6 

Type of lesion Frequency (%) 

EA and distal TEF 88.8 

Isolated EA 7.3 

H-type fistula 4.2 

Distal and proximal TEF 2.8 

Proximal TEF 1.1 

13

14 

Congenital problems of the gastrointestinal tract 

Figure 2.1 Common anatomical variants of esophageal 

atresia (EA)/tracheoesophageal fistula (TEF) anomalies. (a) 

EA with distal TEF; (b) isolated EA with no TEF; (c) H-type 

TEF; (d) proximal and distal TEF; (e) EA with proximal TEF. 

Spitz classification 6 (Table 2.2), incorporating birth 

weight and presence of major congenital heart 

disease status, may be useful in predicting survival. 

Clinical features 

Esophageal atresia is commonly associated with 

maternal polyhydramnios. The diagnosis may be 

made in the antenatal period, particularly if there 

is no tacheoesophageal fistula. In the postnatal 

period, symptoms include excessive salivation, 

feeding difficulties, respiratory distress, and 

cyanotic episodes. Cases of esophageal atresia 

(with the exception of the rare esophageal atresia 

with double fistula) can be confirmed by failure of 

Table 2.2 Spitz classification of esophageal 

atresia (EA)/tracheoesophageal fistula (TEF) 

anomalies and outcome 6 

Group Clinical features Survival (%) 

I BW ≥1500g with no major CHD 97 

II BW

Obstructive lesions of the duodenum, jejunum 

and ileum 

The most common congenital conditions affecting 

the duodenum, jejunum and ileum all result in 

partial or complete gastrointestinal obstruction. 

The presenting features and investigations recommended 

to diagnose the underlying abnormality 

are similar for all conditions. The clinical features 

and investigations of these conditions are therefore 

presented first, followed by a description of each 

type of abnormality and the recommended treatment 

options. 


Obstructive lesions of the small intestine from the 

pylorus down to the ileocecal valve may give rise 

to polyhydramnios in the antenatal period which 

is detectable by antenatal ultrasonography. As a 

general rule, the more proximal the lesion the 

more severe the degree of polyhydramnios; distal 

ileal lesions may be present in the absence of polyhydramnios. 

7 The list of differential diagnoses 

giving rise to polyhydramnios is extensive, and it 

is rare for an obstructive lesion of the GI tract to be 

confirmed before birth. 

Following birth, the most common and important 

clinical manifestation of obstructive lesions of the 

GI tract is bile-stained vomiting. Vomiting with 

truly bilious staining is abnormal in the neonatal 

period and always requires investigation. Lesions 

in the duodenum and jejunum usually result in 

bilious vomiting within hours. In addition, the 

abdomen may appear empty or even scaphoid and 

visible gastric peristalsis may be observed. Lesions 

lower in the ileum result in a distended abdomen 

if the obstruction is complete, and there may be 

failure to pass meconium. Obstructive lesions may 

also give rise to intestinal perforation in the neonatal 

period and occasionally antenatally. In all 

cases of neonatal intestinal obstruction, infants 

become progressively hypovolemic and are prone 

to circulatory and respiratory collapse. They 

require fluid resuscitation and may require ventilatory 

support. GI tract obstruction should therefore 

be considered in any infant who is dehydrated, 

especially if there is a history of vomiting. 

Stenotic lesions of the small bowel in which the 

obstruction is incomplete may give rise to 

Conditions affecting the upper gastrointestinal tract 15 

increased diagnostic difficulty. Affected infants 

often present with intermittent vomiting and 

episodes of partial obstruction. They eventually 

fail to thrive or develop complete obstruction, at 

which stage they are fully investigated and the 

diagnosis becomes apparent. 

Intestinal malrotation is considered separately, as 

it may present with a spectrum of clinical scenarios 

depending on the degree of intestinal obstruction 

or midgut volvulus or both. The clinical 

pictures of all types of abnormal rotation are those 

of acute or chronic intestinal obstruction and/or 

acute or chronic abdominal pain suggestive of 

intestinal ischemia. True malrotation typically 

presents in the first year of life with symptoms of 

upper gastrointestinal tract obstruction including 

vomiting, which is usually bile-stained. A coexisting 

volvulus may be suspected by abdominal 

pain, peritonitis and hypovolemic shock associated 

with intestinal ischemia. However, these 

signs may be relatively non-specific in the young 

infant. Malrotation may also present later in life 

with similar symptoms. 

Investigations 

The aim of investigating cases of suspected 

obstruction of the small intestine is two-fold: first, 

to identify the nature and anatomical location of 

the lesion, to allow for planning of correct treatment; 

and second, to identify patients with 

malrotation in whom there is a risk of midgut 

volvulus and intestinal ischemia. These cases 

require urgent surgical intervention to reduce the 

risk of potentially catastrophic intestinal necrosis. 

The history and examination may give clues as to 

the location of the lesion as described above. An 

abdominal X-ray may simply confirm the presence 

of dilated intestinal loops but may also give further 

clues in some cases. A double-bubble appearance 

on abdominal X-ray with a lack of air in the distal 

intestine (Figure 2.2) is characteristic of duodenal 

obstruction. Multiple air-filled loops of proximal 

bowel often with air–fluid levels along with a 

paucity or complete absence of gas in the distal 

bowel is highly suggestive of obstruction of the 

ileum. Intestinal perforation if present will usually 

be apparent on abdominal X-ray, and in the rare 

cases of antenatal perforation there may be widespread 

or localized flecks of calcification representing 

calcified meconium within the peritoneum.

16 


In cases in which the diagnosis is not clear on 

abdominal X-ray or in which midgut malrotation 

or volvulus is suspected, a limited upper gastrointestinal 

contrast study is indicated. The classical 

finding in cases of malrotation is that the duodenojejunal 

flexure lies to the right side of the 

spine instead of in its normal left-sided position 

(Figure 2.3). This finding should prompt urgent 

surgical treatment, because of the risk of co-existing 

midgut volvulus. The contrast study may also 

identify the presence of a stenotic segment or 

complete obstruction. 

Cases of lower ileal stenosis or atresia are often 

more difficult to diagnose and a contrast enema is 

invaluable in distinguishing between ileal and 

colonic obstruction and could be therapeutic in 

cases of meconium ileus (see below). 

Conditions affecting the duodenum 

Duodenal atresia, duodenal stenosis and annular 

pancreas are the most common congenital condi- 

Figure 2.2 Abdominal X-ray of an infant with duodenal 

atresia showing the ‘double bubble’ appearance 

characteristic of duodenal obstruction. 

tions to affect the duodenum. All are capable of 

giving rise to duodenal obstruction. The incidence 

is reported to be between 1 in 5000 and 1 in 10 000 

live births. 8 

Explanations of the etiology of duodenal atresias 

are not universally accepted. Unlike atresias of the 

ileum, they are not thought to be due to vascular 

accidents and the most widely accepted explanation 

is that of failure of recanalization of the 

intestinal lumen during early embryonic development. 


There are four basic types of duodenal obstruction 

(Figure 2.4). In type 1 there is a stenosis of the 

duodenum resulting from a diaphragm or web 

partially or totally occluding the lumen. Owing to 

the incomplete nature of the obstruction, cases 

Figure 2.3 Upper gastrointestinal contrast study of a 

case of malrotation. The contrast is seen within the 

duodenum (D) and flowing into the upper jejunum (J), 

both of which lie completely to the right of the midline.

may present in childhood rather than in the 

neonatal period. In type 2 duodenal atresia, the 

proximal and distal segments end blindly but 

remain connected by a fibrous cord. There is 

complete separation of the bowel segments in type 

3, and type 4 comprises extrinsic obstruction due 

to an annular pancreas although there may be an 

associated atretic segment. Multiple atresias are 

said to occur in approximately 15% of cases. 9 

Treatment 

The principles of treatment are to restore intestinal 

continuity whilst avoiding interference with the 

ductal system draining the pancreas and biliary 

tree. This is best achieved using a duodenoduo- 

Figure 2.4 Variants of duodenal atresia. (a) Type 1 

atresia due to an internal diaphragm; (b) type 2 atresia 

with blind-ending loops remaining connected by a fibrous 

cord; (c) type 3 atresia with blind ends completely separated; 

(d) type 4 – duodenal obstruction due to an annular 

pancreas. 


denostomy in which the obstructed segment is 

bypassed by the proximal segment being joined 

directly to the distal segment. Following surgery 

the long-term gastrointestinal results are good. 10 

Conditions affecting the ileum and jejunum 

The main congenital problems directly affecting 

the small intestine from the duodenojejunal flexure 

down to the cecum are atresia and stenosis. 

Jejunoileal atresia occurs more commonly than its 

duodenal counterpart, with an incidence varying 

from 1 in 330 to 1 in 3000 livebirths. 11 Such lesions 

are one of the most common causes of neonatal 

intestinal obstruction. The major difference 

between atresias of the ileojejunum and those of 

the duodenum is in their etiology. It is postulated 

that atresia or stenosis of the jejunum and ileum is 

the result of a localized intravascular accident 

during intrauterine life. Subsequent ischemic 

necrosis and reabsorption of the affected segment 

or segments results in a contracted scarred bowel 

wall leading to stenosis at one end of the spectrum 

to a complete intestinal and mesenteric defect at 

the other. Fetal animal experiments have confirmed 

this hypothesis, at least in part, 12 and the absence 

of other congenital abnormalities found in association 

with jejunoileal stenoses and atresias supports 

the localized vascular accident theory. 


Morphological classification of these lesions 

allows different surgeons and centers to compare 

outcomes and is also of therapeutic and prognostic 

value. The most commonly accepted system is that 

proposed by Louw13 and modified by Grosfeld et 

al. 14 Whether the lesion is classified as ileal or 

jejunal is determined by the most proximal 

affected segment (Figure 2.5). 

Stenosis is a localized narrowing of the lumen 

without any break in the continuity or mesenteric 

defect. The intestinal wall may be thickened and 

rigid at the stenotic site and there is a small, often 

minute, lumen. The overall intestinal length is not 

shortened. Type 1 atresia is the result of a membranous 

web occluding the lumen with no mesenteric 

defect and no intestinal shortening. The lumen is 

usually completely occluded and the proximal 

bowel is therefore dilated but remaining in continuity 

with the collapsed distal segment. Type 2

18 


Figure 2.5 Variants of ileal atresia. (a) Type 1 due to an internal web (not shown) with no mesenteric defect; (b) type 2 

atresia with blind ends joined by a fibrous cord; (c) type 3(a) – blind ends separated with a mesenteric defect; (d) type 3(b), 

in which the ileum is coiled like an ‘apple peel’ around a single vessel and completely separated from the proximal dilated 

duodenum; (e) type 4 or multiple atresias. 

atresia arises from a complete obliteration of the 

intestinal segment into a fibrous cord, which joins 

two blind ends and runs in the free edge of the 

mesentery. There is no mesenteric defect and once 

again the total bowel length is usually normal. In 

both type 3(a) and type 3(b) atresia the intestine is 

likely to be shortened and this may have significant 

clinical consequences. Type 3(a) atresia 

consists of blind-ending proximal and distal bowel 

with no connection and an often large mesenteric 

defect. The blind ends are often physiologically 

abnormal with decreased or absent peristaltic 

activity, which may give rise to torsion, distension 

or perforation. Type 3(b) atresia, also known as 

apple peel atresia because of its gross morphology, 

may involve massive intestinal loss. It consists of 

intestinal atresia near the ligament of Treitz, oblit- 

eration of the superior mesenteric artery (SMA) 

beyond the origin of the middle colic branch and 

absence of the dorsal mesentery. The remaining 

intestine is coiled helically (like an apple peel) 

around a single perfusing vessel, often has 

impaired vascularity and is almost inevitably 

short. Furthermore, there may be additional 

segments of type 1 or 2 atresia within the apple 

peel segment. Such a configuration probably arises 

from occlusion of the SMA due to thrombus, 

embolus or strangulation as part of a midgut volvulus. 

In type 4 atresia there are multiple atretic 

segments and the intestine may resemble a string 

of sausages. Overall bowel length is usually shortened 

and the intestine grossly dilated. It has been 

proposed that the etiology of type 4 atresia may be 

due to failure of recanalization of solid epithelial-

ization throughout the length of the intestine 

rather than from multiple single vascular events. 

Whilst it is generally accepted that stenosis and 

atresia of types 1, 2 and 3(b) are the result of 

intrauterine vascular accidents, a genetic component 

has been suggested in types 3(b) and 4. 

Treatment 

The mainstay of surgical treatment for this type of 

lesion is resection of the atretic or stenotic segment 

and primary anastomosis, with closure of the 

mesenteric defect. The proximal intestinal 

segment is usually dilated and functionally abnormal 

with absent or ineffective peristalsis. This 

dilated proximal segment is excised along with a 

short segment distal to the stenosis or atresia. It is 

essential to establish patency of the distal bowel 

by irrigation or wash-out of the intestine and 

subsequently a primary anastomosis is performed. 

There is a balance to be struck between the length 

of the dilated proximal segment resected and the 

risk of leaving the infant with a short length of 

small bowel. It is almost inevitable that the caliber 

of the proximal bowel will be greater than that of 

the distal intestine, and a number of techniques 

including fishtailing and tapering exist to assist 

the anastomosis in such circumstances. 

Outcome following intestinal atresia is dependent 

primarily on the length of remaining intestine and 

the presence of the ileocecal valve. Short bowel 

syndrome is defined as the presence of less than 

75cm of the small intestine or 30% of the 

predicted intestinal length in a premature 

infant. 15,16 Outcomes following short bowel 

syndrome vary and there is a high level of dependence 

on parenteral nutrition. However, intestinal 

adaptation can occur such that more than 80% of 

babies with short bowel syndrome do eventually 

become entirely enterally nourished. 17 

Intestinal malrotation 

The incidence of intestinal malrotation is difficult 

to establish as not all affected patients develop 

symptoms, but autopsy studies estimate the incidence 

at approximately 1 in 500. 

The traditional embryological basis for disorders 

of intestinal rotation is that of abnormal position- 


ing of the intestinal loops in relation to one 

another as they return to the abdominal cavity 

from the yolk sac. During normal development the 

midgut rotates through 270º so that the duodenum 

lies posterior to the colon and the duodenojejunal 

flexure is to the left of the midline. A consistent 

finding in cases of malrotation is abnormal positioning 

of the duodenum. In 1995, an alternative 

hypothesis was proposed based on animal 

studies. 18 Kluth et al proposed that malrotation is 

the result of failure of localized growth of the 

duodenal loop rather than a disorder of rotation. 

The term ‘malrotation’ covers a spectrum of 

anatomical abnormalities. In non-rotation the 

duodenojejunal flexure lies to the right of the spine 

along with most of the small intestine. The cecum 

and colon are typically on the left side of the 

abdominal cavity. Adhesions formed between 

loops of bowel or the intestine and abdominal wall 

are usually responsible for obstructive symptoms 

at presentation. In malrotation the distribution of 

intestinal contents within the abdominal cavity is 

such that the duodenum again lies to the right of 

the spine with the cecum anterior to it. Adhesions 

between these two structures (Ladd’s bands) are 

often present and may result in partial or total 

occlusion of the second part of the duodenum. In 

addition the mesenteric attachment to the posterior 

aspect of the abdominal cavity is typically 

very short and there is a risk of volvulus with 

ensuing intestinal ischemia. Other forms of abnormal 

intestinal rotation (inverse rotation, malrotation 

with mesocolic hernia and malposition of the 

cecum) are all rare. 

Treatment 

There are two aspects to this disorder which 

require surgical intervention. The first and most 

important aspect is that of midgut volvulus. Any 

infant in whom malrotation is suspected based on 

clinical findings and radiological investigations 

should undergo laparotomy as a matter of urgency 

in order to minimize the risk of intestinal ischemia 

due to volvulus. At laparotomy blood-stained peritoneal 

fluid may indicate the presence of ischemic 

intestine. Any volvulus should be derotated 

(usually in the clockwise direction) and the intestine 

examined for viability. Non-viable bowel is 

resected and a primary anastomosis performed. If 

there is doubt about the viability of the remaining

20 


intestine a second-look laparotomy can be 

performed after 24 h. 

In cases of malrotation not complicated by volvulus, 

the procedure of choice for most surgeons is 

the Ladd’s procedure. This involves division of all 

adhesions or adhesive bands between the cecum, 

duodenum and parietal peritoneum, broadening of 

the mesenteric base around the superior mesenteric 

artery and repositioning of the intestine 

within the abdominal cavity so that the duodenum 

is on the right and the cecum lies in the left upper 

quadrant. It has become customary to perform an 

appendectomy, owing to the difficulties of diagnosis, 

should appendicitis develop later in life. 

Meconium ileus 

Meconium ileus is a common cause of neonatal 

intestinal obstruction and the most common cause 

of antenatal intestinal perforation. 19 It should be 

included in the differential diagnosis of infants 

presenting with GI tract obstruction. In approximately 

80% of cases it is associated with cystic 

fibrosis. 20–22 The underlying defect in cystic fibrosis, 

an abnormality in a transmembrane chloride 

channel, results in the production of abnormally 

viscid and sticky meconium. This meconium 

sticks to the intestinal mucosa causing intestinal 

obstruction usually occurring late in gestation. 

Why some infants with cystic fibrosis do not 

develop meconium ileus is unclear. Meconium 

ileus can be classified as: ‘uncomplicated’, when it 

is limited to intraluminal obstruction caused by 

the abnormal meconium; or ‘complicated’, when it 

is associated with intestinal atresia, volvulus or 

meconium peritonitis. 


In cases of uncomplicated meconium ileus, the 

infant usually presents shortly after birth with 

symptoms of lower gastrointestinal obstruction 

including abdominal distension and vomiting 

which may or may not be bile stained. The rectum 

may be empty and narrow and the infant does not 

pass meconium. If meconium ileus is complicated 

by volvulus, intestinal ischemia or perforation, the 

infant can be systemically unwell with acidosis, 

undergo hypovolemic shock and may require 

ventilatory support. Abdominal X-ray showing 

dilated intestinal loops and occasionally abundance 

of meconium in the right lower quadrant are 

supportive of the diagnosis, as is a gastrograffin 

contrast enema revealing a small collapsed colon 

(microcolon) and often inspissated pellets of 

meconium in the right lower quadrant. 

Treatment 

In some cases, the gastrograffin enema mentioned 

above may relieve the obstruction sufficiently to 

be curative. However, a number of uncomplicated 

cases and all complicated cases require surgery. 

The procedure performed depends on the findings 

during laparotomy. Atretic or grossly dilated 

segments of bowel may be resected, the inspissated 

meconium removed from the intestinal 

lumen and the distal bowel flushed through. 

Occasionally a stoma is formed to allow intestinal 

decompression. Outcome of surgical treatment is 

generally good and gastrointestinal complications 

are of lesser significance than the pulmonary 

disease caused by the underlying cystic fibrosis. 

Meckel’s diverticulum 

Meckel’s diverticulum is the most common 

omphalomesenteric remnant with a reported incidence 

of approximately 2%. Of these only a small 

proportion become clinically significant. The 

diverticulum originates from incomplete obliteration 

of the omphalomesenteric duct and exists as a 

free-lying diverticulum on the antimesenteric 

border of the ileum. 


There are a variety of disease entities attributed to 

Meckel’s diverticulum including gastrointestinal 

hemorrhage, intussusception, diverticulitis and 

perforation. The most common presenting 

symptom is that of gastrointestinal bleeding due to 

excessive acid and pepsin production from an 

ectopic gastric mucosa which may be present 

within the diverticulum. Bloody diarrhea in the 

absence of abdominal pain is the classical presenting 

picture. Other complications of Meckel’s diverticulum 

are intussusception in which the diverticulum 

acts as a lead point, diverticulitis with 

symptoms similar to those of appendicitis and 

perforation.

Treatment 

Management of all clinically significant cases of 

Meckel’s diverticulum is resection of the diverticulum 

after adequate preoperative resuscitation. At 

operation the diverticulum and a wedge of ileum 

are resected. The ileal wedge is included, as 

ectopic tissue may not be entirely confined to the 

diverticulum. Following surgical excision the 

outcome is good. 

Congenital hepatic, pancreatic and biliary 

abnormalities 

Abnormalities of the hepaticopancreaticobiliary 

system are all extremely rare. They are included 

here as knowledge of their existence is important, 

as they form part of the differential diagnosis for 

infants with jaundice, malabsorption and hypoglycemia. 

The most common lesions of the biliary tree are 

biliary atresia and congenital biliary dilatation. In 

biliary atresia the biliary tree is obliterated either 

completely or partially. Congenital biliary dilatation 

includes a variety of abnormalities of the 

biliary tree in which the dilated segment may be 

either intrahepatic or extrahepatic and either 

fusiform or cystic in nature. Dilatations of the 

extrahepatic biliary ducts are commonly known as 

choledochal cysts. The dilated bile duct is both 

anatomically and functionally abnormal, resulting 

in cholestasis. Infants with biliary atresia and 

severe cholestasis associated with biliary dilatation 

present in the neonatal period with prolonged 

jaundice due to accumulation of conjugated bilirubin. 

When the degree of obstruction to the biliary 

tree is not so severe, congenital biliary dilatation 

may present later in life with malabsorption, intermittent 

jaundice, abdominal pain or even pancreatitis. 

In addition, a choledochal cyst may present 

as an upper abdominal mass. Treatment of these 

lesions is centered around allowing drainage of the 

biliary tree into the intestine, and the surgery 

involved is often complex. The operation of choice 

for biliary atresia is the Kasai portoenterostomy. 23 

The atretic remnants of the extrahepatic biliary 

ducts are removed and the porta hepatis is anastomosed 

to a defunctioned loop of jejunum. The 

timing of surgery is of paramount importance to 

avoid hepatocellular damage, but even with 

prompt diagnosis and early surgical intervention 

Conditions affecting the lower gastrointestinal tract 21 

infants with biliary atresia often have residual 

hepatic impairment due to intrauterine cholestasis. 

In cases of choledochal cysts the dilated 

portion of the extrahepatic ducts are removed 

together with the gallbladder, and the common 

hepatic duct is anastomosed to the duodenum or a 

defunctioned loop of jejunum. 

There are a number of congenital hepatic anomalies 

that give rise to structural and/or functional 

abnormalities of the liver parenchyma or the intrahepatic 

biliary tree. These include infantile and 

adult-type polycystic disease, congenital hepatic 

fibrosis, biliary hypoplasia and congenital tumors 

of the liver such as hamartomas and hemangiomas. 

Presentation is usually with one of 

hepatomegaly, portal hypertension or cholangitis. 

Treatment is that of resection of suitable lesions 

and prevention or treatment of hepatic disease. 

Congenital lesions involving the pancreas are rare, 

the most common being annular pancreas (see the 

section on the duodenum p. 00). Other anatomical 

anomalies are seen including pancreatic ductal 

anomalies, pancreatic cysts and very rarely pancreatic 

agenesis. There are a group of infants who 

present in the neonatal period with hypoglycemia 

who are found to have inappropriately high levels 

of circulating insulin. The condition hyperinsulinemic 

hypoglycemia (previously commonly 

referred to as ‘nesidioblastosis’) is characterized by 

inappropriate endogenous insulin secretion in the 

presence of low blood glucose. It may result from 

an insulin-secreting tumor in the pancreas (a socalled 

‘insulinoma’) but more commonly no tumor 

is identified and the disease is a result of a genetic 

defect in a membrane channel controlling insulin 

secretion. Infants require high glucose intake to 

maintain normoglycemia whilst they are investigated 

for the presence of an isolated secretory 

tumor. Treatment is by surgical excision of the 

tumor if present, otherwise a 90–95% subtotal 

pancreatectomy is performed. 

Conditions affecting the lower 


Hirschsprung’s disease 

Hirschsprung’s disease is the most common 

congenital malformation of the enteric nervous

22 


system with an incidence of approximately 1 in 

5000 live births. 24–26 Whilst most cases are 

sporadic a positive familial occurrence exists in 

3.6–7.8% of cases 27 and the presence of co-existing 

abnormalities including trisomy 21 suggests a 

genetic involvement (see also Chapter 17). 

This condition is characterized by the absence of 

enteric neurons and hypertrophy of nerve trunks 

in the distal bowel always involving the rectum 

and for a variable distance proximally. There is an 

absence of peristaltic activity in this aganglionic 

segment resulting in symptoms of intractable 

constipation. The bowel proximal to the aganglionic 

segment contains ganglionated cells, and 

peristaltic activity is normal. However, in the socalled 

transitional zone, immediately proximal to 

the aganglionic segment, neuronal cells may exist 

but they are commonly of abnormal architecture 

and the intestinal peristalsis is abnormal. This 

zone is of fundamental importance when considering 

surgical treatment of this disorder. 


In the neonatal period the disease should be 

considered in any infant who fails to pass 

meconium in the first 48h of life. The usual 

presentation in the neonatal period is with constipation, 

abdominal distension and eventually 

vomiting during the first few days of life. More 

severe symptoms may be present in the neonatal 

period including those of gastrointestinal obstruction, 

enterocolitis (see below) and rarely perforation. 

Later in infancy symptoms of intractable 

constipation may signify the presence of 

Hirschsprung’s disease. 

Diagnosis 

One of the most important factors in the management 

of Hirschsprung’s disease is early diagnosis 

and appropriate treatment to avoid complications 

of the disease. Following clinical suspicion a 

number of investigations may be of use in making 

a diagnosis which must always be confirmed by 

histological examination of intestinal tissue. Plain 

abdominal X-ray will often show dilated proximal 

intestinal loops (Figure 2.6) prompting a lower GI 

contrast study to be performed to exclude intestinal 

atresia/stenosis or meconium ileus. This may 

show a prompt transition from narrow distal 

aganglionic bowel to dilated proximal bowel. A 

contrast enema is not necessary for diagnosis in 

many cases of Hirschsprung’s disease. In addition, 

this investigation may be misleading in its indication 

of the length of intestinal aganglionosis. 

The gold standard for diagnosis is the suction 

rectal biopsy. Characteristic histological findings 

are absence of ganglion cells and increase in 

acetylcholinesterase (AChE) staining in the 

parasympathetic nerve fibers. In cases where 

suction rectal biopsy fails to provide adequate 

information, a full-thickness rectal biopsy should 

be considered. 

Treatment 

Treatment in the first instance is aimed at decompression 

of the distal GI tract by regular rectal 

washouts. Subsequently a number of surgical 

options exist, all of which aim to remove the aganglionic 

segment and restore intestinal continuity by 

means of an anastomosis of ganglionated bowel to 

the rectal stump (so-called ‘pull-through’). This may 

be performed either as a primary procedure or as a 

delayed procedure after initial colostomy formation 

Figure 2.6 Plain abdominal X-ray of a child with 

rectosigmoid Hirschsprung’s disease showing extensively 

dilated loops of bowel.

to allow distal intestinal decompression. 28 There are 

a number of surgical techniques, of which three are 

the most commonly used – the Swenson rectosigmoidectomy, 

the Duhammel retrorectal transanal 

pull-through and the endorectal pull-through of 

Soave. These techniques may also be carried out 

laparoscopically in suitable infants. 

Of paramount importance in all surgical approaches 

is removal of the full length of aganglionic intestine. 

Failure to do so may result in recurrence of symptoms 

and complications of Hirschsprung’s disease. 

To ensure normoganglionosis of the segment, 

pulled-through intraoperative biopsies are taken 

and rapidly examined histologically. Biopsies may 

be taken laparoscopically in infants undergoing a 

minimally invasive procedure. A number of authors 

have advocated laparoscopic colonic mapping prior 

to or during definitive surgery for exact characterization 

of the extent of the disease. 29,30 Recently 

there has been interest in infants who have retained 

a portion of the transition zone and have recurrent 

symptoms. 31,32 Attention has been drawn to the fact 

that the transition zone may not be linear around 

the circumference of the intestine, and it has been 

recommended that multiple circumferential biopsies 

be taken. 31,33 

Hirschsprung’s enterocolitis 

Despite appropriate treatment this serious complication 

of Hirschsprung’s disease can develop at 

any stage and may be the presenting condition. 

Profuse, often bloody diarrhea with abdominal 

distension is the main presenting symptom. 

Vomiting and fever may be present and the child 

may become rapidly unwell and dehydrated. 

Treatment is initially with fluid resuscitation and 

intestinal decompression by means of a nasogastric 

tube. Rectal examination should be performed 

as it may produce an explosion of foul-smelling 

gas and stools which aids diagnosis and intestinal 

decompression. The bowel is rested, during which 

time parenteral nutrition may be considered. Our 

practice is to give enteral vancomycin, targeting 

Clostridium species which are often implicated. 

Outcome 

The results following surgery for Hirschsprung’s 

disease are generally good. Long-term outcome 

may be difficult to assess fully, owing to the short 

Conditions affecting the lower gastrointestinal tract 23 

follow-up periods reported in the literature. The 

incidence of incontinence is reported as ranging 

from zero to 82% and that of constipation from 

zero to 56%, these two complications probably 

having the greatest influence on quality of life. 34–36 

Whilst some patients may be relieved of their symptoms 

by surgery altogether, it should be remembered 

that, for some, lifelong symptoms persist particularly 

if the entire colon is involved by the disease. 34,36 

Anorectal anomalies 

Congenital abnormalities of the anorectal region 

occur with an incidence of 1 in 4000 to 1 in 5000 

live births. 37–39 A very small minority may be familial 

with the majority being isolated findings or part 

of a congenital syndrome such as the VACTERL 

syndrome. There are a number of different types of 

anorectal anomalies resulting from the complex 

embryological development of the anorectal region 

involving differentiation of the cloaca. The 

Wingspread classification 40 divides them into high, 

intermediate or low based on the relationship of 

the terminal bowel or any fistula arising from the 

bowel to the pelvic diaphragm. Precise definition of 

the abnormal anatomy is of paramount importance 

when planning corrective surgical treatment. 


Abnormalities of the anorectal region are usually 

diagnosed on inspection during the newborn period, 

but surprisingly this is not always the case. In many 

cases the anus will be absent and meconium may be 

seen to originate from an abnormal site including a 

mucocutaneous fistula, the urethra in males or the 

vagina in females. Anomalies in which the anus is 

present but abnormally sited or stenosed may be 

more difficult to diagnose in the absence of adequate 

experience. The most complex abnormality in 

females is shown by the cloaca, represented by a 

single opening in the perineum with rectum, vagina 

and urethra joining a single channel. 

Treatment 

Treatment is aimed at preventing complications 

associated with the anomaly, including urinary 

tract infection and lower GI obstruction and subsequently 

restoring the anatomy to as near to normal

24 


a functional and cosmetic state as possible. In the 

majority of cases the initial surgery involves 

forming a colostomy in the descending or sigmoid 

colon to allow intestinal drainage and avoid dilatation 

of the lower bowel. 41 Following assessment, 

planning of surgery and growth of the infant reconstructive 

surgery is undertaken most commonly by 

the posterior sagittal approach. 42 Some anomalies 

also require a laparotomy to divide a high 

rectovesical fistula. Surgery of these cases and 

particularly of the cloaca is complex and should be 

performed by an experienced surgeon. 

Outcome 

In similarity to patients with Hirschsprung’s 

disease, incontinence and constipation are the 

most significant long-term complications of 

surgically treated anorectal anomalies and often 

have a significant impact on quality of life. In one 

large series, soiling occurred in 57% of 387 cases. 

The incidence of fecal incontinence was 25% and 

constipation 43.1%. 42 Ongoing medical and, on 

occasion, surgical treatment is necessary to minimize 

disruption to a normal lifestyle. 

Conditions which may occur at any 

point in the gastrointestinal tract 

Gastrointestinal duplications 

Duplication cysts of the GI tract are rare congenital 

abnormalities. They can occur at any point in 

the GI tract from mouth to anus, although they are 

most commonly found around the ileocecal region. 

Duplication cysts are defined according to strict 

criteria, as devised by Ladd and Gross; they are 

closely attached to some part of the GI tract, have 

a smooth muscle coat and have an epithelial lining 

that resembles some part of the alimentary canal. 43 

Duplications may be spherical or tubular in macroscopic 

appearance, those that are tubular accounting 

for 10–20% and often having a communication 

with the bowel. 


Between 25 and 30% present in the neonatal 

period and most have presented by the age of 10 

years. Clinical features at presentation depend on 

anatomical site, size and secondary effects and 

include an oropharyngeal, abdominal or rectal 

mass, respiratory distress, GI bleeding, obstruction 

and intussusception. Duplication cysts may also 

be found as incidental findings at laparotomy and 

some lesions have been detected on antenatal 

ultrasound examination. 44,45 

Treatment 

The recommended management of duplication 

cysts is complete surgical excision wherever possible, 

in order to prevent recurrence and complications 

secondary to ectopic gastric mucosa. When 

complete excision is not possible it is essential to 

remove the mucosal lining. 

Conditions affecting the walls of the 

abdominal cavity 

Whilst not truly conditions of the GI tract, there 

are a number of conditions that cause the abdominal 

contents to develop outside the abdominal 

cavity. These conditions are included as they have 

secondary effects which may significantly affect 

the GI tract and be a cause of GI dysfunction. 

Congenital diaphragmatic hernia 

The incidence of congenital diaphragmatic hernia 

varies from 1 in 3500 to 1 in 5000 live births. 46 Its 

etiology is unknown, although it is probably multifactorial. 

The essential anatomical defect is a 

breach in the continuity of the diaphragm which 

allows herniation of the abdominal viscera into the 

thoracic cavity. This has a secondary effect of 

impeding development of the lungs during 

intrauterine life. The resulting hypoplastic lungs 

are a cause of significant morbidity and mortality 

in this condition. Compression by misplaced 

abdominal contents does not explain the severity 

of lung disease seen and it is well recognized that 

lung development is markedly abnormal in infants 

with congenital diaphragmatic hernia. 


A number of different defects can occur, owing to 

the complex development of the diaphragm. The

majority of cases are of the Bochdalek type, in 

which the defect is posterolateral and most 

commonly on the left side. The defect can range in 

size from a small slit to involve almost the entire 

hemidiaphragm. Defects in the central tendon of 

the diaphragm result in Morgagni hernias, which 

are retrosternal in nature and most commonly on 

the right side. Finally, agenesis of the diaphragm 

may occur which is usually left sided and 

extremely rare. 


In the current era, diaphragmatic hernia is often 

diagnosed during prenatal ultrasound scanning. 

The advantage of prenatal diagnosis is that delivery 

can be planned to take place in a unit with 

appropriate pediatric surgical and intensive care 

facilities. For those infants who avoid prenatal 

diagnosis, for whatever reason, the clinical 

features depend on the volume of abdominal 

contents within the thoracic cavity and the degree 

of lung hypoplasia. In the most severe cases, there 

will be severe respiratory distress and cyanosis 

from shortly after birth. At the other end of the 

spectrum are infants who have minimal if any 

respiratory symptoms or signs and in whom 

intestinal loops are noted to be in the abdomen on 

chest X-ray (Figure 2.7). 

Treatment 

Whilst the definitive treatment of diaphragmatic 

hernia is surgical closure, the timing of this is not 

of paramount importance and should be undertaken 

once the infant is stable from a cardiovascular 

and respiratory point of view. The respiratory 

management of these infants can be problematic 

owing to the severe lung hypoplasia and associated 

pulmonary hypertension. Most require 

conventional ventilatory support as a minimum 

and many require high-frequency oscillatory 

ventilation to ensure adequate oxygenation. Other 

measures to reduce pulmonary hypertension, 

including inhaled nitric oxide, adenosine or sildenafil, 

may be effective. Resistant cases may be 

candidates for extracorporeal membrane oxygenation, 

during which the infant is placed on a 

life-support system in the hope that the lungs and 

in particular the pulmonary vasculature will 

mature. Various criteria for extracorporeal 

membrane oxygenation exist47 with the aim of 

Conditions affecting the walls of the abdominal cavity 25 

Figure 2.7 Chest radiograph of an infant with congenital 

diaphragmatic hernia. Loops of intestine are clearly seen 

within the left hemithorax and there is mediastinal shift to 

the right. 

reserving it for those who have the most severe 

respiratory failure and those who are most likely to 

benefit. Unfortunately, there remain a number of 

infants with congenital diaphragmatic hernia 

whose lung disease presents too great a challenge 

and these do not survive. 

Surgery 

The principles of surgical repair are to return the 

abdominal contents to the abdominal cavity and 

repair the diaphragmatic defect. It may be possible 

to repair the defect by simply suturing the edges 

together. However, if the defect is large a patch 

repair may be undertaken using prosthetic material. 

The long-term outcome of congenital diaphragmatic 

hernia is dependent primarily on the degree 

of pulmonary hypoplasia. The main GI consequence 

appears to be gastroesophageal reflux, seen 

in up to 62% of cases. 48 

Anterior abdominal wall defects 

Although separate clinical entities, the two conditions 

exomphalos and gastroschisis, which comprise 

anterior abdominal wall defects are grouped 

together, owing to similarity in their clinical appearance 

and the recommended course of management. 

In both conditions some portion of the viscera lies 

outside the abdominal cavity extruding through a 

defect in the anterior abdominal wall.

26 


Exomphalos 

The defect on the anterior abdominal wall in cases 

of exomphalos lies in the midline. Viscera herniate 

through this defect but remain contained within 

an avascular hernial sac comprising peritoneum 

and amniotic membrane (Figure 2.8). The size of 

the defect and hence the size of the sac may vary 

from a small swelling at the base of the umbilical 

cord (exomphalos minor) to a much larger sac 

containing liver and a large proportion of the small 

intestine (exomphalos major). The embryological 

origins of exomphalos are believed to be failure of 

complete closure of the anterior abdominal wall 

around a persistent body stalk. Visceral contents 

continue to develop within this body stalk and 

thus remain outside the abdominal cavity. Whilst 

the precise etiology of exomphalos is not clear, it is 

well recognized that exomphalos often co-exists 

with a number of other congenital abnormalities 

and this may suggest at least in part a genetic 

component. Associated abnormalities include 

Beckwith–Wiedemann syndrome, the trisomies 13, 

18 and 21 and the upper and lower midline 

associations. 

Gastroschisis 

The anterior abdominal wall defect in cases of 

gastroschisis is of full thickness and typically to 

the right of the umbilical cord. Unlike exomphalos 

there is no sac covering the eviscerated intestine, 

which is usually dilated and inflamed (Figure 2.9). 

Figure 2.8 Clinical appearance of an infant with exomphalos. 

The abdominal contents are enclosed within an 

avascular hernial sac. 

The liver is not herniated. The precise embryological 

basis of gastroschisis is unclear and a number 

of hypotheses have been proposed. The fact that 

gastroschisis is rarely associated with any other 

congenital abnormalities, with the exception of 

intestinal atresias and malrotation, suggests that it 

is most likely to have a separate embryological 

basis from the events resulting in exomphalos. 

Treatment 

It is now common for these two abnormalities to be 

detected in the antenatal period; delivery in a 

specialist center with pediatric surgical facilities is 

recommended. There is no consensus concerning 

the timing or mode of delivery of these babies and 

there is no convincing evidence to suggest that 

preterm or Cesarean section delivery confer any 

distinct advantage. 49–51 In gastroschisis, however, 

delivery is commonly induced at 37 weeks’ gestation 

to avoid late-gestation fetal death. What is of 

paramount importance is protection of the intestine 

and prevention of fluid loss in cases of gastroschisis 

from the moment of delivery. In exomphalos the 

hernial sac confers a degree of protection to the 

intestine. In cases of gastroschisis the eviscerated 

intestine should be wrapped in clingfilm and 

adequate support provided to prevent fluid loss and 

ischemic damage to the bowel. Cases of exomphalos 

in which the hernial sac ruptures during delivery 

should subsequently be treated as for gastroschisis. 

Surgery and attempted closure should take place as 

Figure 2.9 Clinical appearance of an infant with 

gastroschisis. There is no sac enclosing the herniated 

intestine, which is thickened and inflamed.

soon as possible following stabilization of the infant 

to prevent dehydration. Recent evidence suggests 

that a staged repair may result in favorable outcome 

when compared with primary closure. 52–54 

Intestinal dysmotility is always present in neonates 

with gastroschisis requiring parenteral nutrition for 

a period of usually 2–3 weeks. Parenteral nutrition 

has significantly improved the survival of neonates 

with gastroschisis. 

Surgical closure 

The aim of surgery in both conditions is the return 

of abdominal contents to the abdominal cavity and 

closure of the overlying skin. In some cases this 

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3 

Infectious esophagitis 

Salvatore Cucchiara and Osvaldo Borrelli 

Epidemiology and predisposing 

conditions 

In the recent years the spectrum of infectious 

esophagitis in childhood has expanded, owing to 

the emergence of new conditions, such as the 

acquired immunodeficiency syndrome (AIDS), the 

advancement in therapy and survival of patients 

transplanted and treated with immunosuppressive 

drugs, and the improvement in endoscopic and 

microbiological techniques. The most common 

infectious causes of esophagitis are fungal, viral, 

bacterial and, more rarely, protozoal. Primary 

esophageal infection is quite rare in otherwise 

normal subjects without permissive factors and 

most cases of infectious esophagitis are described 

in immunocompromised patients. 

The immunocompetent subjects developing 

esophageal infections will have predisposing 

conditions that weaken defence mechanisms of 

the esophageal mucosa. Esophageal disorders that 

cause slowing of peristalsis and stasis of intraluminal 

content such as achalasia, systemic sclerosis, 

myopathies, neuropathies and esophageal 

strictures predispose to infections of the esophageal 

mucosa, usually candidiasis. Infections in 

the surrounding organs and structures may also 

involve the esophagus. Other conditions predisposing 

to esophageal infections are malnutrition 

and diabetes mellitus. The latter may derange 

esophageal peristalsis and emptying of intraluminal 

content, and may impair granulocyte function 

through hyperglycemia. Finally, antimicrobial 

drugs can alter the normal oropharyngeal flora 

leading to overgrowth of Candida organisms. 

Conditions affecting both humoral and cellular 

immunological variables also lead to esophageal 

infections. This occurs in children with either 

genetic or acquired immunodeficiency as well as 

in the course of diseases promoting development 

of opportunistic infections. Transplant recipients 

are candidates for infectious esophagitis through 

different mechanisms: drug-induced immunosuppression, 

chemotherapy and neutropenia. Furthermore, 

whereas bacterial and fungal infections 

predominate in the early phases following transplantation, 

when granulocyte number and function 

are more compromised, the cytomegalovirus 

(CMV) infection occurs a few months after 

transplantation when T-cell function is more 

impaired. 

In HIV-infected patients opportunistic infections 

develop and increase in frequency as immunodeficiency 

worsens. Esophageal and other opportunistic 

infections do not occur until immunodeficiency 

is severe, usually when the CD4 

lymphocyte count is below 100–200/mm 3 , according 

to references 1–3. More recently, however, the 

widespread availability of highly active antiretroviral 

therapy has been associated with an apparent 

decline in opportunistic infections in HIV-infected 

patients. The causes of esophageal disease in 

patients with HIV infection and AIDS are reported 

in Table 3.1. In contrast to the findings in other 

immunocompromised hosts, herpes simplex virus 

(HSV) esophagitis is uncommon, whereas by far 

the most common cause is Candida, accounting 

for about 50% of esophageal infections. 4,5 

Esophageal candidiasis can also co-exist with 

other esophageal infections. 6 

Fungal infections 

Candida species are the most common agents 

of infectious esophagitis. Candida albicans is 

the most common pathogen, but C. tropicalis, 

C. parapsilosis and C. glabrata have occasionally 

been reported. These organisms are usually 

29

30 


Table 3.1 Causes of esophageal disease in HIV infection and AIDS 

Common Uncommon Rare 

Candida Herpes simplex virus Neoplasm 

Cytomegalovirus Gastroesophageal reflux disease Mycobacteria 

Idiopathic Protozoa 

present in the normal oral flora, where their 

growth is controlled by commensal organisms. 

Conditions predisposing to esophageal candidiasis 

in immunocompetent subjects are inhaled or 

ingested corticosteroids, prolonged antibiotic 

administration, acid suppressive therapy, disorders 

of esophageal motility, malnutrition, diabetes 

mellitus and neck or head radiotherapy because of 

malignancy. All abnormalities in cellular immunity 

lead to esophageal candidiasis, whereas 

improved management of immunosuppressive 

therapies and antifungal prophylaxis have 

reduced the occurrence of esophageal candidiasis 

in solid-organ transplant recipients. 7 

Esophageal candidiasis has the classical appearance 

of white or yellow plaques coating the 

esophageal mucosa (Figure 3.1). These plaques can 

extend up to the proximal esophagus, are usually 

thick and, characteristically, cannot be washed or 

brushed off, unlike food or milk residues overlying 

esophageal mucosa. They include desquamated 

esophageal epithelial cells intermingled with 

inflammatory cells, bacteria and mycelia and 

spores typical for Candida. 8 The underlying squamous 

esophageal epithelium usually appears 

uninvolved, and ulcerations occur rarely. 

Typical symptoms of esophageal candidiasis are 

painful swallowing (odynophagia) or dysphagia 

(difficulty in swallowing, described as food ‘sticking’) 

(Table 3.2). 3,9 Any patient with risk factors for 

esophageal infection and complaining of dysphagia 

should be suspected for esophageal 

candidiasis. The latter, however, can be detected 

by chance in asymptomatic subjects. When evaluating 

patients with esophageal complaints, an 

important part of the physical examination is a 

close inspection of the oropharynx. However, oral 

candidiasis is not predictive of esophageal involvement 

and the latter can occur in the absence of oral 

candidiasis even in the immunocompromised 

Figure 3.1 Esophageal candidiasis. White plaques 

coating the lower third of the esophageal mucosa. 

subject. Complications from esophageal candidiasis 

occur rarely. Hematemesis suggests underlying 

ulcerative esophagitis that occurs if the disease is 

severe and there is an associated coagulopathy. 

Given that esophageal candidiasis is the most 

common of opportunistic infections of the esophagus 

in subjects with a predisposing condition (e.g. 

HIV infection, transplantation, immunosuppressive 

therapy), an empirical antifungal therapy has been 

proposed, with further diagnostic evaluation based 

on the clinical response (Figure 3.2). Interestingly, a 

prospective study comparing empirical fluconazole 

to endoscopy in HIV-infected adults has shown 

empirical fluconazole to be the best initial management 

strategy. 3 Candida esophagitis usually 

responds rapidly to fluconazole. 10 

Before the advent of upper endoscopy, a barium 

esophagram was used as the initial diagnostic tool. 

However, a number of studies have shown the rela-

Table 3.2 Symptoms and clinical signs in patients with esophageal infection 

Fungal infections 31 

Candida Viruses Bacteria Parasites 

Dysphagia ++++ + + + 

Odynophagia ++ ++++ +++ ++ 

Heartburn + + + + 

Chest pain + +++ ++ + 

Fever - + +++ - 

Hematemesis + ++ + + 

(-), Not occurring; (+), rare; (++), occasional; (+++), common; (++++), always present 

Immunocompetent subject Immunocompromised subject 

Upper gastrointestinal 

endoscopy 

Biopsies 

Pathogen identified and 

specific treatment given 

Dysphagia or 

odynophagia, chest pain 


endoscopy and biopsy 

Pathogen identified and 

specific treatment given 


endoscopy and biopsy 

Figure 3.2 Algorithm for management of infectious esophagitis. 

tive insensitivity and non-specificity of barium 

studies for evaluating esophageal mucosa infection. 

Commonly reported X-ray features in patients with 

esophageal candidiasis are plaque-like lesions in a 

linear configuration that, when severe, become 

systemic 

symptoms 

Refine diagnostic work-up 

and physical examination 

no symptom 

improvement 

no systemic 

symptoms 

+/- oral 

thrust 

Consider empiric treatment 

(systemic fluconazole for 

10–14 days) 

improvement 

of symptoms 

Follow-up program: recurrent 

problems after therapy; 

therapy to correct 

immunosuppression 

confluent; a ‘shaggy’ aspect of the esophagus 

ensues. 11,12 However, a normal barium esophagram 

does not exclude esophageal candidiasis. It should be 

remarked that a well-circumscribed ulceration should 

not indicate Candida infection of the esophagus.

32 


Non-invasive methods to diagnose esophageal 

infections without endoscopy are cytology brush 

and balloon devices. The latter consists of a tube 

with a ridged cytology balloon on the distal end: 

when inflated, it can be withdrawn from the 

esophagus and the brushings removed and submitted 

for cytological evaluation as well as viral 

culture. Whereas these methods are useful to identify 

Candida, they are less sensitive for viral 

disease and have no real advantage over empirical 

antifungal therapy. 13 

Endoscopy with biopsy is the gold standard for 

diagnosing esophageal candidiasis because 

mucosal biopsies can be performed. Despite the 

fact that gross endoscopic features can suggest a 

diagnosis of esophageal candidiasis, this is 

confirmed by the presence of hyphae in biopsies. 

Cytological specimens, which can be obtained at 

the time of endoscopy, are also a sensitive tool for 

the diagnosis, especially when organisms are 

washed off the tissue surface in mild superficial 

candidiasis after processing of bioptic specimens. 

When endoscopy is performed in patients with 

esophageal candidiasis, removal of plaque material 

by scraping with the endoscope is important to 

evaluate the underlying mucosa for ulcers. 6 In 

general, Candida should not be considered a cause 

of esophageal ulcers in HIV-infected patients. 

Both oral and intravenous drugs are available for 

treating esophageal candidiasis. Oral medications 

are generally administered first, whereas intravenous 

therapy is reserved for refractory cases or 

when oral administration is contraindicated. Nonsystemic 

locally acting agents such as nystatin or 

clotrimazole are not very effective and must be 

reserved for the treatment of oropharyngeal 

disease. In patients with mild disease, with 

minimal or reversible immunodeficiency, a short 

course of therapy with a systemically absorbed 

agent can be given, whereas in patients with HIV 

infection or with transplantation immunodeficiency, 

longer courses of azoles are best given. 

Patients with granulocytopenia, at risk for 

systemic Candida infection, require the use of 

systemically acting intravenous agents such as 

azoles or amphotericin B. All available oral agents 

(ketoconazole, fluconazole and itraconazole) are 

efficacious for the treatment of esophageal 

candidiasis (Table 3.3). Ketoconazole and itraconazole 

should be avoided in patients requiring anti- 

acid therapy, as an alkaline pH limits their 

bioavailability. Fluconazole appears to be more 

efficacious than itraconazole; a poor response to 

fluconazole suggests non-compliance, drug resistance 

or other causes for esophageal symptoms. 14 

Randomized trials suggest that fluconazole is 

significantly more effective for the treatment of 

esophageal candidiasis in HIV-infected patients 

than ketoconazole and itraconazole. 14 Fluconazole 

is available in oral and intravenous preparations, 

is minimally metabolized, is highly water soluble 

and is slightly protein bound. The new oral 

suspension formulations of fluconazole and itraconazole 

may have superior efficacy over pills due 

to an additional local antifungal effect and 

improved absorption. 15 The adverse effects of ketoconazole, 

fluconazole and itraconazole are dose 

dependent and include nausea, hepatotoxicity, 

inhibition of steroid production and cyclosporin 

metabolism. 16 The latter effect is more pronounced 

with ketoconazole. 17 Minor increases in aminotransferases 

are commonly found in patients 

treated with oral azoles and do not require drug 

discontinuation. 

Amphotericin B represents the other family of 

antifungal agents (polyene antibiotics), which bind 

irreversibly to sterol in fungal cell membranes, 

causing cell death. This drug has a limited use for 

the treatment of esophageal candidiasis, owing to 

its severe side-effects (nephro- and hepatotoxicity). 

This drug is now available in an oral 

formulation. Patients with esophageal candidiasis 

that is resistant to treatment with fluconazole or 

other azoles can be treated effectively with lower 

doses of intravenous amphotericin B. 

The prophylaxis of esophageal candidiasis in 

malignancy and transplant patients has yielded 

controversial results. 18 

Viral infections 

HSV and CMV are the most common viral agents 

involved in infectious esophagitis, although some 

cases have been ascribed to HIV infection of the 

esophagus. HSV (HSV I or, rarely, HSV II) 

esophagitis causes a self-limited disease in normal 

subjects, but it can be severe and prolonged in the 

compromised patients.

Table 3.3 Drugs for esophageal candidiasis 

Drug/efficacy Duration Dosage Remarks 

HSV esophagitis occurs as a primary infection or 

as a reactivation of previously latent HSV, especially 

in the compromised patient. It is particularly 

common in patients receiving immunosuppression 

for solid organ or bone marrow transplantation, 

19 whereas it is infrequently reported in HIVinfected 

patients. 4 HSV generally infects the 

squamous epithelium, where the earliest lesion is 

a vesicle. As vesicles enlarge and ulcerate, they 

Viral infections 33 

Ketoconazole 7–14 days 5–10 mg/kg/per day Liver disorders can occur during therapy. 

(80%) infections; 6–12mg/kg/per day reactions are most common adverse events. 

for systemic infections May cause clinical hepatitis, cholestasis 

and fulminant hepatic failure with 

underlying clinical conditions (e.g. AIDS, 

malignancy) 

Itraconazole 7–14 days 3–5 mg/kg/per day Caution in liver insufficiencies; nausea, 

(approximately vomiting, diarrhea and abdominal 

80%) discomfort may occur; high doses may 

produce hypertension, hypokalemia or 

edema 

Amphotericin B 7 days 0.3–1.5 mg/kg/per day i.v. Infusion-related toxicity includes acute 

(>95%) infused in 5% dextrose over reactions occurring about 30–45 min after 

2–4 h starting infusion; typically chills, fever and 

tachypnea may present; patients receiving 

any parenteral form of the drug must be 

monitored for renal and liver functions; 

normochromic normocytic anemia may 

develop, usually after 7–10 days of therapy 

Amphotericin B, 7 days ABLC (amphotericin B lipid Novel lipid formulations of amphotericin B 

lipid formulations complex): 5 mg/kg/per day i.v. delivering higher concentrations of the drug 

(>95%) for 1–2 h; ABCD (amphotericin with a theoretical increase in the 

B colloidal dispersion): therapeutic potential and decreased 

3–6 mg/kg/per day i.v. for nephrotoxicity 

1–2 h; L-AMB (liposomal 

amphotericin B): 1–7 mg/kg 

per day i.v. for 1–2 h 

tend to form larger lesions with a characteristic 

central ulceration and raised edges. 

HSV esophagitis usually presents with a sudden 

onset of severe odynophagia, with inability to 

swallow liquids or solids. Herpes labialis and 

herpetic oropharyngeal ulcers can occur during 

the esophageal infection, whereas skin lesions are 

rarely present. 20

34 


A definite diagnosis of HSV esophagitis requires 

endoscopy and histology of the esophageal 

mucosa, even though contrast radiographic 

appearance of the esophagus may be suggestive by 

showing multiple vesicles and ulcers as stellate or 

volcano structures. Endoscopy usually reveals 

small, well-circumscribed ulcers (Figure 3.3), 

rarely vesicles, whereas deep ulcers, as seen with 

CMV, are rare. 21,22 Brushing or biopsies should be 

taken from the edge or periphery of ulcerations, 

given that HSV infects squamous epithelial cells. 23 

Histology reveals intranuclear Cowdry type A 

inclusion bodies (eosinophilic material), ballooning 

degeneration cells, multinucleated giant cells, 

ground-glass-like nuclei and margination of chromatin. 

24 Confirmation may require immunoperoxidase 

staining or positive viral culture. 

Although HSV esophagitis has a spontaneous resolution 

in a normal host, antiviral therapy is 

commonly used both in immunocompetent and 

immunocompromised subjects. Several uncontrolled 

trials and clinical experience indicate the 

efficacy of acyclovir, a nucleoside analog, for the 

treatment of HSV esophagitis. 25 Parenteral 

acyclovir should be initiated until the patient can 

be converted to oral therapy (when dysphagia or 

odynophagia is resolved). Generally, patients are 

treated with acyclovir for 7–10 days. Because resistance 

to acyclovir has been reported, therapy with 

foscarnet should be considered in case of clinical 

failure with acyclovir. 25 Acyclovir is efficacious in 

prophylaxis for patients undergoing transplantation 

and those who are HSV-antibody-positive. 

Table 3.4 lists the available antiviral agents for 

treating viral esophagitis. 

CMV is the most frequent infectious complication 

of organ transplantation, occurring in 60–70% of 

these patients. Esophagitis is one of the most 

common manifestations in this setting. CMV is by 

far the most frequent cause of esophageal ulcer in 

patients with advanced HIV infection and a CD4 

count lower than 100mm 3 (see reference 26). In 

contrast to HSV esophagitis, CMV esophagitis has 

rarely been detected in an immunocompetent 

host; 27 however, CMV and HSV are equally 

common organisms in transplant patients who do 

not receive antiviral prophylaxis. 28 Odynophagia 

is a constant feature and is typically severe; chest 

pain of esophageal origin, mainly occurring upon 

deglutition, is also described. Prior or co-existent 

Figure 3.3 Herpes simplex virus esophagitis. Small, wellcircumscribed 

ulcers (short arrows) and two small vesicles 

(long arrows) in the lower third of the esophageal mucosa. 

CMV infection in other regions (e.g. retinitis, 

colitis) is not uncommonly found. 29 

As with HSV, a definite diagnosis of CMV 

esophagitis requires endoscopy and biopsy. 

Contrast X-ray examination of the esophagus 

reveals either focal or diffuse images of mucosal 

ulcerations. Ulcers may be vertical or linear with 

central umbilication, or may be diffuse and superficial; 

30 they are usually deep and large in patients 

with advanced HIV infection. Endoscopy remains 

the definitive diagnostic tool for CMV esophagitis. 

The endoscopic appearance is variable and may 

include multiple shallow ulcers, solitary ulcers or 

diffuse superficial esophagitis (Figure 3.4). In 

contrast to Candida and HSV, brushing cytology 

has a poor sensitivity and multiple biopsies should 

be taken. Since the cytopathic effect of CMV 

occurs at the level of endothelial and mesenchymal 

cells in the granulation tissue, endoscopic 

biopsies must be taken from the base of the ulcer. 31 

Histology typically shows large cells with intranuclear 

and intracytoplasmic inclusions having an 

eosinophilic appearance. Immunohistochemical 

stains can reveal more infected cells than routinely 

appreciated with hematoxylin and eosin staining. 

Mucosal biopsy is also more specific than viral 

culture as with other esophageal infections. 32

The drugs available for treating CMV disease 

include ganciclovir, an acyclovir derivative, 

foscarnet and cidofovir. CMV esophagitis responds 

clinically and endoscopically to ganciclovir in 

approximately 75–80% of patients (Table 3.4). 29 

Duration of treatment should be based on clinical 

and endoscopic variables, but there is wide agreement 

that a 2–4-week period is usually effective. 

Oral ganciclovir is not effective for treating active 

infection, owing to its low bioavailability 

(≤ 10%). 33 If an acute CMV infection occurs in 

transplant patients, ganciclovir should be given for 

about 1–2 months, until immunosuppressive 

drugs are reduced or discontinued. In patients 

receiving a protracted course of therapy, clinical 

and virological resistance to ganciclovir may 

occur. 34 In this condition foscarnet, a pyrophosphate 

analog inhibiting DNA polymerase and 

reverse transcriptase, is usually effective. 35 The 

relapse rate of CMV esophagitis in HIV-infected 

patients is approximately 50%, 29 but long-term 

ganciclovir maintenance therapy is not routinely 

recommended unless there is a co-existent retinitis. 

33 

Ganciclovir and high-dose acyclovir have been 

used with moderate success for the prophylaxis of 

CMV infection in transplant patients. However, in 

Figure 3.4 Cytomegalovirus esophagitis. A round, 

solitary deep ulcer is evident in the distal esophageal 

mucosa (arrow). 

Other viral pathogens 35 

this setting ganciclovir prophylaxis is limited to 

high-risk patients, i.e. CMV-seropositive patients, 

CMV-seronegative patients receiving CMVseropositive 

organ or blood products, and patients 

treated with immunosuppressive drugs because of 

episodes of rejection. 36 

Other viral pathogens 

Varicella zoster virus (VZV) is a relatively uncommon 

agent of infectious esophagitis in immunologically 

normal subjects, but it causes a severe 

esophagitis in immunocompromised patients, 

usually accompanied by other signs of systemic 

dissemination (e.g. pneumonitis, hepatitis, 

encephalitis). 37 The endoscopic appearance ranges 

from vesicles to necrotic ulcerations. Definite diagnosis 

requires biopsies both for routine histology 

(ballooning degeneration, multinucleated giant cells, 

intranuclear eosinophilic inclusion bodies) and for 

culture and immunohistochemical staining. The 

infection is treated with acyclovir or famciclovir; 

foscarnet is used for resistant viruses. 

In a subject with clinical features consistent with 

infectious mononucleosis due to Epstein–Barr virus 

(EBV), the occurrence of nausea, dysphagia or 

hematemesis should raise the possibility of an infectious 

esophagitis. This however, develops only in a 

small minority of immunocompetent individuals, 

whereas in immunocompromised subjects, EBVrelated 

infectious esophagitis has been reported. 38 

Oral acyclovir may be a reasonable therapy, even if 

benefits of antiviral therapy in EBV-related esophagitis 

are unproven. 

The human papillovirus, like HSV, usually infects 

squamous epithelial cells. The diagnosis requires 

histology 39 (multinucleated giant cells, koilocytosis, 

cellular atypia) and immunohistochemical staining. 

Endoscopy reveals non-specific lesions such as 

yellow plaques, small nodules or patches with small 

villous projections. The condition is generally 

asymptomatic, and specific treatment may be 

unnecessary 

In specific HIV-related esophagitis, HIV is a wellknown 

risk factor for many other infections. 

However, it is agreed that HIV itself can lead to 

esophageal ulcerations, 40 usually presenting as 

multiple, small and shallow lesions. This esophageal

36 


Table 3.4 Drugs for viral esophagitis 

Drug Duration Dosage Remarks 

Acyclovir 7–10 days 20mg/kg per dose orally four A nucleoside analog available for both oral and 

times daily (80 mg/kg per day). intravenous administration. It is well tolerated; 

Severe infections refractory to occasionally, rash, reversible renal failure or 

normal oral dosages or in gastrointestinal symptoms occur. Dose 

which the patient is unable adjustment should be made with renal 

to swallow are treated with impairment. Risk of renal insufficiency is 

i.v. acyclovir, 15–30 mg/kg per reduced with adequate prehydration 

day in 3 divided doses 

Ganciclovir 14–28 days 5 mg/kg given intravenously twice Drugs of first choice for the treatment of serious 

per day systemic CMV infections. The need for 

maintenance therapy of gastrointestinal CMV 

infection remains unclear. Dosage reduction is 

recommended in patients with renal 

impairment. Main side-effects are: neutropenia, 

thrombocytopenia, central nervous system 

symptoms, abnormal liver function tests, fever 

and rash. Simultaneous administration of G- 

CSF or GM-CSF can prevent ganciclovirassociated 

neutropenia 

Foscarnet 14–28 days HSV infection: 40 mg/kg of body Second-line parenteral antiviral, reserved for 

weight given either every 8 or treatment of HSV or CMV infections resistant to 

every 12 h. This dose is injected conventional therapy. Main side-effects are: 

slowly into a vein by an infusion nephrotoxicity, anemia, gastrointestinal 

pump over at least 1 h. CMV toxicity, hyper- and hypocalcemia, 

infection: 60 mg/kg, as above hypomagnesemia, hyper- and 

hypophosphatemia, hypokalemia, seizures. It is 

mainly used in the treatment of acyclovirresistant 

HSV infections and ganciclovirresistant 

CMV infections 

Famciclovir 7 days In adults: 250 mg, three times Consider with acyclovir resistance, but limited 

daily orally experience in infectious esophagitis. Use with 

caution in subjects with renal insufficiency. 

Main side-effects similar to those for acyclovir 

Cidofovir 14 days 5 mg/kg i.v. once per week A novel monophosphate nucleotide analog 

effective against CMV, HVS-1, HVS-2 and EBV. 

Parenteral antiviral recently approved to treat 

CMV retinitis. No reports on the treatment of 

CMV esophagitis. Generally reserved for 

patients with serious CMV disease for whom 

ganciclovir and/or foscarnet therapy has failed. 

Main side-effects are: nephrotoxicity, 

proteinuria, glycosuria, neutropenia and 

metabolic acidosis 

CMV, cytomegalovirus; G, granulocyte; CSF, colony-stimulating factor; GM, granulocyte/macrophage; HSV, herpes 

simplex virus; EBV, Epstein–Barr virus

involvement may occur in the setting of a mononucleosis-like 

illness that develops around the time of 

the primary HIV infection. Biopsy specimens examined 

at electronic microscopy show enveloped viruslike 

particles with morphology compatible with that 

of retroviruses. In the later stages of HIV infection, 

when the CD4 lymphocyte count is below 100/mm 3 , 

large esophageal ulcerations can be observed. These 

ulcers are commonly defined as idiopathic 

esophageal ulcers (IEU) and appear as uniformly 

well-circumscribed lesions, without histological 

features of a viral cytopathic effect. It has been 

observed that HIV-associated IEU are diagnosed 

when biopsy, cytology and cultures are negative. 

Electron micrographs from the margins of some 

superficial ulcers have revealed viral particles 

morphologically similar to retroviruses. The polymerase 

chain reaction (PCR) can identify the HIV 

genome in biopsy specimens, but it remains unclear 

whether HIV is pathogenic in esophageal ulcerations. 

Reports have revealed HIV histopathologically 

in esophageal biopsies from patients with Candida, 

HSV and CMV. It has been hypothesized that most 

esophageal disease in patients with advanced HIV 

infection is associated with specific pathogenic 

processes. However, HIV-induced ulcerations can 

occur and may require treatment with corticosteroids. 

41 IEU present clinically in a fashion similar 

to CMV esophagitis; whereas bleeding is reported, 

strictures are rare. These ulcers usually respond well 

to oral corticosteroids or thalidomide. Despite the 

fact that these drugs may entail some risk for 

patients already immunosuppressed, this treatment 

is usually well tolerated. 

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4 

Introduction 

Gastroesophageal reflux 

disease 

Yvan Vandenplas, Silvia Salvatore and Bruno Hauser 

Gastroesophageal reflux (GER) is defined as the 

involuntary passage of gastric contents into the 

esophagus. GER is a physiological phenomenon, 

occurring in every individual. Most episodes of 

reflux are limited to the distal esophagus, and are 

brief and asymptomatic. The difference between 

physiological reflux and reflux disease is to a 

lesser extent defined by the frequency, duration 

and severity of the reflux episodes, than whether 

the reflux episodes result in the occurrence of 

symptoms, signs severe enough to impair the 

quality of life, or complications. GER disease 

(GERD) is reflux associated with mucosal damage 

or symptoms severe enough to impair quality of 

life. 1,2 When this occurs, and the forces overcome 

the defense, the esophagus may become damaged, 

with significant consequences for the affected 

individual. 

Definitions 

Regurgitation is defined as passage of refluxed 

gastric contents into the oral pharynx and the 

mouth and is accompanied by gastric content 

drooling out of the mouth. Spitting-up is synonymous 

with regurgitation. Vomiting is defined as 

expulsion of the refluxed gastric contents from the 

mouth. 3,4 Only a minority of reflux episodes is 

accompanied by regurgitation or vomiting. 

Rumination is characterized by the voluntary, 

habitual regurgitation of recently ingested food 

that is subsequently spitted up or re-swallowed. 

Sometimes GER is a normal esophageal function, 

serving a protective role, e.g. during meals, or in 

the immediate postprandial period; if the stomach 

is overdistended, GER serves to decompress it. 

Regurgitation may be physiological in healthy, 

thriving, happy infants. Primary GER results from 

a primary disorder of function of the upper 

gastrointestinal tract. In secondary GER, reflux 

results from dysmotility occurring in systemic 

disorders such as neurological impairment or 

systemic sclerosis. It may also result from mechanical 

factors at play in chronic lung disease or upper 

airway obstruction, as in chronic tonsillitis. Other 

causes include systemic or local infections 

(urinary tract infection, gastroenteritis), food 

allergy, metabolic disorders, intracranial hypertension 

and medications such as chemotherapy. In 

some cases, secondary reflux results from stimulation 

of the vomiting center by afferent impulses 

from circulating bacterial toxins, or stimulation 

from sites such as the eye, olfactory epithelium, 

labyrinths, pharynx, gastrointestinal and urinary 

tracts, and testes. 3,4 These stimuli usually cause 

vomiting. The symptoms and signs of primary and 

secondary reflux are similar, but a distinction is 

conceptually helpful in determining a therapeutic 

approach. Secondary GER is not discussed further. 

Epidemiology 

Determination of the exact prevalence of GER and 

GERD at any age is virtually impossible because 

most reflux episodes are asymptomatic, show the 

absence of specific symptoms, undergo selftreatment 

and lack medical referral. In normal 3–4month-old 

infants, three or four episodes of GER 

are detectable during 5 min of intermittent fluoroscopic 

evaluation, 5 and up to 31±21 acid reflux 

episodes are recorded within a 24-h period with 

pH monitoring. 6 

The frequency of regurgitation varies according to 

age. Daily regurgitation is present in 50% of infants 

39

40 

Gastroesophageal reflux disease 

younger than 3 months and in more than 66% at 4 

months, but only in 5% at 1 year of age. 7–9 

Complete resolution of regurgitation is frequent 

and expected, by 10 months in 55%, by 18 months 

in 60–80% and by 2 years of age in 98%. 10 A 

prospective follow-up of 63 regurgitating infants 

reported in all subjects, before 12 months, a 

complete disappearance of symptoms, although 

accompanied by a significant increase in feeding 

refusal, duration of meals, parental feeding-related 

distress and impaired quality of life, even after the 

disappearance of symptoms. 11 

About 5–9% of infants have troublesome GERD. 6,12 

According to parents, heartburn is present in 1.8% 

of 3–9-year-old healthy children and 3.5% of 10– 

17-year-old adolescents; regurgitation is said to 

occur in 2.3% and 1.4%, respectively, and 0.5% 

and 1.9% need anti-acid medication. In selfreports, 

adolescents complain about heartburn in 

5.2% and regurgitation in up to 8.2%, while antiacids 

are taken by 2.3% and histamine receptor 

antagonists (H2RA) by 1.3%, suggesting that symptoms 

of GER are not rare during childhood and are 

underreported by the parents or overestimated by 

the adolescents. 13 In a Western population, GERD 

affected 4–30% of adults 14,15 and heartburn and 

regurgitation resolved within 3–10 years only in 

12–33%, regardless of the presence of esophagitis 

at diagnosis. 1,16,17 In the absence of H2RA or proton 

pump inhibitors (PPI), symptoms improved after 

17–22 years in 60% but disappeared in only 12%. 18 

Despite anti-secretory treatment, a 10-year followup 

of esophagitis showed that over 70% had 

persisting symptoms and 2% had strictures. 19 

Reflux esophagitis is reported in 2–5% of the 

general population. 12 Children with GER symptoms 

present esophagitis in 15 up to 62% of cases, 

Barrett’s esophagus in 0.1–3% and refractory 

GERD requiring surgery in 6–13%. 20–24 In adults 

undergoing endoscopy, esophagitis is diagnosed in 

15 up to 80% of cases. 1,17,25,26 The huge differences 

in incidence are determined by patient recruitment 

and availability of self-treatment. 

Genetic and environmental factors 

It has been demonstrated that physiological reflux, 

heartburn, acid regurgitation and severe GERD are 

more frequent in men than in women. Barrett’s 

esophagus is in part genetically determined. 24 

There is much information (in adults) demonstrating 

the aggravating effects of alcohol, smoking, 

drugs, dietary components, etc. on the incidence 

of GER. A detailed discussion on these environmental 

factors is beyond the scope of this chapter. 

Changes in lifestyle in men and women may result 

in the fact that the differences in incidence in 

GERD between both sexes may be disappearing. 

With pH monitoring, we could not demonstrate a 

male predominance in children. All forms of 

GERD affect Caucasians more often than African- 

Americans or Native Americans (adult data). 14 

However, the same prevalence of troublesome 

infant regurgitation was found in Caucasian and 

Indonesian infants. 27 The importance of the 

genetic background was hypothesized by demonstrating 

that esophagitis and hiatus hernia were 

more common in a population with the same 

genetic background with dyspeptic symptoms in 

England than in Singapore. 28 Race, sex, body mass 

index and age were independently associated with 

hiatus hernia and esophagitis, race being the most 

important risk factor. 28 However, over-the-counter 

use of low-dose aspirin and non-steroidal antiinflammatory 

drugs has a greater impact on severe 

GERD, such as esophageal stricture than age. 29 

Carre et al described the autosomal dominant 

inheritance of hiatal hernia by discovering familial 

hiatal hernia in a large five-generation family, but 

without demonstrating the link to GERD. 30 The 

genetic influence on GERD is supported by 

increased GER symptoms in relatives of GERD 

patients. 31 Moreover, the concordance for GER is 

higher in monozygotic than dizygotic twins. 32 A 

locus on chromosome 13q, between microsatellites 

D13S171 and D13S263, has been linked to 

severe GERD in five multiply affected families, 33 

but not confirmed in another five families, possibly 

owing to the genetic heterogeneity of GERD 

and the different clinical presentations of 

patients. 34 

Pathophysiology 

The pathophysiology of GER is complex and 

diverse, as it is influenced by factors that are 

genetic, environmental (e.g. diet and smoking), 

anatomic, hormonal and neurogenic (Figure 4.1 

and Table 4.1). We have recently reviewed the

Gastric distension 

(gastric mechanoreceptors near cardia) 

Vagally mediated abnormal neural control of LES by CNS 

Defective LES motility 

Increased TLESRs 

Low basal LES tone 

Increase in GER 

pathophysiology of GER in infants and children. 35 

The most relevant factors are gastric (gastric acid 

and non-acid content, gastric emptying, fundus 

tone, triggering of transient lower esophageal 

sphincter (LES) relaxations (TLESRs)), the antireflux 

barrier (LES basal pressure, TLESRs, hiatal 

hernia), the composition of the refluxate 

(air–liquid, acid, non-acid, bile), the esophageal 

tone and the esophageal clearance (volume and 

chemical clearance). 35,36 GER occurs during 

episodes of transient relaxation of the LES or inadequate 

adaptation of the sphincter tone to changes 

in abdominal pressure. 

GERD was classically considered to be an acid 

peptic disease, although as a group, the majority of 

patients with reflux disease do not have a significant 

increase in gastric acid secretion. Three major 

Gastric acid 

Hiatal hernia, obtuse angle of His 

Delayed (acid) clearance 

Delayed volume clearance (motility) 

Impaired pH neutralization (saliva, esophageal secretion) 

Poor mucosal resistance 

Increased abdominal pressure 

Genetic factors 

Posture, handling, physical activity, sleep state, feeding, drugs 

Environmental factors 

Pathophysiology 41 

Figure 4.1 Illustration of multifactorial influences on gastroesophageal reflux (GER). LES, lower esophageal sphincter; 

CNS, central nervous system; TLESRs, transient lower esophageal sphincter relaxations. 

tiers of defense serve to limit the degree of GER, 

and to minimize the risk of reflux-induced injury 

to the esophagus. The first line of defense is the 

‘anti-reflux barrier’, consisting of the LES, and the 

diaphragmatic pinchcock and angle of His; this 

barrier serves to limit the frequency and volume of 

refluxed gastric contents. When this line of 

defense fails, the second, esophageal clearance, 

assumes greater importance, to limit the duration 

of contact between luminal contents and 

esophageal epithelium. Gravity and esophageal 

peristalsis serve to remove volume from the 

esophageal lumen, while salivary and esophageal 

secretions (the latter from esophageal submucosal 

glands), serve to neutralize acid. The third line of 

defense, ‘tissue or esophageal mucosal resistance’ 

comes into play when acid contact time is 

prolonged, such as when esophageal clearance is

42 


Table 4.1 Parameters influencing the incidence 

of gastroesophageal reflux 

Mastication, saliva secretion 

Swallowing 

Esophageal clearance 

Esophageal innervation and receptors 

Mucosal resistance 

Lower esophageal sphincter pressure 

Sphincter relaxation 

Abdominal esophagus 

Sphincter position 

Angle of His 

Gastric volume, gastric accommodation 

Gastric emptying 

Gastric acid output 

Gastric acid feed buffering 

Feeding regimen: type, frequency, volume 

Pepsin/trypsin/bile salts 

Helicobacter pylori 

Intra-abdominal pressure 



Posture 

Physical activity 

Sleep state 

Respiratory disease 

Medication (e.g. xanthines) 

defective or not operative (motility disorders, 

sleep). 35 

Epidemiological data suggest that Helicobacter 

pylori plays a protective role in GERD, presumably 

by decreasing acid secretion. In adults, 

Helicobacter pylori and especially the cagA positive 

strains, which cause more severe gastric 

inflammation, are less prevalent in patients with 

esophagitis or Barrett’s esophagus than in those 

with endoscopically negative reflux disease or in 

control patients. 37–41 

Recent detailed analysis of postprandial acidity in 

the gastroesophageal junction area suggests that 

local acid distribution rather than total gastric 

secretion might be more relevant to the pathogenesis 

of GERD. 42 Differences may exist in the degree 

of mixing of fundal contents leading to different 

distributions of acid in the stomach. Studies using 

pH monitoring and esophageal scintigraphy and 

gastric magnetic resonance imaging suggest that 

gastric mixing can be incomplete and different 

layers of viscosity within the stomach might therefore 

influence the distribution of the gastric 

contents. A collection of acid in the gastric part of 

the esophageal junction was shown in adults in a 

supine position, even in the postprandial period 

when the stomach content was neutralized by the 

meal. 43,44 This newly described mechanism is 

attractive as an explanation for postprandial 

distress in infants lying in the supine position. 

TLESRs are the major mechanism of GER episodes, 

in premature infants and in adults. 35,45,46 TLESRs 

are a neural reflex, triggered mainly by the distension 

of the proximal stomach and organized in the 

brain stem, with efferent and afferent pathways 

traveling in the vagus nerve, activating an intramural 

inhibitory neuron which releases nitric 

oxide to relax the LES. 47,48 When investigated in 

the supine position, the incidence of TLESRs in 

healthy adults and those with GERD did not differ. 

In healthy adults, only 30% of the TLSERs were 

accompanied by acid reflux, but in patients with 

GERD the reflux occurred in 65% of the TLESRs. 

Thus adults, controls and GERD patients have the 

same incidence of TLESRs, but in patients with 

GERD these TLESRs are more than twice as 

frequently accompanied by acid GER. 36,49,50 The 

initial studies performed in the recumbent position 

found a higher frequency of TLSERs in 

patients with GERD than in normals. 51 These older 

studies in the recumbent position may be more 

relevant for infants. 

Delayed gastric emptying may increase postprandial 

reflux possibly by increasing the rate of 

TLESRs and the likelihood of reflux during the 

TLESRs. A disturbed gastric accommodation to a 

meal and prolonged postprandial fundic relaxation 

where described in patients with GERD. 52 Both 

phenomena can influence postprandial fundic 

volume and pressure, which in turn may affect the 

rate of distension-induced triggerings of TLESRs

and the volume of the refluxate. A recent study has 

shown that esophageal acid exposure in patients 

with GERD is directly correlated with the emptying 

time of the proximal stomach. 53 These new 

findings are especially of interest in infants with 

postprandial distress or regurgitation who are not 

responding to dietary treatment with thickened 

casein-predominant formula. This has a delayed 

gastric emptying time, and thus is related to an 

increased incidence of TLESRs. 

Hiatal hernia increases the number of reflux 

episodes and delays esophageal clearance by 

promoting retrograde flow across the esophagogastric 

junction when the LES relaxes after a 

swallow. This mechanism underlies the so-called 

re-reflux phenomenon (acid reflux when the pH is 

still below 4). 

The refluxate might be highly acid, moderately 

acid, or non-acid. Reflux may be a mixture of gas 

and liquid or pure liquid, and may or may not 

contain bile. More than half of the acid and nonacid 

reflux episodes are associated with reflux of 

gas. 36 Non-acid reflux also occurs predominantly 

during TLESRs. With liquid meals, patients with 

reflux disease had a similar total rate of reflux 

episodes but a higher proportion of acid reflux 

events than controls. 54 Non-acid reflux may be 

responsible for the remaining symptoms in 

patients under anti-secretory treatment. 55 

Acid reflux in patients with GERD is associated 

with an inhibition of tone in the esophageal body, 

whereas normals have an increased contractile 

activity. In order to have an effective volume clearance, 

motility of the esophageal body needs to be 

preserved. Acid is emptied from the esophagus 

with one or two sequences of primary peristalsis, 

then the residual acidity is neutralized by swallowed 

saliva. 35 Secondary peristalsis is the 

response to esophageal distension with air or 

water, and is more important during sleep, when 

peristalsis is reduced. Patients may have normal 

primary peristalsis but abnormal secondary peristalsis. 

Thus, non-acid reflux, as occurs in the 

postprandial period, may be inefficiently cleared 

and cause prolonged esophageal distension. The 

esophageal mucosal defense can be divided into 

pre-epithelial (protective factors in swallowed 

saliva and esophageal secretions containing bicarbonate, 

mucin, prostaglandin E2, epidermal 


growth factor, transforming growth factor), epithelial 

(tight junctions, intercellular glycoprotein 

material) and post-epithelial factors. 35 There is a 

very important interindividual variation of reflux 

perception suggesting different esophagussensitive 

thresholds. The esophageal mucosa 

contains acid, and temperature- and volumesensitive 

receptors. A widening of the intercellular 

spaces has been found in patients with esophagitis 

and in patients with endoscopy-negative disease. 

When esophagitis heals, esophageal sensitivity to 

acid decreases. The presence of fat in the duodenum 

increases the sensitivity to reflux. Hyposensitivity, 

as occurs in patients with Barrett’s 

esophagus, is a secondary phenomenon. 56 

Clinical signs/symptoms 

The most typical, although non-specific, symptoms 

of esophageal dysfunction are GER, regurgitation 

and vomiting. While reflux does occur physiologically 

at all ages, there is a continuum 

between physiological GER and GERD leading to 

significant symptoms and complications. GERD is 

a spectrum of diseases that can best be defined as 

the symptoms and/or signs of esophageal or adjacent 

organ injury secondary to the reflux of gastric 

contents into the esophagus or, beyond, into the 

oral cavity or airways. 

Presentation may be with decreased food intake 

and aversive behavior around feeds. There is often 

clearly abnormal sucking and swallowing. Not 

surprisingly, the mother–child interaction is 

affected, making the situation less easily treated. 57 

There may be poor weight gain. These infants have 

no apparent malformations, and may be diagnosed 

as ‘non-organic failure to thrive’ (NOFTT), 58 a 

‘disorder’ that is sometimes attributed to 

social/sensory deprivation, socioeconomic or 

primary maternal–child problems. Primary GERD 

is but one root cause of ‘feeding problems’ in 

infancy, others being structural abnormalities of 

the mouth/pharynx/upper gastrointestinal tract, 

neurological conditions, primary behavior disorders, 

cardiorespiratory problems, or metabolic 

dysfunction. However, no matter what the cause, 

so-called ‘feeding problems’ are bio-behavioral 

conditions, i.e. disorders in which biological and 

behavioral causes interact. 59

44 


A wide spectrum of clinical presentations of GERD 

exists, with relevant differences within ages (Table 

4.2). Regurgitation is the most common presentation 

of infantile GER, with occasional projectile 

vomiting. 7,60 In infants and young children, verbal 

expression of symptoms is often vague or impossible, 

and persistent crying, irritability, feeding and 

sleeping difficulties have been proposed as equivalents 

for heartburn in adults. Nevertheless, the 

descriptions for infants are non-specific and even 

functional. Therefore, poor weight gain, feeding 

refusal, back-arching, irritability and sleep disturbances 

have also been reported to be unrelated to 

GERD. 61,62 Esophageal pain and behaviors 

perceived by the caregiver (usually the mother) to 

represent pain (e.g. crying and retching) potentially 

affect the response of the infant to visceral 

stimuli and the ability to cope with these sensations, 

either painful or non-painful. 63 In addition, 

cow’s milk allergy (CMA) may overlap with many 

symptoms of GER, and may coexist or complicate 

GERD in up to 40% of infants. 64–66 

Table 4.2 Spectrum of gastroesophageal reflux disease manifestations according to different ages 

Symptoms and signs Infants Children Adults 

Vomiting ++ ++ + 

Regurgitation +++ ++ ++ 

Heartburn/pyrosis ? ++ +++ 

Epigastric pain ? + ++ 

Chest pain ? + ++ 

Dysphagia ? + ++ 

Excessive crying/irritability +++ + - 

Anemia/melena/hematemesis + + + 

Food refusal/feeding disturbancies/anorexia ++ + + 

Failure to thrive/poor growth ++ + - 

Abnormal posturing/Sandifer’s syndrome ++ + - 

Persisting hiccups ++ + + 

Dental erosions/halitosis/water brush - + + 

Hoarseness/globus pharyngeus - + + 

Persistent cough/aspiration pneumonia/wheezing + + + 

Laryngitis/ear problems + + + 

Laryngomalacia/stridor/croup + + - 

Laryngostenosis/resistant asthma/chronic sinusitis - + + 

Vocal nodule problems - - + 

ALTE/SIDS/apnea/desaturation + - - 

Bradycardia + ? ? 

Sleeping disturbancies + + + 

Impaired quality of life ? ? +++ 

Esophagitis + + ++ 

Stenosis - (+) + 

Barrett’s esophagus/esophageal adenocarcinoma - (+) + 

ALTE, apparent life-threatening events; SIDS, sudden infant death syndrome 

+++ very common; ++ common; + possible; (+) rare; - absent; ? unknown

Compared to adults, children report more regurgitation 

and emesis and less heartburn, dysphagia 

and chest pain. 13,23,67 The younger the children 

are, the more difficult it is to describe and perceive 

these ‘unpleasant sensations’. In 69 children with 

GERD, regurgitation and vomiting occurred in 

72%, symptoms attributed to the esophagus 

(epigastric/abdominal pain, feeding difficulties, 

irritability and Sandifer–Sutcliffe syndrome) in 

68%, failure to thrive in 28%, chronic respiratory 

symptoms in 13% and recurrent apnea in 12%, 

with more feeding difficulties in toddlers and more 

irritability in infants. 21 Clinical distinction is, 

however, not simple, as GERD may be occult or 

masquerade as respiratory or other manifestations 

co-existing at different ages. 

GERD in adolescents is more adult-like. Heartburn 

is the predominant GER symptom, occurring 

weekly in 15–20% 15,68 and daily in 5–10% of 

subjects. 16 Atypical symptoms such as epigastric 

pain, nausea, flatulence, hiccups, chronic cough, 

asthma, chest pain, hoarseness and earache, 

account for 30–60% of presentations of GERD. 1,16 

GERD is diagnosed in 50% of the adult patients 

with chest pain and in 80% presenting with 

chronic hoarseness and asthma. 69 The incidence 

of GERD in this group with atypical symptoms is 

determined by the selection (bias) of the patients. 

Recent evidence has shown that GERD affects the 

quality of life significantly in adults, and probably 

also in children (and their parents), although 

quality of life is more difficult to evaluate in 

infants and young children. The developing 

nervous system of infants exposed to acid seems 

susceptible to pain hypersensitivity despite the 

absence of tissue damage. 70 The role of hypersensitivity 

to dietary allergens, both in exclusively 

breast-fed and formula-fed infants, is likely to be 

underestimated at present. The ‘hygiene hypothesis’ 

suggests that the Th2-predominant immune 

response at birth in the industrialized world is 

insufficiently skewed towards a well-balanced 

Th1/Th2 response. 71 Lack of controlled chronic or 

repetitive inflammation of the mucosa during the 

first months of life may account for the dramatic 

increase in atopic disease during infancy and 

childhood (which is a Th2 response) and the 

increase in autoimmune diseases such as diabetes 

and Crohn’s disease in adolescents and adults 


(which are a Th1 response). 72 This hypothesis fits 

well with the observations that atopy is inversely 

related to family income and early attendance at a 

day-care center, and positively related to number 

of siblings and living on a farm. Repeated contacts 

with certain infectious organisms and endotoxins 

decrease the incidence of atopic disease. Infant 

distress and colic are now recognized as manifestations 

of food hypersensitivity during early childhood. 

Histology of the duodenal, gastric and 

esophageal mucosa reveals eosinophilic infiltration, 

characteristic of a Th2 type and thus allergic 

response, in many although not all infants. 

Infants with GERD learn to associate eating with 

discomfort and thus subsequently tend to avoid 

eating, although behavioral feeding difficulties are 

common even in control toddlers. 11 In adults, 

impaired quality of life, notably regarding pain, 

mental health and social function, has been 

demonstrated in patients with GERD, regardless of 

the presence of esophagitis. 17 In an unselected 

population, 28% of the adults reported heartburn, 

almost half of them weekly, with a significant 

impact on the quality of life in 76%, especially if 

the symptoms were frequent and long-lasting. 

Despite that, only half of heartburn complainers 

sought medical help, although 60% were taking 

medications. 73 Thus, some adults ‘learn to live 

with their symptoms’, and acquire tolerance to 

long-lasting symptoms, while others accept living 

with an impaired quality of life. 

The reason for the differences in presentation of 

GERD according to age remains unclear. The 

persistence of symptoms and progression to 

complications are unpredictable for a group of 

patients and for an individual patient. Alarm 

symptoms are similar in adults and children: 

weight loss, dysphagia, bleeding, anemia, chest 

pain and choking. 16,69 Additional alarm symptoms 

in children are failure to thrive, irritability/crying 

and feeding or sleeping difficulties. 74 

Gastroesophageal reflux disease and 

respiratory disease 

Reflux may cause respiratory symptoms through 

different pathways, such as (micro-) aspiration or 

vagally mediated mechanisms. Many patients with

46 


chronic cough have gastrohypopharyngeal 

reflux. 35 A consequence of pulmonary aspiration 

of refluxed material may be the presence of an 

increased number of lipid-laden macrophages. 

Although simply observing the presence of lipidladen 

alveolar macrophages is likely to be nonspecific, 

it has been suggested that quantification 

would be a useful marker of silent aspiration. 75 

Data are lacking and are therefore needed on the 

diagnostic accuracy, sensitivity and specificity of 

the detection and quantification of other 

substances in tracheal aspirates, such as lactose, 

pepsin and intrinsic factor. 

In some patients it may not be GER that is causing 

respiratory disease, but the reverse. Respiratory 

difficulties cause greater respiratory breathing 

efforts and thus more pronounced negative 

intrathoracic pressure, and thus respiratory symptoms 

may provoke GER. However, the incidence of 

a direct temporal relation between reflux and 

cough episodes is relatively low. 76 

The relation between respiratory disease and GER 

may also be neurogenic, in this case designated as 

‘gastric asthma’. 77 The tracheobronchial tree and 

the esophagus have common embryonic foregut 

origins and share autonomic innervation through 

the vagus nerve. 78 In other words, it can be speculated 

that GER increases the irritability of the vagal 

nerve endings in the esophagus, and that as a 

result these nerve endings hyper-react together 

with the nerve endings in the airways because 

they have the same embryonic origin. 

Complications 

GERD is associated with severe complications 

such as esophagitis, Barrett’s esophagus, strictures 

and esophageal adenocarcinoma. The severity of 

the complications is not clearly related to the duration 

or severity of symptoms, as severe histological 

changes are detectable at the first investigation. 

Differences in esophageal mucosal resistance and 

genetic factors may partially explain the diversity 

of lesions and symptoms. 16 Esophageal ulcers may 

be diagnosed in adults with dysphagia, odynophagia 

or esophageal bleeding, but are rarely seen in 

children. 20,74 

The incidence of congenital esophageal stenosis is 

approximately 1 in 25000 to 1 in 50000 live births, 

with associated esophageal atresia in one-third of 

cases. 79 More than 40 years ago, in the absence of 

reflux treatment, esophageal strictures were 

reported in about 5% of children with reflux symptoms. 

80 Nowadays, except in Barrett’s esophagus, 

esophageal stenosis and ulceration in children 

have become rare. 20 Esophageal stenosis may be 

related to the initial severity of the esophagitis and 

the persistence of symptoms, even during treatment. 

16 Occasionally, esophageal stenosis is 

reported to have developed after an intervention 

for achalasia. 81 

Reflux esophagitis is reported in 2–5% of the 

general population. 82 Children with GER symptoms 

present esophagitis in 15–62%, Barrett’s esophagus 

in 1.5–3% and refractory GERD requiring surgery in 

6–13%. 20–24 In adults undergoing endoscopy, 

esophagitis is diagnosed in 15–80%. 1,17,25,26 The 

differences in incidence are determined by patient 

recruitment and availability of acid-blocking drugs 

over the counter (self-treatment). A 10-year followup 

of esophagitis showed that over 70% had 

persisting symptoms, and 2% had strictures. 19 

Thus, esophagitis is not a necessary prerequisite 

for diagnosing GERD or starting therapy, either in 

children or in adults. 

Abundant infiltration of the esophageal mucosa 

with eosinophils, as occurs in eosinophilic 

gastroenteritis and eosinophilic esophagitis, is 

increasing in prevalence and necessitates proper 

treatment (hypoallergenic feeding, corticoids, etc.). 

Patients with allergic esophagitis seem to have a 

younger age and common atopic features (allergic 

symptoms or positive allergy tests), but no specific 

symptoms. In children, eosinophilic esophagitis 

accounts for almost 1.0% of esophagitis in some 

selected series. 83 Atopic features are reported in 

more than 90% and peripheral eosinophilia in 

50% of patients. At endoscopy, a pale, granular, 

furrowed and occasionally ringed esophageal 

mucosa may appear. 84 In reflux esophagitis, the 

distal and lower eosinophilic infiltrate is limited to 

less than 5 per high-power field (HPF) with 85% 

positive response to GER treatment, compared to 

primary eosinophilic esophagitis with >20 

eosinophils per HPF. 83–85 In adults, allergic 

esophagitis and eosinophilic esophagitis are rarely 

found, suggesting an age-related regression or a 

possible underinvestigation. Patients with primary 

eosinophilic esophagitis may respond to dietary

elimination, cromolyn sodium or steroids. 84 

Recently, montelukast and fluticasone have also 

been reported to be of benefit. 86,87 

Barrett’s esophagus is a premalignant condition 

with metaplastic columnar epithelium with goblet 

cells in the esophagus, 88 detectable in up to 5–10% 

of the endoscopies performed in adults, 16 but 

rarely seen in children. Children with severe 

reflux, as in those with neurological impairment, 

chronic lung disease (especially cystic fibrosis) 

and esophageal atresia, are at a higher risk of 

developing Barrett’s esophagus. 24 In addition to 

severe reflux, a genetic component is also 

suggested. 20,24,88–91 In a series including 402 children 

with GERD without neurological or congenital 

anomalies, no case of Barrett’s esophagus was 

detected. 20 In another series including 103 children 

with long-lasting GERD, and not previously 

treated with H2-receptor antagonists or a proton 

pump inhibitor, Barrett’s esophagus was detected 

in 13%. An esophageal stricture was present in 

five of the 13 patients with Barrett’s esophagus 

(38%). 90 Reflux symptoms during childhood were 

not different in the adults without, than in the 

adults with, Barrett’s esophagus. 88 

Peptic ulcer, esophageal and gastric neoplastic 

changes in children are extremely rare. In adults, 

over the past 30 years, a decreased prevalence of 

gastric cancer and peptic ulcer with an opposite 

increase of esophageal adenocarcinoma and GERD 

have been noted. 92 This has been attributed to 

independent factors amongst which are changes in 

dietary habits such as a higher fat intake, an 

increased incidence of obesity and a decreased 

incidence of Helicobacter pylori infection. 17,92 

Nevertheless, the frequency, severity and duration 

of reflux symptoms are related to the risk of developing 

esophageal cancer. Among adults with longstanding 

and severe reflux the odds ratios are 43.5 

for esophageal adenocarcinoma and 4.4 for adenocarcinoma 

at the cardia. 93 It is unknown whether 

mild esophagitis or GER symptoms persisting from 

childhood are related to an increased risk for 

severe complications in adults. 

Diagnosis with differential 

GERD is a primary motility disorder, mainly 

caused by reflux of gastric content during TLESRs 

inducing symptoms. None of the symptoms asso- 


ciated with GER and GERD are specific. Reflux 

disease can be a primary condition, or it can be the 

consequence of other abnormalities (such as 

neurological impairment, cystic fibrosis, pyloric 

hypertrophy) favoring GER. The long list of differential 

diagnoses is discussed under the other headings 

of this chapter, and depends on the age of the 

patient and the presenting symptom. 

Because of lack of space, diagnostic procedures are 

not discussed in full detail. Detailed information 

regarding the techniques, indications and pitfalls 

of radiologic contrast studies, reflux scintiscanning, 

ultrasound, pH metry, endoscopy and 

manometry can be found in other textbooks or 

review papers. Interest will be focused on recent 

developments such as impedancometry. The 

development of a validated ‘infant GERD questionnaire’ 

is likely to be the development in diagnostic 

accuracy with the greatest impact. 

Radiological contrast studies, scintiscanning and 

ultrasound are techniques evaluating postprandial 

reflux, and provide some information on gastric 

emptying. Normal ranges are not well established 

for any of the three procedures. Regarding gastric 

emptying, 13-C breath tests are more standardized 

(but the role of delayed gastric emptying in GER(D) 

is controversial). Scintiscanning may show 

pulmonary aspiration, although the sensitivity of 

the technique is extremely low. Contrast radiology 

is of importance to rule out anatomic abnormalities 

such as malrotation, duodenal web, stenosis 

and achalasia. 

There are no age or weight limitations in performing 

endoscopy. Endoscopy shows anatomic 

malformations and esophagitis, not reflux. 

Endoscopy-negative reflux disease is common. 

Biopsies of duodenal, gastric and esophageal 

mucosa are mandatory to exclude eosinophilic 

infiltration. 

Ambulatory 24-h esophageal pH monitoring 

measures the incidence and duration of acid 

reflux, and should be considered the ‘silver standard’. 

It is the best method to measure the presence 

of acid in the esophagus, but not all reflux 

causing symptoms is acid. However, it is likely 

that the majority of GERD patients suffer acid 

reflux. Esophageal pH metry is useful in evaluating 

the effect of any therapeutic intervention on 

reducing esophageal acid exposure. Since medical

48 


treatment currently focuses on reducing gastric 

acid secretion, the technique offers the possibility 

of measuring intragastric and esophageal recording 

of pH simultaneously. Manometry does not 

demonstrate reflux, but is of interest in showing 

the pathophysiological mechanisms causing the 

reflux (by measuring the frequency and duration 

of TLESRs), and is indicated in specific situations 

such as achalasia. Ambulatory 24-h esophageal 

manometry, in combination with pH metry, is now 

technically feasible. Long-lasting investigations 

offer the opportunity of measuring events in 

upright and recumbent positions, awake and 

asleep. Results of pH monitoring depend on the 

hardware and the software used. 94 The correlation 

between results obtained with different types of 

electrodes, glass and antimony, is extremely 

poor. 95 

Impedancometry is a technique gaining more and 

more interest, although it has existed for many 

years. The technique measures electrical potential 

differences, and is therefore not pH-dependent. 

The technique offers the possibility of distinguishing 

between acid and non-acid reflux (in combination 

with pH metry), and between liquid and gas 

reflux. Interpretation of the recording is still quite 

laborious and necessitates sufficient experience. 

(This is of course true for any of the investigation 

techniques.) Impedancometry seems especially of 

interest in patients with endoscopic and pH 

metric-negative symptoms suggesting GERD. 

Because reflux in infants is common, because 

there is no ‘gold standard’ investigation, and 

because investigations are invasive and expensive, 

interest has focused on the development of an 

‘infant GER-questionnaire’. 7 Recently, an improved 

questionnaire was developed. 96 The questionnaire 

offers the advantage of an objective, validated and 

repeatable quantification of symptoms suggesting 

GERD, and thus offers the possibility of measuring 

the impact of therapeutic intervention. However, 

although the correlation between the questionnaire 

and symptoms seems fair, the correlation 

between the questionnaire and results of investigations 

for reflux is poor. 

Investigation methods for GER all test different 

aspects involved in the mechanisms and characteristics 

of reflux. Therefore, it is not unexpected 

that the correlation between different techniques 

is extremely poor; non-acid reflux can cause 

esophagitis, severe heartburn can exist without 

esophagitis, etc. Also, the correlation between 

questionnaires for GER symptoms and results of 

pH metry and endoscopy is quite poor. 

Treatment options 

Because symptoms suggesting GERD are frequent 

and non-specific, especially during infancy, and 

because there is no ‘gold-standard’ diagnostic technique, 

many infants are exposed to anti-reflux 

treatment. Therefore, attention in the paragraphs 

on therapeutic possibilities is focused on safety 

aspects. Therapeutic intervention should always 

be a balance between intended improvement of 

symptoms and risk for side-effects. 

Complications of non-intervention 

It is difficult to know the true natural history of 

GER in infants and children because most patients 

obtain treatment. Knowledge on the natural 

history in untreated patients from the initial 

studies, when effective treatment was unavailable, 

is extremely limited, because of the limited 

description and identification of the patients. The 

paucity of long-term reports, the presence of multiple 

pathogenic factors and the absence of pathognomonic 

symptoms for complications make it 

currently impossible to predict, on an individual 

basis, which child will continue to have GERD into 

and during adult life. However, we know that 

untreated GERD may be associated with severe 

complications such as esophagitis, failure to thrive 

in children, esophageal stricture and Barrett’s 

esophagus. 

Recent observations suggest a decreased quality of 

life in regurgitating infants and their parents, even 

if the regurgitation has disappeared. A 10-year 

follow-up of esophagitis showed that over 70% 

had persisting symptoms, and 2% had strictures. 19 

Untreated or uncontrolled GERD is associated with 

severe complications such as esophagitis, Barrett’s 

mucosa, stricture formation and esophageal 

adenocarcinoma. The frequency, severity and 

duration of reflux symptoms are related to the risk 

of esophageal cancer. It is not known whether mild

esophagitis or GERD symptoms persisting from 

childhood into adulthood carry an increased risk 

for severe complications in adult life. Spontaneous 

improvement and healing of non-ulcerated 

esophagitis may exist. Nevertheless, complications 

and side-effects of medication have to be considered 

in relation to the natural evolution of 

untreated GERD. 

Non-pharmacological and non-surgical 

therapies for gastroesophageal reflux 

Non-pharmacological (and non-surgical) therapies 

for reflux do not have any proven efficacy on 

reflux, although some may decrease the incidence 

of regurgitation. Lifestyle changes (in adults) are 

rarely beneficial. 96 No significant difference was 

shown between the flat and head-elevated prone 

position. Despite gravity, the upright seated position 

leads to significantly more and larger reflux 

episodes than the simple prone and 30° elevated 

prone position, when the infant is awake or 

asleep. 97 This is likely to be due to increased 

abdominal or intragastric pressure. The supine 

(lying on the back) and lateral positions (lying on 

the left or right side) usually result in intermediate 

pH-metric GER values and do not appear to influence 

GER. 97,98 However, there is now ample 

evidence that the prone sleeping position is a risk 

factor in sudden infant death, independent of 

overheating, adult’s smoking or way of feeding. 

The impact of pacifier (‘dummy’) use on reflux 

frequency was equivocal and dependent on infant 

position. The protein content of formula was not 

found to affect reflux. Another study suggested 

that the lower the osmolality, the less acid reflux. 

Larger food volume and higher osmolality increase 

the rate of transient LES relaxations and drifts in 

LES pressure; a reduction of the food volume 

results in a decrease in the number of regurgitations 

but no change in acid reflux. 99 

The data of ten randomized controlled trials of 

non-pharmacological and non-surgical GERD in 

healthy infants were recently reviewed. 100 

Although no study demonstrated a significant 

reflux-reducing benefit of thickened formula 

compared to placebo, one study detected a significant 

benefit of formula thickened with carob bean 

gum compared with rice flour. Milk-thickening 

agents include bean gum preparations prepared 

Treatment options 49 

from St John’s bread, a galactomannan, carboxymethylcellulose, 

a combination of pectine and 

cellulose, cereals and starch from rice, potato, corn 

(maize), etc. There are as many different compositions 

of anti-regurgitation formulas as there are 

companies: some are casein-predominant, and 

others contain protein hydrolysates. Milk thickeners 

have been reported to reduce regurgitation in 

infants. 97 However, their effects on esophageal 

acid exposure are inconsistent. Increased coughing 

has also been demonstrated in infants receiving 

milk thickeners. 97 According to in vitro models 

testing the effect on one meal, bean gum may be 

associated with a malabsorption of minerals and 

micronutrients. 101 Studies of various thickening 

agents, including guar gum, carob bean gum and 

soybean polysaccharides, indicate the potential for 

decreased intestinal absorption of carbohydrates, 

fats, calcium, iron, zinc and copper. 102 Abdominal 

pain, colic and diarrhea may ensue from fermentation 

of bean gum derivatives in the colon. Carob 

bean gum induces frequent, loose, gelatinous 

stools. In some, but not all, animal studies, adding 

carob bean gum to the diet decreased growth. 102 

However, growth and nutritional parameters in 

infants receiving a casein-predominant formula 

thickened with bean gum were normal. 103 

Although rare, serious complications such as acute 

intestinal obstruction in newborns have been 

reported. 97 Milk thickeners are often wrongly 

considered as ‘inexpensive’. Allergic reactions to 

carob bean gum have been reported in adults 

exposed to it at their workplaces and in infants 

after exposure to formula thickened with carob 

bean gum. 102 Nevertheless, in view of their safety 

and efficacy in decreasing regurgitation, milk 

thickeners remain a valuable first-line measure in 

relieving regurgitation in many infants. In 

contrast, their efficacy in GERD is questionable. 

Moreover, they are not devoid of side-effects. 

Prokinetics 

Prokinetic agents, e.g. metoclopramide, domperidone, 

erythromycin and cisapride, act on regurgitation 

through their effects on LES pressure, 

esophageal peristalsis or clearance and/or gastric 

emptying. Metoclopramide and domperidone also 

have anti-emetic properties, owing to their 

dopamine-receptor blocking action, while

50 


cisapride is a prokinetic mainly acting via indirect 

release of acetylcholine from the myenteric plexus. 

Metoclopramide 

Data supporting the efficacy of metoclopramide 

are contradictory, and positive results are limited 

to observations with intravenous administration. 

104 Application in infants is limited because of 

severe adverse events that occur quite frequently 

(in more than 20% of patients) including central 

nervous system effects and interactions with the 

endocrine system. 104 The adverse effects regarding 

the central nervous system are mainly related to its 

dopamine-receptor blocking properties in the 

substantia nigra, and include extrapyramidal 

effects (dystonic reactions, irritability) and drowsiness, 

but also asthenia and sleepiness. Isolated 

cases of metoclopramide-induced methemoglobinemia 

and sulfhemoglobinemia have been 

reported. 104,105 Neuroendocrine side-effects such 

as galactorrhea do occur. 106 Also, metoclopramide 

has been reported to induce torsade de pointes. 107 

Domperidone 

The studies supporting efficacy of domperidone in 

improving GER in infants are limited. 104 The 

ability of oral domperidone to increase the pressure 

of the LES or to promote healing of reflux 

esophagitis has not been demonstrated in placebocontrolled 

trials. Most studies have been 

performed in older children, or investigate the 

effects of domperidone co-administered with other 

anti-reflux agents. 104 Comparing domperidone to 

metoclopramide, elicited adverse effects on the 

central nervous system were more severe and more 

common with metoclopramide. 108 Because very 

little domperidone crosses the blood–brain barrier, 

reports of central nervous system adverse effects, 

such as dystonic reactions, are rare. 109 

Domperidone is better tolerated than metoclopramide, 

since dystonic reactions (tremors) and 

anxiety are infrequent. Prolactin plasma levels 

may increase, owing to pituary gland stimulation. 

110 Somnolence was acknowledged by 49% of 

patients after 4 weeks of metoclopramide treatment 

compared with 29% of patients after 4 weeks 

of domperidone. 108 A reduction in mental acuity 

was acknowledged by 33% of patients compared to 

20% in the domperidone group. Akathisia, asthenia, 

anxiety and depression were also acknowl- 

edged less often, and at a lower severity after 4 

weeks of domperidone, although these differences 

were not significant. Domperidone possesses 

cardiac electrophysiological effects similar to 

those of cisapride and class III antiarrhythmic 

drugs. 104 Intravenously administered domperidone 

clearly causes QT prolongation and ventricular 

fibrillation. 111,112 

Erythromycin 

Erythromycin has a prokinetic activity if it is 

administered intravenously. Systemic administration 

of erythromycin in young infants increases 

the risk of the infants developing hypertrophic 

pyloric stenosis. 113 Similarly, a possible association 

exists with maternal macrolide therapy in late 

pregnancy. 113 Intravenous erythromycin is 

reported to cause QT prolongation and ventricular 

fibrillation. 97,114 The use of erythromycin at doses 

far below the concentrations necessary for an 

inhibitory effect on susceptible bacteria provides 

close to ideal conditions for the induction of bacterial 

mutation and selection. 115 Emergence of bacteria 

increasingly resistant to macrolide antibiotics 

has been reported. 116 New erythromycin-like 

molecules without the antibiotic properties are in 

development. 

Cisapride 

Critical evaluations of published reports on the 

efficacy of different prokinetics (cisapride, 

domperidone and metoclopramide) concluded 

that cisapride was the preferred agent. 117,118 

According to these assessments, the vast majority 

of clinical trials on the efficacy of cisapride 

demonstrated that at least one of the end-points 

changed favorably as a result of the intervention. 

117 Cisapride is more effective than metoclopramide. 

118 A Cochrane review on cisapride in 

children analyzed data from seven trials, including 

236 patients; they compared the effect of cisapride 

to that of placebo on symptom presence and 

improvement. 119 It was concluded that there was a 

statistical difference in the parameter symptoms 

‘present/absent’ but that there was no statistically 

significant difference for ‘symptom change’ 

between placebo and cisapride. The Cochrane 

review also concluded that cisapride compared to 

placebo significantly reduced the number and 

duration of acid reflux episodes, since there was a

significant decrease in reflux index, which is the 

percentage of time that esophageal pH is below 

4.0. 119 In general, cisapride is well tolerated. The 

most common adverse events at therapeutic doses 

are transient diarrhea and colic (in about 2%). The 

effect of cisapride on relevant cardiac events such 

as QT prolongation and arrhythmia is related to 

dose and risk factors. More serious adverse events 

such as extrapyramidal reactions, seizures in 

epileptic patients, and cholestasis in very premature 

infants have been the objects of isolated 

reports. 

The relation between cisapride, the P450 

cytochrome and cardiac effects was considered in 

1996. 120 The cytochrome P450 system and especially 

CYP3A4 metabolizes cisapride in the 

liver. 121 There is little doubt that cisapride has a 

QT-prolonging effect, 117 as do many other drugs or 

clinical situations. 122 Cisapride possesses class III 

antiarrhythmic properties and prolongs the action 

potential duration, delaying cardiac repolarization, 

123 although many studies do not report an 

increase in duration of QTc, in neonates or in older 

children. Torsades de pointes have been reported 

with cisapride use, especially in those receiving 

high doses or macrolides. 124 Co-treatment of 

cisapride and macrolides such as clarithromycin 

and erythromycin clearly prolongs the QT duration. 

125 Underlying cardiac disease, drug interactions 

and electrolyte imbalance are clearly interfering 

factors. 126 Cisapride causes prolongation of 

ventricular repolarization without causing 

increased heterogeneity of repolarization (QT 

dispersion), but all patients in the study remained 

asymptomatic without dysrhythmia. 127 The QTprolonging 

effect of cisapride may be related to 

age. 128 The cytochrome P4503A4, which is 

involved in the metabolism of cisapride, is immature 

at birth and reaches adult activity by the age 

of 3 months. Cisapride accumulation occurs in 

newborns because of enzymatic immaturity. A 

significant QTc prolongation occurs, especially in 

infants younger than 3 months, but not in older 

infants. 129,130 This effect was related to higher 

plasma levels. A more frequent administration of 

lower doses (resulting in a recommended daily 

dose of 0.8mg/kg per day) in premature infants 

results in lower peak levels. 131 Consumption of 

grapefruit juice also alters cisapride metabolism. 

132 According to recent data, gene mutation 

may be the fundamental culprit. 133 Molecular 


screening may allow identification among family 

members of gene carriers potentially at risk if 

treated with I(Kr) blockers. 134 

Other molecules 

From the pathophysiological point of view, prokinetics 

seems a logical therapeutic approach. 

However, efficacy data for the whole group of 

prokinetic drugs are disappointing. Cisapride was 

shown to have some efficacy in esophageal acidexposure 

duration, 135 but it is now banned 

because of cardiac side-effects. Prucalopride, a 5- 

HT4 agonist, as been suggested has a possible 

option, but although the drug seems effective in 

adult constipation, 136 its use was prohibited for 

children because of the extrapyramidal sideeffects. 

Ondansetron is a 5-HT3 receptor antagonist 

that accelerates gastric emptying, inhibits 

chemotherapy-induced emesis, but prolongs 

colonic transit time. 137 The most frequently 

reported adverse events of ondansetron were mild 

to moderate headache, constipation and diarrhea 

in patients receiving chemotherapy. Tegaserod is a 

partial 5-HT4 agonist that has been mostly studied 

in constipation-predominant irritable bowel 

syndrome in adults. 138 Tegaserod was shown to 

accelerate small intestinal transit time, and to 

increase proximal colonic emptying. Tegaserod 

also improves gastric emptying and decreases 

GER, 139 and may be a promising drug. However, to 

date there are no efficacy data published on the 

treatment of pediatric GER. Baclofen, 4-amino-3-(chlorophenyl)-butanoic 

acid, is a γ-aminobutyric 

acid (GABA)-B receptor agonist, which is used in 

children with extreme spasticity. Given orally, it 

has been shown to decrease GER in healthy 

adults. 140 Administration in eight pediatric 

patients was reported to be safe. 141 Alosetron is a 

5-HT3 antagonist that increases colonic compliance 

to distension, delays (ascending) colonic 

transit time and increases basal fluid absorption. 

Alosetron induces severe constipation and causes 

ischemic colitis. 

(Alginate-) antacids 

Experience with antacids is limited in infants. 

Their efficacy in buffering gastric acidity in infants 

is strongly influenced by the time of administration, 

and requires multiple administrations.

52 


Alginate-antacids form a viscous fluid with 

surface-active properties, floating as a raft on the 

surface of the gastric contents, and hence forming 

an artificial protective barrier against reflux. 142 

Their efficacy as monotherapy or in combination 

with prokinetics for reflux is not convincing. 

Important drug interactions with antacids include 

the prevention of the absorption of antibacterials 

such as tetracycline, azithromycin and quinolones. 

143 Antacid ingestion decreased the bioavailability 

of famotidione, ranitidine and cimetidine 

by 20–25%, and the bioavailability of nizatidine by 

12%. 144 Gaviscon ® contains a considerable 

amount of sodium carbonate, so that its administration 

may increase the sodium content of the 

feeds to an undesirable degree (1g of Gaviscon 

contains 46mg of sodium and the suspension 

contains twice this amount). Algicon ® , having a 

better taste than Gaviscon, has a lower sodium 

load, but a higher aluminium content. 142 

Occasional formation of large bezoar-like masses 

of agglutinated intragastric material has been 

reported in association with Gaviscon. Side-effects 

include diarrhea with magnesium-rich preparations, 

and excessive absorption of aluminium in 

infants. 142 Dimethicone is used in some regions for 

regurgitation, although there are no reliable 

studies demonstrating its efficacy in the treatment 

of GER in infants. Although often classified as an 

antacid, it acts more as a feed thickener, as it 

contains more than 50% of bean gum and has 

hardly any acid-neutralizing properties. 

H2-receptor antagonists 

Acid-suppressant therapy is recommended in 

severe esophagitis, but this does not rectify 

primary disordered motility, a major pathophysiological 

mechanism underlying GERD in children. 

Historically, cimetidine was the first H2RA that 

became available. Ranitidine and nizatidine are 

the most popular and best studied (although quite 

poorly) H2RAs in children. 145,146 Experience with 

other H2RAs such as roxatidine or ebrotidine is 

very limited or non-existent in children. In 

general, H2RAs are considered to be quite safe. 

Adverse events reported in clinical trials with ranitidine 

include headache, tiredness and mild 

gastrointestinal disturbances, but the incidence is 

not higher than that for placebo. 146 A high dose of 

cimetidine can cause reversible impotence and 

gynecomastia. 146 The endocrinological side-effects 

associated with long-term administration of cimetidine 

in adults essentially preclude its long-term 

use in children. 147 Fatigue, dizziness, headache, 

dyspepsia, nausea, abdominal pain, flatulence, 

constipation and diarrhea occur in 1–6% of 

patients. 148 H2RAs have been reported to provoke 

central nervous system dysfunction, but these are 

poorly documented in children. Ranitidine 

enhances ischemic neuronal damage. 148 Ranitidine 

has occasionally been associated with acute 

interstitial nephritis in native and transplanted 

kidneys. 149 While ranitidine exhibits no clinically 

significant drug–drug interactions, cimetidine 

interacts with many drugs metabolized by 

cytochrome P450. Theophylline plasma levels 

were 25–32% higher if cimetidine was administered, 

compared to ranitidine. Neither ranitidine 

nor nizatidine increased theophylline levels. 144,150 

H2RAs, PPIs and prokinetic agents undergo metabolism 

by the cytochrome P450 system present in 

the liver and gastrointestinal tract. 143 Cimetidine is 

an inhibitor of CYP3A and it may cause significant 

interactions with drugs of narrow therapeutic 

range and low bioavailability that are metabolized 

by those enzymes. 143 

Whether ranitidine may exceptionally cause QT 

prolongation or not, is still debated. 151 If ranitidine 

is administered intravenously after autonomic 

blockade, the sinus cycle length is prolonged, and 

the systolic and diastolic blood pressures are 

decreased. 152 Thus, ranitidine has to be administered 

by a slow intravenous infusion in patients 

with sinus node dysfunction. 152 The altered 

cardiac sympathovagal balance after oral administration 

of the H2RA ranitidine indicates a shift 

towards sympathetic predominance in the heart 

rate control. 153 Ranitidine modulates highfrequency 

power of heart rate, and this may be the 

underlying mechanism of cardiovascular sideeffects. 

154 Since H2 receptors are present in the 

stomach and the heart, they have a trend towards 

decreasing the heart rate and cardiac contractility. 

Nizatidine and ranitidine are susceptible to metabolism 

by colonic bacteria, but famotidine and 

cimetidine are not (see also the section on PPIs, 

below). 155 Ranitidine alters the gastrointestinal 

flora 156 and causes significantly more pneumonias 

in patients in intensive care units. 157 In the majority 

of patients on H2RAs, there is a relatively

important nocturnal breakthrough of acid secretion, 

sometimes limiting therapeutic efficacy, but 

on the other hand minimizing side-effects related 

to long-term blockade of acid secretion as with 

PPIs. There is a rapid development of tachyphylaxis 

or tolerance to H2RAs, limiting their longterm 

clinical use. 158 

The combination of ranitidine and pirenzipine, a 

muscarinic receptor antagonist, does not aid the 

healing of reflux esophagitis, but does improve 

symptom relief after 4 weeks. 159 However, sideeffects 

were reported in nine of 75 patients in the 

ranitidine group and 19 of 76 patients in the ranitidine 

and pirenpizine group. 159 

Proton pump inhibitors 

The suppression of gastric acid secretion achieved 

with H2RAs has, however, proved to be suboptimal. 

158 In this regard, the advent of the PPIs has 

been a major breakthrough. Drugs of this category 

have in fact been shown to be more effective than 

H2RAs. 96 Esomeprazole seems to be the most effective 

PPI commercialized today. 160 Step-down treatment 

is recommended in adults. 161 Failure to 

control symptoms with high-dose PPI treatment 

raises the likelihood of non-acid-related causes for 

the symptoms. 

The pharmacokinetics and tolerance of pantoprazole 

were similar in patients with moderate and 

severe hepatic impairment. 162 These were also 

evaluated for famotidine in 150 children. 163 Recent 

studies with lansoprazole showed its efficacy in 

reducing symptoms and healing esophagitis in 

children. 164 The availability of a syrup facilitates 

the use of this drug in children. 164 Zimmermann 

and colleagues reviewed the literature on the use 

and administration of omeprazole in children. 165 

In uncontrolled trials and case reports, omeprazole 

was used at a dosage of 0.2–3.5mg/kg per day for 

periods ranging from 14 days to 36 months, and 

found to be effective and well tolerated for the 

acute and chronic treatment of esophageal and 

peptic ulcer disease in children aged 2 months to 

18 years. 165 

The following side-effects of PPI have been 

reported: headache (about 3%); neurological and 

psychiatric side-effects, especially fatigue, dizziness 

and confusion in patients with hepatic 


diseases and/or advanced age; cutaneous reactions, 

generally rash and urticaria; hemolytic 

anemia, leukopenia and agranulocytosis; gynecomastia; 

subacute myopathy; gastrointestinal sideeffects 

such as flatulence, constipation, diarrhea 

(about 4%), dyspepsia and nausea (about 2%), 

vomiting and abdominal pain; hepatic disorders, 

especially moderate elevation of aminotransferases; 

and excessive urinary sodium 

loss. 97,142,166,167 The high cost of PPIs can also be 

considered an important albeit not medical ‘sideeffect’. 

Omeprazole, esomeprazole, lansoprazole, rabeprazole 

and pantaprazole rarely exhibit clinically 

important interactions with other hepatically 

metabolized medications or pH-dependent 

drugs. 168 The absorption of drugs that are pH 

sensitive, as is the case with digoxin and ketoconazole, 

will be influenced by PPIs. 169 

The gastroparietal PPIs lansoprazole, omeprazole 

and pantoprazole are all primarily metabolized by 

a genetically polymorphic enzyme, CYP2C19, that 

is absent in approximately 3% of Caucasians and 

20% of Asians. 143 These drugs may also interact 

with CYP3A, but to a lesser extent. Esomeprazole 

has the potential to interact with CYP2C19. The 

slightly altered metabolism of cisapride was also 

suggested to be the result of inhibition of a minor 

metabolic pathway for cisapride mediated by 

CYP2C19. Esomeprazole did not interact with the 

CYP3A4 substrates clarithromycin and quinidine. 

169 Overall, the potential for drug–drug interactions 

with esomeprazole is low, and similar to 

that reported for omeprazole. 169 Salivary secretion 

is decreased with omeprazole. Prolonged use of 

PPIs can result in vitamin B12 deficiency as a 

consequence of impaired release of vitamin B12 

from food in a non-acid environment. However, 

cystic fibrosis patients treated for at least 2 years 

with a PPIs and cystic fibrosis patients without PPI 

had higher vitamin B12 levels than healthy 

controls. 170 

The safety of long-term administration of acidblocking 

medication needs to be considered in 

relation to potential consequences of prolonged 

acid suppression, including the risk of proliferation 

of gastric flora and the risk of developing enterochromaffin-like 

cell hyperplasia, which could, 

in turn, theoretically, lead to gastric malignancy. 

Hypergastrinemia occurs in nearly all patients

54 


treated with omeprazole, causing hyperplasia and 

pseudohypertrophy of the parietal cells, as recently 

shown in 93% of adult patients on long-term 

omeprazole. Patients on omeprazole therapy for 

5–8 years remained without evidence of significant 

enterochromaffin cell hyperplasia, gastric 

atrophy, intestinal metaplasia, dysplasia or 

neoplastic changes. 171 Because of the excellent 

efficacy profile, these drugs tend to be 

overused. 172 Since PPIs could delay the diagnosis 

of gastric cancer, the long-term uncontrolled and 

unnecessary use of these drugs should be avoided. 

Bacterial proliferation in the gastric content may 

not only change colonic flora, but may also be a 

risk factor for the patient to develop nosocomial 

pneumonia. 

Other drugs 

Sucralfate causes bezoars, especially when given 

to patients in intensive care units, and diarrhea. 

Patients with renal failure treated with sucralfate 

are exposed to aluminium toxicity. 173–175 Other 

anti-emetic drugs such as batanopride also have a 

QTc-prolonging effect. 176 Octeotride is a longacting 

somatostatin, that induces a phase 3-like 

migrating motor complex response, which is not 

inhibited by meals (differing from normal), and 

has an inhibitory effect on the gastric antrum (and 

is therefore indicated in dumping syndrome). 

Motilin agonists have been studied with inconsistent 

results in adults, and are not yet available for 

pediatric use. 177 

Therapeutic endoscopic procedures 

During recent years, new endoscopic techniques 

intending to improve the function of the antireflux 

barrier have been developed. The first 

results of endoscopic gastroplasty (Endocinch ® 

system), radiofrequency delivery at the cardia 

(Stretta ® system) and injection therapy (Enteryx ® 

procedure) in adults have been reported. 178–181 

The first series in adolescents have been 

performed. Although experience is too limited to 

recommend broad use, the theoretical concept of 

these procedures is interesting. Further improvements 

to the techniques are still being introduced. 

Surgery 

While anti-reflux surgery in certain groups of children 

may be of considerable benefit, it also has a 

mortality and a failure rate. 184–187 Ninety per cent 

of patients remained free from significant reflux 

symptoms after a laparoscopic Nissen operation, 

although side-effects occurred in up to 22%. 186 

After a median follow-up of 16 years, the 

Nissen–Rosetti procedure in 24 consecutive children 

without congenital or acquired anomalies of 

the esophagus except GERD showed a result that 

was considered excellent in only 75%, good in 21% 

and poor in 4%. 187 Failure rates of 5–20% have been 

found after objective postoperative follow-up. 187 A 

protective anti-reflux surgical procedure in neurologically 

impaired children needing a gastrostomy 

increased the morbidity and mortality rate of the 

gastrostomy procedure itself. 188 

Conclusion 

GER and GERD are frequent conditions in infants, 

children and adolescents. Symptomatology differs 

with age, although the main pathophysiological 

mechanism, transient relaxations of the LES associated 

with reflux, is identical at all ages. Although 

infant regurgitation is likely to disappear with age, 

little is known about reflux. The majority of symptomatic 

reflux episodes are acid, but non-acid and gas 

reflux can also cause symptoms. Complications of 

reflux disease may be severe and even life threatening, 

such as esophageal stenosis and Barrett’s esophagus. 

There is no gold standard for a diagnostic technique. 

A simple questionnaire may be among the 

best diagnostic aids in infants; non-acid reflux is 

best investigated with impedancometry. Primary 

GERD is mainly a motility disorder. Guidelines for 

treatment struggle with the fact that there is no 

prokinetic drug with a convincing efficacy profile. 

As a consequence, treatment of GERD focuses on 

anti-acid drugs, and particularly on PPIs. There is 

little or no information on how to organize follow-up.

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5 

Introduction 

Achalasia 

Carl-Christian A Jackson and Donald C Liu 

Diseases of the esophagus can generally be categorized 

into four types of abnormality: those of inadequate 

lower esophageal relaxation; those of 

uncoordinated contraction; those of hypercontraction; 

and those of hypocontraction. 1 Classic achalasia 

falls into this first category. Directly translated, 

achalasia means ‘failure to relax’, and 

describes a rare disease in which the lower 

esophageal sphincter (LES) remains constricted 

during swallowing and there is an absence of 

esophageal peristalsis. The first case of achalasia 

was reported in 1674 by Thomas Willis. 2 His 

patient was otherwise healthy, but suffered from 

frequent vomiting and regurgitation of food. 

Successful palliation was achieved through postprandial 

passage of a whalebone with a sponge 

attached to the tip, which accomplished both 

tamping of the food through the LES, as well as 

some degree of forceful dilatation. However, it 

was Sir Cooper Perry in 1913 who first used the 

term ‘achalasia’ to describe this disease. 3–5 

The exact etiology of achalasia is unknown, but 

certain factors remain consistent, namely inflammation 

of the myenteric plexuses with varying 

degrees of ganglion cell loss. When symptomatology 

suggests achalasia, the diagnosis is confirmed 

through radiographic and manometric studies. In 

treating children with achalasia, numerous 

modalities have been employed with varying 

degrees of success, including drug treatment, 

forceful dilatation and surgical esophagomyotomy. 

The purpose of this chapter is to provide 

an overview of this disease process, the tools with 

which to diagnose it and the available treatment 

options. 

Epidemiology 

Epidemiological studies of achalasia have been 

relatively few. A summary of the available investigations, 

which include both adults and children, 

shows an incidence of 0.4–1.2/10 5 persons/year in 

Europe and North America. 6–11 The incidence in 

children is far lower. Approximately 4–5% of all 

cases of achalasia are diagnosed before the age of 

15. More so than the adult form, childhood achalasia 

can occur with associated abnormalities, 

such as familial glucocorticoid deficiency, 

alacrima, autonomic system disorder, short 

stature, microcephaly and nerve deafness. 12–16 

Contrary to the generally accepted view of a female 

predominance, achalasia actually appears to affect 

men and women equally. 17,18 Studies that exhibit 

higher rates in females, when adjusted for their 

higher population of women, show that the incidence 

of achalasia approaches that expected in the 

general population. 6,9 

Etiology 

The etiology of achalasia remains uncertain. 

Proposed mechanisms for the disease include 

genetics, infectious agents, autoimmune destruction, 

and primary neural degeneration. Various 

case reports have identified instances of both horizontal 

and vertical ‘transmission’. 19–24 The majority 

of these familial cases, however, occur in the 

setting of consanguinity. While this raises the 

possibility of a rare, recessive gene being 

expressed, a large-scale study of more than 1000 

first-degree relatives of patients with achalasia 

showed no affected relatives – contrary to expected 

Mendelian genetics. 25 

61

62 

Achalasia 

Five per cent of patients with chronic Chagas’ 

disease develop poor LES relaxation and megaesophagus 

that mimics classic achalasia, 26 which 

suggests that an infectious etiology of achalasia is 

possible. The protozoan Trypanosoma cruzi which 

causes Chagas’ disease acts through direct invasion 

of cells, toxin production or antigenic factors 

to cause degeneration of esophageal neurons. The 

mechanism of this process is also uncertain, and 

may be from direct injury to neurons of the esophagus, 

an inflammatory reaction or the generation 

of autoantibodies against these nerves. 27 Potential 

infectious candidates for idiopathic achalasia 

include measles and varicella viruses, but as yet 

no firm evidence exists to confirm this association. 

25,28–31 

Pathology 

While the etiology of achalasia remains unclear, 

the histopathological changes associated with it 

have been well described. Surgical specimens 

involving strips of esophageal muscle from 

esophagomyotomy or entire resected esophagi 

have formed the basis of study. 32–35 Gross examination 

of esophagectomy specimens from patients 

with severe/recurrent achalasia reveals the classic 

morphology of a dilated proximal esophagus, with 

distal tapering. The muscularis propria is 

frequently hypertrophied, and the mucosa exhibits 

exaggerated longitudinal folds. 32 

Upon microscopic examination, there is a range of 

associated changes in the esophagus. The most 

classic feature is an absence of myenteric ganglion 

cells, which is seen in specimens from patients 

with both early and late achalasia. 32,34–38 While 

there is no apparent association between the 

number of remaining ganglion cells and the degree 

of symptoms, there does seem to be a temporal 

relationship, i.e. patients with longstanding 

disease tend to exhibit fewer ganglion cells. 34,38 

The most consistent histological feature, seen in 

all esophageal specimens, is inflammation. 32,35 

The inflammation occurs in and around the myenteric 

nerves, predominantly involves lymphocytes 

and results in neural fibrosis. Goldblum et al made 

an interesting observation in their study of 

patients with early achalasia. 35 A woman with 

rapid onset of dysphagia and weight loss underwent 

esophagomyotomy only 2.5 months after the 

onset of symptoms. Histological examination was 

significant for mild myenteric inflammation, 

normal numbers of ganglion cells and an absence 

of fibrosis. These findings suggest that the earliest 

pathological feature of achalasia is myenteric 

inflammation. 

Additional histological changes result from 

esophageal obstruction and the associated stasis. 

Esophageal obstruction leads to varying degrees of 

muscular hypertrophy of the muscularis propria, 

most notably in the inner circular layer. 32,36,39 

Further findings include small leiomyomas of the 

inner circular layer, degenerative changes of the 

muscularis propria as well as focal fibrosis of the 

muscularis propria (again, predominantly in the 

inner circular layer). 32 Stasis of luminal contents 

results in both proximal and distal squamous 

hyperplasia, as well as changes similar to those 

seen in reflux esophagitis, namely papillomatosis 

and basal cell hyperplasia. 32 However, owing to 

the increased LES pressure limiting passage of 

gastric contents, these findings are unlikely to be 

due to true gastroesophageal reflux. 

Extra-esophageal pathology accompanies achalasia, 

predominantly related to esophageal innervation. 

Both the vagus nerve and the vagal dorsal 

motor nucleus are affected. Electron microscopy of 

periesophageal vagal nerve biopsies reveals 

changes resembling Wallerian degeneration (i.e. 

secondary to nerve transaction), changes that are 

not seen on light microscopy. 33,38 Whether the 

affected nerves are motor, sensory or vagalassociated 

sympathetic nerves is unclear. 

Evaluation of the dorsal motor nucleus of the 

vagus, performed upon autopsy, also reveals 

degenerative changes, neuron loss and Lewy 

bodies. 40 


The resting state of the LES is one of contraction. 

Cholinergic neurons provide resting tone, whereas 

inhibitory neurons provide vagal-mediated relaxation 

34,41,42 Vagal efferents contain both excitatory 

and inhibitory signals; however, the predominant 

effect of vagal stimulation is LES relaxation, as 

mediated by non-adrenergic, non-cholinergic 

(NANC) nerves. 43 In normal patients, stimuli from 

gastric, esophageal and pharyngeal sensory nerves

are relayed to, and processed by, the dorsal motor 

nucleus of the vagus, which results in modulation 

of both excitatory and inhibitory impulses to the 

LES. 44 

Two strong candidates for mediation of LES relaxation 

are vasoactive intestinal polypeptide (VIP) 

and nitric oxide (NO). After it was realized that 

VIP was found in high concentrations in gut 

sphincters, subsequent investigations showed it to 

be a potent inhibitor of LES contraction in 

vitro. 45,46 Further association of VIP with sphincteric 

relaxation and achalasia is suggested by 

immunohistochemical studies that have shown 

decreased or absent VIP-containing neurons in LES 

specimens from patients with achalasia. 47–49 

Human manometric studies have shown that the 

LES in patients with achalasia, as compared to 

normal controls, is hypersensitive to exogenous 

VIP, again supporting a role for VIP in LES relaxation. 

44 

NO also figures prominently in gastrointestinal 

tract smooth muscle and sphincteric 

mechanisms. 50–57 The role of NO appears to be that 

of sphincter-muscle hyperpolarization, and therefore 

relaxation, and the loss of NO has been associated 

with conditions of persistent contraction, 

such as achalasia. 58–62 Preiksaitis et al elegantly 

demonstrated that blocking NO synthase prevents 

relaxation of LES muscles by NANC nerves, and 

that exogenous NO from sodium nitroprusside can 

overcome this inhibition. 57 Inhibitory regulation of 

gastrointestinal muscles by NANC transmitters 

was generally believed to be direct, until an intermediary, 

interstitial cell was proposed by Cajal (a 

cell that bears his name). 63 Recent work in both 

animal and human models confirms the relationship 

of interstitial cells of Cajal (ICC) to nitric 

Table 5.1 Symptoms of achalasia (from reference 67) 

Symptoms Number of patients Mean (%) Mean range (%) 

Dysphagia 1930 97 82–100 

Regurgitation 1892 75 56–97 

Weight loss 1675 58 30–91 

Chest pain 1894 43 17–95 

Heartburn 127 36 27–42 

Cough 732 30 11–46 

Signs and symptoms 63 

oxide synthase (NOS)-positive neurons. 53,64 It is 

accepted that NO release results in sphincteric 

relaxation; however, the exact mechanism has not 

been fully elucidated. While evaluation of the LES 

in adults shows that ICC are altered, this may be a 

result of disruption of the interaction between 

NOS-positive neurons and ICC, because examination 

of the pediatric esophagus in achalasia (and 

therefore a shorter duration of disease) shows 

morphologically normal ICC, but disrupted 

contact with NOS-positive neurons. 53,54 

The precise cause of achalasia remains to be elucidated 

but the loss of NO- and/or VIP-associated 

neurons appears to be integral to the disease. By 

their destruction, these neurons permit unopposed 

contraction of the LES. 

Signs and symptoms 

Because the incidence of achalasia in children is 

so low, the majority of information regarding the 

diagnosis comes from adults. The earliest, and 

most common, symptom of achalasia is dysphagia. 

This dysphagia initially is for solids, but 

frequently progresses to dysphagia for liquids by 

the time treatment is sought. 65–67 The next most 

common symptom in adults is regurgitation, 

which is non-acidic and non-bilious, owing to the 

contracted LES, and most often occurs right after 

eating or during sleep. Patients often find ways to 

accommodate these dysfunctions, and will ameliorate 

symptoms by such methods as drinking large 

volumes of water with meals, holding their arms 

above the head or performing a Valsalva maneuver. 

67–69 A summary of the most common presenting 

symptoms is provided in Table 5.1.

64 

Achalasia 

The presenting symptoms in children tend to 

correlate with patient age and can mimic those 

seen in adults, or they can be more vague, thus 

requiring a high degree of suspicion for diagnosis. 

Symptoms in older children (more than 7 years) 

tend to parallel those seen in adults, so dysphagia 

and regurgitation predominate, but with substernal 

chest pain and burning also appearing in about 

half the patients. 70 Children aged less than 6 years, 

particularly infants, more commonly present with 

respiratory symptoms, complaints, similar to those 

of gastroesophageal reflux disease (GERD), occasional 

emesis and failure to thrive. 12,71 

Regurgitation and dysphagia are the most common 

symptoms, present in 83% and 71–80% of 

patients, respectively, followed by failure to thrive 

in 54–70%. 70,72 Especially in non-verbal children, 

a diagnosis of achalasia should be entertained 

when presented with a patient experiencing significant 

chronic respiratory symptoms, such as 

choking, recurrent pneumonia, severe asthma, 

chronic bronchitis or chronic cough, because these 

are seen in 25–100% of patients. 12,70 The physical 

examination tends to be unremarkable, but can 

reveal findings secondary to dysphagia (and a 

resultant decrease in oral intake) and food stasis, 

such as weight loss, malnutrition and halitosis. 67 

Laboratory and instrumental 

investigations 

Radiographic studies 

For patients in whom a diagnosis is uncertain, a 

plain chest radiograph may be the first available 

study. The classically described finding on upright 

chest X-ray is an absent gastric air-bubble. This 

finding, present in nearly all normal individuals, is 

absent in approximately half of patients with achalasia. 

73,74 Additional findings include a widened 

mediastinum from esophageal dilatation, a posterior 

mediastinal air–fluid level from retained 

food/secretions and lung parenchymal abnormalities 

from chronic aspiration. 67,73,75 

Barium swallow, however, is the definitive radiographic 

study, and, in a review of the European 

experience with achalasia, it is the most 

commonly performed test. 76 On barium swallow, 

classic achalasia typically shows esophageal 

dilatation with distal narrowing at the gastroesophageal 

(GE) junction, the ‘bird’s beak’ deformity 

(Figure 5.1). Also, retained food/secretions, 

absent peristalsis, tortuosity of the esophagus and, 

occasionally, an epiphrenic diverticulum can be 

seen. 67,73,75 Because a barium swallow is 

performed under fluoroscopy it is a dynamic 

study, and may also reveal back-and-forth sloshing 

of the barium boluses when the patient is in the 

supine position, owing to the esophageal dilatation 

and the ineffective peristalsis. 67,75,77 However, the 

diagnostic accuracy of barium swallow is approximately 

85%, which can be due to a very early stage 

Figure 5.1 ‘Bird’s beak’ appearance characteristic of 

esophageal achalasia on esophogram (courtesy of Hans 

Björknäs, Gastrolabs, Finland).

of achalasia not showing the classic signs, due to a 

tumor of the GE junction mimicking achalasia or 

due to a peptic stricture. 67,73,76 

Computed tomography (CT) has no real role in the 

diagnosis of achalasia. 67 The findings are consistent 

with those already seen on plain X-ray or 

barium swallow, such as a dilated esophagus, 

esophageal air–fluid levels, and possibly displacement 

of mediastinal structures by a dilated esophagus. 

Furthermore, masses that may cause 

pseudoachalasia are infrequently identified on a 

CT scan. 78,79 

With the desire to limit radiation exposure, particularly 

in children, alternative means of diagnosis 

are sought. Radionuclide bolus transport has been 

evaluated as one such alternative, with achalasia 

diagnosed when esophageal emptying time is 

prolonged. When evaluating patients with manometrically 

diagnosed achalasia using radionuclide 

transport, Stacher et al found that sensitivity for 

this evaluation was 68%, with a specificity of 

95%. 80 Their criteria were an esophageal emptying 

time of ≥ 20 s (the time for 95% of the bolus to 

enter the stomach), compared to a normal median 

time of 7.3 s (range 5.5–12.0 s). Because radionuclide 

bolus transport is a functional study with 

relatively low sensitivity (other esophageal motility 

disorders also show prolonged transit time), 

this study may be best suited for follow-up of 

patients after treatment, or in the few cases in 

which achalasia is suspected, despite normal LES 

pressure on manometry. 67,73,80 

Manometry 

The gold standard for accurate diagnosis of achalasia 

remains esophageal manometry, using either 

a perfused-catheter or a solid-state system. The 

minimum information collected from manometry 

will include resting LES pressure, relaxed LES 

pressure and peristaltic function of the esophageal 

body. Depending on local protocol, upper 

esophageal sphincter (UES) pressure may also be 

assessed. Fluoroscopy may be used to assist in 

positioning of the sensors. Manometry is usually 

performed with a catheter containing multiple, 

evenly spaced sensors, which is passed by the oral 

or nasal route into the stomach. Resting gastric 

pressures are measured to provide a baseline. The 

Laboratory and instrumental investigations 65 

catheter is slowly withdrawn until the sensor is 

measuring LES pressure. Under quiet respirations, 

resting LES pressure is measured at midrespiration. 

Swallow-induced LES relaxation is 

measured with the patient taking several wet swallows 

using small volumes of liquid. The catheter is 

further withdrawn until the distal sensor is a few 

centimeters above the LES and the proximal 

sensors are spaced throughout the esophageal 

body. Esophageal peristalsis and wave progression 

are assessed during several more wet swallows. 

Because achalasia affects the smooth muscles of 

the esophagus, the manometric findings involve 

the mid- and distal esophagus, sparing the proximal 

regions of predominantly striated muscle. The 

two manometric abnormalities found in all patients 

with achalasia are aperistalsis of the esophageal 

body and abnormal LES relaxation. 1,67–69 

Simultaneous, low-amplitude contractions 

(< 40 mmHg) throughout the esophageal body are 

characteristic of the aperistalsis seen after wet 

swallows. Abnormal LES relaxation is characterized 

by either absent/incomplete relaxation 

(70–80% of patients) or normal relaxation of short, 

and therefore ineffective, duration – typically less 

than 6 s each (20–30% of patients). 69, 81 This latter 

finding commonly accompanies early stage achalasia. 

68 Manometric findings associated with achalasia, 

but not required for diagnosis, include 

elevated resting LES pressure and resting 

esophageal body pressure exceeding baseline 

gastric pressure. 1 Table 5.2 summarizes normal 

and abnormal manometric findings. 

Endoscopy 

Despite radiographic and manometric evidence 

typical of achalasia, pseudoachalasia secondary to 

a tumor at the GE junction must be ruled out. 67,73 

Findings consistent with achalasia may include a 

dilated, atonic esophageal body; mucosal thickening 

and/or erythema; and a puckered LES which 

fails to open with insufflation, but which is easily 

passed with the endoscope. If there is visual 

evidence of extrinsic compression or the endoscope 

fails to pass through the GE junction with 

gentle pressure, then a tumor must be excluded. 

Biopsies should be taken from suspicious areas 

seen above the GE junction or seen on retroflexion 

from within the stomach.

66 

Achalasia 

Table 5.2 Normal and abnormal manometric findings (from references 1, 67 and 68) 

Treatment 

Until such time as the primary cause of achalasia 

can be reversed, namely the loss of esophageal 

innervation by inhibitory neurons, treatment of 

achalasia must address the relief of symptoms. 

Since the primary disorders are aperistalsis and 

abnormal LES relaxation, the goal of non-invasive 

and invasive treatments is relief of the obstruction 

and its associated dysphagia. Medical treatment 

focuses on promoting LES relaxation, whereas 

endoscopic and surgical treatments address 

disruption of the LES muscle itself. 

Medical options 

Swallow-induced Peristaltic wave Distal wave 

Basal LES pressure LES relaxation progression amplitude 

Normal 10–45 mmHg complete (less than 2–8 cm/s from 30–180 mmHg 

8 mmHg above gastric UES to LES 

baseline, or 95% of 

LES baseline) 

Achalasia >45 mmHg (up to 40% incomplete (more simultaneous

Surgical options 

The gold standard in treatment of achalasia is 

surgical esophagomyotomy – the modified Heller 

procedure. It is against this procedure that other 

surgical, and medical, treatments are compared. 

Surgical treatments include endoscopy with botulinum 

toxin injection, forceful dilatation, open 

Heller myotomy and laparoscopic Heller myotomy. 

Endoscopic botulinum toxin injection 

With endoscopy playing an important role in the 

work-up of achalasia, it seems attractive to initiate 

therapy concurrently. Botulinum toxin (BoTox) is a 

potent inhibitor of presynaptic acetylcholine 

release, and can be injected into the LES through 

an endoscope. After a pilot study had demonstrated 

efficacy, Pasricha et al undertook a randomized, 

blinded and controlled study of BoTox. 89 

This study showed significant decreases in 

symptom scores, resting LES pressure and 

esophageal food retention. Approximately half of 

the injected patients, however, had no response or 

relapsed within 2 months of initial treatment and 

required either repeat injection or pneumatic 

dilatation. Subsequent studies in adults have 

shown that BoTox generally provides good initial 

results, but these improvements typically are not 

long-lasting. 90–92 Follow-up showed that 10–35% 

of patients had no initial response, 30–40% 

relapsed within 4 months, and 38–67% had 

‘lasting’ effects to an average of 1.3–2.5 years. 90–92 

An initial experience with BoTox in an 11-year-old 

child showed encouraging initial results, with 

repeat injection required 1 year after initial 

therapy. 93 Two recent studies have evaluated the 

role of BoTox in a series of children. 94,95 In both, 

the mean duration of symptomatic relief was 

short-lived (3–7 months) and required repeat injections 

or eventual Heller myotomy. Among the 

limited patients who did not progress to surgical 

treatment, a few showed lasting benefit over 

several years, and some opted for frequent 

repeated injections rather than undergoing 

surgery. While BoTox is generally considered safe, 

complications such as gastroesophageal reflux, 

esophageal inflammation and ulceration with 

hemorrhage have been noted. 96 The consensus at 

this time relegates BoTox injection to patients who 

are unwilling or medically unsuitable for more 

Treatment 67 

invasive correction, or as a subsequent adjunct to 

patients who are symptomatic after myotomy or 

dilatation. 67, 90,91,94,95 

Esophageal dilatation 

In contrast to the above-described treatments, 

esophageal dilatation addresses achalasia through 

forceful disruption of the LES muscle fibers. The 

largest experience with dilatation has been in 

adults, and current therapy involves the use of 

balloon dilators. The balloons are placed across 

the LES, rapidly inflated and then deflated after a 

period of 30 s to several minutes, depending on 

patient tolerance. As the procedure is performed 

under fluoroscopy, the dilatations are repeated 

until the waist of the LES is obliterated by the 

balloon. ‘Excellent’ to ‘good’ results, based on 

patient survey, are obtained in 65–93% of patients 

(this higher number was based on pooling results 

from multiple, graded dilatations). 82,97–99 With 

long-term follow-up, trends were seen in patients 

who either failed initial treatment or quickly 

relapsed, with the most significant in younger age 

(under 45 years). 73,100 While dilatation is relatively 

safe, early and late complications do occur. The 

most significant early complication is perforation 

(0–12%), which if recognized early can be treated 

conservatively with good effect. 73,82,101 

One of the major benefits of esophageal dilatations 

in adults is avoidance of general anesthesia, which 

is generally lost when treating children, making it 

a less attractive option. Despite showing some 

degree of success in a small series, 102 the typical 

experience is poor long-term response requiring 

frequent re-dilatation, and eventually surgery, 

particularly in younger children. 71,95,99,103 This 

requirement for multiple dilatations in children, as 

well as the need for monitored general anesthesia, 

also decrease the proposed benefit of lower hospital 

costs. 104 Given these results, balloon dilatation 

plays a minimal role in the treatment of children 

with achalasia. Balloon dilatation should be 

reserved for patients unwilling to undergo surgery, 

or as a treatment adjunct in patients with residual 

symptoms after surgery. 

Esophagomyotomy 

Surgical esophagomyotomy for achalasia was first 

performed in Germany by Ernest Heller, and

68 

Achalasia 

involved a laparotomy with both an anterior and a 

posterior esophagomyotomy. 105 The procedure 

was modified by Zaaijer in 1923 to utilize only an 

anterior esophagomyotomy; 106 all surgery for achalasia 

now employs a variant of this procedure. 107 

An example of the affected esophageal segment 

pre- and post-myotomy is shown in Figure 5.2. A 

consensus on the optimal surgical technique 

remains to be resolved. Traditional approaches 

have been through a standard midline laparotomy 

or a left thoracotomy, with equally good 

results. 108–111 A review of the literature by 

Ferguson showed that, regardless of operative 

approach, an open Heller procedure resulted in 

(a) (b) 

(c) (d) 

symptomatic improvement in 89% of patients, a 

mortality rate of 0.3%, a reoperative rate of 2.9% 

and a postoperative GERD incidence of 10%. 73 

The benefits of minimally invasive surgery, 

decreased pain, shorter hospital stay, and 

improved cosmesis have prompted surgeons to 

apply this approach to esophagomyotomy. As with 

open surgery, both thoracoscopic and laparoscopic 

approaches are in current use, and by nature of 

similar results to the open surgery, minimally invasive 

procedures are becoming the standard. 112–118 

In addition to controversy over whether an abdominal 

or thoracic approach is better, there is no 

Figure 5.2 (a) Transition between dilated (normal) and narrowed (abnormal) segment of esophageal achalasia prior to 

myotomy. (b) Performing myotomy with an endoscopic spreader. (c) Myotomy completed to the gastroesophageal junction. 

(d) Completed myotomy including dissection onto the lesser curvature of the stomach (circularis muscle seen distally).

consensus on the benefit of performing a simultaneous 

fundoplication. For example, at our institution 

we do not routinely perform concomitant 

fundoplication. Proponents of a fundoplication 

cite increased risk of late GERD, whereas opponents 

state that limiting the gastric portion of the 

esophagomyotomy to less than 1 cm limits the 

incidence of GERD and that a fundoplication may 

actually result in pseudoachalasia from making an 

over-tight wrap. 73,119–124 

The complications of Heller myotomy include 

intraoperative perforation (treated by over-sewing 

the tear, and buttressing with gastric fundus), 

recurrence of symptoms (typically the result of 

incomplete myotomy or addition of a fundoplication 

that is too tight) and esophageal 

leak. 67,70,109,125 Concern exists about performing a 

Heller myotomy after previous non-surgical therapies, 

as this may incur a higher complication rate. 

While previous treatment by balloon dilatations 

or BoTox injection seems to result in scar forma- 

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76. Moreno Gonzalez E, Garcia Alvarez A, Landa Garcia I et 

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79. Vilgrain V, Mompoint D, Palazzio L. Staging of 

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80. Stacher G, Schima W, Bergmann H et al. Sensitivity of 

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81. Cohen S, Lipshutz W. Lower esophageal sphincter 

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82. Tack J, Janssens J, Vantrappen G. Non-surgical treatment 

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84. Christensen J. Effects of drugs on esophageal motility. 

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72 

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6 

Introduction 

Helicobacter pylori gastritis 

and peptic ulcer disease 


In adults, peptic disease (PD) is an important 

public health problem because of its clinical and 

economic implications. In children it is a wellknown 

problem, but its prevalence and relative 

complications are less well defined. 

PD includes some gastric and duodenal diseases 

characterized by the presence of the digestive 

symptoms of dyspepsia, the endoscopic appearance 

of mucosal lesions, and the histological 

features of chronic inflammation. However, these 

three characteristics might be expressed in different 

ways, producing a mix of clinical pictures, 

which range from the asymptomatic patient with 

normal endoscopic picture and mild gastritis, to 

the patient with a bleeding peptic ulcer. 

Gastritis, duodenitis, gastric and duodenal ulcer 

are the definitive diagnoses of a patient who has 

gone through the appropriate endoscopic and 

histological investigation of the upper gastrointestinal 

tract. This means that most of the findings 

belonging to the pre-endoscopic era (in children, 

before 1980) are not reliable and not 

comparable with more recent data. 

The strict link between the above-mentioned 

pictures is based on two major pieces of evidence. 

First, is the presence of mucosal inflammation and 

ulcer in the same patient. Even if gastroduodenitis 

and ulcer could be seen as a continuum in the 

natural history of PD, the evolution toward the 

crater (ulcer) is not mandatory, and the majority of 

patients with PD show only gastritis. Second, is 

the existence of a common etiological factor of 

both gastritis and ulcer in the majority of patients: 

the Helicobacter pylori (H. pylori) infection. 

The history of the H. pylori infection begins in 

1982, and it is one of the most exciting examples of 

how a fortuitous observation has produced one of 

the greatest impacts on our knowledge and treatment 

of an old disease. The oversight of cultures of 

antral biopsies taken from patients with PD during 

some days of vacation allowed two Australian 

investigators, Barry Marshall and Robert Warren, 

to observe and describe the growth of colonies of 

previously unknown bacteria. 1 As these Gramnegative, 

spiral bacteria had been isolated on 

Campylobacter-specific media, they were initially 

identified as Campylobacter-like organisms, but it 

soon became clear that H. pylori belonged to a new 

genus, taxonomically identified as Helicobacter, 

which, to date, consists of 19 zoonotic species with 

another ten potentially novel species. The official 

species differ in site of infection, which is the 

stomach in eight and the gut in 11, and in the host, 

but they show great homology in the analysis of 

165 rRNA sequences (Table 6.1). 2 

During the past two decades, an impressive 

number of papers, consensus conferences, position 

documents and statements of the 

Gastroenterological Associations and Public 

Health Organizations (NIH) confirmed the existence 

of a strong association between H. pylori and 

PD. In particular, in 1994 a Consensus Conference 

of the NIH established the role of H. pylori in the 

pathogenesis and recurrence of peptic ulcer, 

emphasizing that the treatment of this condition 

should be considered the eradication of the H. 

pylori infection and not only the healing of the 

ulcer. 3 In the same year, the International Agency 

for Research on Cancer included H. pylori in the 

list of the carcinogenic factors of class I, as the 

main developing factor in gastric carcinoma. 4 

73

74 

Helicobacter pylori gastritis and peptic ulcer disease 

Table 6.1 Natural hosts and usual site of isolation of Helicobacter 

species 

Helicobacter species Main host Origin 

H. pylori human gastric 

H. mustelae ferret gastric 

H. nemestrinae macaque monkey gastric 

H. felis cat, dog gastric 

H. acinonychis cheetah gastric 

H. bizzozeronii dog gastric 

H. salomonis dog gastric 

H. heilmannii human, cat, dog, pig gastric 

H. cinaedi human, hamster intestinal 

H. fennelliae human, hamster intestinal 

H. muridarum rat, mouse intestinal 

H. canis dog intestinal 

H. pullorum poultry intestinal 

H. pametensis tern intestinal 

H. hepaticus mouse intestinal 

H. bilis mouse intestinal 

H. cholecystus hamster intestinal 

H. trogontum rat intestinal 

H. rodentium mouse intestinal 

Epidemiology 

Epidemiological data about peptic ulcer disease 

(PUD) are scanty and often related to series investigated 

by X-rays. Endoscopic data appeared after 

1980 and showed a three-fold increase of cases of 

PUD over earlier findings. 5 A review of more than 

1000 cases stated that the expected number of new 

PUD cases in a large children’s hospital was evaluated 

as 3.5 per year. 6 Others found that the incidence 

of PUD was 4.4/10000 children with a 

frequency of 3–6% in children who had undergone 

gastroscopy. 7 

However, there is now evidence that the incidence 

of PUD is decreasing in adults as well as in children. 

The progressive decrease of PUD is probably 

related to modifications in the epidemiology of H. 

pylori infection. The slow but continuous improve- 

ment of socioeconomic conditions, the diffuse use 

of antibiotics, and the decrease of the so-called 

ulcerogenic strains of H. pylori might reasonably 

explain this phenomenon. 

H. pylori infection is one of the most diffuse infections 

in the world. There are areas at high risk of 

infection (in developing countries, such as those in 

the African or South American continents) and 

areas at low risk (such as Europe and North 

America). 8 In high-risk countries, the rate of infection 

is very high in the first 2 years of life, and 

older children and adults are almost totally 

infected. In a study on a cohort of 248 Gambian 

children aged 3–45 months, the prevalence of positive 

breath tests (a specific and non-invasive test to 

detect H. pylori infection, see below) rose from 

19% at 3 months of age to 84% by the age of 30 

months. Reversion to a negative breath test, in

association with declining specific antibody 

levels, occurred in 20% of children, suggesting 

that in the first years of life children may acquire 

and clear the infection before ultimately being 

infected with a persistent strain. 9 

In developed countries, transverse serological 

studies have demonstrated that the rate of infection 

increases slowly and regularly by 10% with 

each decade of life. 8 In Italy, a recent epidemiological 

study showed that 11% of subjects from 6 to 

18 years were infected, 10 while the prevalence rate 

in people of 50–60 years was 50–60%. 

Longitudinal studies demonstrated that this 

increase of infected subjects with aging was 

related to an effective decrease of infection in the 

youngest cohorts, rather than to an increase of new 

cases with aging. 11 This phenomenon is explained 

by the fact that each generation or cohort has a 

distinct and possibly unique environmental risk of 

exposure to the infection (cohort effect), linked to 

specific risk factors. These risk factors are well 

known and are socioeconomic, so that the cohort 

effect is considered to be the consequence of the 

improvement of socioeconomic conditions in the 

most recent decades. In Japan, a country that has 

had an impressive and fast economic development 

after the Second World War, epidemiological 

studies demonstrated a high prevalence rate of H. 

pylori infection in subjects born before the war, 

and a dramatic decrease in those born after the war 

and the industrial revolution. 12 

When the improvement of socioeconomic conditions 

was slow, but constant, as in the 

Netherlands, the decrease of the infection rate in 

childhood was continuous. 13 

The relationship between socioeconomic status 

and H. pylori infection has been emphasized by 

studies in subjects belonging to the same city or 

community, but with different socioeconomic 

conditions. Using family income as a measure of 

the socioeconomic class, the rate of acquisition of 

H. pylori in those children with family income less 

than $5000/year was twice that of those with 

incomes greater than $75 000/year in a study from 

Arkansas. 14 Absence of a fixed hot-water supply 

and domestic crowding in childhood were powerful 

independent risk factors for current infection 

with H. pylori. Among current living conditions, 

only the number of children living in the house- 

Epidemiology 75 

hold was independently associated with H. pylori 

infection. 15 Different studies showed that the age 

of infection is in the first years of life. 16–18 

In a cohort of 224 children followed up retrospectively 

for 21 years by stored serum samples, the 

crude incidence rate per year was 1.4% for the 

whole cohort, ranging from 2.1% at 4–5 years and 

1.5% at age 7–9 years to 0.3% at 21–23 years. The 

median age for seroconversion was 7.5 years. Nine 

of the 58 seropositive children cleared the infection 

during follow-up. The rate of seroreversion 

per year was 1.1%; it was highest among children 

at age 4–5 years (2.2% vs 0.2% at ages 18–19). 16 

The finding that children infected before 5 years of 

age could eradicate the infection spontaneously, as 

well as be re-infected more easily than older children, 

has been confirmed by others. 14,17 A study of 

follow-up of 52 children successfully treated for H. 

pylori demonstrated that 11.5% of children who 

had eradicated the bacterium suffered reinfection, 

with the majority under 5 years of age. Only 4.3% 

of children older than 5 years were re-infected, 

even those living with H. pylori-positive parent in 

81% of cases. The age of < 5 years was the major 

risk factor for re-infection. 17 In adults, the infection 

rate is approximately 0.3–0.5% per year and 

infection is rarely eradicated spontaneously, as 

demonstrated by longitudinal studies on stored 

samples. 19,20 

In addition to socioeconomic factors, genetic 

factors could play a role in the acquisition of the 

infection. A sibling study showed that the seroprevalence 

rate was similar in genetically identical 

twins living under different socioeconomic 

circumstances. 21 It should be acknowledged, 

however, that ethnic, genetic and socioeconomic 

factors are often intertwined and their various 

contributions are difficult to assess. 

An important issue in the study of an infectious 

disease is its route of transmission. The absence of 

an animal reservoir, the demonstration of intrafamilial 

clustering, 22 as well as clustering of the 

infection among institutionalized children 23 

suggests that person-to-person transmission is the 

most probable route. Approximately 90% of 

parents and 70% of siblings of H. pylori-positive 

children showed seropositivity for H. pylori. 22 In 

institutionalized children, including those living 

in a monastery, an inverse relationship between

76 


seroprevalence and age was demonstrated, with 

the increased rate of infection correlating with the 

age of entry more than the length of stay in the 

community. 23 Both vertical transmission (from 

mother to child as well as from father to child), 

and horizontal transmission from sibling to 

sibling, have been demonstrated. 24 

H. pylori has been isolated from saliva and dental 

plaque, 25 as well as from vomitus, 26 suggesting 

that the most diffuse routes of transmission 

between siblings or children in communities could 

be the oro-oral or gastro-oral. Epidemics of vomiting 

could easily diffuse the infection. 

In developing countries, H. pylori has been identified 

in water 27 and in feces 28 by studies using the 

polymerase chain reaction (PCR). Clusters of infection 

independent of income, but strictly related to 

water source, have been demonstrated; the infection 

rate was 12-fold higher in children from highincome 

families using community wells rather 

than municipal water in a study in Peru. 27 The 

fecal-oral route of transmission typical of waterborn 

diseases is quite possible, particularly in 

conditions where there is a lack of a municipal 

water supply. 

Etiology 

PUD is the progressive loss of the mucosal 

integrity up to the formation of a crater (ulcer). 

This is the final process of different etiological 

factors, which produce lesions by different mechanisms. 

These factors and mechanisms are not 

mutually exclusive and may co-operate to bring 

about their damage. The classical pathogenic 

theory was that an ulcer develops when the equilibrium 

is lost between defensive factors and 

aggressive factors. Defensive factors are the mucus 

layer, constituted by glycoproteins, bicarbonate 

and prostaglandins; and the gastric mucosa barrier, 

constituted by the epithelial layer, submucosal 

tissue and microcirculation. The best known 

aggressive factors are gastric acid, pepsins, 

gastrolesional substances, such as alcohol, drugs, 

non-steroidal anti-inflammatory drugs (NSAIDs) 

and, last to be identified, H. pylori infection). In 

primary ulcers (deep erosive lesions not secondary 

to other known causes) the most important factor 

was considered to be the acid output of the 

stomach. Both research and therapeutic interventional 

studies were directed towards evaluating 

and suppressing acid secretion (according to the 

theory ‘no acid, no ulcer’) until the discovery of H. 

pylori. The demonstration that duodenal ulcer is 

almost invariably associated with H. pylori infection, 

and recurrence depends on its persistence, 

established the importance of H. pylori as the main 

etiological factor in PUD. 3,29 Indeed, H. pylori 

infection has been demonstrated in 92% 

(33–100%) of children with duodenal ulcer in 14 

studies, and in 25% (11–75%) of children with 

gastric ulcer in four studies. 30 Recurrence of ulcer 

after healing has been reported in 47% of children 

where Helicobacter was not eradicated, but it is 

rare, if not exceptional, in patients in whom eradication 

was achieved. 31 H. pylori is the main known 

etiological factor in chronic gastritis in adults as 

well as in children. 30 

H. pylori is a Gram-negative, unipolar flagellated 

bacterium with a spiral appearance (Figure 6.1). It 

was the first recognized bacterium of a new genus 

whose different species colonize the gastrointestinal 

tract of the human (H. pylori and H. heilmannii) 

and animals (all remaining species) (Table 

6.1). 2 

Figure 6.1 Electron micrograph of Helicobacter pylori 

attached to the cell membrane of gastric epithelial cells 

with evident cytoplasmic vacuolization.

H. pylori colonizes only the gastric mucosa, wherever 

it may be present: in the stomach or in heterotopic 

areas, as in Barrett’s esophagus or in gastric 

metaplasia of the duodenum. 2 H. heilmannii is a 

rare (0.5% prevalence in humans) cause of dyspeptic 

symptoms and inflammation in adults, and its 

pathogenic role in children seems limited. 32 

The H. pylori genome (1.65 million bp) codes for 

about 1500 proteins and shows an extraordinary 

heterogeneity, 33 which could in part explain the 

wide spectrum of clinical pictures. Multiple 

strains may be present in the same patient, particularly 

in developing countries. Recombination and 

mutation between strains produces continuous 

changes of the genome during long-term gastric 

colonization in the same host. 34 

Pathogenesis 

Role of acid and pepsinogen secretion 

The bulk of our knowledge on acid secretion is 

derived from studies in adults. Gastric acid secretion 

begins in the newborn from the first day of 

life; it is not sensitive to gastrin, but rather to 

pentagastrin stimulation, which is the best way to 

evaluate it. Serum gastrin is usually elevated in the 

newborn period. 35,36 

Maximal acid output after pentagastrin stimulation 

increases from 0.031 mEq/kg per h at 1 month 

to 0.122 mEq/kg per h at 3 months, and up to 

0.218 mEq/kg per h at 20 months, reflecting the 

increase of the mass of parietal cells. 37 In another 

Table 6.2 Causes of gastric acid hypersecretion 

Zollinger–Ellison syndrome 

Antral G-cell hyperplasia or hyperfunction 

Mastocytosis 

Chronic renal failure 

Hypertrophic gastropathy 

Small intestinal resection – short gut 

Hyperparathyroidism 

Pathogenesis 77 

study, maximal acid output values were demonstrated 

not to change from 3 months to 12 years of 

life. 38 

Basal acid output has been found to be normal in 

children with PUD in all 39–41 but one study. 42 

Although children with PUD have been shown to 

have a higher average maximal acid output 

compared to age-matched controls, the occasional 

child with peptic ulcer may well have a 

completely normal maximal acid output. 

Similarly, control children may occasionally show 

increased maximal acid output. 39–42 This important 

overlap of values between children with or 

without ulcer is similar to that reported in adults. 

Interestingly, children with more severe PUD 

(requiring surgery, or presenting severe digestive 

bleeding) have been reported to have values of 

maximal acid output significantly higher than 

those with milder forms of disease or in remission. 

40,42 Basal 41 or meal-stimulated serum 

gastrin 43 can be normal or slightly increased in 

children with ulcer. 

Other disorders associated with severe gastric and 

duodenal ulcers secondary to increased gastric 

acid secretion are listed in Table 6.2. These situations 

are usually the consequence of an increased 

basal (Zollinger–Ellison syndrome, ‘ZES’) or stimulated 

(pseudo-ZES or antral G-cell hyperplasia/ 

hyperfunction syndrome) 44 gastrin or histamine 

secretion. 

Pepsins are proteolytic enzymes generated by the 

action of hydrochloric acid on their precursor 

pepsinogens. Pepsinogens are secreted by the 

principal cells of the gastric fundus (PGI) and by

78 


the mucous cells of the remaining stomach and 

part of the duodenum (PGII). Seven molecular 

forms (Pg1–Pg5 for PGI and Pg6–Pg7 for PGII) can 

be identified electrophoretically. Only traces of 

pepsins have been demonstrated in neonatal 

gastric juice, and their increase with age is slow. 37 

In children with PUD, as well as in members of 

families with a high incidence of PUD, an increase 

of serum pepsinogen I has been demonstrated, and 

high serum pepsinogen I has been considered a 

marker of ulcerogenicity. 45 

Helicobacter pylori-related mechanisms 

H. pylori may induce inflammation by two different 

pathways: direct toxicity mediated by secretion 

of specific toxins and other aggressive factors 

(Table 6.3); and immune-mediated toxicity secondary 

to stimulation of both innate and adaptive 

immune responses in the host. 46 

The gastric mucosa is a niche relatively resistant to 

bacterial infection. The main protective mechanism 

is the bactericidal activity of the gastric acid. 

However, H. pylori has developed some mechanisms 

to evade protection and to allow the colonization 

of the mucosa: urease production and 

motility. Urease activity is mediated by a unique 

pH-dependent urea channel, UreI, which works at 

low pH, and allows the influx of urea followed by 

hydrolysis into CO2 and ammonia, which buffers 

acid conditions close to the bacterium. 47,48 By 

means of flagellar motility, H. pylori swims into the 

mucous layer, and attaches to epithelial cells by 

multiple bacterial-surface adhesins. The best characterized 

adhesin is Baba, a 78-kDa outer 

membrane protein, which binds to the fucosylated 

Lewis B blood-group antigen. 49 

Table 6.3 Virulence factors demonstrated in Helicobacter pylori strains 

Colonization factors Toxicity factors 

Approximately half of the genomic variants of H. 

pylori are able to produce the thermolabile 95-kDa 

cytotoxin, called Vac-A, with a cytopathic effect 

induced by direct vacuolating action on epithelial 

cells (Figure 6.1). 50 The toxin inserts itself into the 

epithelial cell membrane, forming a channel 

through which bicarbonate and organic anions can 

reach the bacterium. Other mechanisms involved 

in the Vac-A-mediated epithelial damage are the 

release of cytochrome C from mitochondria, and 

apoptosis. 51 Even if the pathogenic role of Vac A is 

still under debate, it is relevant that Vac-A positive 

strains are isolated in 60% of patients with PUD, 

and in only 30% of patients with gastritis. 52 

Sixty-five to eighty per cent of strains of H. pylori 

have a chromosomal region called cag-PAI (37-kb 

genomic fragment containing 29 genes) which 

codifies a type IV secretory apparatus translocating 

the 120–128-kDa Cag-A protein inside the host 

cell. 53,54 At the cellular level, a direct proliferative 

response and cytokine production are induced. 

Cag-A-positive strains are usually isolated from 

80–100% of patients with more severe peptic 

lesions and in 60–75% of patients with milder 

forms of disease. 

Even if the majority of strains isolated from 

patients with PUD are positive for both Cag-A and 

Vac-A, it is not possible to distinguish ulcerogenic 

from non-ulcerogenic strains with certainty. 

The second pathway involved in gastric injury is 

secondary to activation of an immune response. 

H. pylori produces gastric inflammation in virtually 

all infected persons. 55 This inflammatory 

response is triggered by bacterial attachment to 

epithelial cells, followed by recruitment of 

neutrophils, macrophages, T and B lymphocytes, 

Urease (acidity inhibition) vacuolizing cytotoxin (Vac-A) 

Flagellins (motility) cag pathogenicity island (cag-PAI) 

Adhesins (adhesivity) 

Catalase, superoxide dismutase (phagocytosis resistance) 

ammonium, lipopolysaccharide, phospholipase

and plasma cells. In the inflamed gastric epithelium, 

a high concentration of proinflammatory 

cytokines has been found. Increased production 

of interleukin (IL)-8, a potent neutrophil-activating 

cytokine, is induced by activation of NFKβ 

from Cag-A-positive, more than Cag-A-negative, 

strains. 56 IL-8 and other chemokines amplify the 

immune as well as the inflammatory response, 

producing severe epithelial damage. The multiplicity 

of possible pathogenic mechanisms is 

shown in Figure 6.2. 

A systemic and mucosal immune response is 

elicited by H. pylori infection. 57 This does not lead 

to eradication, but it may contribute to further 

damage. Immunological studies have demon- 

Pathogenesis 79 

strated that an IL-18-driven Th1 immune 

response, instead of the expected Th2, combined 

with Fas-mediated apoptosis of H. pylori-specific 

T-cell clones, may contribute to the persistence of 

the infection. Some patients produce autoantibodies 

against the H + /K + ATPase of gastric parietal 

cells that play a role in the induction of gastric 

atrophy. 58 

In addition to the direct and inflammatory mechanisms 

of mucosal injury, H. pylori may play an 

ulcerogenic role by interfering with acid and 

pepsin secretion. In children, H. pylori infection 

seems to increase serum PGI 59 and in some, but 

not all, children with H. pylori, a meal-induced 

hypergastrinemia secondary to G-cell hyperplasia 

Figure 6.2 Helicobacter pylori-host interactions in the pathogenesis of mucosal lesions from reference 46, with 

permission.

80 


has been reported. Eradication of H. pylori usually 

normalizes pepsinogen and gastrin secretion 59 as 

well as G- and D-cell hyperplasia. 60 H. pylori 

infection may interfere in the gastrin–HCl axis 

increasing gastric acid secretion, which in turn 

results in duodenal ulceration: in adults, an 

increased maximal acid output has been demonstrated 

to differentiate ulcer from non-ulcer H. 

pylori-positive patients. 61 

Clinical aspects 

Peptic ulcers are classified as either primary, 

when they occur in the absence of an underlying 

systemic disease, or secondary, when they are 

caused by medications or other diseases. Acute 

secondary (stress ulcers), which represent the 

majority of PUD during infancy and early childhood, 

occur in association with shock, burns, 

surgery, sepsis, or intracranial hypertension 

(Cushing’s ulcers). 62 Chronic PUD secondary to 

diseases which produce an increase of gastric acid 

secretion (Table 6.2) are rare at any age. 

Since its discovery, many clinical pictures have 

been attributed to H. pylori infection. Table 6.4 

shows the main conditions associated with H. 

pylori according to evidence-based criteria. By 

comparison of the results from different studies, it 

appears that there are two main populations of 

children with PUD: the first, predominantly 

constituted by females younger than 8 years of 

age, usually has a gastric localization of the 

ulcer, 6,7 which is not associated with H. pylori and 

rarely proceeds to relapse; the second, more 

similar to the adult PUD, is mainly found in males 

older than 8–10 years and shows an H. pyloriassociated, 

highly relapsing, bulbar ulcer. 

Symptoms depend strictly on the age of the 

subjects. 6,62,63 In infancy and in early childhood, 

PUD is characterized by vomiting and/or digestive 

bleeding. Children with ulcer may be referred for 

abdominal pain and/or vomiting. Epigastric localization, 

nocturnal pain, and meal or antacid relief 

of pain, are typical of so-called ‘ulcer-like’ dyspepsia, 

and might frequently be reported by older 

subjects. Hematemesis, weight loss and other 

alarm signs should alert the physician and 

strongly suggest further evaluation. 62 

Table 6.4 Human digestive diseases 

associated with Helicobacter pylori infection 

Acute gastritis 

Chronic gastritis 

Duodenal ulcer 

Gastric ulcer 

Gastric carcinoma 

B-Lymphoma (MALToma) 

Children with H. pylori-associated gastritis 

without ulcer are asymptomatic in the majority of 

cases 10 or, rarely, they may suffer from the same 

dyspeptic symptoms as patients with ulcer. No 

clinical picture has been found to be specific for H. 

pylori-associated gastritis. 

The clinical picture of recurrent abdominal pain 

(RAP) was first described over four decades ago by 

Apley and Naish. 64 They found RAP, defined as at 

least three bouts of abdominal pain, severe enough 

to affect the child’s activity, over a period of not 

less than 3 months, in 10.8% of 1000 school-age 

children. 64 The etiology, based on patient history 

and clinical grounds, was attributed to social and 

familial environment stress rather than to an 

organic disease. This generic definition served 

pediatricians for many years, but the development 

of new techniques (ultrasound, endoscopy, motility 

probes) and new acquisitions (identification of 

H. pylori, the role of motility disorders, etc.) ultimately 

proved that RAP is a description and not a 

single, homogeneous diagnosis 65 (see also Chapter 

7). 

Is H. pylori gastritis a cause of RAP? In a very large 

pediatric series, abdominal pain occurred in 90% 

of 110 cases of duodenal ulceration, and it was the 

main presenting feature in 88% of them. 63 Since 

1986, when H. pylori infection was first described 

in pediatric patients, 66 many endoscopic series 

supported the association between the infection 

and gastroduodenal pathology in children. 67–69 

However, abdominal pain was not more frequent 

in H. pylori-positive than in H. pylori-negative children 

submitted to endoscopy. 70–72 In addition, 

eradication did not resolve symptoms in all cases,

eing very effective only in those rare cases with 

ulcer. 73 

Moreover, population-based studies failed to show 

any association between RAP and H. pylori infection 

in both school-aged and pre-school-aged 

populations. 10,74,75 Nevertheless, it is evident that 

discordant results may also be dependent on the 

heterogeneity of the clinical populations studied 

(endoscopic series vs. school populations), and the 

differences in the inclusion criteria (age, duration 

of the pain, etc.) 30 

A recent report from the Committee on Childhood 

Functional Gastrointestinal Disorders 76 states that 

‘it seemed more appropriate to apply the most 

specific diagnostic category to a symptomatic 

child’, defining clinical criteria of functional 

dyspepsia as in adults. Gastroenterologists 

working on adults with upper gastrointestinal 

symptoms prefer to aggregate more symptoms in 

the complex picture of ulcer-like and dysmotilitylike 

forms of dyspepsia. Recent studies have 

shown that a relationship between dyspeptic 

symptoms and some pathogenic factors (mainly H. 

pylori infection and motility disturbances) is 

apparent. 77 However, a large intervention study on 

adults failed to demonstrate that symptoms are 

dependent on H. pylori infection and, by extrapolation, 

on gastritis. 78 In the eradication trials, the 

summary odds ratio for improvement in dyspeptic 

symptoms in patients with non-ulcer dyspepsia in 

whom H. pylori was eradicated was 1.9 (1.3–2.6). 

The presence of severe epigastric pain, associated 

with nocturnal pain, fasting pain and relief of pain 

after meal intake, characterizing the picture of 

ulcer-like dyspepsia in subjects aged over 10 

years, 10 could be the clinical picture more suggestive 

of gastroduodenitis, suggesting the need for 

further evaluation. 

Complications 

The most frequent complication of PUD is digestive 

bleeding, with hematemesis and melena 

reported in more than half the cases. 6 

Gastrointestinal bleeding may be present even in 

the absence of ulcer, if diffuse varioliform gastritis 

with erosions is present at endoscopy. Another 

complication of PUD is perforation (10%), which 

Complications 81 

may result in peritonitis, if anterior, or in pancreatic 

penetration, if posterior. Pyloric stenosis as a 

consequence of a parapyloric ulcer is quite rare; a 

malignant ulcer is exceptional in children. 

A vicious cycle between chronic diarrhea, malnutrition 

and H. pylori infection is evident, especially 

for children in developing countries. 79 Some other 

gastrointestinal disorders based on the presence of 

heterotopic gastric mucosa, such as Barrett’s 

ulcer 80 and Meckel’s diverticulum bleeding, 81 have 

been anecdotally associated with H. pylori infection, 

but further studies suggested that H. pylori 

did not play a causal role in their determination. 

Extraintestinal manifestations have been controversially 

reported in patients with H. pylori infection; 

iron deficiency and sideropenic refractory 

anemia, short stature and growth failure, and 

sudden infant death are the most conflicting areas 

in childhood. 82 

Iron deficiency anemia may be a consequence of 

H. pylori infection in children. Case reports and 

series of children with sideropenic refractory 

anemia have been reported. 83 Iron deficiency 

without anemia has also been demonstrated in 

adults. 84 The efficacy of eradication in raising the 

hemoglobin level and in restoring ferritin values 

has been demonstrated in adults as well as in 

teenagers. 85 Potential mechanisms involved in 

producing iron deficiency are fecal occult blood 

loss, reduction in duodenal absorption and the 

iron-scavenging capability of the bacterium. 

Some studies have reported the existence of an 

effect of the infection on the final height of the 

patient. H. pylori-positive children have been 

demonstrated to be shorter than those who are H. 

pylori-negative. 27 Growth velocity has been 

demonstrated to be decreased by 1.1 cm in affected 

females between 7 and 11 years of age. 86 However, 

this association has not been confirmed by other 

studies, which showed, instead, that reduced 

growth is related to genetic determinants, such as 

parental height, and to mixed genetic and environmental 

factors, such as birth weight. Low socioeconomic 

status was clearly relevant. 87 

Concerning the role of Helicobacter infection in 

causing infant deaths by sudden infant death 

syndrome (SIDS), one study detected H. pylori in 

lungs from 25 out of 32 SIDS cases. 88 However, a

82 


further study utilizing both histology and 

immunohistochemistry on 25 cases of infants 

with SIDS failed to confirm this hypothesis. 89 

Diagnosis 

Diagnosis of ulcer is based on the endoscopic 

examination of the stomach and the duodenal 

Figure 6.3 Endoscopic appearance of a Helicobacter 

pylori-associated peptic ulcer of the posterior wall of the 

duodenal bulb in an 11-year-old girl. 

Figure 6.4 Endoscopic appearance of Helicobacter 

pylori-associated multiple peptic ulcers of the gastric body 

and hyperplastic regeneration of the surrounding mucosa 

in a 12-year-old girl. 

bulb. Primary ulcers are often single and localized 

at the duodenal bulb (Figure 6.3) or in the 

distal part of the stomach (Figure 6.4) (antrum, 

lesser curvature); while secondary ulcers 

(NSAIDs, stress ulcer) can be located in all parts 

of the stomach and can be multiple. Endoscopy 

may show changes of the gastroduodenal mucosa 

typical of gastropathy. Dohil et al 90 have 

suggested an easy and quite useful endoscopic 

classification of gastropathies in erosive and 

non-erosive forms (Table 6.5). Even if some 

disorders may show both erosive and nonerosive 

lesions, each is classified by its most 

common clinical manifestation. The endoscopic 

picture of H. pylori-associated gastritis is characterized 

by the presence of micronodularity of the 

antral mucosa in more than 50% of cases (Figure 

6.5). 90 

Some endoscopic pictures might be suggestive of 

inflammation and/or be specific for a given etiology, 

but confirmation of the initial impression 

and definitive diagnosis is dependent on histological 

examination. For this reason, each endoscopic 

examination must be completed by biopsy 

sampling of both endoscopically abnormal and 

normal mucosa. At least two biopsies for H. 

pylori detection must be taken at the antral site. 

Further sampling from the fundus may be useful, 

especially after treatment, because of the 

tendency of the bacterial colonization to migrate 

proximally. Biopsies for other procedures 

(culture, urease test) should be considered after 

sampling for routine histology. 

H. pylori-associated gastritis is the most frequent 

microscopic finding. It is predominantly an 

antral gastritis, but in some patients, and particularly 

in adults, inflammation may involve the 

entire stomach (pangastritis). In children, its 

severity is usually less, and features of activity 

(presence of polymorphonuclear leukocytes) are 

reported in 40% of cases. 69,90 The presence of 

lymphoid follicle hyperplasia (follicular gastritis) 

(Figure 6.6), suspected of being the histological 

counterpart of the nodular appearance of the 

gastric mucosa at endoscopy, has been reported 

in 20% of patients. 69,90 In adults, pangastritis 

may show gastric atrophy and/or focal intestinal 

metaplasia, particularly in association with 

gastric ulcers. In children, these findings are 

rarely reported (Figure 6.7).

Table 6.5 Classification of gastritis and gastropathy in children* 90 

Erosive and/or hemorrhagic gastritis or gastropathy 

‘Stress’ gastropathy 

Neonatal gastropathies 

Traumatic gastropathy 

Aspirin and other non-steroidal anti-inflammatory drugs 

Other drugs 

Portal hypertensive gastropathy 

Uremic gastropathy 

Chronic varioliform gastritis 

Bile gastropathy 

Henoch–Schönlein gastropathy 

Corrosive gastropathy 

Exercise-induced gastropathy or gastritis 

Radiation gastropathy 

Non-erosive gastritis or gastropathy 

‘Non-specific’ gastritis 

Helicobacter pylori gastritis 

Crohn’s gastritis 

Allergic gastritis 

Proton pump inhibitor gastropathy 

Celiac gastritis 

Gastritis of chronic granulomatous disease 

Cytomegalovirus gastritis 

Eosinophilic gastritis 

Collagenous gastritis 

Graft-versus-host disease 

Ménétrier’s disease 

Pernicious anemia 

Gastritis with autoimmune disease 

Other granulomatous gastritides 

Phlegmonous and emphysematous gastritis 

Other infectious gastritides 

*Although some disorders can present as either erosive or non-erosive, each is 

classified by its most common manifestation 

In recent years, the importance of the histological 

diagnosis of gastritis, on the basis of routinely 

obtained antral and body biopsies, has increased 

enormously, particularly because of the discovery 

Diagnosis 83 

of H. pylori. The introduction of the Sydney 

system made it possible, for the first time, to grade 

histological parameters, to identify topographic 

distribution and, finally, to make a statement about

84 


(a) (b) 

Figure 6.5 Endoscopic appearance of antral nodularity associated with Helicobacter pylori infection (a). After biopsy, 

mucosal bleeding enhances the evidence of the picture (b). 

Figure 6.6 Immunohistochemical staining for B lymphocytes 

of a mucosa-associated lymphoid follicle in a child 

with Helicobacter pylori-associated antral nodularity. 

the etiopathogenesis of the gastritis in H. pylori- or 

non-H. pylori-associated gastritis. 91 

Multiple samplings from the antrum, the body 

and the fundus of the stomach allow further 

subdivision of the group of H. pylori-associated 

gastritis into forms of gastritis whose morphological 

distribution patterns usually identify them as 

sequelae of H. pylori infection. Moreover, the 

group of gastritis not associated with H. pylori can 

be differentiated into autoimmune, chemically 

induced reactive gastritis, ex-H. pylori gastritis, H. 

heilmannii gastritis, Crohn’s gastritis and a 

Figure 6.7 Giemsa-stained antral specimen showing, on 

the left side, typical intestinal metaplasia and, on the right 

side, Helicobacter pylori-associated chronic gastritis. 

number of special forms of gastritis (see Table 

6.5). 

Diagnosis of H. pylori infection is based on the 

demonstration of H. pylori by either direct (invasive) 

or indirect (non-invasive) methods. H. pylori 

can be demonstrated on the gastric mucosa specimen 

by staining with Warthin–Starry, Giemsa 

(Figure 6.7) or orange acridine stain, or it can grow 

in culture of gastric biopsies on specific media and 

in microaerophilic conditions. 2 Culture may be 

particularly useful for specific antibiotic sensitivity 

testing. An easy, diffuse and rapid test is the

urease test, which is based on the color reaction 

induced by the presence of urease in the gastric 

specimen within 1 h. 92 

Indirect tests are based on the demonstration of an 

elevated titer of IgG or IgA antibodies against H. 

pylori in serum 22 or in saliva, 93 or the presence of 

a positive immunoassay for H. pylori in the 

stools. 94 For research purposes, H. pylori may be 

detected by PCR in some human samples, such as 

dental plaque or feces. 25,28 Results obtained using 

these diagnostic methods are variable, but among 

invasive tests, histology and culture are superior. If 

indirect tests are considered, the 13 C-urea breath 

test (UBT) and fecal antigen tests show the best 

accuracy. In a recent study comparing more tests 

on 53 children, 1 all the diagnostic tests except 

serology were excellent methods of diagnosing H. 

pylori infection. The diagnostic accuracy was 

96.2% for the stool antigen test, 96.2% for the 

biopsy urease test, 98.1% for histology, 94.3% for 

PCR, 98.1% for culture, 100% for the 13 C-UBT and 

84.9% for serology. 95 

The North American Society of Pediatric 


(NASPGHAN) clinical practice guidelines (Table 

6.6), 96 as well as the European (EPTFHP) (Table 

6.6) 97 and Canadian 98 pediatric consensus conferences 

on H. pylori infection, recommend making a 

definitive diagnosis of H. pylori infection through 

Treatment 85 

endoscopy with multiple biopsies of the stomach. 

The role of non-invasive methods has to be 

reserved to the demonstration of eradication and 

for follow-up. For this purpose, the 13 C-UBT is the 

best validated method, 99 even though some problems 

may exist in patients younger than 6 years of 

age. 

Treatment 

One of the most debated problems is who should 

be treated for H. pylori infection. In adults, the 

most recent indications for H. pylori treatment are 

listed in the Table 6.7, derived from the Maastricht 

2-2000 Consensus Report. 100 

Each of the three Pediatric Consensus Reports 

(North American, European and Canadian) 

outlined recommendations for the detection of 

H. pylori infection. 96–98 Regarding the H. pyloripositive 

subjects to be treated, the NASPGHAN 

supports the treatment only in case of PUD and 

MALToma. 96 The European Pediatric Task Force on 

Helicobacter pylori (EPTFHP) consensus statement 

suggests providing treatment for the infection if H. 

pylori is identified in a child at endoscopy (Table 

6.6). 97 

Children with H. pylori-positive PUD must be 

submitted to eradicating treatment, because 

Table 6.6 Guidelines for the management of Helicobacter pylori infection in children 

Diagnosis Evidence Treatment Evidence 

North American Society of Pediatric Gastroenterology, Hepatology and Nutrition 

Endoscopy and histology II peptic ulcer disease I 

13C-urea breath test II MALToma 

atrophic gastritis 

III 

I. metaplasia 

triple therapy for 1–2 weeks 

III 

European Pediatric Task Force on Helicobacter pylori 

Endoscopy and histology peptic ulcer disease 

13C-urea breath test for follow-up all Helicobacter pylori-positive children after 

endoscopy (information of the possibility 

of symptoms’ persistence)

86 


Table 6.7 The Maastricht 2-2000 guidelines for the treatment of 

Helicobacter pylori infection in adults 

Strongly recommended indications 

Peptic ulcer disease 

MALToma 

Atrophic gastritis 

Post-gastric cancer resection 

First-degree relatives of gastric cancer patients 

Patient’s wishes (after physician consultation) 

Advisable indications 

Functional dyspepsia (subset of patients) 

Gastroesophageal reflux disease (in patients requiring long-term proton pump 

inhibitor therapy) 

Users of non-steroidal anti-inflammatory drugs 

relapse after effective ulcer healing has been 

demonstrated in 47–80% of children with persistent 

H. pylori infection, and exceptionally in those 

in whom H. pylori has been eradicated. 31,37,97 

Symptomatic relief of dyspeptic symptoms is 

usually achieved. 73 

H. pylori eradication in children with chronic 

active gastritis is associated with evident 

histological improvement, 69 but remission of 

symptoms does not necessarily follow. 73,97 However, 

if the infection is not treated, worsening of 

gastritis and of the clinical picture, particularly in 

males and in children infected with Cag-A-positive 

strains, has been documented in a close follow-up 

study. 101 In adults as well as in teenagers with 

iron-deficient anemia, H. pylori eradication was 

associated with a rise in hemoglobin levels and in 

ferritin values, suggesting that treatment should be 

considered. 82–85 

In adults with peptic esophagitis, the treatment of 

associated H. pylori infection is a question of 

debate. 102 Some authors have suggested that 

esophagitis and gastroesophageal reflux disease 

(GERD) may be exacerbated by eliminating the 

protecting buffering effect of H. pylori infection. 103 

Nevertheless, a causal relationship between these 

phenomena remains unproven, and is mainly 

based on retrospective analyses or epidemiological 

hypothesis. The small number of prospective trials 

in adults has not consistently demonstrated an 

increased risk of GERD after H. pylori eradication. 

104 

In a study planned to answer the question of 

whether eradication of H. pylori infection in 

children with RAP should result in clinical 

improvement, no correlation was seen between 

eradication and disappearance of RAP, after 3 or 

after 6 months of observation. 105 

To date, extrapolation of data from randomized 

controlled trials in adults has been the basic 

approach to treating children with H. pylori infection. 

A systematic review of the small published 

open trials in 870 children from 1987 to 2000 has 

recently been published. 106 A total of 79 children 

were treated with one drug (monotherapy); 345 

were treated with dual therapy, including two 

antibiotics or one antibiotic plus bismuth 

compounds or H2-receptor antagonists (H2RA) or 

proton pump inhibitors (PPIs); and 446 with a 

bismuth- or PPI-based triple therapy plus two 

antibiotics. In pediatrics, the most frequently 

utilized antibiotics were amoxicillin, clar-

ithromycin, and the nitroimidazoles, metronidazole 

or tinidazole. The reasons for the development 

of combined therapies were: 

(1) Different strains with different antibiotic 

sensitivity may colonize the same patient. 

Sensitivity to amoxicillin, clarithromycin and 

nitroimidazoles is one of the key factors in 

the eradication rates. Unpublished data 

collected by the EPTFHP showed metronidazole, 

clarithromycin or double resistance 

before the first therapy in 24.5%, 20% and 

7%, respectively, of 400 H. pylori-infected 

children aged under 15 years. 

(2) Stability and efficacy of antibiotics are often 

impaired in the acid environment. This 

consideration prompted the combination of 

antibiotics with drugs able to increase the 

gastric pH (H2RA or PPI). 

In general, monotherapy with one antibiotic, or 

bismuth compounds, or H2RA or PPI showed a 

very low eradication rate and it is not recommended. 

Combination of one antibiotic with PPI 

was not satisfactory (mean eradication rate of 

39%), while combination of amoxicillin with 

nitroimidazole or one of the two antibiotics with 

bismuth salts was tried in 248 children, with a 

mean eradication rate of 73–76%. 106 

Table 6.8 Protocols of Helicobacter pylori treatment in children 

First-line therapy 

PPI (1 mg/kg per day up to 20 mg bid) plus 

Amoxicillin (50 mg/kg per day bid up to 1 g bid) plus 

Clarithromycin (15 mg/kg per day up to 500 mg bid) or 

Metro(ti)nidazole (20 mg/kg per day up to 500 mg bid) for 1 week 

In case of failure to eradicate the bacterium: 

Second-line therapy 

Treatment 87 

Triple therapy schedules did not work much 

better. A recent randomized clinical trial 

confirmed that 1 week of omeprazole–amoxicillin– 

clarithromycin resulted in successful eradication 

of H. pylori in 75% of 73 children

88 


the most recommended. 97 Recent data showed that 

fecal H. pylori antigen assays could be an effective 

alternative. 109 Re-infection after eradication is 

uncommon in children, and treatment of the 

affected family member at present is not 

supported. 17 

In the case of relapse, biopsy culture for antibiotic 

sensitivity testing should be proposed for a better 

chance of eradication. If culture is not available or 

if H. pylori does not grow, substitution of clarithromycin 

with a nitroimidazole (and vice versa) 

is the first step, because of the high probability of 

development of a resistance to either drug. A 2week 

regimen should be offered to relapsing 

patients (Table 6.8). 

Short- and long-term prognosis 

In patients with H. pylori-associated PUD, successful 

eradication is followed by ulcer healing and 

usually evident clinical improvement. PUD does 

not relapse and reacquisition of the infection is 

rare after 5 years of age. 31,42,97 Children with 

abdominal complaints associated with chronic 

gastritis have a more unpredictable clinical outcome, 

even if H. pylori is eradicated. 73,97 

Among long-term complications of H. pyloriassociated 

chronic gastritis, the most important is 

the multistep disease progression towards gastric 

atrophy, intestinal metaplasia, dysplasia and 

gastric cancer. 110 In general, this is a rare evolution, 

affecting no more than 1% of H. pyloripositive 

patients. This multifactorial process 

includes host, bacterial and dietary factors. 

Family studies have shown that gastric cancer is 

significantly higher in first-degree relatives of 

gastric cancer patients. 111 Epidemiological 

case–control and cohort studies have demonstrated 

that H. pylori is strongly associated with 

non-cardia gastric carcinoma of both the intestinal 

and the diffuse type. 112,113 An extensive review on 

this topic showed the best estimate of the relative 

risk of non-cardia gastric cancer associated with H. 

pylori infection to be 5.9. 113 The odds ratio 

decreased significantly with aging, from 9.29 in 

patients with carcinoma at age 20–29 years, to 1 in 

those older than 70 years of age. 112 For some 

authors, the basis of the genetic predisposition lies 

either in genetic susceptibility to the infection 20 or 

in mechanisms of DNA repair and carcinogenesis. 

114 Mutation in p53 is one of the most common 

genetic alterations found in human cancer, including 

gastric cancer. 115 Inhibition of apoptosis 

secondary to up-regulation of cyclo-oxygenase 2 

by H. pylori-induced inflammation could play a 

role in inducing intestinal metaplasia. In a 

subgroup of gastric cancer, as well as in intestinal 

metaplasia, microsatellite instability, secondary to 

germline mutation of the DNA mismatch repair 

genes, has also been demonstrated. The mechanisms 

inducing intestinal metaplasia and carcinogenesis 

have recently been reviewed. 114 

Acid output has long been investigated as a key 

factor of ulcer development and gastric cancer. 

Indeed, patients with higher acid output are likely 

to have antral-predominant gastritis and eventually 

duodenal ulcer, but they do not show any 

predisposition towards gastric cancer. 116 Patients 

with lower acid output, on the other hand, are 

more likely to have a body-predominant gastritis, 

which predisposes to gastric ulcer and to the 

multistep progression of disease that, in rare cases, 

leads to gastric carcinoma. Polymorphisms of the 

IL-1β promoter have been linked to altered gastric 

acid secretion and pre-malignant histological 

features. Severity of the host response to H. pylori 

infection was related to individual ability to 

produce IL-1, which has been demonstrated to be 

a potent inhibitor of gastric acid secretion, as well 

as a proinflammatory cytokine. 117 The histological 

pathways of H. pylori infection and mechanisms 

involved in carcinogenesis are shown in Figure 

6.8. Genetic as well as acquired (H. pyloridependent) 

determinants co-operate, increasing 

the risk of gastric cancer up to 90-fold in patients 

with intestinal metaplasia. 

Despite the strong causal link between H. pylori 

and gastric carcinoma, evidence that treatment for 

H. pylori infection may actually prevent gastric 

cancer is lacking. The long development time of 

gastric cancer is the main problem in performing 

such studies. It has been estimated that a trial with 

sufficient power to answer the question would 

have to recruit 100 000 infected subjects with a 20year 

follow-up. 118 In addition, studies planned to 

investigate the regression of pre-malignant lesions 

after eradication gave conflicting results. The 

progression rate of intestinal metaplasia does not

OR Cancer H. pylori+ 

duodenal ulcer 

0 

gastric ulcer 

3.4 

NAG 

2–4.7 

Atrophic gastritis (MAG) 

p53 mutation 

MSL hypermethylation 

TGF-alpha EGFR 

intestinal metaplasia 

6.4 - > 90 

Metaplasia Dysplasia 

Cancer 

(intestinal type) 

appear to be arrested by eradication; however, eradicating 

H. pylori leads to resolution of inflammation, 

elimination of DNA damage and reduction of 

proliferation, all changes possibly preventing 

gastric cancer. 114 

Another malignancy strongly associated with H. 

pylori infection is gastric B-cell lymphoma, known 

as MALToma. Even if the stomach is the most 

common site of the extranodal lymphomas, 

MALTomas are rare in adults (0.71 cases/100 000 

per year in the USA) and definitely exceptional in 

children. The association of H. pylori infection and 

MALTomas is based on these considerations: H. 

pylori is found in more than 90% of cases; 119 H. 

pylori infection precedes the development of the 

malignancy; and eradicating the infection results in 

the regression of MALToma in approximately 70% 

of cases of low-grade disease (stage IE). 120 Thus, H. 

pylori infection in a patient with MALToma is a 

strong indication for eradication treatment. 100 

Regression of MALToma after H. pylori eradication 

was described in a 14-year-old female. 121 

Prophylactic and therapeutic immunization 89 

Antral gastritis 

(± duodenal ulcer) 

+ 

Acid output 

–/= 

Corpus gastritis or 

pangastritis 

(± gastric ulcer) 

(NAG) non-atrophic 

gastritis 

Cancer 

(diffuse type) 

MALToma 

Figure 6.8 The natural history of Helicobacter pylori infection and associated diseases depends on aging, as well as 

genetic and bacterial factors (see text). Determinants of diseases are the acid output for the development of peptic ulcer, 

and the existence of carcinogenetic mechanisms which trigger the multistep gastric carcinogenesis pathway. On the left, 

are the odds ratios for gastric cancer associated with different clinical pictures. EGFR, epidermal growth factor receptor; 

MSL, microsatellite instability; TGF, transforming growth factor. 

A 

G 

I 

N 

G 

Prophylactic and therapeutic 

immunization 

As we have seen, effective therapies against 

Helicobacter require the child to ingest multiple 

drugs several times a day for at least 1 week. 106 

The common occurrence of adverse effects 

(nausea, diarrhea, abdominal pain and, more 

rarely, pseudomembranous colitis), the frequently 

observed low compliance and the high costs 

suggest the need to evaluate different approaches. 

Despite the fact that patients infected with H. 

pylori have a systemic and local immune 

response, 57 this response does not resolve the 

infection. Studies on H. pylori-specific cellular 

immunity suggested that H. pylori induces a proinflammatory 

cascade and a Th1 response that 

contributes to the chronicity (Figure 6.2). Since 

1993, several groups have developed animal 

models of Helicobacter infection. 122 Using the 

mouse model, oral immunization with H. felis

90 


lysates with cholera toxin (CT) as adjuvant 

resulted in 76–96% of protection. Others challenged 

the same models using H. pylori antigens 

such as Vac-A, Cag-A, catalase or urease B subunit. 

On the basis of the results of clinical therapeutic 

vaccination trials, it is likely that several antigens 

are needed for a subunit vaccine in humans. 

Several groups administered the vaccine to 

infected animals for therapeutic and not for 

prophylactic use. Oral vaccination of H. felisinfected 

mice with either bacterial sonicate or H. 

pylori urease B subunit plus CT cured approximately 

half of the mice. Several groups have now 

developed murine models of H. pylori infection. 

Eradication in 70–92% was achieved by using 

recombinant Cag-A or Vac-A as oral antigens, 

respectively. 

Studying the H. mustelae ferret model, which 

represents a natural host–pathogen disease, therapeutic 

immunization with H. pylori urease and CT 

achieved eradication in one-third of ferrets. 

Recently, a clinical trial tested an oral therapeutic 

vaccine consisting of recombinant H. pylori urease 

apoenzyme coupled with Escherichia coli LT in 

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statement. J Pediatr Gastroenterol Nutr 2000; 30: 

207–213. 

98. Sherman P, Hassall E, Hunt RH et al. Canadian 

Helicobacter Study Group Consensus Conference on the 

Approach to Helicobacter pylori infection in Children 

and Adolescents. Can J Gastroenterol 1999; 13: 553–559. 

99. Bazzoli F, Cecchini L, Corvaglia L et al. Validation of the 

13C-urea breath test for the diagnosis of Helicobacter 

pylori infection in children: a multicenter study. Am J 


100. Malfertheiner P, Megraud F, O’Morain C et al. Current 

concepts in the management of Helicobacter pylori 

infection – the Maastricht 2-2000 Consensus Report. 


101. Ganga-Zandzou PS, Michaud L, Vincent P et al. Natural 

outcome of Helicobacter pylori infection in asymptomatic 

children: a two-year follow-up study. Pediatrics 

1999; 104: 216–222. 

102. Malfertheiner P, O’ Connor HJ, Genta MR et al. 

Symposium: Helicobacter pylori and clinical risks – 

focus on gastro-esophageal reflux disease. Aliment 

Pharmacol Ther 2002; 16 (Suppl. 3): 1–10. 

103. Labenz J, Blum AL, Bayerdorffer E et al. Curing 

Helicobacter pylori infection in patients with duodenal 

ulcer may provoke reflux esophagitis. Gastroenterology 

1997; 112: 1442–1447. 

104. Moayyedi P, Bardhan C, Young L et al. Helicobacter 

pylori eradication does not exacerbate reflux symptoms 

in gastroesophageal reflux disease. Gastroenterology 

2001; 121: 1120–1126. 

105. Wewer V, Andersen LP, Paerregaard A et al. Treatment of 

Helicobacter pylori in children with recurrent abdominal 

pain. Helicobacter 2001; 6: 244–248. 

106. Oderda G, Rapa A, Bona G. A systematic review of 

Helicobacter pylori eradication treatment schedules in 

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children. Aliment Pharmacol Ther 2000; 14 (Suppl 3): 

59–66. 

107. Gottrand F, Kalach N, Spyckerelle C et al. Omeprazole 

combined with amoxicillin and clarithromycin in the 

eradication of Helicobacter pylori in children with 

gastritis: a prospective randomized double-blind trial. J 

Pediatr 2001; 139: 664–668. 

108. Walsh D, Goggin N, Rowland M et al. One week treatment 

for Helicobacter pylori infection. Arch Dis Child 

1997; 76: 352–355. 

109. Roggero P, Bonfiglio A, Luzzani S et al. Helicobacter 

pylori stool antigen test: a method to confirm eradication 


110. Correa P. Human gastric carcinogenesis: a multistep and 

multifactorial process. First American Cancer Society 

Award Lecture on Cancer Epidemiology and Prevention. 

Cancer Res 1992; 52: 6735–6740. 

111. Woolf CM. A further study on the familial aspects of 

carcinoma of the stomach. Am J Hum Genet 1956; 8: 

102–109. 

112. Huang J-Q, Sridhar S, Chen Y et al. Meta-analysis of the 

relationship between Helicobacter pylori seropositivity 

and gastric cancer. Gastroenterology 1998; 114: 

1169–1179. 

113. Helicobacter and Cancer Collaborative Group. Gastric 

cancer and Helicobacter pylori: a combined analysis of 

12 case control studies nested within prospective 

cohorts. Gut 2001; 49: 347–353. 

114. Leung WK, Sung JJY. Intestinal metaplasia and gastric 

carcinogenesis. Aliment Pharm Ther 2002; 16: 

1209–1216. 

115. Shiao YH, Rugge M, Correa P et al. p53 alteration in 

gastric precancerous lesions. Am J Pathol 1994; 144: 

511–517. 

116. Hansson LE, Nyren O, Hsing AW et al. The risk of 

stomach cancer in patients with gastric or duodenal 

ulcer disease. N Engl J Med 1996; 335: 242–249. 

117. El-Omar EM, Carrington M, Chow WH et al. 

Interleukin-1 polymorphisms associated with increased 

risk of gastric cancer. Nature 2000; 404: 398–402. 

118. Forman D. Should we go further and screen and treat? 

Eur J Gastroenterol Hepatol 1999; 11(Suppl 2): S69–S71. 

119. Parsonnet J, Hansen S, Rodriguez L et al. Helicobacter 

pylori infection and gastric lymphoma. N Engl J Med 

1994; 330: 1267–1271. 

120. Bayerdorffer E, Neubauer A, Rudolph B et al. Regression 

of primary gastric lymphoma of mucosa-associated 

lymphoid tissue type after cure of Helicobacter pylori 

infection. Lancet 1995; 345: 1591–1594. 

121. Blecker U, McKeithan TW, Hart J, Kirschner BS. 

Resolution of Helicobacter pylori-associated gastric 

lymphoproliferative disease in a child. Gastroenterology 

1995; 109: 973–977. 

122. Blanchard TG, Czinn SJ. Immunology of Helicobacter 

pylori and prospects for vaccine, Gastroenterol Clin 

North Am 2000; 29: 671–685. 

123. Michetti P, Kreiss C, Kotloff KL et al. Oral immunization 

with urease and Escherichia coli heat-labile enterotoxin 

is safe and immunogenic in Helicobacter pylori-infected 

adults, Gastroenterology 1999; 116: 804–812. 

124. Bumann D, Metzger WG, Mansouri E et al. Safety and 

immunogenicity of live recombinant Salmonella enterica 

serovar Typhi Ty21a expressing a urease A and B 

from Helicobacter pylori in human volunteers Vaccine 

2001; 20: 845–852.

7 

Introduction 

Other gastritides 


Epithelial damage, mucosal inflammation and 

epithelial cell regeneration represent the histological 

response of the stomach to injury. The term 

‘gastritis’ implies the microscopic evidence of 

inflammation, in which all processes of mucosal 

response to injury are present, whereas the term 

‘gastropathy’ is used for conditions in which 

epithelial injury is associated with cellular regeneration 

and the inflammation is not the prominent 

feature. 1 The definite diagnosis of gastritis is thus 

exclusively based on histological assessment of 

biopsy specimens, whereas gastropathies are occasionally 

diagnosed on endoscopic appearance. For 

this reason, great confusion has been generated by 

the inappropriate use of the term gastritis. 

Gastritis and gastropathy were previously classified 

either as primary (idiopathic) or secondary on 

the basis of the underlying etiology. 2 It is now clear 

that most cases of unexplained gastritis are caused 

by previously unrecognized Helicobacter pylori (H. 

pylori) infection. Recently, an endoscopic classification 

of gastritis and gastropathy, has been 

proposed, that differentiates between erosive 

and/or hemorrhagic gastritis or gastropathy and 

non-erosive gastritis or gastropathy. 3 The 

confounding aspect lies in the fact that some disorders 

can be either erosive or non-erosive. The most 

common causes of gastritis are summarized in 

Table 7.1. 

Infectious gastritides 

Bacterial gastritides 

Helicobacter heilmannii 

Although H. pylori is by far the most common 

agent in bacterial gastritides (discussed in detail in 

Chapter 6), a spirochete-like organism, Helicobacter 

heilmannii (formerly Gastrospirillum 

hominis), has been found to infect the human 

stomach. H. heilmannii is closely related to 

Helicobacter types found in dogs and cats, such as 

Helicobacter felis. In a pediatric population, Oliva 

et al found a prevalence of infection of 0.3%, 

whereas in domestic cats and dogs the frequency 

of infection was up to 100%. 4,5 H. heilmannii 

infection is thought to be a zoonosis, and a 

fecal–oral route of transmission is suggested. 

Recently, van Loon et al found an identical H. heilmannii 

strain in a 5-year-old boy and his cats. 6 

Histology shows a typical chronic inflammation, 

milder than H. pylori gastritis, and the presence of 

a spiral organism with four to six coils per cell and 

up to 12 flagella at each pole. The bacterium is 

usually recognized focally and in small groups in 

the foveola, maintaining a large distance from the 

surface epithelium. Endoscopic features such as 

erosions, peptic ulcerations and antral nodularity 

have rarely been reported. Eradication treatment, 

as with H. pylori infection, should be considered in 

both humans and animals. 

Tuberculosis gastritis 

Tuberculosis infection of the stomach is very rare 

and usually occurs in patients with immune 

deficiency or after transplantation. 7 In adults, 

gastric tuberculosis typically involves the antrum 

and extends to the lesser curvature, although in 

patients with AIDS it may also involve the esophagogastric 

junction. Endoscopic features include 

hypertrophic nodular lesions and multiple ulcers, 

whereas outlet obstruction, caused by prepyloric 

narrowing or mass effect, has rarely been 

described. Histology can show both caseous and 

non-caseous granulomas. Culture of biopsy specimens 

is essential to establish the diagnosis, 

95

96 


Table 7.1 Common causes of gastritis and gastropathy 

Infectious gastritis 

Bacteria Helicobacter pylori 

Helicobacter heilmannii 

Mycobacterium tuberculosis, 

Mycobacterium avium-intracellulare 

Viruses cytomegalovirus 

herpes simplex virus 

varicella zoster virus 

Fungi – Protozoa Candida albicans 

Histoplasma, Mucormycosis 

Anisakis simplex 

Giardia lamblia 

Cryptosporidium 

Drugs and other agents 

Aspirin and other non-steroidal anti-inflammatory drugs 

Corticosteroids 

Potassium chloride, calcium 

Chemotherapeutic agents, antibiotics, prostaglandin E1 

Ethanol, cocaine, methamphetamines 

Gastrostomy tubes 

Endoscopic procedures 

Foreign-body ingestion 

Stress 


Bile reflux gastropathy 


Zollinger–Ellison and pseudo-Zollinger–Ellison syndrome 

Lymphocytic gastritis 



Helicobacter pylori lymphocytic gastritis 

Crohn’s disease 

Chronic granulomatous disease 



Proton pump inhibitor gastritis 


Gastritis associated with other autoimmune diseases 

Graft-versus-host disease

ecause the organism may not be seen microscopically. 

Organisms of the Mycobacterium avium–intracellular 

complex are common pathogens in immunosuppressed 

patients, and mainly occur in the small 

and large intestines. However, the stomach may 

occasionally be involved, with refractory gastric 

ulcerations. 8 

Viral gastritides 

Viral infections of the stomach typically affect 

immunocompromised or severely debilitated children. 

Their frequency substantially increases in 

such children, whereas they are quite rare in 

healthy subjects. Rare cases of gastric involvement 

by herpes simplex virus (HSV) or disseminated 

varicella zoster virus (VZV) infections have been 

reported. 9,10 Bleeding from hemorrhagic gastropathy 

has been described in children with influenza 

A infection. 11 Cytomegalovirus (CMV) is the main 

recognizable viral agent, occurring in both healthy 

and immunodeficient children, and has been 

involved as an etiologic agent in Ménétrier’s 

disease. 

Fungal and protozoan gastritides 

Fungal infections, such as Candida albicans, histoplasmosis 

and mucormycosis, rarely affect the 

stomach, although bleeding, gastric ulcers and 

perforation during disseminated infections have 

been described in preterm or sick neonates, as well 

as in malnourished or immunodeficient children. 

In adults, acute gastric anisakiasis frequently 

occurs in countries where the consumption of raw 

or undercooked fish is high. It is caused by ingesting 

the organism’s larvae. Because humans represent 

an aberrant host, it is a dead-end infection 

characterized by an intense acute eosinophilic 

inflammation. Acute gastrointestinal symptoms, 

such as upper abdominal pain, nausea and vomiting 

occur within a few hours, and acute anaphylactic 

reactions have been described in patients 

previously exposed to the organism. 12 Endoscopic 

findings include multiple erosions, edema and 

single or multiple worms, while histology shows 

an acute eosinophilic inflammation. The removal 

Gastropathies due to drugs 97 

of worms with endoscopic forceps induces rapidly 

symptomatic relief. 

Gastric colonization of Giardia lamblia has been 

reported in 0.3% of adults undergoing upper 

gastrointestinal endoscopy. 13 Because giardiasis is 

associated with intestinal metaplasia of the 

stomach, some authors suggest that this organism 

is not a gastric pathogen. 

Gastric outlet obstruction due to enteric cryptosporidiosis 

has been reported in immunocompromised 

patients. 14 

Gastropathies due to drugs, toxins 

and other agents 

Acetylsalicylic acid and other non-steroidal 

anti-inflammatory drugs 

It is well known that acetylsalicylic acid and other 

non-steroidal anti-inflammatory drugs (NSAIDs) 

can cause gastric injury including gastritis, gastric 

ulcers and gastrointestinal hemorrhage. 

Gastroduodenal damage can be seen at endoscopy 

in 20–40% of adults taking NSAIDs, and the 

overall risk for peptic complications (hemorrhage 

and perforation) in these patients is about three 

times greater than in controls. 15 There are no data 

on the frequency of upper gastrointestinal injury 

in children related to NSAID use. Because of the 

risk of Reye syndrome and the availability of 

different types of antipyretic drugs, the use of 

acetylsalicylic acid and NSAIDs in children has 

significantly diminished. 

The routine use of these drugs in different clinical 

conditions is associated with severe complications 

such as mucosal erosions and ulceration, and 

gastrointestinal bleeding. Endoscopic features 

include hemorrhagic gastric erosions (most often 

in the corpus) and gastric ulcers (mainly in the 

antrum). Histology shows foveolar hyperplasia, 

edema, vascular dilatation and congestion, 

increased smooth muscle fibers in the lamina 

propria and, characteristically, a relative paucity of 

inflammation. The term ‘chemical gastritis’ is 

usually employed for this condition. 

Several mechanisms are thought to play a role in 

the pathogenesis of NSAID-induced injury,

98 


including inhibition of prostaglandin (PG) synthesis, 

increased platelet-activating factor, platelet 

dysfunction, increased oxygen free radicals, 

increased neutrophil adherence, decreased 

mucosal blood flow and topical irritant effects. 16 

Endogenous PGs are well-known mucosal defense 

factors, protecting the gastric mucosa against 

injury caused by a variety of toxic stimuli. PGs are 

synthesized through cyclo-oxygenase (COX), 

which is the target of NSAIDs. Two isoforms of 

COX molecules (COX-1 and COX-2) have been 

recognized. COX-1 is a constitutively expressed 

enzyme in many tissues, including the gastrointestinal 

tract, and is usually active, while COX-2 

is an inducible enzyme predominantly expressed 

at the site of inflammation. It has been shown that 

the side-effects of NSAIDs are related to COX-1 

affinity, while their therapeutic effects are dependent 

on activity against COX-2. 17 


The association between peptic ulcer disease and 

corticosteroids has never been accepted unequivocally. 

Ng et al described two cases of gastric perforation 

in preterm babies treated with dexamethasone 

for bronchopulmonary dysplasia. 18 A 

meta-analysis of 71 controlled studies performed 

by Messer et al demonstrated an increased risk for 

gastrointestinal ulceration and hemorrhage among 

adult patients who had received corticosteroids, 

and the risk was correlated with the dosage 

employed. 19 Although to date there are no similar 

studies in childhood it is commonly agreed that, 

when steroids are administered to children for 

long periods, prophylactic therapy for gastric 

mucosal damage should be started concomitantly 

(see p.109). 

Other agents 

Gastropathies can be caused by a variety of drugs 

including potassium chloride, calcium, valproic 

acid, chemotherapeutic agents and antibiotics, 

such as penicillin, chloramphenicol, sulphonamides, 

tetracyclines and cephalosporins. In 

neonates the administration of PGE1 can induce 

gastric outlet obstruction due to antral hyperplasia. 

20 

In experimental animals, exposure to a high 

concentration of ethanol rapidly produces grossly 

evident focal hemorrhagic erosions. Chronic ingestion 

of alcohol may also result in human gastric 

pathology. Endoscopic findings include subepithelial 

hemorrhages (‘blood under plastic wrap’), 

usually in the fundus and corpus, and small whitebased 

erosions. 21 Histology reveals areas of subepithelial 

hemorrhage, associated with superficial 

and deep epithelial damage, and marked edema of 

the surrounding mucosa. Inflammatory cell infiltrate 

is usually minimal. Experimental studies in 

animals have shown that alteration of the mucosal 

microcirculation might be an early event in the 

evolution of ethanol-induced gastric injury, as 

suggested by the occurrence of focal damage of 

mucosal capillaries and increased permeability 

within 1 or 2 min after intragastric instillation of a 

high concentration of ethanol. 22 

Gastric ulcerations have been reported in association 

with cocaine and methamphetamine abuse. In 

children requiring enteral nutrition, ulcers and 

small multiple erosions, usually localized in the 

proximal stomach, have been described after 

placement of gastrostomy feeding tubes. 

Subepithelial hemorrhages and focal erosions are 

commonly detected after ingestion of a foreign 

body or endoscopic procedures. 

Stress gastropathy 

Although the overall prevalence is unknown, most 

critically ill infants and children are prone to 

develop stress-related gastropathy. In infants, 

stress gastropathy is usually related to traumatic 

delivery, respiratory or cardiac failure, sepsis, 

hypoglycemia or dehydration, while in older children 

it is related to severe life-threatening illness 

(e.g. respiratory or cardiac failure), intracranial 

lesion, trauma, burns, coagulopathy, or vasculitis. 

23 Endoscopic features include isolated gastroduodenal 

erosions, usually in the fundus and 

proximal body, and, in severe cases, mucosal 

ulcerations occurring at multiple sites within the 

stomach and duodenum (Figure 7.1). The majority 

of patients develop erosions and ulcers within 

minutes to hours after the initial insult, and the 

most common presenting symptoms are 

hematemesis and melena rather than abdominal

Figure 7.1 Congested gastric mucosa in an infant with 

stress hemorrhagic vomiting. The mucosa shows nonconfluent 

cherry red spots on a finely granular background. 

pain. Recently, Chaibou et al showed that more 

than 10% of children admitted to an intensive care 

unit experienced upper gastrointestinal bleeding, 

but the bleeding was clinically significant in only 

1.6% of them. 24 

Alterations of the mucosal microcirculation and 

mucosal ischemia have been implicated in the 

pathogenesis of stress-induced gastropathy, even 

though other mechanisms have been suggested, 

such as increased acid output, decreased production 

of mucus and impairment of local 

prostaglandin synthesis. 


Ménétrier’s disease, a rare disorder of unknown 

etiology, is characterized by enlarged gastric folds 

due to mucosal thickening in the gastric body. To 

date, fewer than 100 pediatric cases have been 

described. Significant differences between adult 

and pediatric disease in terms of onset, presentation, 

course and prognosis have been 

observed. 25,26 In children, the disease often begins 

abruptly and is usually self-limited, with resolution 

of clinical features within weeks or months. In 

contrast, in adults, Ménétrier’s disease is a persis- 

Ménétrier’s disease 99 

tent and more severe condition often associated 

with gastrointestinal bleeding, in most cases 

requiring surgical resection. 

Although this disease has also been reported in the 

neonatal period, the mean age of onset is 5 years 

(ranging from 2 days to 17 years). Common 

features include vomiting, abdominal pain, 

anorexia, hypoproteinemia and, in some cases, 

eosinophilia and raised IgE levels. Several studies 

have confirmed that hypoproteinemia is due to a 

non-selective increased loss of proteins through 

the gastric mucosa, occurring in a paracellular 

fashion via widened tight junctions. 27 In childhood, 

hematemesis and melena occur rarely, 

whereas in adults the incidence of gastrointestinal 

bleeding ranges from 20 to 40%. 

The etiology of Ménétrier’s disease is unknown, 

although its acute presentation and self-limited 

clinical course in childhood suggest an infectious 

cause. Nearly 30% of affected children show 

evidence of CMV infection, either through the 

presence of characteristic inclusion bodies and 

CMV antigen in the gastric tissue or by serology. 25 

It has also been proposed that an increase in both 

serum IgE levels and the number of peripheral 

blood eosinophils might be an idiosyncratic antibody-mediated 

response to the penetration of the 

gastric mucosa by allergens after the cytopathic 

effect of CMV on the gastric mucosa. 

H. pylori infection has also been reported in children 

with enlarged gastric folds and protein-losing 

enteropathy, and its eradication has resulted in 

disease resolution. 28 However, the classic clinical 

and histological features of Ménétrier’s disease 

were absent in all reported cases. 

Insights into the disease pathogenesis have been 

gained through the investigation of the mediators 

of gastric mucosal growth and function, such as 

transforming growth factor-α (TGFα). The latter 

stimulates gastric epithelial cell proliferation and 

mucin secretion, and inhibits parietal cell acid 

production, in transgenic mice reproducing many 

altered mucosal features of Ménétrier’s disease. As 

in adult patients, elevated levels of TGFα have 

been found in gastric mucosal biopsies taken from 

children with Ménétrier’s disease, suggesting a 

role for this polypeptide in the development and 

progression of the disesase. 29

100 


Upper gastrointestinal X-ray series identifies the 

characteristic gastric rugae hypertrophy, predominantly 

in the fundus and in the corpus of the 

stomach. Thickened gastric mucosal folds have 

also been demonstrated by additional diagnostic 

imaging modalities, such as ultrasound and 

computed axial tomography. Endoscopy and 

histology should be performed in all patients to 

confirm the diagnosis, to search for the pathogen 

and to exclude different diagnoses, such as 

eosinophilic gastritis, primary gastric lymphoma, 

gastric carcinoma, Crohn’s disease of the stomach 

and other conditions in which hypertrophic 

gastric rugae occur. Endoscopy shows swollen 

gastric folds predominantly in the greater curvature 

of the stomach or within the entire body 

region of the stomach, large quantities of gelatinous 

mucus and, less commonly, multiple areas of 

focal erosions in the fundus. Histology usually 

shows considerable elongation and complexity of 

the superficial epithelium, so-called foveolar 

hyperplasia (gastric pit), with reduction of chief 

and parietal cell glands and often with cystic 

dilatation, which may extend into the submucosa. 

An inflammatory infiltrate of eosinophils, 

neutrophils, lymphocytes and, occasionally, 

plasma cells is found in the edematous lamina 

propria. 

Bile reflux gastropathy 

This is also known as alkaline gastritis and 

describes an ongoing, chronic condition in which 

bile-containing intestinal contents reflux into the 

stomach. In animal studies it has been shown that 

bile salts and other intestinal contents, such as 

lysolecitin, break down the gastric mucosal 

barrier, leading to back-diffusion of H + ions and 

histological injury. Bile acid salts are also potent 

releasers of histamine and other mediators from 

mast cells and induce non-specific cytotoxicity. 30 

Duodenogastric bile reflux is thought to be a physiological 

event during the second phase of the 

interdigestive motor complex and during the postprandial 

phase, but it is rapidly flushed out during 

the third phase of the interdigestive period. It may 

be considered abnormal when it is frequent, when 

it is abundant or when it is associated with 

delayed gastric emptying. 

Typical endoscopic findings are ‘beefy’ redness or 

erythema and, occasionally, erosions, but the presence 

of bile in the stomach during endoscopy does 

not have clinical significance. The distinctive 

histological features, also defined as ‘chemical 

gastropathy’, include foveolar elongation, complexity 

and hypercellularity, together with edema, 

vasodilatation and a paucity of acute and chronic 

inflammatory cells in the lamina propria. 31 These 

findings do not correlate with gastric bile concentration. 

The diagnosis of bile reflux gastropathy should be 

considered in adults with abdominal pain and 

bile-stained vomiting, who had previously undergone 

partial gastric resection or drainage procedures, 

even though reflux of duodenal contents 

has been linked to the development of a number of 

pathological gastric conditions, such as nonspecific 

gastritis, gastric ulcer, gastric carcinoma 

and non-ulcer dyspepsia. In adults, an association 

between bile reflux and intestinal metaplasia in 

the gastric and cardiac mucosa has been reported, 

suggesting that the latter represents a defense 

response against a sustained adverse environment, 

in the same way that gastric metaplasia develops 

in the duodenum when subjected to a high acid 

load. 32 


Involvement of the gastric mucosa is common in 

children with intrahepatic or extrahepatic causes 

of portal hypertension. 33 Endoscopic findings vary 

from mild involvement, including a snake-skin 

mosaic pattern of the mucosa, a fine pink speckling 

and superficial erythema (scarlatina-type 

rash), to a severe gastropathy, defined by cherry 

red spots with a diffuse confluence of reddened 

areas and a hemorrhagic appearance. These 

patterns seem to be specific for portal hypertensive 

gastropathy and have not been found in any of 500 

endoscopic examinations performed in children 

without hepatic disease. The fundus and corpus 

are usually involved, although antral involvement 

is occasionally observed. Histologically, portal 

hypertensive gastropathy is characterized by 

ectasia of mucosal capillaries and venules and by 

submucosal venous dilatation, with no acute or 

chronic inflammation.

Hemodynamic disturbances are thought to be 

involved in the pathogenesis of portal hypertensive 

gastropathy, because gastric perfusion alterations 

parallel the severity of mucosal involvement 

and previous endoscopic sclerotherapy of 

esophageal varices both in adults and children 

may exacerbate mucosal congestion and the severity 

of gastropathy. 34 

Zollinger–Ellison and pseudo- 

Zollinger–Ellison syndromes 

It is intuitive that excessive acid production can 

result in multiple erosions and frank ulcers in the 

stomach, duodenum and jejunum. Although rare, 

this condition may arise from a gastrinoma 

(Zollinger–Ellison syndrome (ZES)) or from antral 

gastrin cell hyperfunction with or without 

hyperplasia (pseudo-Zollinger–Ellison syndrome 

(PZES)). 

ZES is the most frequent ulcerogenic syndrome 

associated with increased gastrin levels and, in 

adults, represents the most common of the malignant 

islet cell tumors. 35 ZES is characteristically 

associated with increased levels of serum gastrin 

(hypergastrinemia), which, in turn, causes an overproduction 

of gastric acid and results in complicated 

ulcer disease. As would be expected, the 

most common presenting signs are abdominal 

pain, nausea, vomiting, hematemesis and melena. 

Diarrhea occurs less commonly in childhood than 

in adulthood. ZES can be sporadic or associated 

with multiple endocrine neoplasia type I (MEN I). 

ZES-associated MEN-I patients often become 

symptomatic in childhood and at an earlier age 

than those with the sporadic form. Thus, if 

patients show severe peptic ulceration, kidney 

stones, watery diarrhea and malabsorption with a 

positive family history of endocrinopathy, MEN-I 

and nephrolithiasis, ZES should be strongly 

suspected. The diagnosis of ZES is made if the 

patient shows an elevated fasting serum gastrin 

level, gastric acid hypersecretion and either a positive 

secretin test or a histologically proven gastrinoma. 

36 Typically, patients have fasting serum 

gastin levels of > 100 pg/ml, even though adult 

patients usually show a level greater than 

500 pg/ml, a level greater than 1000 pg/ml is nearly 

diagnostic of the disease. The basal acid output 

Zollinger–Ellison syndrome 101 

(BAO) is generally more than 10 mEq/h. The 

secretin provocative test (2units/kg, intravenously) 

has a high diagnostic value; in adults, a rise in the 

serum gastrin level of 200 pg/ml above the fasting 

concentration is considered a positive diagnosis. 

Endoscopic findings are characterized by multiple 

peptic ulcers, most of which are localized in the 

duodenum, but the stomach and jejunum are 

involved less commonly. Recent developments of 

both radiological and nuclear medicine studies 

have increased the capability for identifying 

neoplastic lesions in the majority of patients with 

ZES. Recommended imaging procedures are 

computed tomography (CT), magnetic resonance 

imaging (MRI) and somatostatin receptor scintigraphy 

(octreoscan); more recently, endoscopic ultrasound 

has been proposed as the most sensitive 

imaging modality. 37 

‘PZES’ is usually used for two distinct entities: 

antral G-cell hyperplasia, described as an 

increased number of G cells, and antral G-cell 

hyperfunction, in which hypergastrinemia occurs 

in the absence of detectable G-cell hyperplasia. 38 

The clinical manifestation of PZES varies from 

vague features, such as non-specific abdominal 

pain, vertigo, anemia and occult bleeding, to 

severe gastrointestinal bleeding. The differentiation 

between ZES and PZES is based on the 

response to provocative tests. PZES is characterized 

by exaggerated serum gastrin release in 

response to a feeding test, and unchanged or even 

depressed serum gastrin values after injection of 

secretin. 

Lymphocytic gastritis 

Lymphocytic gastritis is characterized by an 

increase of intraepithelial lymphocytes in surface 

and foveolar epithelium, together with a variable 

amount of inflammation in the lamina propria of 

the gastric mucosa, which ranges from a predominantly 

lymphocytic pattern to a mixed chronic 

active pattern. The generally accepted criterion for 

the diagnosis of lymphocytic gastritis is the 

finding of 25 or more lymphocytes per 100 epithelial 

cells. 39 

Lymphocytic gastritis is thought to be a histologic 

response of the gastric mucosa to several antigens. 

The main interest comes from its association with

102 


Table 7.2 Conditions associated with lymphocytic gastritis 

Varioliform gastritis 

Celiac disease 

Helicobacter pylori infection 


Drug administration (ticlopidine) 

seemingly diverse groups of disorders (Table 7.2), 

among them celiac disease, where this type of 

gastritis is very prevalent (see below). 


Chronic varioliform gastritis is a rare disorder of 

unknown origin, commonly affecting middle-aged 

and elderly men. To date, few cases have been 

reported in the pediatric literature. In children, 

clinical signs arise insidiously, are often subacute 

or chronic and include epigastric pain, nausea 

and vomiting, anorexia, weight loss, anemia, 

protein-losing enteropathy and, in some cases, 

peripheral eosinophilia and increased serum IgE 

levels. 40 

The endoscopic features of chronic varioliform 

gastritis are enlarged and thickened rugal folds 

bearing erosions and widespread small nodules 

frequently surmounted by an umbilicated central 

crater or small rounded erosions (aphthoid 

nodules). According to the topography of the 

lesions, three forms can be distinguished: diffuse, 

when the whole stomach is involved; corporeal, 

when the lesions are limited to the fundus and 

proximal body of the stomach; and antral, when 

they are present only in the antrum. Histology 

shows a focal or diffuse infiltrate of intraepithelial 

lymphocytes in the surface and foveolar epithelium. 

Throughout the lamina propria an inflammatory 

infiltrate consisting of IgE plasma cells, 

lymphocytes, neutrophils and eosinophils is 

observed. 

The etiology of chronic varioliform gastritis is still 

unsettled. An immunological mechanism related 

to food antigens is suggested by raised serum IgE 

levels and increased numbers of IgE staining 

plasma cells. However, owing to a decreased incidence 

of the disorder and to the fact that the histological 

pattern is highly reminiscent of celiac 

gastritis (see below), it has been suggested that 

chronic varioliform gastritis is only a crude endoscopic 

expression of a disease that has the characteristic 

features of lymphocytic intraepithelial 

infiltration. The macroscopic appearance might 

appear only at some periods in the evolution of 

the disease. 


An association between lymphocytic gastritis and 

celiac disease has been reported in both adults and 

children. Lymphocytic gastritis is found in up to 

45% of adults with celiac disease, with a range of 

prevalence from less than 10% to 45%. Wolberg et 

al identified ten of 22 adult patients with lymphocytic 

gastritis characterized by marked infiltration 

of the surface and superficial pit epithelium by 

lymphocytes, primarily T cells, with sparing of the 

deep glandular epithelium both in the antrum and 

in the body. The lamina propria showed an infiltrate 

of plasma cells, lymphocytes and rare 

neutrophils. 41 Recently, it has been shown that the 

pattern of involvement of the gastric mucosa is 

predictive of duodenal villous atrophy. Patients 

with corpus-predominant lymphocytic gastritis are 

unlikely to have duodenal pathology, whereas 

those with an antrum-predominant or a diffuse 

pattern have a 50% chance of coexistent villous 

atrophy. 42 In a study of 60 children with chronic 

gastritis, De Giacomo et al found lymphocytic

gastritis in nine of 25 children with celiac disease, 

but in none of 35 children without gluten-sensitive 

enteropathy. Children with celiac gastritis showed 

an average of 40 lymphocytes per 100 epithelial 

cells, compared with an average of three to five in 

control subjects or patients with H. pylori-associated 

gastritis. Interestingly, at endoscopy, all children 

showed resolution of the lymphocytic infiltrate 

after strict adherence to a gluten-free diet. 43 

Recently, some authors have suggested that celiac 

lymphocytic gastritis may represent an abnormal 

immunological response to gliadin. It is now 

recognized that there is a spectrum of gluteninduced 

intestinal changes, ranging from the 

classic ‘celiac’ lesions of total and/or subtotal 

villous atrophy to more subtle manifestations, 

such as an abnormal density and subtype distribution 

of intraepithelial lymphocytes in the small 

intestinal mucosa. It is conceivable that lymphocytic 

gastritis, such as lymphocytic colitis, is 

another manifestation of a mucosal immune 

response to a luminal antigen, which is maximally 

expressed in the small intestine. 44 Thus, it is 

believed that the presence of lymphocytic gastritis 

in dyspeptic children may be used as an indication 

to perform a small-bowel biopsy to rule out covert 

celiac disease. 

Helicobacter pylori lymphocytic gastritis 

Some authors have suggested that lymphocytic 

gastritis may represent an idiosyncratic immune 

response to some local antigen, such as H. pylori, 

although the relationship is still not clear. It has 

been shown that many cases of lymphocytic gastritis 

are associated with H. pylori infection, and that 

the eradication brings about significant reduction 

in the gastric intraepithelial lymphocytic infiltration 

and dyspeptic symptoms. On the other hand, 

in adults and pediatric series, H. pylori has been 

detected in a minority of patients with lymphocytic 

gastritis, whereas the infection was more 

frequent in control biopsy specimens. 


Although Crohn’s disease (CD) most commonly 

affects the terminal ileum and/or the colon, 

involvement of the upper gastrointestinal tract is 

Crohn’s disease 103 

frequently found in both adults and children. 

Symptoms such as epigastric pain, early satiety, 

nausea, vomiting, weight loss and, less frequently, 

hematemesis and melena are commonly reported 

in these patients and have previously been related 

to reflex inhibition of foregut motility secondary to 

inflammation and partial obstruction of the distal 

small bowel. It has been shown that macroscopic 

and/or histological abnormalities are found in up 

to 70% of adults and 90% of children with CD. 45 

Endoscopic findings include patchy or streaky 

mucosal reddening, edema, single or multiple 

nodularities, a cobblestone appearance, rigidity of 

the antrum wall, narrowing of the lumen, aphthoid 

erosions and linear or serpiginous ulcers (Figure 

7.2). Histological diagnosis of gastric CD is best 

achieved by the detection of epithelioid granulomas 

and giant cells in biopsy specimens, although 

focal, non-specific gastritis containing a mixed 

inflammatory cell infiltrate is observed in a high 

percentage of patients. Endoscopic and/or histological 

gastric involvement in CD may be present 

in the absence of upper gastrointestinal symptoms 

and may precede diagnostic findings in the small 

and large bowel. The prevalence of granulomas in 

bioptic specimens of adult patients is highly variable, 

ranging from 7 to 83%, whereas in children it 

is up to 40%. 46 Table 7.3 lists the most common 

causes of granulomatous gastritis in children. In 

Figure 7.2 Small pre-pyloric ulcers (arrows) in a 14year-old 

girl with Crohn’s disease.

104 


Table 7.3 Causes of granulomatous gastritis 

in children 

Systemic disease 



Sarcoidosis 

Other vasculitides 

Infectious causes 

Tuberculosis 

Helicobacter pylori 

Histoplasmosis 

Syphilis 

Parasites 

Isolated 

Idiopathic 

Foreign substances 

recent years a characteristic pattern of inflammation, 

the so-called focal enhanced gastritis, has 

caused great interest, because of the observation 

that it is quite common and is certainly seen with 

greater frequency than granulomas in both adults 

and children. It is found more commonly in the 

antrum than in the body and is characterized by at 

least one foveola/gland or small groups of foveolae/glands 

surrounded by infiltrated inflammatory 

cells that consist mainly of lymphocytes, monocytes 

and occasionally neutrophils, resembling 

focal inflammation observed in the intestinal and 

colonic mucosa of patients with CD. 

In adults, two prospective studies have evaluated 

the prevalence of focal enhanced gastritis in 

patients with CD compared with a control population. 

Histological focally enhanced gastritis was 

observed in more than half of CD patients, suggesting 

that it could be a diagnostic marker of the 

disease. 47,48 However, in both studies no patients 

with ulcerative colitis were included. Subsequently, 

Parente et al found, in an adult population, 

focally enhanced gastritis in 43% of H. pylorinegative 

CD patients, 12% of ulcerative colitis 

(UC) patients and 19% of controls with no inflammatory 

bowel disease (IBD). The authors reported 

a specificity and positive predictive value of 

focally enhanced gastritis for CD of 84% and 71%, 

respectively. 49 These results have been confirmed 

in two pediatric studies. Sharif et al showed that 

focally enhanced gastritis was present in 65.1% of 

children with CD, 20.8% of children with UC and 

2.6% of children without IBD. 50 More recently, 

Kundhal et al found focally enhanced gastritis in 

52% of children with CD and 8% of patients with 

UC. 51 This suggested that, although this histological 

finding was highly suggestive of CD, it could 

not be seen as a specific diagnostic marker. 


Chronic granulomatous disease is a rare group of 

inherited disorders characterized by impaired 

phagocyte oxidative metabolism caused by 

missing components or subunits of the NADPH 

oxidative complex, resulting in defective intracellular 

killing of catalase-positive micro-organisms. 

The most common form of chronic granulomatous 

disease is inherited as an X-linked recessive trait, 

although autosomal-type mutations have been 

described. The disease usually appears during the 

first two years of life with symptoms and signs of 

recurrent pyogenic infections, although milder 

forms of the disease have been described, with 

onset occurring in adulthood. Characteristic granulomas 

may develop in any organ system, including 

the skin, lungs, genitourinary, bone and 

reticoloendothelial systems. Gastrointestinal involvement 

has commonly been described. 

Narrowing of the gastric antrum, with signs of 

gastric outlet obstruction, such as vomiting, 

weight loss and epigastric pain, is a rare but 

distinctive feature of chronic granulomatous 

disease. 52 Endoscopic features are usually not 

specific, whereas histology shows mild edema of 

the lamina propria, chronic inflammatory cells 

and granulomas characterized by phagocytes, 

giant cells and lipid-containing histiocytes. Upper 

gastrointestinal series reveal gastric rugae hypertrophy 

and narrowing of the antral lumen. Recent 

developments of nuclear medicine studies have 

increased the capability of evaluating thickness 

and inflammatory involvement of the gastric wall.


Eosinophilic gastritis is a component of 

eosinophilic gastroenteropathy, a rare disease 

characterized by prominent eosinophilic infiltration 

of the gastrointestinal tract. The cause is 

unknown and the mechanisms responsible for 

gastrointestinal infiltration by eosinophils remain 

poorly understood. Recently, it has been shown 

that the production of eotaxin, a protein with 73 

amino acid residues and a member of the chekines 

family, at the site of inflammation promotes 

recruitment and aggregation of eosinophils in the 

tissue by up-regulating integrins and enhancing 

eosinophilic adhesion to endothelial cells. Finally, 

it may contribute to tissue damage by stimulating 

the release of highly cytotoxic granular proteins. 53 

It has been suggested that food allergy might be a 

triggering factor in childhood. Associations 

between eosinophilic gastritis and parasitic infection 

of the stomach have been described. 

Any part of the gastrointestinal tract, from the 

esophagus to the rectum, can be affected, even 

though the stomach seems to be the most frequent 

site. 54 Eosinophilic infiltration may involve the 

mucosa, the muscularis propria and the serosa. On 

the basis of the predominant affected layer, the 

enteropathy has been classified into three different 

forms: mucosal, which produces clinical features 

of inflammatory diseases; submucosal, usually 

producing obstruction; and serosal, producing 

eosinophilic ascites. The clinical picture depends 

on the site and depth of the inflammatory involvement. 

Gastric involvement is commonly associated 

with abdominal pain, bloating, growth failure, 

weight loss, nausea and non-bilious vomiting 

secondary to gastric outlet obstruction. Gastric 

perforation has also been reported. Patients with 

associated small bowel involvement may develop 

protein-losing enteropathy, malabsorption and 

iron-deficiency anemia. In some patients, an 

elevated circulating eosinophilic count and raised 

serum IgE level can be found, although their clinical 

significance remains unclear. 

Endoscopy and biopsy are the main ways to establish 

the diagnosis. Endoscopic findings, when 

present, are non-specific and include erythema, 

antral nodular lesions, ulcers and, rarely, a 

narrowed lumen. In mucosal involvement, histology 

is diagnostic in more than 80% of patients, 

Eosinophilic gastritis 105 

revealing a striking eosinophilic infiltrate of the 

lamina propria and penetration of eosinophils into 

the epithelium. Although eosinophils may be a 

prominent inflammatory component in other types 

of gastritis, such as H. pylori gastritis and chemical 

gastropathy, the diagnosis can be made in almost 

all cases through multiple biopsies. Rarely, 

laparoscopy and full-thickness biopsies are needed 

to confirm the suspicions. 


Collagenous gastritis is an extremely rare disorder 

of unknown etiology, To date, fewer than ten cases 

have been reported in the literature. The condition 

is characterized by deposition of a subepithelial 

collagen band greater than 10 µm in thickness. The 

disorder was originally described by Colletti and 

Trainer in a 15-year-old girl with refractory H. 

pylori-negative chronic gastritis. 55 It has been 

reported either as an isolated entity or with 

synchronous collagenous colitis, collagenous 

duodenitis, lymphocytic colitis or celiac disease. 

Clinical features, such as epigastric pain, vomiting, 

anorexia, postprandial fullness and weight 

loss are reported. Endoscopic findings include 

diffuse nodularity, patchy or diffuse erythema, 

erosions and frank ulcers with hemorrhage. The 

diagnosis relies on mucosal histology, usually of 

the fundus and corpus, sharing discontinuous 

subepithelial collagen deposition with entrapped 

capillaries and fibroblasts, in association with 

mild glandular atrophy and mixed inflammatory 

infiltrate in the lamina propria, including lymphocytes, 

neutrophils, degranulating eosinophils and 

mast cells. 56 Depending on the extension of the 

inflammatory infiltrate, the corresponding surface 

epithelium may show an increased number of 

intraepithelial lymphocytes and degenerative 

changes. 

Three major pathogenic theories have been 

proposed for the increased subepithelial collagen 

deposition: inflammatory origin, abnormality of 

the pericryptal collagen sheath and autoimmune 

injury. It has been suggested that an initial stimulus 

caused by an infective agent, drug or food allergen 

may damage the mucosal surface and, in 

susceptible individuals, determine subepithelial 

collagen deposition irrespective of the course of

106 


gastritis in the rest of the mucosa. However, this 

theory remains to be demonstrated. 

Proton pump inhibitor gastritis 

Omeprazole, a proton pump inhibitor (PPI) is now 

widely used for severe erosive esophagitis in both 

adults and children. Long-term omeprazole treatment 

is associated with increased levels of serum 

gastrin (hypergastrinemia) and gastric mucosal 

change, including parietal cell hypertrophy, an 

increased number of antral G cells and an 

increased number of argyrophil cells. 

Pashankar and Israel found gastric nodules or 

polyps in seven of 31 children receiving omeprazole 

for more than 6 months. 57 At histology, 

nodules, ranging from 2 to 4 mm, showed only 

mucosal edema and disappeared spontaneously 

during treatment, whereas gastric polyps, of 

hyperplastic or fundic gland types, persisted 

during ongoing therapy. Two different pathogenetic 

mechanisms for polyp formation have 

been suggested: it has been proposed that glandular 

obstructions and dilatation may be caused by 

increased viscosity of gland secretion, because of 

decreased gastric acid and fluid output; it has also 

been speculated that hypertrophy of parietal cells, 

induced by omeprazole therapy, may increase 

outflow resistance and induce dilatation of the 

gland. 

This gastropathy seems to be benign, but a careful 

endoscopic follow-up is suggested in children 

receiving long-term omeprazole therapy. 


Pernicious anemia is an autoimmune disorder 

caused by production of autoantibodies against the 

parietal cell antigen, H + /K + -ATPase, and against 

the parietal cell secretory product, intrinsic factor, 

resulting in the loss of parietal cells in the fundus 

and body of the stomach. The loss of these cells is 

associated with achlorhydria, vitamin B12 deficiency 

and megaloblastic anemia. 58 

Macroscopically, it is characterized by loss of 

mucosal folds and thinning of the gastric mucosa. 

Histology shows a marked infiltration into the 

submucosa by mononuclear cells, including 

autoantibody-containing plasma cells, T and B 

cells, which can extend into the lamina propria 

between the glands. Cellular infiltration of the 

mucosa is accompanied by degenerative change in 

parietal cells. In the fully established lesion, as 

mentioned, there is a marked reduction in number 

of gastric glands and the parietal cells are replaced 

by mucus-containing cells. Recently, studies in 

murine models of autoimmune gastritis have 

suggested that macrophages and CD4 + T cells 

might play a role in the pathogenesis of the disease 

and that the interaction between the Fas antigen on 

the target cells and its ligand on the effector cells 

might be responsible for target cell destruction. 59 

In children the ‘adult form’ of pernicious anemia 

has been reported in association with other 

autoimmune diseases, such as thyroiditis and 

diabetes mellitus, and with precancerous and 

malignant lesions. In childhood, pernicious 

anemia has been attributed to dietary lack of cobalamin, 

to absence of cobalamin in the ileum or to 

so-called juvenile pernicious anemia. The last is 

characterized by absent or very low levels of 

intrinsic factor in the gastric juice, in the absence 

of achlorhydria and the absence of intrinsic factor 

or H + /K + -ATPase autoantibodies. 58 It has been 

suggested that this defect could be due to abnormal 

synthesis and biological elaboration in the 

gastric lumen of intrinsic factor. 

Gastritis associated with other 

autoimmune disease 

Gastritis with or without atrophy has been 

described in association with several autoimmune 

diseases, such as connective tissue disorders, 

autoimmune thyroiditis and vitiligo. Histological 

gastritis has been reported in 25 of 27 diabetic 

children undergoing gastroscopy for upper 

gastrointestinal symptoms; only half of them had 

evidence of macroscopic involvement of the 

gastric mucosa, including erosion and ulcers. 60 A 

teenage girl with scleroderma and atrophic gastritis 

has been reported. 3 


Acute graft-versus-host disease (GVHD) begins 3 or 

4 weeks after transplantation with mucositis,

dermatitis, enteritis and hepatic dysfunction. 

Upper non-specific gastrointestinal symptoms, 

such as nausea, vomiting, bloating and food intolerance, 

occur in a large proportion of patients, 

even in the absence of lower gastrointestinal 

symptoms. 61 These symptoms seem to be more 

frequent than those arising from lower involvement 

and are thought to represent an early manifestation 

of GVHD. Endoscopic findings vary 

considerably, ranging from normal-appearing 

mucosa to exensive mucosal sloughing. 

Histological findings are diagnostic, including 

gastric epithelial cell apoptosis and a marked 

lymphocytic infiltrate in the lamina propria. 

Upper gastrointestinal GVHD appears to be highly 

responsive to immunosuppressive therapy. 

Clinical assessment 

Symptoms of gastritis and gastropathy are usually 

not specific. The most common presenting clinical 

features are upper gastrointestinal bleeding and 

abdominal pain, which can also characterize other 

clinical conditions (Table 7.4). In very young children, 

abdominal pain is usually poorly localized 

and in some cases may manifest as feeding refusal 

or irritability, whereas in older children and 

adolescents, the site of pain is more often defined 

and a mealtime relationship may be present. 

Rarely, acute abdominal pain, resulting from ulcer 

perforation, may dominate the clinical presentation. 

Gastric blood losses can be revealed by 

chronic signs such as iron deficiency anemia or, 

alternatively, by acute hemorrhage, with hematemesis 

and/or melena. Severe bleeding and perforation 

may occur, resulting in a high mortality rate. 

Diagnosis 

Both single- and double-contrast barium studies 

show poor sensitivity in documenting gastritis and 

gastropathy, although in some conditions they may 

be helpful. Double-contrast studies of the upper 

gastrointestinal tract can reveal an irregular 

mucosal profile, nodularity, ulceration, lumen 

narrowing or mass effect in almost 50% of children 

with Crohn’s disease. 62 A double-contrast upper 

gastrointestinal tract series in varioliform gastritis 

revealed multiple, well-defined, circular filling 

Clinical assessment 107 

defects, 3–10 mm in diameter, with central punctate 

flecks of barium reflecting central superficial 

ulceration, usually located on antral and/or gastric 

body hypertrophied rugae. 40 In patients with 

Ménétrier’s disease, upper gastrointestinal series 

identified the characteristic gastric ruga hypertrophy, 

localized predominantly in the fundus and 

proximal corpus. However, in the evaluation of 

children with suspected organic abdominal pain, a 

radiology study of the upper gastrointestinal tract 

is performed to exclude anatomic abnormalities 

such as malrotation, duodenal bands or antral 

web. 

Upper gastrointestinal endoscopy represents the 

first-line procedure for investigating gastric 

mucosal pathology. Endoscopic features have been 

previously discussed in each section. Although 

upper gastrointestinal endoscopy is the most reliable 

method for identifying the bleeding source, 

defining the lesions and localizing the anatomic 

site of mucosal damage, the ability to make a definitive 

diagnosis based on endoscopic appearance 

alone is limited, because of a poor correlation 

between endoscopic abnormalities and histological 

findings. The diagnosis and definition of gastritis 

and gastropathy are primarily established by 

histology. A sampling strategy dealing with 

number and size of specimens taken during 

endoscopy is recommended. Biopsy specimens 

should be taken from both endoscopically visible 

lesions and normal-appearing sites, adjacent to the 

lesions. Ideally, at least two specimens from each 

site should be taken. Visualization and knowledge 

of endoscopic and histological findings of other 

sites of the gastrointestinal tract (esophagus, 

duodenum and colon) can be helpful for a correct 

assessment of the gastric mucosa. 

Treatment 

Stress-associated gastric ulcer 

Controlled data on management and outcome of 

acute upper gastrointestinal bleeding in children 

are lacking. Generally, therapy should start by 

replacing the depleted blood volume with human 

albumin, saline or Ringer’s lactate. If patients have 

massive bleeding, blood transfusion should be 

started within a few hours. The use of a nasogastric 

tube to decompress the stomach, remove

108 


Table 7.4 Differential diagnosis of gastritis and gastropathy 

Upper abdominal pain 

Esophagitis 

Non-ulcer dyspepsia 

Cholelithiasis 

Cholecystitis 

Pyelonephritis 

Urolithiasis 

Ureteropelvic junction stricture 

Spinal cord lesion 

Colitis involving transverse colon 

Pancreatitis 

Gastrointestinal bleeding 

Non-gastrointestinal sources 

nasopharynx 

chest 

maternal blood 

Munchausen’s syndrome by proxy 

Gastrointestinal sources 

esophagitis 

Mallory–Weiss tear 

erosions/ulcerations 

hematobilia 

duodenitis 

structural lesions 

ectopic pancreas 

duplication 

polyp 

duplication cyst 

pancreatitis 

Vascular causes 

hemangioma (Klippel–Trenaunay–Weber syndrome, blue rubber bleb nevus 

syndrome) 

arteriovenous malformation 

connective tissue disorders 

bleeding diathesis 

gastric secretions and stop the bleeding with saline 

lavage is routinely recommended, although the 

efficacy of the gastric lavage has not been 

confirmed. PPIs have been shown to be effective in 

the treatment of active bleeding from gastric and 

duodenal ulcers in adults, and they are widely 

used in children as well, although scarce data are 

available. While in adults therapeutic endoscopy 

is effective in reducing further bleeding and lowering 

mortality, its efficacy in children has not been

formally addressed. However, it is conceivable that 

endoscopic treatment by an experienced endoscopist 

might be effective in the treatment of 

highly selected children with active gastrointestinal 

bleeding. Surgery should be performed when 

medical treatment has not stopped the bleeding. 

(See also Chapter 36). 

The use of prophylactic treatment remains controversial. 

Although in adults the results of a recently 

published meta-analysis indicated a decreased 

frequency of stress-associated gastrointestinal 

bleeding with prophylaxis using the H2-receptor 

antagonist, the prophylactic use of cimetidine in a 

pediatric intensive care unit has not been shown to 

be effective in preventing gastrointestinal bleeding 

episodes. 63,64 However, prophylactic treatment 

with PPIs or sucralfate can be suggested in patients 

with severe life-threatening illness. 

Other gastritis or gastropathy 

Two major issues confront clinicians using 

NSAIDs: prevention of induced ulcers, especially 

in high-risk groups, and their treatment. In adults, 

patients at high risk for gastrointestinal hemorrhage 

and perforation from aspirin and NSAIDs 

should be considered for prophylactic treatment. 

65,66 Risk factors include a history of gastrointestinal 

complications, age > 60 years, high dosage, 

concurrent use of corticosteroids and concurrent 

use of an anticoagulant. Several randomized 

controlled trials have shown that concomitant use 

of the PGE1 analog misoprostol is effective in 

preventing NSAID-related gastropathy. In a retrospective 

study, the use of misoprostol during 

NSAID therapy resolved symptoms in 82% of 

arthritic children with gastrointestinal complaints, 

while 18% had recurrence of symptoms after initial 

improvement. 67 However, no controlled trials are 

available in childhood and the concerns raised 

about its use do not support widespread prophylactic 

treatment at this time. PPIs are certainly a 

good alternative for prevention of NSAID-related 

complications. It has been shown in three large 

randomized controlled trials in adults that omeprazole 

significantly reduced the total number of 

NSAID-related ulcers when compared with placebo 

and ranitidine, and was also more effective than 

misoprostol in preventing duodenal ulcers and 

equally so in reducing gastric ulcers. 66 

Treatment 109 

NSAID-related ulcers may be treated effectively 

with any approved therapy for peptic ulcer 

disease. In patients who develop severe dyspeptic 

symptoms during NSAID use it is preferable to 

discontinue the therapy. A PPI is the drug of 

choice for a large ulcer or if NSAIDs must be 

continued. Despite the fact that several epidemiological 

studies have shown little interaction 

between H. pylori and NSAIDs in the development 

of ulcer disease, it has been shown that eradication 

of H. pylori before NSAID therapy can reduce the 

incidence of peptic disease, suggesting that the 

organism should be eradicated in any infected 

patients before they start NSAIDs. 66 

A new class of agents, the so-called selective COX- 

2 inhibitors, are thought to be associated with 

greater short-term and long-term gastrointestinal 

safety compared to regular NSAIDs (non-selective 

COX inhibitors). 17 These newly introduced drugs, 

by sparing the COX-1 enzyme and its physiological 

function, reduce PG-dependent inflammation 

while leaving protective gastric mucosal PG 

synthesis intact. Although in adulthood initial 

studies have shown that they are associated with 

fewer ulcer complications compared to nonselective 

NSAIDs and they have already been 

approved for arthritis treatment, prospective 

clinical data are still needed to establish the shortand 

long-term safety profiles in childhood. 

In patients with Ménétrier’s disease, treatment is 

generally supportive, with the majority of patients 

(about 90%) responding to a high-protein diet, 

diuretic drugs, intravenous albumin transfusion, 

and salt and fluid restriction. 25–27 Some patients 

can require an 8-week course of antisecretory 

agents (H2-receptor antagonist or PPIs). In rare 

cases, parenteral nutrition, due to enteral feeding 

intolerance, or gastric resection for controlling 

protracted hemorrhage, is necessary. 

In ZES, although the occurrence of peptic acid 

disease can be significantly reduced with an 

adequate control of gastric acid secretion, through 

appropriate doses of PPIs, surgical resection of a 

neoplastic lesion is recommended for any patient. 

In patients with PZES, antrectomy was usually 

suggested before the advent of antisecretory drugs. 

Currently, however, the treatment of choice has 

become the long-term maintenance of acid 

suppression by PPIs. 35

110 


Crohn’s disease gastritis usually responds to 

systemic anti-inflammatory therapies, even 

though PPIs are effective for symptomatic relief. 

Gastric-outlet obstruction in chronic granulomatous 

disease has been successfully managed with 

prolonged antimicrobial therapy, corticosteroids 

and immunosuppressive drugs, such as 

cyclosporin. 68 In eosinophilic gastritis, although 

an elemental amino acid-based diet occasionally 

appears helpful, corticosteroids remain the main- 

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cytomegalovirus infection in a child with Ménétrier’s 


27. Kelly DG, Miller LJ, Malagelada J-R et al. Giant hypertrophic 

gastropathy (Ménétrier’s disease): pharmacologic 

effects on protein leakage and mucosal ultrastructure. 


28. Bayerdörffer E, Ritter MM, Hatz R et al. Healing of 

protein losing hypertrophic gastropathy by eradication 

of Helicobacter pylori – Is Helicobacter pylori a pathogenic 

factor in Ménétrier’s disease. Gut 1994; 35: 

701–704. 

29. Sferra TJ, Pawel BR, Qualman SJ et al. Ménétrier’s 

disease of childhood: role of cytomegalovirus and

trasforming growth factor alpha. J Pediatr 1996; 128: 

213–219. 

30. Bechi P, Amorosi A, Mazzanti R et al. Reflux-related 

gastric mucosal injury is associated with increased 

mucosal histamine content in human. Gastroenterology 

1993; 104: 1057–1063. 

31. Dixon MF, O’Connor HJ, Axon ATR et al. Reflux gastritis: 

distinct histopathological entity? J Clin Pathol 1990; 

39: 524–530. 

32. Dixon MF, Mapstone NP, Neville PM et al. Bile reflux 

gastritis and intestinal metaplasia at the cardia. Gut 

2002; 51: 351–355. 

33. Hyams JS, Treem WR. Portal hypertensive gastropathy 

in children. J Pediatr Gastroenterol Nutr 1993; 17: 

13–18. 

34. Yachha SK, Ghoshal UC, Gupta R et al. Portal hypertensive 

gastropathy in children with extrahepatic portal 

venous obstruction: role of variceal obliteration by 

endoscopic sclerotherapy and Helicobacter pylori infection. 


35. Pisegna JR. The effect of Zollinger-Ellison syndrome 

and neuropeptide-secreting tumors on the stomach. 

Curr Gastroenterol Rep 1999; 1: 511–517. 

36. Hirschowitz BI. Zollinger–Ellison syndrome: pathogenesis, 

diagnosis and management. Am J Gastroenterol 

1997; 92 (S): 44S–48S. 

37. Modlin IM, Tang LH. Approaches to the diagnosis of gut 

neuroendocrine tumors: the last word (today). 


38. Annibale B, Bonamico M, Rindi G et al. Antral gastric 

cell hyperfunction in children: a functional and 

immunocytochemical report. Gastroenterology 1991; 

101: 1547–1551. 

39. Haot J, Hamichi L, Wallez L et al. Lymphocytic gastritis: 

a newly described entity: a retrospective/endoscopic 

and histological study. Gut 1988; 29: 1258–1264. 

40. Couper R, Laski B, Drumm B et al. Chronic varioliform 

gastritis in childhood. J Pediatr 1989; 115: 441–444. 

41. Wolberg R, Owen D, DelBuono L et al. Lymphocytic 

gastritis in patients with celiac sprue or spruelike 

intestinal disease. Gastroenterology 1990; 98: 310–315. 

42. Hayat M, Arora DS, Wyatt JI et al. The pattern of 

involvement of the gastric mucosa in lymphocytic 

gastritis is predictive of the presence of duodenal 

pathology. J Clin Pathol 1999; 52: 815–819. 

43. De Giacomo C, Gianatti A, Negrini R et al. Lymphocytic 

gastritis: a positive relationship with celiac disease. J 

Pediatr 1994; 124: 57–62. 

44. Verkarre V, Asnafi V, Lecomte T et al. Refractory coeliac 

sprue is a diffuse gastrointestinal disease. Gut 2002; 52: 

205–211. 

45. Schmidt-Sommerfeld, Kirschner B, Stephens J. 

Endoscopic and histologic findings in the upper 

gastrointestinal tract of children with Crohn’s disease. J 


46. Tobin JM, Sinha B, Ramani P et al. Upper gastrointestinal 

mucosal disease in pediatric Crohn disease and 

ulcerative colitis: a blinded, controlled study. J Pediatr 


47. Oberhuber G, Puspok A, Oesterreicher C et al. Focally 

enhanced gastritis: a frequent type of gastritis in 

patients with Crohn’s disease. Gastroenterology 1997; 

112: 698–706. 

48. Meining A, Bayerdorffer E, Bastlein E et al. Focally 

inflammatory infiltrations in the gastric biopsy specimens 

are suggestive of Crohn’s disease. Scand J 


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49. Parente F, Cucino C, Bollani S et al. Focal gastric inflammatory 

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immunohistochemical characteristics, and diagnostic 

role. Am J Gastroenterol 2000; 95: 705–711. 

50. Sharif F, McDermott M, Path MRC et al. Focally 

enhanced gastritis in children with Crohn’s disease and 

ulcerative colitis. Am J Gastroenterol 2002; 97: 

1415–1420. 

51. Kundhal PS, Stormon MO, Zachos M et al. Gastral 

antral biopsy in the differentiation of pediatric colitides. 


52. Dikerman JD, Colletti RB, Tampas JP et al. Gastric outlet 

obstruction in chronic granulomatous disease of childhood. 

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54. Kelly KJ. Eosinophilic gastroenteritis. J Pediatr 

Gastroenterol Nutr 2000; 30: S28–S35. 

55. Colletti RB, Trainer TD. Collagenous gastritis. 


56. Pulimood AB, Ramakrishna BS, Mathan MM. 

Collagenous gastritis and collagenous colitis: a report 

with sequential histological and ultrastructural findings. 

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57. Pashankar DS, Israel DM. Gastric polyps and nodules in 

children receiving long-term omeprazole therapy. J 


58. Toh BH, van Driel IR, Gleeson PA. Pernicious anemia. N 

Engl J Med 1997; 337: 1441–1448. 

59. Nishio A, Katakai T, Oshima C et al. A possible involvement 

of Fas–Fas ligand signaling in the pathogenesis of 

murine autoimmune gastritis. Gastroenterology 1996; 

111: 959–967. 

60. Burghen GA, Murrell LR, Whitington GL et al. Acid 

peptic disease in children with type I diabetes mellitus: 

a complicating relationship. 1992; 146: 718–722. 

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evaluation of upper gastrointestinal mucosal lesions in 

children with ulcerative colitis and Crohn’s disease. J 


63. Cook DJ, Reeve BK, Guyatt GH et al. Stress ulcer 

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64. Lacroix J, Nadeau D, Laberge S et al. Frequency of upper 

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2037–2046. 

67. Gazarian M, Berkovitch M, Koren G et al. Experience 

with misoprostol therapy for NSAID gastropathy in children. 

Ann Rheum Dis 1995; 45: 277–280. 

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intractable gastrointestinal manifestations of chronic 

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69. Neustrom MR, Friesen C. Treatment of eosinophilic 

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1999; 104: 506.

8 

Introduction 

HIV and the intestine 


It was estimated that at the end of 2002 there were 

42 million people worldwide with HIV-1 infection, 

over 29 million of whom were living in sub- 

Saharan Africa. Despite some encouraging signs 

that the rate of new infections is stabilizing, there 

are still about 3 million children under 15 years of 

age living with HIV. As a case in point, approximately 

68000 children with HIV infection were 

born in South Africa in 2002, and AIDS-related 

complications now account for 60–80% of pediatric 

admissions there and 70% of hospital deaths. 

Gastrointestinal disease, mainly diarrhea, accounts 

for about a third of these admissions. 

Pathophysiology: transmission and 

progression of HIV disease 

The gut, more than any other organ in the body, 

plays a critical role in the vertical transmission 

and progression of HIV infection. This reflects not 

only its nutritional function but also its central 

activity in immune programming and regulation. 

More than half the body’s total lymphoid tissue is 

found in the bowel; as HIV infects lymphocytes 

with CD4 or other co-receptors, this makes the 

bowel an ideal target for primary infection and a 

site for viral replication and seeding. 

Intestinal lymphoid tissue is organized into 

distinct structures including the tonsils, Peyer’s 

patches (mainly in the ileum) and mesenteric 

lymph nodes, and is also diffusely spread 

throughout the mucosal epithelium and lamina 

propria. Activation of both the organized and 

diffuse elements of the gut immune system 

depends on presentation of antigens to T and B 

lymphocytes lying beneath the epithelium. M 

cells are specialized epithelium found in the follicle-associated 

epithelium (FAE) that overlies 

Peyer’s patches in the small intestine and 

lymphoid follicles in the rectum, and are also 

found in rich supply in the tonsils. These are 

capable of transporting macromolecules and 

micro-organisms, including viruses such as polio, 

to macrophages or possibly dendritic cells in the 

lamina propria. These latter cells are the professional 

antigen-presenting cells that facilitate 

presentation of antigens to activated and possibly 

non-activated T cells. However, intestinal epithelium 

itself can also generate antigen-specific 

responses and may be able to function as antigenpresenting 

cells. Complementing these responses 

are intraepithelial lymphocytes, interspersed 

throughout the mucosa, that produce cytokines 

which support humoral and cell-mediated 

responses. Finally, the lamina propria throughout 

the gut contains the bulk of the immune effector 

cells including T and B lymphocytes, plasma 

cells, macrophages, mast cells and some 

eosinophils and neutrophils. 

Primary infection with ingested HIV depends on 

the virus gaining access to the lamina propria, 

where, in early infection, it replicates primarily 

in lymphocytes. 1,2 The exact mechanism for entry 

to the lamina propria is not fully understood, but 

may be through a variety of routes, and is likely 

to be a complex process modified by viral characteristics, 

gut mucosal receptors and the factors 

that promote or impede the interaction. 

Direct passage through disruptions in mucosa or 

between immature mucosal junctions is possible. 

However, longitudinal gut permeability studies in 

children born to HIV-infected mothers do not 

support this mechanism. 3 Rather, increased 

permeability, without clinical symptoms, may be 

present soon after children become infected. 

113

114 


Recent work shows that gut mucosa does not 

express the familiar CD4 binding sites that the 

HIV-1 gp120 protein commonly uses for attaching 

to and thereby infecting mononuclear cells. 4 

Rather, early infection is dependent on HIV strains 

binding to alternative sites, namely the primary 

receptor galactosyl ceramide (GalCer) and the 

CCR5 co-receptor, which are expressed on upper 

gastrointestinal epithelium. 5 This is supported by 

the observation that HIV-1 isolates from acutely 

infected persons are predominantly R5 viruses, i.e. 

macrophage-tropic HIV that require CCR5 for cell 

entry (in contrast to R4 viruses, which are lymphocyte-tropic 

requiring the CXCR4 chemokine coreceptor). 

6 Once attached, the virus is probably 

translocated across the epithelial cell and 

presented to T lymphocytes that express the same 

CCR5 co-receptor. The lamina propria now 

becomes a potent site for viral replication. M cells, 

in mouse and rabbit ex vivo systems, can transport 

HIV-1 to mononuclear cells, but human M cells 

have not been shown to take up and transport HIV 

in the same way. 7 

The gut has a number of defense mechanisms 

against primary infection apart from maternal 

factors. The rapid passage of ingested amniotic 

fluid or maternal blood limits contact time with M 

cells expressed on the surface of the tonsils. 

Gastric acid would normally inhibit HIV in the 

stomach, but this is reduced in neonates and 

young infants. Mucin produced by goblet cells and 

the rapid turnover of the intestinal mucosa provide 

additional mechanical barriers to HIV attachment. 

However, mother-to-child transmission of HIV 

through breast feeding depends on a number of 

risk factors other than the susceptibility of the gut 

to HIV. Increased viral load in breast milk is correlated 

with high plasma viral load and decreased 

CD4 count in the mother, and is associated with 

higher transmission. 8–10 These conditions are 

found in the early stages of new infection or in 

advanced disease. It is not clear, however, whether 

it is cell-associated or cell-free virus that is more 

important for transmission. Other breast-milk 

factors such as HIV-1-specific IgG and secretory 

leukocyte protease inhibitor (SLPI) have HIV-1 

inhibitory activity in vitro. 11 SLPI acts on the target 

cell rather than the virus and inhibits internalization 

of HIV-1 rather than initial binding. 12 

Infant feeding practices may significantly influence 

the way in which these non-intestinal factors 

interact: exclusive breast feeding results in a 

greater volume of milk being ingested and hence 

increases the HIV load presented to the infant gut. 

However, it also increases the protective breastmilk 

factors reaching the infant and that promote 

the development and maintain the integrity of the 

mucosa and which may have direct anti-HIV 

effects. 13 Exclusive breast feeding is associated 

with fewer breast health problems, e.g. clinical 

and subclinical mastitis that are associated with 

increased breast-milk viral load. 14 Infant feeding 

practices also contribute to the establishment of 

different enteric microflora that might significantly 

affect the priming or responses of intestinal 

lymphoid cells or dendritic cell. 15–17 This could, 

theoretically, modify adherence or facilitate infection 

of HIV, although this interesting concept has 

not been explored to date. Innate responses such 

as lactoferrin and lysozymes that are secreted by 

exocrine glands onto mucosal surfaces are bactericidal, 

but their protective capacity in HIV is 

unknown. There is also renewed interest around 

secretory IgA and IgM that can inhibit transcytosis 

of HIV-1 across enterocytes in in vitro models. 18,19 

Passive immunization of macaque monkeys with 

monoclonal antibodies against the HIV-1 gp120 

protein, given either orally or applied locally, 

protected against mucosal challenges with HIV- 

1. 20 This raises the possibility of a vaccine strategy, 

similar to that used against hepatitis B, of combining 

active and passive immunization to induce 

effective mucosal protection against HIV-1. 

Once HIV infection is established the gut serves as 

a major reservoir for viral amplification. CD4 

lymphocytes in the lamina propria are infected 

and progressively depleted; 21 this precedes the 

eventual decrease in CD4 counts in the peripheral 

circulation and other sites. 22,23 IgA-secreting 

plasma cells, especially the IgA2 subclass, are lost 

early in disease, resulting in reduced secretory 

IgA, thereby predisposing the gut to infection with 

enteric pathogens. 24–27 Responses to oral vaccines 

may also be impaired, raising concern about the 

effectiveness of putative rotavirus vaccines in 

areas of high HIV seroprevalence. 28 Local cytokine 

responses have been extensively reported, 

although it is still not entirely clear whether they 

influence the development of AIDS or HIV

enteropathy or are simply the consequence of the 

latter. 29,30 These responses may be the consequence 

of opportunistic infections or the direct 

effect of HIV on the mucosa. 

Diarrhea 

Persistent and recurrent diarrheas are amongst the 

most frequent manifestations of HIV/AIDS in both 

children and adults, especially in developing 

countries, where diarrhea is associated with 

growth failure, weight loss and death. In Zaire, 

85% of adults admitted with persistent diarrhea 

had HIV infection. 31 Among children presenting to 

a primary health care facility in South Africa, a 

history of persistent diarrhea in the preceding 3 

months strongly predicted HIV infection (odds 

ratio 4.8; CI 2.5–9.3 and positive predictive value 

of 63%). In South Africa, the profile of children 

admitted with diarrheal diseases has changed, 

with increasing prevalence of persistent diarrhea 

and loss of seasonal peaks of acute diarrhea. HIVinfected 

children admitted to hospital with diarrhea 

have more severe symptoms than children 

uninfected by HIV; 32 they frequently have severe 

co-infections such as pneumonia, pseudomonal 

skin sepsis and tuberculosis (TB). These result in 

longer periods of admission and case fatality rates 

in the order of 27%. In Zaire, children with HIV 

and persistent diarrhea had an 11-fold increased 

risk of death compared with uninfected controls. 

Hence, in developing countries, HIV-related diarrheal 

diseases represent a major burden on both 

caregivers and health resources. The availability of 

antiretroviral drugs in North America and Europe 

has dramatically altered the natural history of HIV 

infection and has reduced the incidence of 

gastrointestinal disease due to opportunistic infections. 

33,34 This has shifted much of the scientific 

interest and research funding to other complications 

such as lipodystrophy. 

Although there is considerable knowledge of the 

pathophysiology and management of diarrhea in 

adults with AIDS, less is known about this 

problem in children. Opportunistic infections and 

fat malabsorption are common causes of prolonged 

and recurrent diarrhea in infected adults. 35,36 

Among children with HIV, carbohydrate intolerance 

is common and may follow acute infections 

Diarrhea 115 

with rotavirus or other common enteropathogens. 

37–39 In resource-poor settings, the 

optimal management of HIV-related diarrhea 

remains largely unexamined. Even after 25 years of 

the epidemic, fewer than 40% of countries with a 

high HIV seroprevalence have published national 

recommendations for the management of HIVassociated 

diarrhea. 40 

Mucosal structure and function in HIV-related 

diarrhea 

A number of intestinal mucosal structural and 

functional abnormalities have been described in 

HIV-infected children with diarrhea. Their pathogenesis 

is multifactorial and includes the direct 

effect of pathogens, other inflammatory processes, 

malnutrition and the direct effect of HIV itself. 

Variable degrees of villous atrophy, crypt hyperplasia 

and increased inflammatory cells in the 

lamina propria are found in the small intestine of 

children with diarrhea (Figure 8.1), although these 

can be present without symptoms, and are often 

diffusely spread throughout the upper duodenum 

and jejunum. 41,42 Even when the mucosa appears 

normal on conventional histology, short and irregular 

microvilli may be evident on electron 

microscopy and tubuloreticular inclusions may be 

seen in endothelial cells. 43 In the large bowel, loss 

Figure 8.1 Villous blunting with crypt hyperplasia and 

increased inflammatory cells in the lamina propria are 

evident in this small-intestinal biopsy of an HIV-infected 

child.

116 


of mucin-producing cells is accompanied by an 

increase in inflammatory cells, especially mast 

cells; crypt abscesses and apoptosis are also 

detected. Although up to 75% of adult HIV-related 

diarrhea has been attributed to enteric pathogens, 

causal agents have not been demonstrated with the 

same frequency in children. 44 This may be 

explained by the difficulty of obtaining appropriate 

specimens from small children or identifying 

pathogens such as microsporidia; in addition, 

alternative pathways of diarrhea may be involved, 

as seen in other causes of severe malnutrition. 

Carbohydrate malabsorption is commonly found 

in HIV-infected children with persistent diarrhea. 

37 This may be the consequence of preceding 

enteric infection but in most cases the precipitant 

is unknown. Intestinal biopsies in these children 

do not always demonstrate villous atrophy. 45,46 An 

abnormal breath H2 analysis in the presence of 

relatively normal mucosal architecture suggests a 

non-specific brush-border disorder rather than a 

specific enzyme deficiency. 37,46 Gut permeability, 

measured by the dual sugar absorption test, is 

increased, especially in patients with more 

advanced disease; 41 however, this may also be 

increased in asymptomatic patients and early in 

disease. 3,47 Furthermore, lactose malabsorption is 

not always associated with clinical symptoms 

such as diarrhea or growth failure. 48 Monosaccharide 

intolerance has been described in 

African children with HIV and severe diarrhea, 

and has an 87% positive predictive value for identifying 

HIV infection in children presenting with 

diarrhea. 49 It is associated with prolonged recovery, 

probably due to delayed regeneration of enterocytes 

and return of absorptive capacity. In 

adults, monosaccharide intolerance is associated 

with accelerated small bowel transit times, especially 

in protozoal infections such as cryptosporidiosis, 

50 but this is unlikely to be the sole 

explanation. Although monosaccharide intolerance 

does occur in HIV-uninfected children with 

severe malnutrition, in settings where HIV is 

highly prevalent, it can be useful as an indication 

for HIV testing. 

Other macronutrients and micronutrients may not 

be adequately absorbed or there may be increased 

losses in stools. Bile salt and fat malabsorption are 

associated with low-grade enteropathies in adult 

patients with AIDS, 51 but are not consistent find- 

ings in HIV-infected children. 39,52 Protein maldigestion 

and malabsorption are seen in children with 

severe carbohydrate malabsorption and indicate a 

profound disruption of normal gastrointestinal 

function and absorptive capacity. Enteric 

cytomegalovirus or bacterial infections, and occasionally 

intestinal Kaposi’s sarcoma, may present in 

adults as a protein-losing enteropathy. 53,54 In children, 

protein-losing enteropathy, suggested by 

increased fecal α1-antitrypsin, has also been 

reported, but specific enteric pathogens were not 

identified. 39 Iron malabsorption has been reported 

in children with symptomatic HIV with decreased 

D-xylose absorption, suggesting a general loss of 

absorptive capacity rather than a specific iron transport 

defect. 55 Vitamin A is absorbed even in the 

presence of severe diarrhea; 56 health-care personnel 

should aim, therefore, to provide vitamin A supplements, 

according to the WHO/UNICEF Integrated 

Management of Childhood Illnesses protocol, to all 

children presenting with persistent diarrhea at 

primary health-care facilities. 57 

Host responses and susceptibility 

The relationship between the risk and type of 

enteric infection and HIV-viral activity, or host 

immune competence as measured by CD4 counts, 

has been established in HIV-infected adults in 

developed countries, and to a limited extent in 

developing countries. The rapid and pronounced 

loss of CD4 T-helper cells in gut mucosa that 

precedes losses in the peripheral blood might 

explain the loss of local defenses to opportunistic 

infections. In Uganda, HIV-infected adults with 

lower CD4 counts were at greater risk of non-typhi 

salmonellae septicema and other opportunistic 

infections 58 (Figure 8.2). 

Children with reduced CD4 counts have more 

severe diarrhea, i.e. higher fluid losses and more 

prolonged disease; this is often due to cryptosporidiosis. 

45,59 Local gut immunity may also play 

an important role in both local susceptibility and 

disease progression. Total IgA in stool is decreased 

in symptomatic children with severe diarrhea; 

elevated serum IgA, which may be due to selective 

increase of the IgA1 subclass, is related to decreased 

CD4 counts. 26,60 These changes occur early in pediatric 

HIV infection and reflect the disturbance of the 

gut mucosal immune system.

HIV enteropathy 

Cases/1000 person-years 

120 

100 

80 

60 

40 

20 

0 

< 200 200–500 > 500 

CD4 + count 

HIV enteropathy is typified by weight loss, diarrhea 

and characteristic endoscopic and pathological 

appearances without any identifiable enteric 

pathogens. 61 These include reduced villous height, 

increased crypt length, focal enterocyte vacuolization, 

and hyporegeneration and dysmaturation of 

intestinal cells. 62,63 Several hypotheses have been 

proposed to explain these findings, including a 

mucosal immune reaction to HIV-infected cells 64 

or to signals from regulatory T cells, the effect of 

bacterial overgrowth or bile salt malabsorption, 

65,66 unidentified enteric pathogens, or direct 

small-intestinal damage by HIV itself. The latter 

hypothesis is supported by the finding of HIVinfected 

mononuclear cells in the gut, epithelial 

hypoproliferation, altered intestinal cell differentiation 

67 and reduced apoptotic lymphoid cells 

following the onset of antiretroviral therapy. 68 

Intestinal cell lines directly infected with HIV 

clade B strains have reduced brush-border enzyme 

activity and altered calcium responses, suggesting 

that direct infection of enterocytes with HIV may 

modify absorptive and secretory function. 69 Some 

of these effects may be due to activation of the 

HIV-1 transactivating factor protein gene (Tat) 

which is an early immediate regulatory gene that is 

essential for virus integration and protein expression. 

70 Circulating cytokines and lymphokines 

such as interleukin-1β and tumor necrosis factor-α 

may have a role in diarrhea due to bacteria, proto- 

Enteric infections in HIV-infected children 117 

Plasmodium falciparum malariae 

Tuberculosis 

Cryptococcus 

Non-typhi salmonellae 

Pneumococci 

Gram-negative bacteremia 

Figure 8.2 CD4 counts in HIV-infected adults presenting with specific infections in Uganda. 

zoa, cytomegalovirus or where there is no identifiable 

infection. 30,53 These may produce diarrhea 

through their secretory effects in the colon rather 

than by altering mucosal barriers. There are 

isolated reports of collagenous colitis in adults 

with chronic watery diarrhea, but none in children. 

71 

Enteric infections in HIV-infected 

children 

Surprisingly little is known about the patterns of 

enteric infection in HIV-infected children, timing 

of their acquisition, their individual effects on 

children’s health and nutrition, and their relationship 

to HIV activity and host immune status. 

There is reasonable consistency between the few 

studies that have been conducted in Africa 

describing the pathogens isolated in children 

presenting with HIV and diarrhea. 44,72 Enteric 

pathogens that commonly cause acute diarrhea in 

children uninfected by HIV also frequently result 

in diarrhea in HIV-infected children. 73 Adenovirus 

40/41 and astrovirus have been identified in children 

with persistent diarrhea, but their relative 

contribution to the burden of diarrheal disease in 

HIV infection is not known. 74–76 Only a few 

pathogens seem to be opportunistic in HIVinfected 

children with diarrhea. The most prevalent 

of these are Candida, Cryptosporidium

118 


parvum and cytomegalovirus (CMV); these usually 

cause oropharyngeal lesions and invasive lesions 

elsewhere in the gut or persistent diarrhea. 

Additional pathogens, which occasionally cause 

diarrhea or other symptoms in children with 

symptomatic HIV disease, may include herpes 

simplex virus and Mycobacterium avium intracellulare. 

Mycobacterium tuberculosis may be isolated 

from stools in both adults and children with no 

evidence of pulmonary TB. Perhaps surprisingly, 

there is little to suggest any association between 

shigellosis and HIV. One study from North 

America described an increase in prevalence in 

HIV-infected homosexuals; however, numerous 

reports from the African continent do not support 

this finding. It may be that the virulence of 

Shigella readily overcomes even the intact 

mucosal defense system and so the immunocompromised 

individual is not at any greater risk. 

Another possibility is that because Shigella must 

be taken up by enteric immune cells in order to be 

invasive, an immune system that is not competent 

may, paradoxically, be protective. Isospora belli, a 

significant enteric pathogen in HIV-infected 

adults 77–79 has not been commonly reported 

amongst HIV-infected children in Africa. 72,80 Little 

is known about the role of the Microsporidia spp 

and the newly recognized protozoan enteric 

pathogen Cyclospora cayetanensis in AIDS-associated 

diarrhea in children. 81–83 Laboratory identification 

of several of these infections may be very 

difficult, requiring special stains or techniques 

that are expensive or unavailable in most developing 

countries. In children, the proportion of diarrhea 

cases due to infective agents may, therefore, 

be underestimated. 

Cryptosporidium parvum 

C. parvum is a common cause of diarrhea in both 

HIV-infected and uninfected children, but in the 

immunocompromised child it results in prolonged 

disease and high fluid losses. 84–86 It may be 

responsible for up to 25% of persistent diarrhea in 

HIV-infected children in sub-Saharan Africa. 59,72 

Infection is usually through person-to-person 

contact, food contamination (e.g. unwashed raw 

vegetables or fruit) and contaminated water. Two 

distinct genotypes cause clinical disease in HIVinfected 

children: human and bovine (calf) 

types. 87 The clinical and epidemiological differ- 

ences between these genotypic variations is 

unclear, but the human genotype may be associated 

with a less severe clinical course in HIVinfected 

adults. Identifying C. parvum is difficult 

on direct microscopy; without experienced laboratory 

staff and appropriate stains, the diagnosis is 

easily missed. 88 In most developing countries, 

enzyme-linked immunosorbent assay (ELISA) or 

immunofluorescence methods to enhance identification 

rates are not routinely available. Shedding 

of the parasite is sporadic, and several stools 

should be examined to confirm or reject the diagnosis. 

Endoscopy and duodenal biopsy and aspirate 

examination further enhance the diagnostic 

yield. 45 

The most common site of infection is the duodenum, 

where it causes marked, though sometimes 

patchy, villous atrophy and reactive epithelial 

changes. Co-infection with CMV may exacerbate 

these responses. Other sites of infection include 

the stomach and colon (where cryptitis and apoptosis 

may occur) and the bile tract (which may be 

associated with pancreatitis). 89 Gut permeability 

may be markedly increased and fat malabsorption 

may be significant. 90,91 Protracted, or even 

intractable, secretory diarrhea with high fluid 

losses follows. It is often associated with weight 

loss, and up to 2–4% loss of body weight has been 

reported. 36 In HIV-infected children infection and 

a higher case fatality rate are more common in 

those with a lower CD4 count. 59 

In developing countries management is largely 

supportive to prevent severe dehydration and to 

recover lost weight through extended nutritional 

support. Several antimicrobial agents including 

spiromycin, parmomycin, azithromycin and nitazoxanide, 

and other approaches such as oral bovine 

immunoglobulin have been used with limited 

benefit. 92–94 The most effective treatment by far 

remains highly active antiretroviral treatment, 

which restores gut mucosal CD4 cells with eradication 

of opportunistic infections including C. 

parvum. 95 

Candida 

Oral thrush is one of the most characteristic signs in 

young children with HIV/AIDS, appearing as 

white–yellow plaques that cannot be easily scraped 

off the buccal mucosa. It is not, however, reliable or

specific as an indicator of HIV infection; recurrent 

episodes are better markers of HIV-infection in both 

children and adults. Thrush is often reported as a 

risk factor for breast-feeding transmission of HIV, 

presumably by inducing mucosal breaks facilitating 

viral entry, but the direction of causality is unclear 

from the available data. 96,97 Gut colonization 

follows oral infection with Candida species. 

Candidiasis of the mouth and esophagus is 

associated with poor appetite and weight loss. 

Esophageal inflammation is reported in up to 40% 

of children with AIDS and can be severe; 45,98 occasionally 

a necrotizing esophagitis which may bleed 

or even perforate can occur. The main differential 

diagnosis is herpes, CMV and Mycobacterium 

avium intracellulare. Candida may also produce 

inflammation and erosions in the gastric mucosa 

and the large and small intestines. The parasite can 

occasionally cause local abscesses, which may 

disseminate resulting in generalized candidiasis. 

Endoscopy and biopsy are generally required to 

diagnose invasive Candida, but in developing countries 

a high index of suspicion may be all that is 

available. Fluconazole is generally effective, 

although resistance does occur and higher doses are 

sometimes needed. 

Cytomegalovirus 

Gastrointestinal CMV infection in children most 

commonly presents with fever and persistent diarrhea. 

99,100 CMV-associated disease including retinitis, 

pneumonia, encephalitis and gastrointestinal 

involvement is estimated to affect up to 40% of 

adult AIDS patients, but is probably less frequent in 

children. 101 Symptomatic infection is more 

common and severe in HIV-infected children less 

than 12 months of age and with low age-corrected 

CD4 counts. 99 In children the colon is the most 

common site of gastrointestinal infection, followed 

by the small intestine and then the esophagus. 

Mucosal ulceration may sometimes result in 

massive hemorrhage and perforation of the large 

bowel, and strictures may follow CMV infection of 

the esophagus. 102 Diagnosis can be difficult. The 

virus may remain latent for long periods of time and 

neither serological tests nor positive urine cultures 

necessarily imply active disease. Children with 

chronic diarrhea, fever and no other identifiable 

pathogen should be investigated for CMV infection 

with lower gastrointestinal endoscopy and biopsy. 

Enteric infections in HIV-infected children 119 

CMV DNA quantification (CMV viral load) by polymerase 

chain reaction (PCR) can be used to decide 

when to offer prophylactic or active treatment. 

Prophylaxis and treatment with ganciclovir can 

prevent complications and significantly reduce 

morbidity, although the infection is not eradicated 

and relapses are still frequent. 103 Multiple pinpoint 

perforations or near perforations of the bowel may 

occur in the small bowel, ascending colon or 

both. 104 The prognosis is poor with or without 

ganciclovir. 

Rotavirus 

Studies in sub-Saharan Africa show that rotavirus is 

a common cause of diarrhea in HIV-infected children. 

105 It is not, however, found more commonly, 

shed for longer or associated with greater clinical 

severity than in children uninfected by HIV in 

similar settings; nor do children with more 

advanced HIV disease demonstrate any additional 

susceptibility. 106 Rotavirus was not associated with 

changes in viral load or CD4 counts in a small study 

in Malawi. 107 The pending availability of two new 

live oral rotavirus vaccines highlights the importance 

of understanding the relationship, and potential 

interaction, between these two viral infections. 

Clinical trials are necessary to ensure that any 

vaccine is safe and immunogenic in this population. 

Microsporidia spp 

Intestinal microsporidiosis is increasingly being 

reported in patients with HIV. 83,108 These intracellular 

protozoa are able to infect most animal species 

and, in humans, five genera (Enterocytozoon, 

Encephalitozoon, Septata, Pleistophora and 

Nosema) are associated with pulmonary, ocular, 

muscular, renal, intestinal and hepatic clinical 

disease. In Thailand, Enterocytozoon bieneusi was 

diagnosed in 25% and 15% of HIV-infected and 

uninfected children presenting with diarrhea, 

respectively. 81 In Uganda, however, it was found in 

17% of children of unknown HIV status attending 

hospital out-patient clinics for conditions other 

than diarrhea. 82 In contrast, microsporidiosis in 

HIV-infected adults produces chronic watery diarrhea 

and wasting, suggesting that responses in children 

may be quite different. 82,109 Villous atrophy 

and reduced brush-border enzyme activity may 

cause lactose intolerance. 110

120 


Diagnosis is made on stool microscopy using a 

modified trichrome stain, but this requires considerable 

technical skill to identify organisms 

correctly. Identification of parasites in stool or 

biopsy can be optimized by using PCR methods or 

electron microscopy on upper gastrointestinal 

biopsy. 111 Albendazole is an effective treatment for 

Encephalitozoon spp infections. 77 

Management of diarrhea and 

nutritional support 

HIV infection in children is often thought to be a 

rapidly and uniformly lethal disease. In Rwanda, 

however, 40% of children with perinatal infection 

survive for 5 years without antiretroviral treatment, 

and there are many children in sub-Saharan 

Africa with vertically acquired HIV infection 

attending schools and growing into adolescence. 

112 Optimizing the quality of life for these 

children is a necessary challenge, especially when 

the option of effective antiretroviral therapy is 

absent. The approaches outlined below are 

intended for developing countries. 

Diarrhea 

In most clinical settings in southern Africa it is not 

possible to investigate children presenting with 

recurrent or persistent diarrhea extensively. Using 

a syndromic approach for managing diarrhea in 

both HIV-infected and uninfected children is 

therefore appropriate. The WHO/UNICEF 

Integrated Management of Childhood Illnesses 

(IMCI) recommends that children with a history of 

persistent diarrhea and/or reported weight loss in 

the previous 3 months should be assessed for 

possible HIV infection. 113 Where there are no 

specific guidelines for HIV-infected children, the 

WHO guidelines for the management of severe 

malnutrition, including persistent diarrhea, are 

helpful. 

An approach for resource-poor countries would 

be: 

(1) Assess for and correct dehydration, hypoglycemia, 

hypothermia and electrolyte disturbances, 

especially K + deficiency; 

(2) Treat concurrent bacterial infections, e.g. 

pneumonia, Pneumocystis carinii pneumonia 

(PCP) and urinary tract infection, and exclude 

TB. This often means giving antibiotics empirically, 

e.g. cefuroxime, gentamycin and cotrimoxazole; 

(3) Start low lactose (< 3.2 g/kg) containing feeds 

such as F-75 (WHO) and porridge; 

(4) Provide vitamin A, zinc and multivitamins, 

including folate. See below for comment on 

zinc supplements; 

(5) If diarrhea persists then test stools for lactose 

intolerance using Clinitest ® tablets; 

(6) If Clinitest is positive then exclude all lactose 

from diet – use milks containing maltodextran 

as the main carbohydrate; 

(7) If Clinitest is negative then send repeat stools 

for routine microbiological assessment, 

including for Shigella, non-typhi Salmonella, 

Cryptosporidium, microsporidia and TB. Treat 

accordingly. Cryptosporidia may be shed intermittently; 

three stools should be sent to 

exclude diagnosis. Experienced staff are 

required to identify cryptosporidia and 

microsporidia on routine stool analysis. 

Prolonged fluid and nutritional support is 

often required for patients with cryp- 

(8) 

tosporidiosis; 

If no pathogen is identified then treat for bacterial 

overgrowth, e.g. cholestyramine for 5 days 

and neomycin for 3 days; 

(9) If diarrhea persists check for monosaccharide 

intolerance; test for glucose in stool using 

Clinitest or Glucostix ®. If positive, check for 

excessive intake of oral rehydration solution 

(ORS). Use maltodextran (glucose polymer) 

containing feeds and deliver milk by continuous 

slow infusion through a nasogastric tube. 

Use plain boiled water for oral rehydration 

rather than ORS. Only revert back to bolus 

feeds once the stool becomes formed again and 

glucose is not present. This takes longer in 

children who are more wasted or who have 

severe diarrhea; 

(10) Where resources are available, perform upper 

gastrointestinal endoscopy to increase the 

microbiological diagnostic yield. If visible or 

microscopic blood is present in stools then 

perform sigmoidoscopy for biopsy and culture;

(11) Where there is persistent pyrexia consider 

CMV colitis and exclude TB; 

(12) If no cause for persisting diarrhea is evident 

then consider antimotility drugs such as 

loperamide (HIV enteropathy is a diagnosis of 

exclusion); 

(13) Older children should be asked about abdominal 

pain and on these occasions underlying 

opportunistic infections such as TB, 

Cryptosporidium or CMV should be excluded; 

opiates such as codeine phosphate may be 

helpful; 

(14) Attention must be given in the weeks following 

discharge to restoring, as much as possible, 

any weight loss that has occurred. It is 

often very difficult to achieve this during 

hospitalization, and in busy hospitals significant 

weight gain cannot be used as a criterion 

for discharge (see Nutrition, below). 

Parenteral nutrition is not generally feasible in 

most developing countries because of the risk of 

systemic infection and metabolic complications. 

Terminal care 

When children are admitted with evidence of clinically 

advanced HIV infection such as diarrhea 

and severe wasting, clinicians and carers must 

consider what is reasonable and right for the child. 

The first admission with diarrhea often results in 

HIV testing. Many mothers discover for the first 

time that both she, and her child, are HIV-infected. 

In this situation it is appropriate to use all 

resources available to ensure that the child recovers 

and is able to go home. However, the treatment 

paradigm and objectives for care often change 

when the child has suffered several admissions, 

and the family has had some time to adapt to the 

diagnosis. In the absence of antiviral drugs, relieving 

discomfort becomes the overriding priority, 

and being less aggressive when complications 

such as concurrent severe bacterial infections 

intervene may be more caring for the child. 

In resourced settings 

While the same principles apply, the use of invasive 

diagnostic methods, i.e. upper and lower 

intestinal endoscopy, should be used early to 

Management of diarrhea and nutritional support 121 

determine whether a treatable enteric pathogen is 

present. Parenteral feeding may be a safe option if 

severe malabsorption is present. Antiretroviral 

drugs should be initiated if the child has not been 

previously treated. 

Micronutrients and HIV-related diarrhea 

Multiple micronutrient deficiencies have been 

reported in both HIV-infected adults and children 

with, or without, diarrhea. Biochemical indicators 

of vitamin and trace element status may be 

misleading and reflect redistribution or acutephase 

responses rather true body depletion. A few 

studies have shown that micronutrient supplementation 

in HIV-infected or exposed children is 

associated with improved morbidity or immune 

function. 114–116 In children uninfected with HIV, 

zinc supplementation reduces the incidence, duration 

and severity of acute and chronic diarrhea and 

promotes recovery of the mucosal lining. 117,118 

This effect has not so far been demonstrated in 

HIV-infected children. 

Vitamin A does not seem significantly to influence 

the course of acute or persistent diarrhea in uninfected 

children, but does decrease the severity 

and likelihood of recurrence. 119 HIV-infected children 

with persistent diarrhea should receive 

vitamin A (0–6 months, 50000IU; 6–12 months, 

100000 IU; >12 months, 200000IU daily for 2 

days), zinc sulfate or gluconate 2mg/kg for 2 weeks 

and multivitamin preparations including folate for 

2–4 weeks. 

Nutrition 

Much of the impact of diarrheal illnesses and 

repeated opportunistic infections on the health of 

HIV-infected children is mediated by its effect on 

nutrition. Loss of lean body tissue is consistently 

seen in adults and children with advanced disease 

and is a strong predictor of death. 120 Resting 

energy expenditure (REE) in adults increases by 

about 10% once they are infected with HIV, but 

this does not been seem to be the case in 

children. 53,121 However, even if REE increases 

modestly, total energy expenditure may not 

increase, because of inactivity. Rather, weight loss 

is most likely to be due to decreased energy intake,

122 


especially during the recovery period from opportunistic 

infections. Nutritional interventions, 

however, have generally only reversed weight loss 

through gain of fat rather than lean body tissue. 

There is work to suggest that different opportunistic 

infections may have differential effects on 

nutrition with some being capable of impairing 

anabolism and effective utilization of energy from 

food. 

WHO currently recommends that infected children 

should increase their overall energy intake by 

about 10% in order to maintain normal health, 

growth and activity. In chronic illness such as TB 

infection or chronic lung disease, energy intake 

should increase by 25–30%. During acute 

illnesses, particularly when recovering from acute 

weight loss, these requirements may increase to 

50–100% extra energy. Protein should represent 

about 10–15% of energy. These goals should 

ideally be achieved through dietary approaches 

rather than by specialized supplements which 

may not be available or affordable in most developing 

countries. 122 

Surgical aspects of HIV infection 

The prevalence of HIV disease among pediatric 

surgical patients in southern Africa has increased 

dramatically and is frequently considered as part 

of the differential diagnosis. Abdominal pain is not 

uncommon in adults with HIV, but there are no 

data on children. An underlying pathological 

cause can be identified in most cases 123 and 

include TB abdomen, cryptosporidia and CMV. 

There are four common surgical manifestations of 

gastrointestinal HIV disease: destructive lesions, 

opportunistic infections, primary peritonitis and 

tumors. 

Destructive lesions 

Rectovaginal fistulae are an extremely common 

presentation of HIV disease in female 

infants. 124,125 In the past this was treated with a 

defunctioning colostomy followed by closure of 

the fistula. Recurrence was frequent. Antiretroviral 

therapy may improve surgical results, but in the 

absence of such treatment it is generally better to 

leave the fistula alone. 126 In males, there is the less 

common presentation of a rectourethral fistula 

which always requires surgical repair. 

Occasionally stricture formation may follow sclerosis 

of the lower esophagus after repeated ulcerative 

disease such as CMV or invasive candidiasis. 

Opportunistic infections 

Intestinal perforations due to CMV are described 

above. 104 HIV occasionally presents as cancrum 

oris, where early treatment with penicillin and 

metronidazole may help, but excision and reconstruction 

may be required for large areas of fullthickness 

skin and tissue loss. 

Primary peritonitis 

This is sometimes seen in the older child who 

presents with a clinical picture suggestive of 

appendicitis. At surgery an odorless pus is found 

in the abdomen; pneumococcus is often isolated. 

Tumors 

Kaposi’s sarcoma in the gut may present with 

rectal bleeding, and other less common smoothmuscle 

tumors may rarely present as an intussusception 

and intestinal obstruction. 127,128 

Condyloma accuminata that may vary in size from 

isolated lesions to large pancake lesions can cover 

the perineum and genitalia. The more extensive 

lesions cause severe discomfort and problems with 

local hygiene. Isolated lesions may respond to 

podophyllin, but diathermy results in annular 

scarring and anal stenosis. Treatment with interferon 

may be helpful. 

Sialadenitis is a frequent complaint. Parotid size 

may increase and decrease intermittently, and pain 

may be due to superimposed bacterial infection, 

TB, bleeding into cysts or malignant change. Acute 

pain should be treated with antibiotics and analgesia; 

if the parotid continues to enlarge and is 

painful, then fine-needle or open biopsy should be 

performed to exclude TB or malignant change. 

Corticosteroids may be helpful.

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9 

Epidemiology and etiology 

Viral diarrhea 

Alfredo Guarino and Fabio Albano 

While infectious gastroenteritides are the second 

most common diseases in childhood worldwide, 

viruses are the most frequent agents of infectious 

diarrhea. Viral infections of the gastrointestinal 

tract cause 2 billion cases of diarrhea in children 

per year, resulting in 18 million hospitalizations 

and as many as 3 million deaths. 1 

Acute diarrhea is thus an enormous problem both 

in developing and in industrialized countries, but 

with two distinct consequences. In the former, 

enteric infections are extremely frequent, as the 

incidence of diarrhea is estimated at 3.8 episodes/ 

child per year in infants and 2.1 episodes/child per 

year in children 1–4 years of age. 2 A cumulative 

incidence of 2.5–3 million deaths each year has 

been estimated, corresponding to 25% of all deaths 

in childhood up to 5 years of age. In the developing 

world, one out of 40 children will die because 

of diarrhea. 3 

In industrialized countries, on the other hand, the 

incidence of diarrhea is approximately 1–2 

episodes/child per year in subjects younger than 3 

years. The case/fatality ratio is far from the figures 

in poor countries, but not negligible. In the USA, 

150–300 infants or younger children die each year 

because of acute diarrhea, and substantial 

resources are needed for hospitalizations and 

medical visits. Diarrhea was associated with an 

annual average of 35 hospitalizations per 10000 

children younger than 5 years, corresponding to 

4% of all hospitalizations. 4 It was estimated that 1 

in 57 children would be hospitalized by 5 years of 

age for diarrhea-associated illness. The rate of outpatient 

visits was 943/10000 children, corresponding 

to 2% of all visits. Rotavirus is the leading 

agent of infectious diarrhea, being responsible for 

approximately 40% of all cases of diarrhea in the 

USA. 4 Similar figures have been recorded in 

Europe, 5 with rotavirus consistently playing a 

leading role in younger subjects. 6 The estimated 

average costs for an episode of diarrhea requiring 

hospital admission may be as high as US$ 2300. 

Costs for acute diarrhea are not negligible even in 

less severe cases, particularly when the so-called 

societal costs are considered. It has been estimated 

that the cost of an episode of diarrhea requiring an 

office visit in the USA averages approximately 

$300, 7 half of which is related to the loss of 

working days by the parents of sick children. 

During the past three decades, there has been a 

dramatic increase in the number of newly recognized 

etiological agents of gastroenteritis. Before 

1970, a pathogen could be identified in fewer than 

10% of patients hospitalized with diarrhea; the 

remaining 90% of cases represented a ‘diagnostic 

void’ consisting of various idiopathic, poorly 

defined conditions. Since 1970, more than 20 

different micro-organisms – bacteria, parasites and 

viruses – have been recognized as etiological 

agents, and most cases of gastroenteritis are now 

presumed to have an infectious etiology. Nevertheless, 

a pathogen is currently identified in only a 

small proportion of cases. Although numerous 

viruses have been identified in fecal samples of 

patients with diarrhea, causal relationships have 

been determined for relatively few (Table 9.1). 

Most children are infected with viruses belonging 

to four distinct families: rotaviruses, caliciviruses, 

astroviruses and enteric adenoviruses. Other 

viruses, such as the toroviruses, picornaviruses 

(the Aichi virus), and enterovirus 22, play a minor 

epidemiological role. Finally, selected viruses 

induce diarrhea only in children at risk. These 

include cytomegalovirus, Epstein–Barr virus and 

picobirnaviruses. Recent evidence suggests that 

127

128 


Table 9.1 Etiological role of viruses in childhood diarrhea 

Conclusively established Probable Possible in selected children 

Rotavirus Torovirus HIV 

Adenovirus Aichi virus Cytomegalovirus 

Astrovirus Enterovirus 22 Epstein–Barr virus 

Calicivirus Picobirnavirus 

HIV-1 virus may directly induce diarrhea through 

the production and release of TAT, its transactivating 

transfer factor. 8 

Enteric infections are usually associated with 

diarrhea and, less frequently, with vomiting. 

Diarrhea usually lasts a few days and resolves 

spontaneously without any major problem. 

However, in selected cases it may be severe, leading 

to dehydration, requiring hospital admission and 

possibly even resulting in fatal outcome. 

The impact of viral diarrhea is related to the 

specific strain, but occasionally also to the 

epidemiological setting, the host baseline features 

and the efficacy of early medical intervention 

(Table 9.2). Viral diarrhea may have a major impact 

in closed communities such as day-care centers 

and hospitals. It may be severe in malnourished or 

immunocompromized children, but also in children 

not belonging to groups at risk. Finally, diarrhea 

may become severe if rehydration is not initiated 

in the initial phases of the disease. 

Pathophysiology of viral diarrhea 

In the classic and simple view, the pathogenesis of 

diarrhea may be divided into osmotic and secretory 

(Figure 9.1). Viral diarrhea was originally 

believed to be caused by cell invasion and 

epithelial destruction by enteropathogenic agents, 

therefore being the result of endoluminal fluid 

accumulation osmotically driven by non-absorbed 

nutrients. It is now known that several mechanisms 

are responsible for diarrhea, depending on 

the specific agents and the host features. In 

addition, selected viruses possess multiple virulence 

pathways that act synergistically to induce 

diarrhea. 

The mechanisms of diarrhea induced by group A 

rotaviruses have been extensively investigated 

and provide a paradigm of the pathophysiology of 

viral diarrhea. Rotavirus has tissue- and cellspecific 

tropisms, infecting the mature enterocyte 

of the small intestine. The first step is virus 

binding to specific receptors located on the cell 

surface, the GM1 ganglioside. However, different 

rotavirus strains bind in either a sialic acid-dependent 

or an -independent fashion. 9 Most 

rotaviruses, including all human strains, infect 

polarized enterocytes through both the apical and 

the basolateral side, in a sialic acid-independent 

manner, suggesting the presence of different 

receptors. 10 The early stages of rotavirus binding 

involve the viral protein (VP)4 spike attachment 

and cleavage. This outer capsid protein contains 

ligand sequences for α2β1 and α4β1 integrins, and 

for complement receptor 4, located on the enterocyte 

surface. After binding, the rotavirus enters 

into the cell by a multistep process that requires 

both VP7 and VP4 proteins. The route of internalization 

remains controversial. Two mechanisms 

have been proposed: direct penetration through 

the cell membrane, which could be mediated by 

the VP5 cleavage product of VP4, or a receptorprimed 

calcium-dependent endocytosis. 

Infection of the villous enterocyte leads to cell 

lysis, compromising nutrient absorption and 

driving water into the intestinal lumen through an 

osmotic mechanism (Figure 9.1). However, the 

destruction of villus-tip cells induces a compensatory 

proliferation of crypt cells. These immature 

enterocytes physiologically maintain a secretive 

tone, thus contributing to diarrhea with ion secretion, 

as the result of the imbalance between 

absorptive villous and secretory crypt cells. Thus, 

the cytopathic action by rotavirus results in both 

osmotic and secretory diarrhea.

Pathophysiology of viral diarrhea 129 

Table 9.2 Epidemiological features and associated impact of viral diarrhea in specific settings 

Setting Features Impact Viruses 

Developing high frequency high mortality rotavirus 

countries 

Industrialized high frequency high costs all 

countries 

Day-care centers high frequency high costs for the society rotavirus + others 

Seasonal pattern major outbreaks winter/early spring rotavirus 

Food-related food poisoning massive attack rates calicivirus, 

transmission rotavirus, 

Aichi virus 

Age maximal incidence in increased severity in younger infants rotavirus 

children

130 


Figure 9.1 Diagram of osmotic and secretory mechanisms 

of viral diarrhea. The arrows indicate the water’s movements 

and their volumes. In osmotic diarrhea, water is driven into 

the intestinal lumen by the osmotic force of non-absorbed 

nutrients. In secretory diarrhea, ions are actively pumped 

within the lumen and are passively followed by water. From 

Guandalini S. Acute diarrhea. In Walzer WA et al. Pediatric 

Gastrointestinal Disease, 3rd edn. Hamilton, Ontario: BC 

Decker Inc. 2000, with permission. 

actin, the perturbation of cellular protein trafficking, 

the damage of tight-junctions, with disruption 

of cell–cell interaction and cytolysis. 16,17 This is 

reflected by the loss of epithelial integrity, as 

shown by the progressive decrease in tissue resistance 

measured in Caco-2 cell monolayers 

mounted in Ussing chambers 18 (Figure 9.2). 

In children with rotavirus infection, the onset of 

diarrhea is abrupt and occurs in the absence of 

histological changes, even if oral feeding is withdrawn, 

suggesting that a secretory pathway is 

responsible for diarrhea, at least in the initial 

phases of infection. A major advancement in the 

understanding of rotavirus pathophysiology came 

from the identification of the non-structural 

protein NSP4 as a viral enterotoxin, defined by its 

ability to cause fluid secretion, but not epithelial 

changes. 19 

NSP4 is a multifunctional virulence factor, as it 

possesses the following features (Figure 9.3): 

(1) It is released from infected cells; 20 

(2) It enters the cells through a specific receptor; 

21–24 

(3) It causes calcium-dependent chloride secretion, 

with an age-dependent pattern; 19 

Figure 9.2(a) Cytopathic effects induced by rotavirus (5 

PFU/cell) in a model based on the morphology of Caco-2 

cell monolayers. a, Uninfected Caco-2 cell monolayers; b, 

Caco-2 cells at 48 h post-infection: cellular vacuolization, 

opening of intracellular junction and spotting cell detachments 

are observed; c, Caco-2 cells at 96 h post-infection: 

extensive cellular detachment is observed with only a few 

picnotic cells yet present. From reference 18.

TEER (Ohm/cm 2 ) 

800 

700 

600 

500 

400 

300 

200 

100 

0 

Virus-free control 

Virus 25 PFU/cell 



0 12 24 36 48 

Time (h) 

72 96 


Figure 9.2(b) Cytopathic effects of rotavirus infection in a Caco-2 cell model, as measured by transepithelial electrical 

resistance (TEER). The decrease of TEER reflects progressive cell damage, which is shown in Figure 9.3. Increasing loads of 

virus induce an earlier and steeper fall of TEER, with a clear relationship with virus multiplicity. The TEER value decreases 

below a detectable level within approximately 36 h postinfection with 25 PFU/cell, 60–72 h post-infection with 

5 PFU/cell, and 96 h post-infection with 1 PFU/cell. From reference 18. 

Figure 9.3 Combined effects by NSP4 in the pathophysiology of rotavirus diarrhea. Rotavirus infects epithelial cells of the 

small intestine, replicates, and induces cell lysis. NSP4 is released by infected cells and functions as a Ca 2+-dependent 

enterotoxin triggering Cl - secretion. It decreases fluid and electrolyte transport by inhibiting Na–glucose symport SGLT1 

and, possibly Na–K ATPase. It also impairs disaccharidase expression. Furthermore, rotavirus and/or NSP4 may diffuse 

underneath the intestinal epithelium activating secretory reflexes in the enteric nervous system. Late during the infection, 

an inflammatory response in the lamina propria may be detected, and the production of inflammatory substances and 

cytokines may further contribute to the increase of intestinal permeability and diarrhea. 

131

132 


(4) It alters plasma membrane permeability and 

is cytotoxic; 25–27 

(5) It is sensitive to specific antibody, which 

prevents or reduces diarrhea; 28,29 

NSP4 is the only rotavirus gene product capable of 

eliciting intracellular calcium mobilization. 30 

NSP4 was demonstrated to stimulate a calciumdependent 

chloride secretion, in mouse small 

intestinal mucosa sheets mounted in Ussing chambers, 

suggesting that this enterotoxin triggers diarrhea 

in the early phase of infection in animal 

models. 14,31 NSP4 further contributes to diarrheal 

pathogenesis by directly altering enterocyte actin 

distribution and paracellular permeability. 32 

Finally, NSP4 plays a role in the inhibition of the 

Na + -dependent glucose transporter SGLT-1. 33 

Glucose absorption is impaired in rotavirus diarrhea 

as well as disaccharidase activities, whereas 

the Na/amino acid co-transporters are not 

involved. 

Rotavirus diarrhea may also have an inflammatory 

component. The induction of cytokines is important 

in developing an inflammatory and immune 

response, especially in intestinal infection caused 

by bacteria. In rotavirus infection, limited inflammation 

is detected by histological studies, suggest- 

Isc (µA) 

4 

3 

2 

1 

0 

0 1 2 3 6 12 24 36 

Hours after infection 

ing that cytokines are effective in inducing a host 

immune response to rotavirus diarrhea. However, 

it has been shown that the rotavirus-infected enterocyte 

activates NF-κB and the production of 

chemokines interleukin (IL)-8, Rantes and GRO-a, 

and of cytokines interferon (IFN)α and granulocyte/macrophage–colony-stimulating 

factor (GM- 

CSF). 34,35 

In conclusion, the primary target of rotavirus is the 

enterocyte, which is induced to secrete fluids and 

is subsequently destroyed. On the other hand, the 

enterocyte acts as a sensor to the mucosa with the 

production of viral and endogenous factors and 

the activation of other cell types including nerves. 

Thus, rotavirus-induced diarrhea is a multistep 

and multifactorial event, in which fluid secretion 

and cell damage are observed in sequence, as 

shown in an intestinal cell line-based experimental 

model (Figure 9.4). A summary of the multiple 

mechanisms involved in the rotavirus–intestine 

interaction is given in Table 9.3. 

Clinical signs and symptoms 

The predominant symptoms of vomiting and diarrhea 

are common to enteric infections, regardless 

of the causative role of more than 20 different 

Figure 9.4 Biphasic effect of rotavirus in Caco-2 cells. Rotavirus induces a biphasic response, in an in vitro model of 

infection in Caco-2 enterocytes mounted in Ussing chambers. An early secretion is evident in the first few hours of infection, 

with a peak at 2h post-infection, as shown by the increase in short circuit current (Isc, - -). Subsequently, rotavirus 

exerts a cytotoxic effect with a loss of tissue integrity, as demonstrated by the fall of transepithelial resistance 

(Ohm/cm 2 , - -) which is evident at 24h post-infection. The results suggest that rotavirus diarrhea is initially the result of an 

early secretory mechanism and of a subsequent osmotic pathway, due to cell damage and loss of functional absorptive 

surface, leading to nutrient malabsorption. From G. De Marco et al, unpublished data. 

600 

400 

200 

0 

Resistance (Ohm/cm 2)

Table 9.3 Pathogenesis of rotavirus diarrhea 


Key process Pathway Consequences 

Villous cell destruction cytoskeleton disruption, cell lysis nutrient 

malabsorption, 

osmotic diarrhea 

Crypt cell proliferation compensatory secretory cell proliferation secretory diarrhea 

NSP4 enterotoxin increase in intracellular calcium, secretory diarrhea 

chloride secretion 

NSP4-induced inhibition of SGLT-1 osmotic diarrhea 

glucose malabsorption 

Neuromediated neurotransmitter microcirculation secretory diarrhea 

vascular ischemia impairment 

Inflammation NF-κB, IL-8, Rantes osmotic/secretory diarrhea 

microbial agents, including bacteria, parasites and 

viruses. 

Usually, viral diarrhea lasts for 3–5 days. In 

selected cases, viral diarrhea may be persistent 

and even become life-threatening. In a series of 

children with intractable diarrhea syndrome, 

rotavirus was detected in five out of 38 children 

who had no evident risk factors. 36 

The history may provide valuable clinical information. 

Diarrheal onset may be abrupt or 

progressive. The child’s age, admission to a daycare 

center, the time of year, exposure to diarrheal 

contacts, previous antibiotic courses, and ingestion 

of contaminated food such as eggs or water 

should be evaluated to define the origin of diarrhea. 

Risk factors for severe diarrhea include 

malnutrition, immune derangement and AIDS, 

and history of repeated episodes of diarrhea. 

Recent weaning from breast milk or introduction 

of feedings other than milk may be associated with 

a more severe course of the disease (Table 9.2). 

Dehydration is the key symptom to define the 

severity of the disease and the need for fluid 

replacement. The degree of dehydration should be 

evaluated at first observation and followed up to 

evaluate the ongoing losses and the efficacy of 

fluid intake to replace them. The gold standard for 

133 

determining dehydration is acute weight loss. 

Because a patient’s pre-illness weight is rarely 

known, an estimate of fluid deficiency is made on 

clinical grounds. 

Vomiting may be associated with diarrhea and 

induce additional fluid losses. In addition, vomiting 

may prevent oral rehydration, thus requiring 

parenteral fluid replacement. 

Body temperature may be elevated, as a consequence 

of dehydration or reflecting an inflammatory 

response. Abdominal pain is not frequent and 

suggests colonic involvement, but may also 

indicate a surgical problem. 

Stool characteristics should be carefully considered: 

large volumes of watery stools indicate 

small bowel involvement and are frequently 

associated with dehydration, whereas frequent 

outputs of a small amount of mucus or bloody 

stools are associated with colitis. In severe cases 

the entire intestine is involved. 

Colonic involvement is more often associated with 

bacterial rather than viral etiology. Some features 

may help in distinguishing viral from bacterial 

diarrhea (Table 9.4). 37 Viral diarrhea is more 

frequently associated with vomiting and dehydration. 

It affects younger children compared to

134 


Table 9.4 Main clinical features associated with the most frequent enteric pathogens (modified from 

reference 37) 

bacterial diarrhea. Selected features are more 

frequently associated with specific enteric viruses 

(Table 9.5). 38 However, signs and symptoms in the 

individual child do not reliably allow identification 

of specific etiological agents of gastroenteritis. 

Salmonella Campylobacter Giardia 

species species Rotavirus NLV lamblia 

Fever ++++* ++++* ++++* + + 

Blood in stool ++ ++++* + ++ +++ 

Abdominal cramps ++++* ++ -* + + 

Vomiting + + ++++ * ++++* + 

>6 stools per day + ++++* ++ + + 

Duration of 7 7

disease. 39 Acute diarrhea may be a side-effect of 

various drugs including antibiotics. History and 

clinical evaluation may aid in the differential diagnosis. 

However, close follow-up is required. 

Generally, microbiological investigations are not 

necessary in children with acute gastroenteritis. 

Several studies have reported a low yield and 

cost/efficacy ratio per identified agent even in 

hospitalized children. Microbiological examination 

should be considered: in cases of persistent 

diarrhea; when a specific antimicrobial treatment 

is considered, such as for children belonging to a 

group at risk; when an intestinal infection must be 

excluded in order to support a different etiology; 

and to investigate an outbreak. 

The search for enteric viruses is made by several 

techniques, including culture in sensitive cells, 

electron microscopy, immune-based assays and 

molecular probes (Table 9.6). Virus culture is the 

gold standard, but it is cumbersome and the 

results are available only with delay, limiting its 

clinical applications. Immune-based methods are 

widely used, but a progressive increase in the use 

of polymerase chain reaction (PCR) techniques is 

leading to a shift of diagnostic techniques. The 

choice of a specific technique is based on the clin- 

Features of specific etiologies and virology 

135 

ical need, the availability of technical skills and 

the efficacy ratio. In most clinical institutions, 

immune-based assays are available to detect 

rotavirus and less frequently enteric adenovirus. 

The search for other viruses is generally available 

in reference centers or research institutions. 

However, trying to identify the etiology may not be 

clinically useful, as treatment of diarrhea is relatively 

independent of the responsible agent. 

Rather, it is the evaluation of the child’s clinical 

condition that provides information for case 

management. 

Features of specific etiologies and 

virology 

Rotaviruses 

Table 9.6 Etiological diagnosis of viral infections of the gastrointestinal tract 

Reovirus-like particles were first identified in 1973 

by electron microscopy in duodenal biopsies from 

children with acute diarrhea. 40 This led to a 

cascade of clinical and laboratory studies that have 

established the rotavirus as the single most 

common agent causing diarrhea in childhood. 

Viruses Antigen detection EM PCR Preferred test method 

Rotavirus EIA, latex agglutination ++++ RT-PCR EIA 

Calicivirus EIA + RT-PCR RT-PCR 

Astrovirus EIA + RT-PCR EIA 

RT-PCR 

Adenovirus EIA +++ RT-PCR EIA 

Cytomegalovirus PCR histology, 

immunohistochemistry 

Picornavirus EIA RT-PCR EIA 

Epstein–Barr virus PCR histology, 


EM, electron microscopy; PCR, polymerase chain reaction; EIA, enzyme immunoassay; RT, reverse transcriptase; 

+, detectable with low sensitivity by a skilled microscopist; +++, visible; ++++, easily visible

136 


The global illness and deaths caused by rotavirus 

in children were recently estimated by reviewing 

studies between 1985 and 2000. Rotavirus caused 

111 million episodes of gastroenteritis requiring 

home treatment, 25 million clinic visits, 2 million 

hospitalizations and 350–600000 deaths in children 

less than 5 years of age, worldwide. All children 

were expected to be infected with rotavirus 

within 5 years of age, one in five children were 

expected to need a clinic visit and one in 65 to be 

hospitalized. Finally, one out of 293 children 

would die because of rotavirus infection, 84% in 

the poorest countries. 41 

Also, in countries with high economic standards, 

rotaviruses are a major problem. In industrialized 

countries, the estimates were: a total of 7122000 

episodes of rotavirus gastroenteritis requiring only 

home care in children less than 5 years of age, a 

total of approximately 1781000 clinic visits and a 

total of 223000 rotavirus-associated hospitalizations. 

41 There are an estimated 3.5 million cases 

annually among children less than 5 years of age 

in the USA, leading to 500000 office visits, 50000 

hospitalizations, and approximately 20 deaths. 42 

These numbers translate into costs, resulting in 

US$ 1 billion/ year. 43 

Infection is widespread throughout the world. 

Rotavirus infection may occur repeatedly in 

humans from birth to old age. The first infection is 

predominant among children aged 6–24 months, 

although cases may occur in older children. 

Neonatal infections appear to be nosocomial in 

origin, because they are rarely seen in babies born 

at home or at village health centers. 

Approximately 90% of children in both developed 

and developing countries experience rotavirus 

infection by 3 years of age. The cumulative incidence 

of rotavirus illness by the age of 5 years 

approaches 0.8 episodes/child per year. 

Several factors are responsible for the high spreading 

of rotavirus. Rotavirus shedding averages 6 

days per episode, but may be persistent. 

Asymptomatic carriers contribute to infection 

spreading. Infected children develop a protective 

immunity and, although repeated infections generally 

occur in growing children, their clinical severity 

decreases. 44 Despite differences among studies 

in geographical areas, years and age groups, an 

increase in rotavirus cases is consistently reported 

in the winter months, with a peak in February to 

April. In tropical areas, rotaviruses are identified 

throughout the year. 

Transmission occurs through the fecal–oral route. 

However, droplet transmission has been suggested 

to explain the rapidity with which the rotavirus 

can spread through a community. 45 

Virology 

Rotavirus is a double-stranded RNA virus belonging 

to the Reoviridae family. The virion, 70–75 nm, 

is composed of a three-layered protein capsid that 

encloses 11 distinct segments of genomic RNA, 

each coding for a different capsid or non-structural 

protein. The internal core contains viral proteins 

(VP) 1, 2 and 3; the inner capsid contains VP4; the 

two outer capsid proteins encoded by genes 4 and 

7, namely VP4 and VP7, represent the only established 

neutralization antigens of the virus. The 

protective role of antibodies directed at these 

proteins has been confirmed both in experimental 

animal models and in humans. A possible role has 

been suggested for antibodies directed at the inner 

capsid protein VP6, which is not associated with 

in vitro neutralization. The non-structural proteins 

NSP1, NSP2 and NSP4 are virulence factors in 

mice. 

Rotavirus groups A–F have been described, but 

only groups A, B and C have been identified in 

humans. Most human infections are caused by 

group A rotaviruses that are classified into 

serotypes by a dual classification system based on 

neutralizing antigens on two outer capsid proteins, 

VP7 (G serotype) and VP4 (P serotype). To date, 10 

G types and almost as many P types have been 

identified in infected humans. There is great 

genetic diversity within each G and P type, as 

shown by gel electrophoretic analysis of gene 

patterns (electropherotypes). Epidemiological and 

molecular studies in many countries show 

complex changes from year to year in the serotypes 

and electropherotypes that cause diarrhea in children 

from the same geographical areas. 46,47 The 

majority of severe diseases have been caused by 

serotypes G1 to G4, P1A and P1B, worldwide. 48 

Epidemiological studies in Bangladesh, 49 Brazil, 50 

India, 51 Kenya 48 and the USA 52 show that other G 

and P types (G5 to G10, P2A and P8) can be

common and may be of emerging importance in 

communities. 53 Specific strains may express 

stronger virulence factors, which could be related 

to the severity of symptoms. More severe diseases 

may also be related to the reintroduction of strains 

in areas where they have been previously absent. 54 

Astroviruses 

Human astroviruses (HAstVs) were first identified 

in 1975 in an outbreak of diarrhea in infants, and 

were named astrovirus because of the distinctive 

five- or six-pointed stars seen at electron 

microscopy. 55 

Recent studies have established that astrovirus is 

the third most frequent cause of diarrhea in children 

and the second in selected settings. The 

reported infection rates depend on detection 

methods. These include electron microscopy (EM), 

enzyme immunoassay (EIA) or reverse transcriptase-polymerase 

chain reaction (RT-PCR). 56 

Incidence rates also depend on the population 

under study. The reported incidence of HAstV 

diarrhea ranges from 2% of children seeking 

medical care in Baltimore, to 17% of children with 

persistent diarrhea in Bangladesh. 57 Younger 

infants are at greater risk of developing diarrhea 

than older children. In a child-care center, attack 

rates among infants and toddlers ranged between 

11 and 89%. 58 

HAstV may be an important agent of diarrhea in 

immunocompromised hosts such as those infected 

with HIV 59 and bone marrow transplanted 

patients. 60,61 Current evidence supports foodborne, 

water-borne and person-to-person transmission. 

The incidence peaks in winter months in 

temperate climates. 

Virology 

HAsVs are non-enveloped, single-stranded RNA 

viruses with a distinctive star appearance and a 

smooth particle edge. The genomic organization is 

unique among positive stranded RNA and 

warrants classification of astroviruses as a separate 

family, the Astroviridae. 62 Eight antigenic types 

have been identified. The complete genomic 

sequence of types 1 and 2 and the sequence of the 

Features of specific etiologies and virology 

137 

capsid gene of types 3, 4, 5, 6, 7 and 8 have been 

obtained. 63 

HAstV-1 is the dominant genotype followed by 

HAstV-2. It is not known whether infection with 

one serotype confers protection against subsequent 

infection with other serotypes. 

Caliciviruses 

In 1972, the ‘Norwalk agent’ was discovered in 

fecal specimens during a gastroenteritis outbreak 

in an elementary school in Norwalk, Ohio. 64,65 

This was the first discovered viral agent of 

gastroenteritis in humans using EM. Subsequently, 

a large number of other small round structured 

viruses (SRSVs) were detected. These agents 

appeared morphologically indistinguishable from 

the Norwalk virus by EM, but they were antigenically 

distinct by immune EM. SRSVs were discovered 

during investigations of gastroenteritis 

outbreaks and were named for the investigation 

site (e.g. Bristol, Hawaii, Snow Mountains, etc.). In 

addition, a morphologically distinct SRSV, defined 

as ‘classic human calicivirus’, was first described 

in the UK, 66 and the prototype strain – the Sapporo 

agent – was subsequently identified in Japan. 67 

This rather confusing classification system of 

these viruses has been recently revised and is now 

based on genetic sequences of the viruses and of 

their genomic organization. All viruses belong to 

the family Caliciviridae, and fall into two provisionally 

named genera: ‘Norwalk-like viruses’ 

(NLV) and ‘Sapporo-like viruses’ (SLV). 

Molecular epidemiological studies showed that 

caliciviruses are the main cause of non-bacterial 

gastroenteritis outbreaks causing over 90% of 

outbreaks of acute, non-bacterial gastroenteritis in 

the USA. 68 They are spread by the fecal–oral route, 

but outbreaks are often caused by contaminated 

food or water. 69 Contaminated surfaces carry calicivirus 

in detectable amounts, thereby providing 

another important substrate for explosive 

outbreaks. 70 Droplets or person-to-person transmission 

explain outbreaks in which other spreading 

routes cannot be identified. 71 Infections rates 

increase in cold seasons, 72 almost disappearing in 

the warm summer months. NLVs have been found 

in 5–20% of stool specimens from sporadic cases

138 


of diarrhea using RT-PCR. 73 SLVs cause predominantly 

diarrheal diseases, while NLVs cause 

‘winter vomiting disease’ in young children. 74 

Virology 

Caliciviruses are single-stranded, positive sense 

RNA viruses closely related to picornaviruses. 

Based on morphology, typical and atypical caliciviruses 

have been described. SLVs have the 

typical calicivirus morphology, with a six-pointed 

star appearance similar to those of many animal 

caliciviruses. In contrast, the surface structure of 

NLVs is rather smooth, leading to the designation 

‘small round structured viruses’. 

The family Caliciviridae encompasses four distinct 

virus genera. Two, the NLVs and SLVs, contain the 

human calicivirus (previously referred to as small 

round structured viruses) and the classic human 

caliciviruses, respectively. Phylogenetic analyses 

of sequences in the RNA polymerase and the 

capsid regions of the genome revealed that 

currently identified NLVs and SLVs can be divided 

into genogroups and genetic clusters. The NLV 

genus includes two genogroups (I and II) and at 

least 15 genetic clusters. 75 The SLV genus has 

fewer members, with a total of 4–5 genetic clusters. 

Enteric adenoviruses 

There are six different groups of adenovirus, but 

only group F, including serotypes 40 and 41, are 

referred to as enteric adenoviruses. Both cause 

endemic diarrhea and outbreaks in hospitals, 

orphanages and day-care centers. 

The enteric adenoviruses are non-enveloped particles, 

containing double-stranded DNA. 76 

These viruses infect children more than adults; 

more than 50% of children are seropositive by 

years 3–4 of life. 77 Enteric adenoviruses are 

detected in 1.5–4% of children with diarrhea and 

are isolated throughout the year with no specific 

seasonal distribution. 78,79 Transmission is fecal– 

oral. The incubation lasts from 3 to 10 days. 

Adenovirus diarrhea lasts for 6–9 days and may be 

associated with vomiting and fever. Stools are 

watery, without blood or fecal leukocytes. EM 

initially was used to detect enteric adenoviruses, 

but commercial enzyme-linked immunosorbent 

assays are now widely available. 

Toroviruses 

Toroviruses include the Breda virus of cattle and 

Berne virus of horses, 80–82 and were first documented 

in 1984 by EM in humans with gastroenteritis. 

83 These enveloped RNA viruses contain a 

tightly coiled tubular nucleocapsid that generally 

assumes a ‘donut’ torus shape in the virion. 80 

Toroviruses were classified on the basis of the 

Berne virus genome sequence as members of the 

family Coronaviridae, which together with the 

family Arteriviridae are now classified in the order 

Nidovirales. 84–86 

Study of torovirus infections in calves indicates 

that Breda viruses infect differentiating crypt cells, 

expecially in the large intestine. 81,82 

The incidence of torovirus infection remains relatively 

constant throughout the year. Early studies 

indicated that toroviruses infect school-age children, 

and are responsible for nosocomial infections, 

more frequently in immunocompromised 

patients. 87 

The clinical manifestations of torovirus infection 

are similar to those of rotavirus or astrovirus, 

except that children with torovirus infection had 

less vomiting and bloodier diarrhea. 83,87 Symptom 

duration is similar to that of rotavirus infection, 

but toroviruses more frequently induce persistent 

diarrhea. 87 Further epidemiological studies are 

needed to determine its frequency in the 

community. 

Picornaviruses (the Aichi virus) 

In 1989, a cytopathic small round virus was 

isolated from a patient with oyster-associated 

gastroenteritis. 88 Genetic analyses of this virus, 

named Aichi virus, led to its classification into the 

Picornavirus family. It is distinct from any other 

genus such as the enterrhino-, cardio-, aptho-, 

hepato- and parechovirus group. 89 The Aichi virus 

is presently an unassigned species in the 

Picornavirus family. 90 Recently, it has been

proposed to assign the Aichi virus to a new genus 

named Kobuvirus. 91 

The Aichi viruses cause acute gastroenteritis 

outbreaks. The main clinical symptoms are diarrhea 

(59%), abdominal pain (83%), nausea (92%), 

vomiting (71%) and fever (58%). 92 

Coronaviruses 

Coronaviruses are large enveloped single-stranded 

RNA viruses related to toroviruses. These viruses 

are a well-documented cause of gastroenteritis in 

animals and of the common cold in humans. 

Coronaviruses have been identified in the stools of 

children with diarrhea, but their role as a cause of 

diarrhea is unknown. They have been detected 

more commonly in the diarrheal stools of older 

children and young adults. The prolonged virus 

excretion makes it difficult to assess their etiological 

role. Recently, coronavirus mutants have been 

implicated in the severe acute respiratory 

syndrome (SARS). 93 

Picobirnaviruses 

These viruses have icosahedral symmetry with 

triangulation number (T) equal to 3. 94 They have 

been detected in diarrheic as well as non-diarrheic 

animals, and occasionally in children and in 

humans with HIV infection. Their etiological role 

in immunocompetent children is unknown. 

Treatment 

For the cornerstone of treatment of acute diarrhea, 

i.e. the restoration of fluid and electrolyte homeostasis 

95,96 see Chapter 39. 

For children hospitalized with severe rotavirus 

diarrhea, passive immune treatment should be 

considered. Several studies have shown that oral 

administration of human serum immunoglobulin 

is associated with an effective antiviral effect. 

Human immunoglobulin, including pooled 

gammaglobulin, bovine colostrums, or human 

milk, may decrease the frequency and duration of 

diarrhea. 97 Human immunoglobulin was initially 

used to treat children with life-threatening 

Treatment 

139 

rotavirus diarrhea. 98 In a double-blind, placebocontrolled 

study oral administration of human 

serum immunoglobulin, in a single bolus of 

300 mg/kg body weight, resulted in faster recovery 

and early discharge of immunocompetent children 

admitted to hospital with severe rotavirus diarrhea, 

without adverse effects 99 (Figure 9.5). The 

same treatment was given to children with AIDS 

and severe rotavirus infection, and led to rapid 

remission of diarrhea and permanent clearance of 

the virus. 100 We currently give human immunoglobulin 

to children hospitalized with severe 

rotavirus infection and to patients at risk of a poor 

outcome. 101 

Human immunoglobulin, although expensive, is 

widely available. Its efficacy might be related to 

high titers of specific neutralizing antibodies to 

rotavirus. Specific titers are consistently detected 

in preparations commercially available for intravenous 

use, because of the high frequency of 

rotavirus infection and the consequent widespread 

immune response. The efficacy of immunoglobulin 

is probably related to dose- and time-related 

direct neutralization of rotavirus, which prevents 

enterocyte infection and cell death. 18 Preliminary 

experimental evidence indicates that immunoglobulin 

prevents both the cytotoxic and the enterotoxic 

effect induced by rotavirus in human enterocytes. 

102 Thus, immunoglobulin should be 

administered orally early in the course of the 

disease for maximum efficacy. 

This information may be of practical relevance, 

while awaiting the development of safer vaccines 

that will hopefully be effective, for normal or 

compromised immune function. 

Vaccine development 

Rotavirus 

A review of the global prevalence of rotavirus 

disease was published in 1985, showing that 

rotavirus accounted for 6% of diarrhea episodes 

and 20% of deaths caused by diarrhea in children 

less than 5 years of age in developing countries. 103 

The incidence of rotavirus disease was similar in 

both industrialized and developing countries, 

suggesting that adequate control may not be 

achieved by improvements in water supply,

140 

Stool output/24 h 


8 

7 

6 

5 

4 

3 

2 

1 

0 

0 1 2 3 4 5 

Days 

Figure 9.5 Stool frequency (stools/24 h) in children hospitalized because of Rotavirus treated with human serum 

immunoglobulin administered per oral route in a single dose of 300 mg/kg body weight (•) and control children (o). Values 

are means ± SEM. *p

though a rotavirus vaccine was licensed, correlates 

of protective immunity remain relatively unclear. 

‘Norwalk-like viruses’ 

Some human study volunteers never become 

infected after challenge with NLV, perhaps reflecting 

the recent finding that NLVs recognize human 

histoblood group antigens as receptors, defining 

host susceptibility. Immunity to NLV infections is 

believed to be short lived, as volunteers were reinfected 

with the same strain within months of 

previous challenge. 

Conclusions/summary 

Table 9.7 Live, attenuated, oral rotavirus vaccines currently in human trials (modified from 

reference 105) 

Product Company Concept 

LLR Lanzhou Institute of Biological monovalent lamb strain (P[12]G10) 

Products (China) 

Rotateq Merck (USA) WC-3 based multivalent human-bovine 

reassortant 

Rotarix (89-12) GlaxoSmithKline (Belgium) monovalent human strain (P[8]G1) 

UK-reassortant vaccine Wyeth Ayerst/NIH (USA) UK-based multivalent human–bovine 

reassortant 

RV3 University of Melbourne (Australia) neonatal strain (P[6]G3) 

116E Bharat Biotech (India) neonatal strain (P[11]G9) 

I321 Bharat Biotech (India) neonatal strain (P[11]G10) 

Self-assembled recombinant capsid proteins of 

Norwalk virus (rNV) into VLPs have been tested as 

oral immunogens. 106 Preclinical studies in mice 

and phase I studies in healthy adult volunteers 

have shown that these VLPs are immunogenic in 

the absence of adjuvant, and high doses (250mg) 

delivered orally were safe and elicited antibody 

responses in all volunteers. The positive results 

obtained with oral delivery of rNV VLPs have stimulated 

new vaccine developments, including the 

expression of rNV in tobacco and potato tubers. 107 

RNV VLPs expressed in potato tubers were also 

immunogenic when given to volunteers orally. 108 

The protective efficacy of these candidate vaccines 

in human volunteers is currently under study. 

Conclusions/summary 

141 

Viral diarrhea still represents a major threat to 

childhood health, worldwide. It has an immense, 

but distinct, impact in poor and rich countries, 

being responsible for a substantial number of 

deaths in the former and of heavy money loss in 

the latter. Rotavirus is the leading agent and its 

pathophysiology involves multiple mechanisms, 

several of which are triggered by NSP4 enterotoxin. 

Diarrhea is the hallmark of viral diarrhea 

and is usually self-limiting. However, it may run a 

severe course and have a fatal outcome in children 

with malnutrition or immune impairment and in 

those who have no access to rehydration. 

Diagnosis is usually based on clinical grounds, and 

investigations are not necessary. Treatment is 

based on carbohydrate and electrolyte solution 

administered through the oral or parenteral route. 

Selected probiotics may be effective in reducing 

the duration of symptoms, whereas, in severe 

cases in which rotavirus is involved, oral administration 

of human serum immunoglobulin may be 

effective. Efforts towards vaccine development 

have been hampered by withdrawal of antirotavirus 

vaccine, because of its association with 

intussusception, but novel vaccines are currently 

under investigation.

142 


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10 

Bacterial infections 


Enteric infections exact a heavy toll on human 

populations, particularly among children. Despite 

the explosion of knowledge on the pathogenesis of 

enteric diseases experienced during the past 

decade, the number of diarrheal episodes and 

childhood deaths reported worldwide remains of 

apocalyptic dimensions. In the next 15s, a child 

somewhere in the world will die from diarrhea. 

Worldwide, it is estimated that 6–60 billion cases 

of gastrointestinal illness occur annually, the vast 

majority being severe enough and affecting so 

many unprivileged populations to pose a serious 

global health burden. In overpopulated developing 

countries, poor sanitation and hygiene, unsafe 

water supplies and limited education contribute to 

the propagation of diarrheal diseases. In industrialized 

nations, diarrhea had been thought of as 

more of an inconvenience rather than a serious 

cause of illness, but recent attention to food contamination 

by pathogens such as Salmonella and 

Escherichia coli, in combination with a growing 

population of immunosuppressed patients, has led 

to increased recognition of their impact. The situation 

is further complicated by the recent escalation 

of international terrorism that is raising the 

risk of epidemics of enteric pathogens beyond the 

boundaries of natural endemic areas. 

The appreciation of these multifaceted aspects of 

the problem is pivotal for full comprehension of 

the threat that diarrheal diseases pose to public 

health and for appropriate allocation of resources 

and efforts to tackle them. However, there are a 

series of obstacles that have historically hampered 

this process, including non-standardized definitions 

of disease and symptoms; failure to identify a 

causative agent in many, if not most, cases of 

disease; failure to report episodes to health authorities; 

and the existence of incompatible reporting 

systems. Most of all, the lack of long-term commit- 

ment of rich countries to finance sanitation 

campaigns to treat and prevent diarrheal diseases 

in endemic areas has been a key limiting factor in 

tackling the burden of gastrointestinal diseases. 

Nevertheless, bacterial genome sequencing and 

better understanding of the pathogenic mechanisms 

involved in the onset of diarrhea, particularly 

concerning the elaboration of toxin (Figure 

10.1), are finally leading to preventive interventions, 

such as enteric vaccines, that may have 

a significant impact on the magnitude of this 

human plague. 

The majority of acute infectious diarrheal illnesses 

in both children and adults in developing countries 

are due to bacteria (Table 10.1). The risk 

factors for transmission of these pathogens are 

higher in these countries, owing to increased exposure 

to the organisms (by contact with feces, water, 

food and fomites) and increased susceptibility of 

the host due to malnutrition. 

Cholera 

Of all enteric pathogens, Vibrio cholerae is responsible 

for the most rapidly fatal diarrheal disease in 

humans. 1 Although cholera is rare in developed 

countries, it remains a major cause of diarrheal 

morbidity and mortality in many parts of the 

developing world. 2 However, with the occurrence 

of both natural (e.g. earthquakes) and humangenerated 

calamities (such as ethnic wars), the 

spreading of cholera infection in refugee camps, 

where sanitary conditions resemble those in 

cholera endemic areas, represents a significant 

threat worldwide. Vibrios (from the Greek for 

‘comma’) are single, short, curved Gram-negative 

rods, with a single, long, polar flagellum that 

allows for the organism’s characteristic motility. 

145

146 


Figure 10.1 Enterocyte intracellular signaling leading to intestinal secretion. Four main pathways seem to be involved in 

the intestinal secretion of water and electrolytes: cAMP, cGMP, Ca and the cytoskeleton. These pathways are activated by 

several enteric pathogens, either directly or through the elaboration of enterotoxic products. CT, cholera toxin; LT, heatlabile 

enterotoxin; TDH, thermostable direct hemolysin; C.D., Clostridium difficile; EAST1, enteroaggregative Escherichia 

coli heat stable toxin 1; STa, heat stable toxin a; AC, adenylate cyclase; GC, guanylate cyclase; CM, calmodulin; PKC, 

protein kinase C; ZOT, Zonula Occludens Toxin; EGF-r, epidermal growth factor receptor; ECM, extracellular matrix. 

Table 10.1 Percentage of identified bacterial pathogens in symptomatic patients from industrialized 

and developing countries 

Agent Industrialized countries (%) Developing countries (%) 

Vibrio cholerae

Vibrio cholerae O1 is transmitted by the fecal–oral 

route and is spread through contaminated food 

and water, with a period of incubation of a few 

hours to 5 days. The vast majority of subjects 

infected remain asymptomatic or experience mild 

disease with watery stools, rare nausea or vomiting, 

and no significant dehydration. Stools are 

classically described as ‘rice water’ due to the 

presence of mucus in clear stools. In cholera 

gravis, profuse watery diarrhea and vomiting lead 

to massive fluid and electrolyte loss that can occur 

at a rate of 1 litre/h, and can reach a total volume 

loss of 100% of body weight. Vibrios can be easily 

identified from the stool by Gram stain. 

Cholera has been a recognized human plague for 

over two millennia. The study of this disease has 

spanned from ancient Greece, and the Roman 

Empire, to the famous John Snow’s tracing of an 

outbreak to a water pump in Broad Street, London, 

in 1854. Thirty years later Robert Koch proposed 

that the agent responsible for cholera produced ‘a 

special poison’ acting on the intestinal epithelium 

and that the symptoms of cholera could be 

‘regarded essentially as a poisoning’. Considerable 

time elapsed before the existence of this hypothesized 

toxin was demonstrated in 1959. Ten years 

later, cholera toxin (CT) was purified to homogeneity. 

It was only recently, however, that we 

learned that vibrios produce a variety of other 

extracellular products that enable these microorganisms 

to activate different intracellular signaling 

in the host mammalian cells, all leading to 

diarrhea. One of the most intriguing new toxins 

discovered in V. cholerae is zonula occludens toxin 

(Zot), 3 an enterotoxin that increases the intestinal 

permeability by interacting with a mammalian cell 

receptor, with subsequent activation of intracellular 

signaling leading to the disassembly of the 

intercellular tight junctions (Figure 10.2). 

The introduction of oral rehydration solutions 

(ORS) decreased the mortality from this illness 

from over 50% to less than 1%. The use of antibiotics 

has limited indications, but has been 

demonstrated to reduce the volume and duration 

of diarrhea by half and reduce the duration of 

excretion to one day. Tetracycline (500 mg/dose, 

given four times per day) is the most widely used 

antibiotic, but large outbreaks of tetracycline-resistant 

organisms have been reported. Furazolidone 

(1.25mg/kg four times per day), trimethoprim 

Cholera 147 

(TMP, 5mg/kg twice per day), sulfamethoxazole 

(SMX, 25mg/kg twice per day), and erythromycin 

(10mg/kg three times per day) have been 

suggested for children. 

Both killed whole-cell and live attenuated cholera 

vaccines have been proposed as a preventive 

intervention for cholera. 3 A large double-blind 

field trial of the killed vaccine showed 85% efficacy 

for a period of 4–6 months, dropping to 50% 

over 3 years of follow-up. 4 A locally produced 

killed vaccine in Vietnam provided a 66% protection 

against El Tor cholera during an outbreak 

occurring 8–10 months after vaccination. 5 A 

genetically engineered attenuated cholera vaccine 

(CVD 103-HgR), obtained by deleting the active 

subunit of cholera toxin (see below) from a V. 

cholerae O1 classic biotype, was well tolerated 

when administered to volunteers. This vaccine 

elicited a high level of protection (82–100%) 

against homologous challenge with a strain of the 

same biotype. 6 Protection across biotypes was also 

observed, albeit to a lesser extent, 7 lasting for at 

least 6 months after a single oral dose. 8 Live attenuated 

V. cholerae O139 vaccines have been developed, 

with promising preliminary results. 9,10 

Non-01 Vibrio species 

V. parahaemolyticus, V. fluvialis, V. mimicus, V. 

hollisae, V. furnissii and V. vulnificus cause 

sporadic cases of gastroenteritis, and are present 

in coastal and estuarine areas throughout the 

world. 11 Virtually all cases of non-O1 Vibrio infections 

in the USA are associated with eating raw 

shellfish, 12 and the gastroenteritis can range from 

a mild illness to profuse, watery diarrhea comparable 

to that seen in epidemic cholera. Diarrhea, 

abdominal cramps and fever are the most 

common symptoms, with nausea, vomiting and 

bloody stools occurring less frequently. 11 As with 

V. cholerae O1, the mainstay of therapy for diarrheal 

disease is oral rehydration. In cases of 

septicemia (which typically occur in immunocompromised 

patients), supportive care and 

correction of shock are essential interventions 

associated with the antibiotic treatment (tetracycline). 

In countries such as the USA non-O1 infections 

can be prevented by not eating raw or undercooked 

seafood, particularly during the warm 

months.

148 


Figure 10.2 Proposed zonula occludens toxin (Zot) intracellular signaling leading to the opening of intestinal tight junctions. 

Zot interacts with a specific surface receptor (1) whose distribution within the intestine varies. The protein is then 

internalized and activates phospholipase C (2) that hydrolyzes phosphatidyl inositol (PPI) (3) to release inositol 1,4,5-tris 

phosphate (IP3) and diacylglycerol (DAG) (4). Protein kinase Cα (PKCα) is then activated (5), either directly (via DAG) (4) or 

through the release of intracellular Ca ++ (via IP3) (4a). PKCα catalyzes the phosphorylation of target protein(s), with subsequent 

polymerization of soluble G actin in F actin (7). This polymerization causes the rearrangement of the filaments of 

actin and the subsequent displacement of proteins (including ZO1) from the junctional complex (8). As a result, intestinal 

tight junctions become looser. 

Salmonella 

Salmonella typhi and S. paratyphi are Gramnegative, 

motile bacilli that colonize only humans. 

Therefore, disease is acquired through close 

personal contact or through the ingestion of water 

or food contaminated with human excrement. 

Typhoid fever continues to represent a global health 

problem, with more than 12.5 million annual cases, 

and subequatorial countries reporting mortality 

rates of up to 32% despite antibiotic treatment. 13 In 

the USA, substantial progress has been made in 

their eradication, with better sanitation, foodhandling 

and water treatment. These bacteria cause 

systemic illnesses characterized by fever, gastrointestinal 

symptoms and occasionally psychosis, 

confusion or rose spots on the trunk. 14 The incubation 

period varies between 5 and 21 days (depending 

on the inoculum ingested), and chills, 

headache, cough, weakness and muscle pain are 

frequent prodromes. Most symptoms resolve by the 

4th week without antimicrobial treatment. 

However, some patients relapse with high fever, 

abdominal pain from inflammation of Peyer’s 

patches, and intestinal microperforation followed 

by secondary bacteremia with normal enteric flora. 

The definitive diagnosis of enteric fever requires the 

isolation of S. typhi or S. paratyphi from blood, 

stool, urine, rose spots, bone marrow, or gastric or 

enteric secretions. Chloramphenicol is the treatment 

of choice and has been shown to reduce the 

duration of fever and mortality.

In contrast to S. typhi, the cases of infection with 

non-typhoidal salmonellae infections have been 

increasing in the developed world. Patients as 

higher risk for infection include those with 

immunodeficiencies, age younger than 3 months, 

alterations in intestinal defenses (achlorhydria, 

antacids, rapid gastric emptying post-gastrectomy), 

impaired reticuloendothelial function, 

(sickle cell and hemolytic anemias) and ingestion 

of antibiotics to which the organism was resistant. 

Reservoirs include a wide range of domestic and 

wild animals, including poultry, swine, cattle, 

rodents and reptiles. S. enteriditis is the leading 

reported cause of food-borne disease outbreaks in 

the USA, with eggs and contaminated raw fruits 

and vegetables identified as vehicles. 15 Transmission 

from person to person and from pets has 

also been reported. The incubation period is 

6–48 h, after which fever, headache, vomiting, 

abdominal pain and watery diarrhea (which may 

contain blood, mucus, and leukocytes) occur for 

about 1 week. Severe extraintestinal infections can 

range from life-threatening sepsis to focal infections 

in the meninges, bones and lungs. The 

micro-organism is easily isolated from fresh stools 

or blood culture. Antimicrobials are not indicated 

to treat asymptomatic carriage or uncomplicated 

infections in the normal host, as they may prolong 

excretion or induce relapse. Although efficacy is 

unproven, it is common clinical practice to administer 

oral or parenteral antibiotics to high-risk 

patients or to those who have an extraintestinal 

focus of infection. Increasing resistance to 

commonly used antibiotics is seen, so the choice 

of regimens should be guided by susceptibility 

data. Suggested therapies include TMP–SMX 

(Bactrim ® , Septra ® , Sulfatrim ® ), ampicillin 

(10–20% of isolates in the USA are resistant), cefotaxime, 

ceftriaxone or chloramphenicol. 

Hygienic practices for preventing food-borne 

transmission is the most efficient prevention for 

non-typhoidal Salmonella infections, since the 

vast majority of outbreaks and sporadic cases 

result from culinary practices that allow the organisms 

to survive and multiply in food. Parents 

should be instructed to avoid serving food containing 

raw or undercooked eggs and meat (especially 

poultry). Food should be thawed in the refrigerator, 

microwave, or under cold water but not at room 

temperature, because surface bacteria begin to 

multiply when the outer layers warm. Eggs should 

Shigella 149 

be cooked until both the yolk and the white are 

firm, and meats must reach an internal temperature 

of at least 74°C (165°F). Frequent hand 

washing is important. High-risk pets (especially 

chicks, ducklings and reptiles) are not advisable 

for young children. 

An extremely problematic situation is the management 

of an infected child who is attending day 

care. Excretion can go on for weeks and create a 

hardship to working parents if the child must be 

excluded from day care. While the decision to 

admit such a child must be made in concert with 

day care and public health officials, it is generally 

recommended that the infected children be 

excluded from day care if they are symptomatic or 

if adequate hygiene cannot be ensured. There is no 

vaccine to prevent non-typhoidal salmonellosis. 

Enteric fever 

The definitive diagnosis of enteric fever requires 

the isolation of S. typhi or S. paratyphi from the 

patient. Cultures of blood, stool, urine, rose spots, 

bone marrow and gastric and enteric secretions 

may all be useful in establishing the diagnosis. 

Chloramphenicol has been the treatment of choice 

since its introduction, given its low costs and its 

high efficiency after oral administration. 

Treatment with chloramphenicol reduced typhoid 

fever mortality from approximately 20 to 1% and 

reduced the duration of the fever from 14–28 days 

to 3–5 days. 16 

The most effective attenuated vaccine for typhoid 

fever currently available, Ty21a, has proved to be 

free of adverse reactions in large-scale efficacy 

field trials involving almost 600000 pediatric 

subjects. 17 When administered as a liquid suspension, 

Ty21a protected both young (82% vaccine 

efficacy) and older children (69% vaccine 

efficacy). 17 Currently, there are three new-generation 

attenuated vaccines, genetically engineered 

by deleting different pathogenic factors, that are 

undergoing extensive phase II trials. 

Shigella 

Kiyoshi Shiga first isolated Shigella dysenteriae 

type 1 during a severe dysentery epidemic in Japan

150 


in 1896, when more than 90000 cases were 

described with a mortality rate approaching 

30%. 18 Shigellae are Gram-negative, non-lactose 

fermenting, non-motile bacilli, with S. sonnei the 

main type found in industrialized countries, and 

S. flexneri and S. dysenteriae predominating in 

underdeveloped countries. Humans are the only 

natural hosts and transmission occurs by 

fecal–oral contact. The low infectious inoculum 

(as few as ten organisms) 19 renders shigellae 

highly contagious. Shigella causes 250 million 

cases of diarrhea and 650 000 deaths worldwide. 20 

In the USA, S. dysenteriae infection is seen almost 

exclusively among travelers. After an incubation of 

1–4 days, shigellosis begins with fever, headache, 

malaise, anorexia and occasional vomiting and 

watery diarrhea with progression to dysentery 

within hours to days. Unusual extraintestinal 

manifestations may occur, including hemolytic 

uremic syndrome (HUS) in children and thrombotic 

thrombocytopenic purpura in adults. Most 

episodes of shigellosis in otherwise healthy individuals 

resolve within 7 days. Shigellae are 

extremely fastidious and are best isolated from 

fresh stool rapidly inoculated onto selective 

culture plates incubated immediately at 37 o C. 

Appropriate antibiotics (ampicillin or TMP–SMX) 

given for 5 days significantly decrease the duration 

of fever, diarrhea, intestinal protein loss and 

pathogen excretion. However, Shigella strains that 

are resistant to one or both drugs have been 

identified. Several promising Shigella mutants 

with deletions in virulence genes have entered 

clinical trials as oral vaccine candidates. 

Campylobacter 

These organisms are small, microaerophilic, 

spiral-shaped Gram-negative organisms that enjoy 

a widespread reservoir in the intestines of both 

wild and domestic animals. 21 It is the most 

frequently identified bacterial cause of diarrhea in 

the USA. Common vehicles are poultry, unpasteurized 

milk and contaminated water. 22–24 

After an incubation of 3–6 days, enteritis begins 

abruptly with cramps and watery diarrhea, which 

may progress to blood-containing stools. The 

abdominal pain may mimic appendicitis. Diarrhea 

usually lasts 4–5 days, with the duration of fecal 

excretion 1 month. The micro-organism can be 

identified only from stool. Indications for anti- 

biotics remain controversial, with some studies 

showing a shortened course of diarrhea, and others 

no clear benefit. It is advisable to reserve antibiotics 

for patients in high-risk groups with severe 

symptoms. Erythromycin remains the drug of 

choice. Campylobacter vaccine development has 

proceeded cautiously, because of concerns about 

post-exposure arthritis or Guillain–Barré syndrome. 

However, a monovalent, formalininactivated, 

C. jejuni whole-cell vaccine with a 

mucosal adjuvant has entered human trials. 

Yersinia 

Yersinia enterocolitica and Y. pseudotuberculosis 

are two important human enteropathogens distributed 

widely in the environment, with swine 

serving as the major reservoir. The incubation 

period is 3–7 days, with food-borne transmission 

the suspected route for most infections. Yersinia’s 

preference for cool temperatures makes this 

pathogen more common in Northern Europe, 

Scandinavia, Canada, the USA and Japan, where it 

is responsible for up to 8% of sporadic diarrhea 

episodes. Yersinia enterocolitis occurs most often 

in children younger than 5 years 25 and is characterized 

by fever, vomiting, exudative pharangitis, 

cervical adenitis, abdominal pain and watery 

diarrhea, which may contain blood. 26,27 Diarrhea 

typically lasts for 14–22 days but fecal excretion 

may persist for 7 weeks or longer. Abdominal 

complications include appendicitis, pseudoappendicitis, 

diffuse ulceration of the intestine 

and colon, intestinal perforation, peritonitis, 

ileocecal intussusception, toxic megacolon, 

cholangitis and mesenteric vein thrombosis. 

Bacteremic spread may result in abscess formation 

and granulomatous lesions in the liver, spleen, 

lungs, kidneys and bone, as well as mycotic 

aneurysms, meningitis and septic arthritis. Infection 

can also be associated with immunopathological 

sequela including reactive arthritis, uveitis, 

Reiter’s syndrome and erythema nodosum. 28 It 

may be isolated from stool or pharyngeal exudate 

on commonly used selective media, and appears as 

gram-negative colonies after 48h of growth at 

25–28 o C. Most uncomplicated cases resolve 

without treatment, which is reserved for patients 

with severe symptoms, extraintestinal infections 

and immunocompromised hosts. Production of 

β-lactamases generally renders all but third-

generation cephalosporins, aztreonam and 

imipenem ineffective. Treatment is generally 2–6 

weeks, with an initial intravenous antibiotic 

(third-generation cephalosporin often in combination 

with aminoglycosides), followed by an oral 

agent to which the clinical isolate is sensitive. 

Escherichia coli 

An extremely heterogeneous group of micro-organisms, 

Escherichia coli encompasses almost all 

features of possible interactions between intestinal 

microflora and the host, ranging from a role of 

mere harmless presence to that of a highly pathogenic 

organism. In fact, the E. coli species is made 

up of many strains that profoundly differ from 

each other in terms of biological characteristics 

and virulence properties. 29 

Escherichia coli is a Gram-negative, lactosefermenting 

motile bacillus of the family 

Enterobacteriaceae. Currently, 171 somatic (O) and 

56 flagellar (H) antigens are recognized. Six 

distinct categories of E. coli are currently considered 

enteric pathogens (based on either outbreak 

data or volunteer studies) (Table 10.2). The diagnosis 

of diarrheagenic E. coli relies on isolation 

from stool and subsequent differentiation from 

commensal E. coli either by using genetic probes 

or by phenotypic assays. With the exception of E. 

coli O157:H7, assays for detection are not routinely 

available in clinical laboratories. 

Enteropathogenic E. coli 

This was the first group of E. coli serotype shown 

to be pathogens for humans and has been responsible 

for devastating outbreaks of nosocomial 

neonatal diarrhea and infant diarrhea in virtually 

every corner of the globe. Strains of enteropathogenic 

E. coli (EPEC) are distinguished from other E. 

coli strains by their ability to induce a characteristic 

attaching and effacing lesion in the smallintestinal 

enterocytes and by their inability to 

produce Shiga toxins. Between the 1940s and the 

1960s, EPEC was associated with infant diarrhea 

in summertime and nursery outbreaks of diarrhea 

in the USA and other industrialized countries. 

Since then, it has become extremely uncommon in 

industrialized countries, although it is 

occasionally reported in child-care settings. 30 

Escherichia coli 151 

Table 10.2 Pathogenic Escherichia coli 

Enteropathogenic E. coli (EPEC) 

Enterotoxigenic E. coli (ETEC) 

Enteroinvasive E. coli (EIEC) 

Enterohemorrhagic E. coli (EHEC) 

Diffusely adherent E. coli (DAEC) 

Enteroaggregative E. coli (EAggEC) 

However, EPEC persists as an important cause of 

infantile diarrhea in many developing countries. 31 

In nursery outbreaks, transmission was thought to 

occur via the hands of caregivers and via fomites. 

In less developed countries, contaminated formula 

and weaning foods have been incriminated. 

Volunteer studies and epidemiological observations 

suggest that the infective dose for EPEC is 

high (approximately 10 9 colony-forming units 

(CFU)). 32 EPEC causes a self-limited watery diarrhea 

with a short incubation period (6–48h). There 

may be associated fever, abdominal cramps and 

vomiting, and EPEC is a leading cause of persistent 

diarrhea (lasting 14 days or longer) in children in 

developing countries. 33 Although few data exist to 

guide antibiotic therapy of EPEC diarrhea, administration 

of appropriate antibiotics seems to diminish 

morbidity and mortality. A 3-day course of 

oral, non-absorbable antibiotics such as colistin or 

gentamicin (if available) has been shown to be 

effective. 34 Some clinicians also advocate the use 

of oral neomycin; however, this drug causes diarrhea 

in about 20% of people. In a placebocontrolled 

trial among Ethiopian infants with 

severe EPEC diarrhea, TMP–SMX and mecillinam 

resulted in significant clinical and bacteriological 

cure rates by the third day, as compared with 

placebo. 35 Strategies for the prevention of EPEC 

infection include efforts to improve social and 

economic conditions in developing countries, 

efforts to encourage breast feeding and prevention 

of nosocomial infections. 

Enterotoxigenic E. coli 

Strains of enterotoxigenic E. coli (ETEC) are an 

important cause of diarrheal disease in humans

152 


and animals worldwide. The clinical importance 

of these micro-organsims was first outlined in the 

1970s by epidemiological studies in India that 

identified them as a major cause of endemic diarrhea. 

36 Their pathogenicity is related to the 

elaboration of one or more enterotoxins that are 

either heat stable (ST) or heat labile (LT) (see 

Pathogenesis section) without invading or damaging 

intestinal epithelial cells. Together with 

rotavirus, ETEC is the leading cause of dehydrating 

diarrheal disease among weaning 

infants in the developing world. These children 

experience 2–3 episodes of ETEC diarrhea in each 

of the first 2 years of life. This represents over 25% 

of all diarrheal illness 37 and results in an estimated 

700000 deaths each year. 38 In industrialized countries, 

ETEC does not contribute to endemic 

disease, but is notorious for being the leading 

agent of travelers’ diarrhea, accounting for about 

half of all episodes. 39 Transmission occurs by 

ingestion of contaminated food and water, with 

peaks during the warm, wet season. Like EPEC, 

ETEC requires a relatively high inoculum 40 and a 

short incubation period (14–30h). The cardinal 

symptom is watery diarrhea, sometimes with 

associated fever, abdominal cramps and vomiting. 

In its most severe form, ETEC can cause choleralike 

purging, even in adults. The illness is typically 

self-limited, lasting for less than 5 days and with 

few cases persisting beyond 3 weeks. Infection 

with ETEC has also been associated with shortand 

long-term adverse nutritional consequences in 

infants and children. 

Most diarrheal illnesses due to ETEC are selflimited 

and do not require specific antimicrobial 

therapy. Empirical therapy is reserved for those 

whose diarrhea is moderate to severe despite rehydration 

and supportive measures. Antibiotic 

regimens that have been efficacious in clinical 

trials, shortening the duration of illness by 1–2 

days, include doxycycline, TMP–SMX, ciprofloxacin, 

quinolones, and furazolidone. 41 In the 

past, the drug of choice for children has been 

TMP–SMX; however, except in Central Mexico, 42 a 

large proportion of ETEC is now resistant. An alternative 

regimen for children is furazolidone. 

Prevention of ETEC infection is based on avoiding 

contaminated vehicles. Although antibiotics are 

effective as prophylactic agents, their use is not 

recommended. Some experts advocate the use of 

bismuth subsalicylate to diminish the risk of 

travelers’ diarrhea. 43 The development of vaccines 

against ETEC has received a great deal of attention 

because of its disease burden. Oral vaccines for 

ETEC are being developed by five different 

strategies, including killed whole cells, toxoids, 

purified fimbriae, living attenuated strains and 

live carrier strains elaborating ETEC antigens. A 

killed whole-cell Vibrio cholerae vaccine given 

with cholera toxin B (CTB) provided 67% 

protection against LT-producing ETEC diarrhea for 

3 months. 44 A formalin-inactivated whole-cell oral 

vaccine consisting of ETEC strains bearing 

colonization factor antigens (CFAs) in combination 

with CTB has entered field trial. 45 

Enteroinvasive E. coli 

This group consists of invasive E. coli strains that 

are genetically, biochemically and clinically nearly 

identical to Shigella. This section will serve only to 

highlight relevant characteristics that distinguish 

this pathogen. Strains of enteroinvasive E. coli 

(EIEC) are endemic in developing countries, where 

they exhibit similar epidemiology to Shigella and 

cause an estimated 1–5% of diarrheal episodes 

among patients visiting treatment centers. 46 The 

occurrence of EIEC in industrialized countries is 

limited to rare food-borne outbreaks. 47 From 

volunteer studies, it appears that the infectious 

inoculum contains more organisms than that 

required to cause shigellosis. 48 Like Shigella, EIEC 

can produce dysentery, but watery diarrhea is 

more common. 49 The rare episodes for which 

treatment is desired are treated with antibiotics 

recommended for shigellosis. The same general 

preventive measures used for Shigella infections 

apply to EIEC-associated diarrhea. 

Enterohemorrhagic E. coli 

These E. coli strains produce either one or both 

phage-encoded potent cytotoxins termed Shigalike 

toxin I (SLT I) (which is neutralized by antisera 

to Shiga toxin produced by S. dysenteriae type 

1) or Shiga-like toxin II (SLT II) (which is not 

neutralized) and can cause diarrhea or HUS. E. coli 

O157:H7 is the prototypic (but not the exclusive) 

enterohemorrhagic E. coli (EHEC) serotype, since it 

is the predominant SLT-producing E. coli, the one 

most commonly associated with HUS in North

America and the type most readily identified in 

stool specimens. 50 In 1982, a multistate outbreak 

of hemorrhagic colitis that was linked to the 

consumption of hamburgers at the same fast-food 

restaurant led to the identification of EHEC. 51 The 

causative organism was E. coli O157:H7, a serotype 

not previously recognized as a human pathogen. 

Soon after, Canadian investigators uncovered an 

association between O157:H7 and other SLTproducing 

strains of E. coli and HUS. 52 EHEC is 

now recognized as a global health problem; in 

1996, an outbreak in Japan linked to eating radish 

sprouts affected over 6000 persons. 53 One the most 

severe EHEC outbreaks in the USA took place in 

New York State in 1999, with more than 1000 

ascertained cases, two HUS-related casualties, and 

eight children in dialysis because of renal failure. 

Most of the infected individuals attended a fair 

whose underground water supply was contaminated 

by cow manure from a nearby cattle 

barn. The predominant mode of transmission is 

ingestion of contaminated, undercooked ground 

beef. However, the spectrum of vehicles is widening 

to include raw fruits (including apple juice) 

and vegetables, 54,55 raw milk, 56 processed meats, 57 

and drinking 58 or swimming 59 in contaminated 

water. The uncooked food vehicles are usually 

contaminated with manure from infected animals 

during growth or processing. Person-to-person 

transmission is the mode of spread in day-care 

outbreaks, where secondary transmission rates of 

22% have been reported. 60 

EHEC also causes sporadic diarrhea. Isolation from 

stools of unselected patients is low (

154 


a risk factor for the development of HUS and 

should be avoided. 

Prevention of E. coli O157:H7 is a complex 

process. From a public health standpoint, control 

measures at the level of farms, slaughterhouses 

and processing plants can decrease the risk of 

colonization of cattle and contamination of beef. 

Since these procedures are unlikely to achieve 

complete success, regulations governing proper 

processing and cooking of contaminated foods are 

also required. Advice to consumers should include 

recommending complete avoidance of raw foods of 

animal origin. Hamburger should be cooked until 

no pink remains and until the juices are clear. 

Because of the severity of disease, there has been a 

recent focus on vaccine development for EHEC 

infection. Efforts have concentrated on three 

approaches: parenteral toxoids and live oral carrier 

strains elaborating the B subunit of Shiga toxin; 74 

vaccines expressing the adhesin intimin, designed 

to prevent intestinal colonization; 75 and a 

parenteral O157 polysaccharide protein conjugate. 

76 

Diffusely adhering E. coli 

Until recently, diffusely adhering E. coli (DAEC) 

was considered a non-pathogenic E. coli, since 

early studies failed to find an association between 

this micro-organism and diarrheal disease. 77–79 

However, more recent studies have demonstrated 

such an association, particularly in children older 

than 2 years of age. A community-based 

case–control study in southern Mexico revealed 

that DAEC was significantly associated with diarrhea 

in children less than 6 years of age. 80 

Prospective cohort studies in Chile 81 and 

Bangladesh 81 also demonstrated a diarrheagenic 

role for DAEC that peaked in the 48–60-month age 

group. 81 This micro-organism was more frequently 

isolated from cases of prolonged diarrhea, 82 and it 

showed a seasonal pattern similar to that of ETEC, 

occurring more frequently in the warm season. 81 

The gastrointestinal symptoms that characterize 

DAEC infection are practically indistinguishable 

from those caused by ETEC, with self-limiting 

watery diarrhea rarely associated with vomiting 

and abdominal pain. The diagnosis is mainly 

based on the DNA probe technique and on the 

pattern of adherence of the micro-organism to HE- 

2 cells. Given the technical challenge of both 

assays, their use is limited to epidemiological 

surveys rather than the diagnosis of single individuals. 

Enteroaggregative E. coli 

Enteroaggregative E. coli (EAggEC) are diarrheagenic 

E. coli defined by a characteristic aggregating 

pattern of adherence to HEp-2 cells and the 

intestinal mucosa. They have been particularly 

associated with cases of persistent diarrhea in the 

developing world. It has been hypothesized that 

the aggregating pattern of adherence may be a 

result of non-specific, possibly hydrophobic interaction, 

and therefore, not all organisms meeting 

the definition of EAggEC may be pathogenic in 

humans. Moreover, since epidemiological studies 

have not uniformly implicated EAggEC as pathogenic, 

some investigators have questioned the 

virulence of all EAggEC isolates. Volunteer studies 

performed to address both of these questions 82 

confirmed that at least some EAggEC strains are 

genuine human pathogens but that virulence is not 

uniform among isolates. More recently, EAggEC 

pathogenicity has also been proven in several 

outbreaks. 

From the earliest epidemiological reports, EAggEC 

was most prominently associated with persistent 

cases of pediatric diarrhea (i.e. lasting ≥ 14 

days), 84 a condition that represents a disproportionate 

share of diarrheal mortality. On the Indian 

subcontinent, several independent studies have 

demonstrated the importance of EAggEC in pediatric 

diarrhea. 85 These studies include hospitalized 

patients with persistent diarrhea, 78 outpatients 

visiting health clinics, 85 and cases of 

sporadic diarrhea detected by household surveillance. 

77 In Fortaleza, Brazil, Fang et al have demonstrated 

a consistent association between EAggEC 

and persistent diarrhea; 86 in this area, EAggEC 

accounts for more cases of persistent diarrhea than 

all other causes combined. 86 EaggEC have been 

implicated as a cause of sporadic diarrhea in other 

developing countries (including Mexico, Chile, 

Bangladesh, Congo and Iran) as well as in industrialized 

countries such as Germany and 

England. 87 Besides being responsible for sporadic 

cases of diarrhea, EAggEC has also been associated

with outbreaks in India, 88 Serbia, 89 Japan 90 and the 

UK. 69 

The clinical features of EAggEC diarrhea are 

becoming increasingly well defined in outbreaks, 

in sporadic cases and in the volunteer model. 

Typically, illness is manifested by a watery, 

mucoid, secretory diarrheal illness with low-grade 

fever and little or no vomiting. 77,91 However, in 

epidemiological studies, grossly bloody stools 

have been reported in up to one-third of patients 

with EAggEC diarrhea. 92 This phenomenon may 

well be strain-dependent. In volunteers infected 

with EAggEC strain 042, diarrhea was mucoid, of 

low volume, and notably, without occult blood or 

fecal leukocytes; all patients remained afebrile. In 

such volunteers, the incubation period of the 

illness ranged from 8 to 18 h. 82 

Perhaps even more significant than the association 

of EAggEC with diarrhea are the recent data from 

Brazil that link EAggEC with growth retardation in 

infants. 92 In this study, the isolation of EAggEC 

from the stools of infants was associated with a 

low z-score for height and/or weight, irrespective 

of the presence of diarrheal symptoms. Given the 

high prevalence of asymptomatic EAggEC excretion 

in many areas, 84,93 such an observation may 

imply that the contribution of EAggEC to the 

human disease burden is significantly greater than 

is currently appreciated. Colonization of EAggEC 

is detected by the isolation of E. coli from the 

stools of patients and the demonstration of the 

aggregative pattern in the HEp-2 assay. Implication 

of EAggEC as the cause of the patient’s disease 

must be cautious, given the high rate of asymptomatic 

colonization in many populations. 84,93 If no 

other organism is implicated in the patient’s 

illness and EAggEC is isolated repeatedly, then 

EAggEC should be considered a potential cause of 

the patient’s illness. A DNA-fragment probe has 

proven highly specific in the detection of EAggEC 

strains. A polymerase chain reaction (PCR) assay 

using primers derived from the aggregative probe 

sequence shows similar sensitivity and specificity. 

94 

The optimal management of EAggEC infection has 

not been studied. Acute diarrhea is apparently 

self-limiting; however, more persistent cases may 

benefit from antibiotic and/or nutritional therapy. 

Given the high rate of antibiotic resistance among 

Clostridium difficile 155 

EAggEC, 95 susceptibility testing is recommended 

when available. 

Clostridium difficile 

Even though Clostridium difficile is now recognized 

as the single most common cause of bacterial 

diarrhea in hospitalized patients, its role as a 

pathogen had not been established as recently as 

the late 1970s. C. difficile has the ability to become 

established in the gastrointestinal tract once the 

natural microflora have been modified by antibiotic 

therapy. The organism causes intestinal 

disease ranging from mild diarrhea to fatal 

pseudomembranous colitis (PMC). While C. difficile 

is associated with almost all cases of PMC, 

only 25% of antibiotic-associated diarrheas are 

due to this pathogen. C. difficile is a Gram-positive 

anaerobe that forms spores, making this microorganism 

very difficult to remove from the hospital 

environment. Unlike some toxigenic clostridia, 

the production of spores is not associated with 

toxin production. C. difficile spreads from patient 

to patient 96 and tends to persist in the environment 

because of the formation of spores. The 

micro-organism is not only present in the infected 

patient and soiled linens but can be isolated from 

bookshelves, curtains and floors of rooms of 

infected patients where it can persist for as long as 

5 months. 96–98 The organism is spread primarily by 

health-care workers; up to 60% of personnel 

attending patients infected with C. difficile in one 

study had the organism on their hands. 96 The 

isolation of C. difficile toxins from the feces of 

asymptomatic normal-term neonates and (in 

higher proportion) those admitted into neonatal 

intensive care units, 99 further support the concept 

of the nosocomial spreading of the infection. 

Several outbreaks of C. difficile infection have 

been reported in the USA and throughout the 

world, and the incidence continues to rise. 

Whether this increase represents a true increment 

or represents an increased awareness of the 

disease is not clear at this stage. Infections with C. 

difficile range in severity from asymptomatic forms 

to clinical syndromes, such as severe diarrhea, 

PMC, and toxic megacolon, and can even lead to 

death. 100 The onset of symptomatic forms usually 

begins several days after antibiotic therapy is

156 


started up to 2 months following cessation of treatment. 

Diarrhea and abdominal cramps are usually 

the first symptoms, followed by the development 

of fever and chills in severe cases. Mild forms of 

colitis, with bloody stools and mucus, particularly 

if they are preceded by antibiotic treatment, 

should be considered suspicious for C. difficile 

infection. Clinical microbiologists face an array of 

methods and commercial tests when considering 

what procedure to use for the detection of C. difficile 

and its toxins. Culturing of the organism, latex 

agglutination, tissue culture assay and enzymelinked 

immunosorbent assay (ELISA) are all used 

as aids for the diagnosis of C. difficile infection. 

In many instances, C. difficile disease is selflimiting, 

and the patient may respond simply to 

the withdrawal of the offending antibiotic. In more 

severe forms, particularly if complicated by PMC, 

antibiotic treatment with either oral vancomycin 

101 (5–10mg/kg, maximum 500mg, given 

every 6h for 7 days) or metronidazole 102 

(5–10 mg/kg, maximum 500mg, given every 8h for 

7 days) is recommended. Despite pharmacological 

treatment, the rate of relapse is significant (up to 

40–50% of cases). In these complicated cases, the 

use of probiotics, particularly Lactobacillus GG 103 

and Saccharomyces boulardii, 104 has been associated 

with a significant eradication of C. difficile 

and a substantial decrease in the recurrence of the 

infection. 

Evaluation of diarrheal diseases 

The patient’s history, signs and symptoms should 

direct the diagnostic evaluation of the patient with 

acute infectious diarrhea. With a history of travel 

to developing nations, E. coli, Salmonella, Shigella, 

Campylobacter, cholera, Entamoeba histolytica, 

and Giardia lamblia should be high on the differential. 

Vomiting after the ingestion of fast foods, 

canned products, or raw seafood and meats should 

prompt the clinician to look for toxin-producing 

enteropathogens associated with food poisoning, 

such as Staphylococcus aureus and Bacillus cereus, 

as well as hepatitis A, parasites (tapeworms, 

flukes, trichinae), Salmonella and E. coli. The 

hospitalized patient may experience diarrhea not 

only from C. difficile, but also from procedures and 

medications (such as antibiotics, antacids, and 

medications with a high osmolality). The immunocompromised 

host presents a special challenge in 

the work-up of acute diarrhea, in the face of 

polypharmacy and malabsorpsion due to enteropathy 

and pancreatic insufficiency (see Chapter 8). 

With potential multiple pathogens, gastrointestinal 

endoscopy with biopsy and aspiration of fluid and 

fecal contents may give the highest yield of diagnosis 

in the immunocompromised patient. 

Direct examination of the stool for the presence of 

mucus, blood, or leukocytes may be helpful in 

classifying infectious agents. For example, 

profusely watery stools without mucus, blood or 

leukocytes are characteristic of cholera, 

Salmonella, ETEC, C. parvum, Giardia and most 

viral agents. The presence of mucus, blood and 

leukocytes in the stool are more consistent with 

inflammatory infections such as Campylobacter, 

EIEC, Shigella, C. difficile, Yersinia, Entamoeba 

and cytomegalovirus. 

General guidelines for treatment of 

diarrheal diseases 

As outlined in the various sections of this chapter 

(see also Chapter 37), the treatment of the majority 

of infectious diarrheal episodes is supportive, with 

ORS representing the cardinal intervention to 

minimize life-threatening dehydration, particularly 

in young children. 105 Breast feeding should 

be continued, as it may confer protection. 

Intravenous rehydration should be reserved for 

high-risk patients who are unable to tolerate enterals 

due to recurrent vomiting or diminished 

mental status. The use of antimotility agents, such 

as bismuth subsalicylate (Pepto-Bismol ® ), loperamide 

(Imodium ® ), and atropine sulfate with diphenoxylate 

hydrochloride (Lomotil ® ) should be 

discouraged, owing to the possible risk of salicylate 

intoxication, ileus, toxic megacolon, bowel 

perforation, and HUS in subjects infected with 

EHEC. Probiotics, such as Lactobacillus GG, have 

been recently shown to be effective both in the 

prevention, and in the treatment of viral 

(rotavirus) and antibiotic-associated (C. difficile) 

diarrheas, as well documented by two recent metaanalyses. 

106,107

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11 

Introduction 

Intestinal parasites 


The parasites of humans are classified into 

five major divisions: Protozoa (amebae, flagellates, 

ciliates, sporozoans, coccidia, microsporidia); 

Platyhelminths (cestodes, trematodes), Acanthocephela 

(thorny headed worms); Nematodes 

(roundworms) and Arthropods (insects, spiders, 

mites, ticks). Geohelminths are a sub-group of soiltransmitted 

intestinal nematodes with similar 

epidemiological characteristics. They include 

Strongyloides, hookworm, Ascaris and Trichuris. 1 

In this chapter, we focus on the common protozoa, 

nematodes and trematodes which affect the intestine 

(Table 11.1). Out of the large numbers of children 

infected by these parasites in the developing 

world, most are asymptomatic and do not present 

to the health services for treatment. 

The World Health Organization (WHO) estimates 

that some 3.5 billion people worldwide are 

infected by intestinal parasitic and protozoan 

infections, including 350 million with morbidity 

from ascariasis, 220 million from trichuris and 150 

million from hookworm. 2 A nationwide survey of 

intestinal parasites in China during 1988–92 on 

1.5 million people reported a prevalence of 62.6%, 

of whom 43.3% had multiple parasites. The five 

common parasites were Ascaris lumbricoides 

(47.0%), Enterobius vermicularis (26.4%), Trichuris 

trichiura (18.8%), Giardia lamblia (2.5%) and 

Entamoeba histolytica (0.9%). 3 In sub-Saharan 

African schoolchildren, on the other hand, estimates 

of the prevalence of helminth infections 

were: hookworms 32.1%, Ascaris 30.2%, Trichuris 

29.5% and Schistosoma mansoni 14.0%. 4 These 

prevalence rates have been fairly stable over the 

past 50 years with only a modest decrease in 

ascariasis. However, higher rates have been 

reported, such as surveys reporting that only 14% 

of Tanzanian and 37% of Ghanaian children were 

free from worm infections. 5 Intestinal parasites 

also occur in industrialized countries, with a third 

of 5792 fecal specimens positive for parasites in 

the USA in 2000, peaking between July and 

October. 6 

The peak age for intestinal parasites tends to be 

school-age children but overt sickness from them 

is the exception. A large Tanzanian morbidity 

survey of schoolchildren found that no sign or 

symptom was significantly associated with any 

helminth infection, only blood in stool and 

hepatomegaly with Schistosoma mansoni. 7 The 

major determinant of morbidity from parasitic 

diseases is the intensity of infection, but this is 

rarely reported in children. A Zairean study found 

that the highest mean intensities (measured as 

eggs per gram of feces (epg)) of Ascaris and 

Trichuris were among 2–4-year-olds, whereas 

school-age children excreted the most hookworm 

ova. 8 Using disability-adjusted life years lost 

(DALY), WHO estimated that intestinal helminthiasis 

caused 39 million DALYs, with 57% attributed 

to hookworm, 27% to ascariasis and 16% to 

trichurasis. 2 

The most common symptoms of intestinal parasites 

are diarrhea and/or failure to thrive from 

anorexia and malabsorption. The protozoa Giardia 

lamblia and Cryptosporidium parvum are common 

causes of diarrhea in children, but other protozoa 

such as Cyclospora cayetanensis, Entamoeba 

histolytica, and Microsporidia species may also 

cause diarrhea, and these include Isospora belli in 

immunodeficient (e.g. HIV-seropositive) patients. 

Only five helminthic parasites are associated with 

diarrheal disease: Strongyloides stercoralis, 

Trichuris trichiura, Schistosoma mansoni, 

Trichinella spiralis and Capillaria philippinensis. 9 

Strictly intraluminal worms (e.g. Ascaris lumbricoides) 

only rarely affect intestinal function 

161

162 

Table 11.1 Classification of intestinal parasites 


Infection Other name Symptoms Transmission Alternative treatments Treatment of choice 

PROTOZOA 

Intestinal amebae 

Entamoeba histolytica amebiasis dysentery fecal–oral metronidazole 

Entamoeba dispar asymptomatic fecal–oral nil 

Flagellates 

Giardia lamblia (duodenale giardiasis chronic diarrhea, fecal–oral metronidazole tinidazole 

or intestinalis) malabsorption 

Ciliates 

Balantidium coli asymtomatic fecal–oral nil 

Coccidia 

Cryptosporidium parvum cryptosporidiosis persistent diarrhea fecal–oral nitazoxanide* 

Cyclospora cayetanensis cyclosporiasis diarrhea fecal–oral co-trimoxazole 

Isospora belli isosporiasis diarrhea with AIDS fecal–oral co-trimoxazole 

NEMATODES 

Ascaris lumbricoides roundworm intestinal obstruction fecal–oral levamisole, pyrantel albendazole † 

Enterobius vermicularis pinworm, threadworm nocturnal anal pruritis fecal–oral levamisole, pyrantel albendazole † 

Ancylostoma duodenale hookworm iron deficiency anemia percutaneous levamisole, pyrantel albendazole † 

Necator americanus hookworm iron deficiency anemia percutaneous levamisole, pyrantel albendazole † 

Strongyloides stercoralis strongyloidiasis diarrhea percutaneous albendazole ivermectin 

Trichuris trichiura whipworm, trichuriasis dysentry, rectal fecal–oral levamisole, pyrantel albendazole † 

prolapse (rare) 

CESTODES 

Hymenolepis nana dwarf tapeworm asymptomatic fecal–oral praziquantel nitazoxanide* 

TREMATODES 

Schistosoma mansoni bilharzia melena, portal percutaneous oxamniquine praziquantel 

hypertension 

Fasciolopsis buski giant intestinal fluke percutaneous praziquantel 

*Nitazoxanide is the drug of choice (if available) where treatment is indicated; †or mebendazole

adversely when the intensity of infection is high. 

Infections such as giardiasis, cryptosporidiosis and 

severe trichuriasis may contribute to growth 

failure via malabsorption, so their resolution or 

treatment should lead to catch-up growth. 

Malnutrition appears to predispose children to an 

acute diarrheal syndrome in strongyloidiasis, 

which may then exacerbate the nutritional status 

through anorexia and enteropathy. 10 Owing to the 

prolonged carriage of many parasites, only 

Strongyloides and Cryptosporidium have a consistently 

significant association with diarrheal 

disease when compared to non-diarrheal controls 

(Table 11.2). 

Giardiasis 

Introduction 

Giardia lamblia (also called intestinalis or duodenale) 

is a flagellate protozoan with two stages: 

motile trophozoites (Figure 11.1) and cysts. 

Life cycle 

Infection may result from ingesting cysts, which 

release trophozoites in the upper small intestine, 

attaching to the mucosa by a ventral disc. Giardia 

trophozoites undergo significant biological 

changes to survive outside the host by 

differentiating into infective cysts, which is 

promoted by exposure to conjugated bile salts and 

Figure 11.1 Giardia lamblia trophozoite. Courtesy of UK 

Tropical International Health. 

Table 11.2 Parasites in diarrhea in children: case–control studies 

Guinea-Bissau 16 Bangladesh 207 Five Countries †208 Tropical Australia 10 South Africa 209 Total 

Cases Controls Cases Controls Cases Controls Cases Controls Cases Controls Cases Controls 

n 1219 511 814 814 3640 3279 290 85 373 371 6336 5060 

Giardia 233 128 7 23 109 98 9 5 24 22 6.0% 5.5% 

Cryptosporidium* 69 11 11 3 20 1 9 2 4.0% 1.0% 

Strongyloides* 54 15 21 2 5.0% 2.9% 

Entamoeba 50 31 5 1 11 3 0 0 1 0 1.1% 0.7% 

Ascaris 7 1 0 0 40 53 2.5% 5.6% 

Hookworm 31 28 1 0 2.1% 4.7% 

Trichuris 5 2 22 4 13 23 2.1% 3.0% 

Hymenolepis 2 0 2 4 1 3 0.3% 0.7% 

Giardiasis 163 

*Significantly associated with diarrhea, odds ratio 4.4 (95% CI 2.6–7.6) for Cryptosporidium and 1.8 (95% CI 1.0–3.3) for Strongyloides 

†China, India, Mexico, Myanmar, Pakistan

164 


low levels of cholesterol. 11,12 A specific proteolytic 

event caused by a constitutively expressed 

membrane-associated dipeptidyl peptidase IV is 

necessary for encystation. 13 The incubation period 

is 1–2 weeks. 

Epidemiology 

Giardia lamblia is one of the most common parasitic 

infections in humans with a prevalence of 

2–5% in industrialized countries, and high transmission 

rates in day-care center outbreaks among 

12–36-month-old children who are not toilet 

trained. 14,15 In developing countries, prevalences 

of 20–30% occur with up to 60% of children 

infected at some time during childhood. Since 

cysts are excreted for prolonged periods, community 

studies often find higher rates of infection in 

children without diarrhea than in diarrheal 

cases. 16 Giardia accounts for about 5% of travelers’ 

diarrhea and is more common in children with 

immunodeficiency, although not HIV infection. 

The main routes of transmission are water, food 

and fecal–oral. Infection may occur after the ingestion 

of only 10–100 cysts and unfiltered water has 

been a common source of outbreaks in developed 

countries. 

A Brazilian 4-year cohort study of 157 children 

from an urban slum documented substantial 

morbidity from giardiasis, with a similar frequency 

between diarrheal and non-diarrheal cases (9.7% 

vs. 7.4%), an association with persistent diarrhea 

(20.6% of episodes) and recurrent or relapsing 

infections (46%) and poorer nutritional status for 

those with symptomatic infections. 17 A study of a 

rural Egyptian cohort of 152 infants documented 

4.5 episodes per child-year with a mean duration 

of excretion of 7.2 weeks, and reduced risk in 

breast-fed infants, particularly for symptomatic 

illness. 18 A Kenyan cohort study of 84 rural children 

aged 10–28 months reported a 44.7% prevalence, 

an estimated incidence of 2.8 episodes per 

year and a duration of 75.3 days per child for giardiasis. 

19 


Despite intensive investigations, the exact mechanisms 

by which Giardia causes diarrhea and 

malabsorption are still unclear. There is evidence 

of a secretory mechanism, malabsorption, 

decreased brush-border surface area and interference 

with intraluminal digestion. Another possible 

mechanism for diarrhea is small-bowel bacterial 

overgrowth, but mucosal invasion is uncommon. 

Duodenal morphology may be normal, but partial 

or even total villus atrophy may occur, as well as a 

mucosal inflammatory response with increased 

intraepithelial lymphocytes. Giardia parasites are 

able to adhere to the gut mucosa and may cause a 

direct effect on intestinal function by disrupting 

the brush border and its enzymatic system. 

The effect of giardiasis on intestinal structure and 

function is quite variable, but animal and in vitro 

studies have documented villus atrophy, malabsorption, 

increased paracellular permeability and 

reduced brush-border enzymes. 20,21 Giardia 

trophozoites are known to produce glycosidase 

enzymes which may affect the barrier function of 

mucins secreted by mucosal epithelial cells. 22 An 

Italian study of 61 children with symptomatic giardiasis 

documented lactose malabsorption on 

breath testing, resulting in intolerance to cows’ 

milk but not to yogurt. 23 However, a breath hydrogen 

study in asymptomatic Mexican children with 

giardiasis did not find significant carbohydrate 

malabsorption. 24 Another study found only 

modest effects of Giardia treatment on biopsy 

changes, absorptive studies and bile salt conjugation, 

suggesting that the parasite’s effect was 

synergistic with other organisms in contributing to 

tropical enteropathy. 25 

A Danish study of 29 children with chronic diarrhea 

from giardiasis documented enteropathy in 

20, vitamin B12 malabsorption in nine, folate 

malabsorption in only five, no evidence of smallbowel 

bacterial overgrowth (SBBO) or iron malabsorption 

and more severe manifestations in those 

who acquired giardiasis overseas. 26 A study of 210 

urban Nepali children found no association 

between helminth infection and growth or intestinal 

permeability, but the eight children with giardiasis 

had significantly higher mean permeability 

ratios (L : M ratio 0.43) than for either helminth 

infected (0.27) or uninfected (0.25). 27 A Canadian 

study in a mouse model showed that Giardia 

trophozoites increase small-intestinal permeability, 

mediated by a myosin light chain kinasedependent 

cytoskeletal effect on tight junctions. 28 

This disrupted enterocyte barrier function was 

T-cell independent and did not affect the stomach

or colon. It is still unclear whether it is these 

effects or other mechanisms that cause the T-celldependent 

shortening of the brush-border 

microvilli with reduced disaccharidases and 

impaired absorptive function. 

The immune response to Giardia involves both 

humoral and cellular mechanisms. 29 Humans 

produce IgG, IgM, IgA and IgE responses including 

cytotoxic antibodies and an important intestinal 

IgA response to acute infection. Nevertheless, 

there is still no direct evidence that antibodies 

control infection. A Gambian study of six children 

with giardiasis, persistent diarrhea and malnutrition 

who failed to clear infection after treatment 

had raised only Giardia-specific IgM antibodies, so 

poor serum and secretory IgA response may be a 

marker for ineffective parasite clearance. 30 

Children with agammaglobulinemia, but not HIVinfected 

children, are susceptible to giardiasis and 

it is difficult to eradicate. Breast feeding provides 

protection from symptomatic disease, but not from 

infection. 31 

An association between giardiasis and allergy has 

been suggested based on the hypothesis that 

increased antigen penetration through damaged 

intestinal mucosa enhances sensitization to food 

antigens. One study documented allergy symptoms 

in 70% of children with giardiasis who had 

mean IgE levels of 1194 IU/ml compared to 43% 

and 822 IU/ml, respectively, for controls. 32 The 

giardiasis group also had higher levels of specific 

serum IgE antibodies to food allergens compared 

both to controls and to other parasitic infections, 

whereas IgE responses to house dust mite were 

similar. 


The clinical manifestations of Giardia infection 

vary from asymptomatic passage of cysts to 

chronic diarrhea with malabsorption and weight 

loss. The usual clinical syndrome is characterized 

by watery diarrhea, foul-smelling stools, bloating 

and abdominal cramps. Only about half of patients 

develop symptoms following ingestion of cysts, 

with 15% passing cysts asymptomatically and the 

remainder showing no trace of infection. Although 

older children may be asymptomatic, infection 

early in life usually causes acute symptoms with 

watery diarrhea, anorexia, abdominal distension 

Giardiasis 165 

and foul stools which persist untreated and may 

result in malabsorption. The course of giardiasis is 

frequently prolonged and, although many eventually 

resolve without treatment, some go on to 

syndromes of chronic diarrhea or frequent 

relapses. The severity of disease may be determined 

by strain-dependent virulence factors in the 

parasite, as well as age, nutritional status and 

immunocompetence of the host. 33 Young children 

are more likely to be severely affected, with failure 

to thrive, hypokalemia and malabsorption (fat, 

vitamins A and B12, protein and lactose). Children 

in the developing world with chronic diarrhea and 

malnutrition often have giardiasis, but it is not 

always clear how much Giardia is contributing to 

the illness, since they are often co-infected with 

other enteric pathogens. The results of a small 

Venezuelan trial suggested that the therapeutic 

control of giardiasis could be important in 

programs to combat anemia in children living in 

settings with high prevalence. 34 

Diagnosis 

The diagnosis of giardiasis relies upon stool 

microscopy finding trophozoites or cysts. The 

sensitivity of a single stool is only 50–70% but 

increases to 90% if three stools are examined. 

Commercial assays for Giardia antigen are more 

sensitive and use polyclonal or monoclonal antibody 

directed against cyst or trophozoite antigens, 

usually as an enzyme-linked immunosorbent 

assay (ELISA) or immunofluorescent assay. These 

antigen detection assays are most useful for population 

screening such as children at day-care 

centers. Duodenal aspirates or biopsies are invasive, 

so are not justified exclusively to diagnose 

giardiasis, but when done for other reasons are 

reliable, particularly in the immunocompromised 

subject. 

Prevention 

Giardia is waterborne and cysts are highly resistant 

to chlorine and ozone, so filtration provides 

the best protection against transmission through 

tap water. 35 Hygiene measures to prevent 

fecal–oral transmission need to focus on young 

children. The drug treatment of choice for symptomatic 

disease (not just cyst excretors) is tinidazole 

(see p.183).

166 


Ascariasis 

Introduction 

Ascaris lumbricoides is a large, 15–35cm long 

white roundworm that is specific to humans. 

Ascaris is one of 63 species of nematode infecting 

humans, and the adult roundworm has a biologically 

inert surface, so the main antigenic stimuli to 

the host are excretory and secretory antigens from 

the orifices. A. suum is the related pig species 

which may migrate through human tissues in the 

larval stage, 36 but cannot complete its life cycle in 

man. 

Life cycle 

The female Ascaris worm produces about 200000 

eggs/day, which embryonate in soil in about 3 

weeks to become infectious, but are sensitive to 

excessive heat, drying and sunlight. Ingested eggs 

moult to form larvae (0.2mm long) which penetrate 

blood vessels or lymphatics and travel to the 

lung via the portal vein or thoracic duct to 

pulmonary capillaries and alveoli, where they 

moult, grow in size, migrate up the airways and 

down the esophagus, and mature and reproduce in 

the small intestine. Adult Ascaris are large white 

roundworms (females 2–4cm long) which, unlike 

hookworm and Trichuris, do not attach to the 

mucosa but live free in the small-intestinal lumen. 

The duration of the life cycle from ingestion of 

Ascaris ova to new egg excretion in feces by the 

mature worm takes about 2 months. Adult worms 

are expelled from the intestine after about 18 

months. 

Epidemiology 

Ascariasis is one of the most prevalent infections 

in the world affecting approximately 1400 million 

people (23% of the world population) with 59 

million (mostly children) at risk of morbidity, 

including 95% of the population of Africa and 45% 

of inhabitants of Central and South America. 37 

Highest prevalences are found in countries where 

sanitation is deficient, and children have higher 

mean worm loads than adults. There is some 

evidence of a predisposition to high infestation of 

Ascaris worms due to a genetic or immunological 

predisposition. Morbidity is related to worm load, 

which is indirectly assessed by egg concentration 

per gram (epg) of feces (e.g. light infection, 

< 5000epg, heavy infection, > 50000epg). 

Community prevalence levels greater than 70% are 

associated with high worm burdens, likelihood of 

morbidity and rapid reinfection, so warrant antihelminthic 

control programs (see below). 38 

Geophagy (eating soil) is a risk factor for ascariasis 

in African schoolchildren. 39,40 

Immunology of helminths 

An important principle of helminth immunology 

is that very few responses elicited by infection are 

likely to be functionally protective and some have 

severe pathological consequences for the host. 

Immune responses can also be divided into innate 

(immediate response on exposure with little 

memory and broad molecular specificity not 

involving lymphoid cells) and adaptive (lymphocyte-mediated 

and antigen-specific with 

memory). 41 Although immune responses in the 

intestinal mucosa are similar to systemic 

responses, an important difference is the predominance 

of IgA antibodies. 

Immune responses against helminth invasion 

rarely eliminate them directly. Effective immunity 

against reinfection is also difficult to demonstrate 

for helminth infections, since worms persist in the 

face of specific immune responses, although agerelated 

declines in infection rates do occur in 

endemic areas. However, detailed epidemiological 

and animal model studies have demonstrated that 

acquired protective immunity is important for 

control of hookworm, Trichuris and schistosomiasis. 

41 Ascaris produces the lipid-binding protein 

ABA-1 which can stimulate IgE antibodies, high 

levels of which correlate with protection against 

Ascaris. 42 

The traditional view of the host immune response 

was that with time it reduced their fecundity and 

survival via mechanisms such as induction of 

intestinal mast cells and eosinophils. More recent 

evidence suggests that other indirect host 

responses may result in parasite starvation or 

depletion of energy sources for defending itself 

against the host’s immune responses, leading to 

reduced fecundity or survival. 43 However, there is 

also a cost to the host from mounting an immune

esponse to the parasite, particularly on nutritional 

status in children. For example, zinc deficiency 

may prolong nematode survival in the host by its 

known effect on mucosal immune function. 44 In 

addition, many helminths release immunomodulatory 

molecules which inactivate components of 

the host’s immune response, but this may also 

predispose the host to other infections such as 

tuberculosis (TB) or AIDS. There is also evidence 

that ascariasis impairs immune responses to 

vaccines in that albendazole treatment increased 

the seroconversion rate and antibody titers after 

cholera immunization, mediated by suppression of 

interleukin (IL)-2 responses. 45,46 Moreover, treatment 

of helminths in HIV-infected individuals was 

associated with significant reductions in viral 

load. 47 

Immune-mediated inflammation occurs in most 

parasitic infections, particularly involving IgE 

antibodies, eosinophils, cytokines and T cells, but 

there are important differences between helminths 

and protozoa. First, although protozoa may be 

phagocytosed by macrophages, cell-mediated 

immunity against helminths involves attachment 

to its surface with antibody or complementmediated 

mechanisms and release of mediators 

which damage its surface. Second, whereas protozoa 

tend to elicit T-helper lymphocytes with activation 

of macrophages, cytokines (IL-12) and 

specific IgG antibodies (Th1 responses), helminths 

elicit Th2 responses with IL-4 stimulating IgE antibodies 

and inflammatory cells (e.g. eosinophils 

and mast cells). Thus, compared to controls, 

cytokine responses in Ascaris-infected subjects 

involved mononuclear cell IL-4 and IL-5 stimulation 

with no difference in IL-10 and interferon-γ 

responses, consistent with a highly polarized Th2 

cytokine response. 48 

Helminth infections are characterized by 

increased mast cells and eosinophils. The key 

function of IL-5, which is produced by activated 

CD4 T cells, is control of eosinophils, although 

early differentiation of eosinophils is controlled by 

granulocyte-macrophage–colony-stimulating 

factor (GM-CSF) and IL-3. It is now recognized that 

eosinophils, together with antibody and complement, 

have a role in the killing of infective larval 

stages of most helminths, but not of adult worms. 

Recent studies in mice suggest that the effect of IL- 

5 and eosinophils differs for each parasite species, 

Ascariasis 167 

but they do have a role in host protection which is 

not yet clearly defined. 49,50 

IgE antibodies are an important component of 

host-protective immune responses against 

helminthic parasites, including both parasitespecific 

IgE and non-specific polyclonal IgE mediated 

by IL-4. Excessive polyclonal stimulation of 

IgE synthesis by helminths, which is prevented by 

anthelminthic treatment, suppresses allergic reactivity 

by saturating mast cell receptors and inhibiting 

specific IgE antibodies (e.g. to inhaled antigens 

such as house dust mite) and skin test reactivity. 51 

Compared to urban children, rural Kenyan children’s 

total IgE and Ascaris-specific IgE antibodies 

were much higher, and evidence of atopy (skin 

testing, bronchial hyper-reactivity) were much 

lower. 52 A Venezuelan study examined two groups 

of children with comparable living conditions and 

Ascaris prevalence but with very different prevalences 

of allergic disease. 53 Those in the atopic 

group had an intrinsic propensity for specific over 

polyclonal IgE responses to the parasite and had 

significantly lower intensities of infection than the 

non-atopic group, suggesting that the atopic state 

conferred a selective evolutionary advantage. 

Immune responses are useful as a means of diagnosing 

infection by ELISA tests. The major drawback 

of antibody-based tests is that a positive test 

does not prove current infection in an endemic 

area, although use of particular classes of antibody 

(e.g. IgG4, IgM) may improve the specificity. 

Newer diagnostic tests by antigen-capture ELISA 

for coproantigens in feces are becoming available, 

which are highly sensitive and specific. 


Ascaris infection is not associated with mucosal 

damage, increased intestinal permeability or 

lactose malabsorption, 54,55 since 85% of infected 

individuals have light infections which remain 

asymptomatic. Heavy infection (ingestion of 

> 2000 eggs) may induce a pneumonitis from 

migrating pulmonary larvae, with cough, wheeze, 

eosinophilia and transient patchy infiltrates which 

may be difficult to differentiate from pneumonia, 

asthma or bronchitis. This syndrome of tropical 

pulmonary eosinophilia (Loeffler’s) is rarely 

recognized clinically in children with Ascaris or

168 


hookworm, but is more often symptomatic with 

filariasis or toxocara infections. 56 

The most common clinical feature of ascariasis is 

intestinal obstruction from a bolus of worms, 

which occurs in 0.2% of infections in children, 

accounting for 72% of all complications of 

Ascaris. 57 The mean age of cases is under 5 years 

and the case fatality rate about 5.7%. Surgical 

management can invariably be avoided with experience 

with this syndrome, and daily nasogastric 

administration of anthelminthics with supportive 

therapy until the bolus is passed. Worms are often 

vomited or passed in stool on presentation of 

febrile children with severe malaria or bacterial 

infections, which invariably prompts comments 

from health workers about them ‘abandoning a 

sinking ship’. Fever, acute phase reactants and 

certain irritants (e.g. carbon tetrachloride, a former 

hookworm therapy) are associated with worm 

expulsion or aberrant migration. Less frequent 

complications of migrating Ascaris worms are 

biliary colic, pancreatitis, appendiceal abscess and 

appearance through a surgical abdominal wound. 

Diagnosis 

The diagnosis of ascariasis is based upon identification 

of the characteristic eggs on microscopy of 

stool or identification of the adult worm passed 

spontaneously or after treatment. Eggs are plentiful 

in feces since each female produces a mean of 

200 000 daily, although the correlation between 

eggs per gram of feces and intensity of infection is 

imperfect. 

Prevention 

If human feces are used as fertilizer for growing 

vegetables, they need to be stored at 30°C for 40 

days to ensure destruction of ova. A number of 

reports have examined environmental risk factors 

for ascariasis. A Brazilian study, for example, gave 

the following relative risks with 95% CI for ascariasis 

intensity: over crowding 2.2 (1.0–4.5), poor 

household water availability 2.4 (1.1–5.0), poor 

hygiene 2.4 (1.0–5.6), less than 4 years’ schooling 

5.9 (2.6–14.3) and no recent anthelminthic treatment 

2.0 (1.0–4.0). 58 A Kenyan study found that 

household overcrowding and the absence of 

latrines increased the risk of hookworm infection, 

whereas a lack of soap and other household children 

under 5 years increased the risk of Ascaris 

infection. 59 Since the lack of latrines and soap 

usage were identified as risk factors for infection, 

helminth control interventions should focus on 

these. Mass chemotherapy campaigns for 

geohelminths is discussed below. 

Hookworm 

Introduction 

The two major species of hookworms are 

Ancylostoma duodenale and Necator americanus 

(Figure 11.2). They will be considered together 

here, because they have similar life cycles and 

disease. However, Ancylostoma tends to be more 

virulent than Necator, and adult females are larger 

(10–13 vs. 9–11 mm), survive for a shorter time in 

the host (1 vs. 4 years), produce more eggs 

(10 000–30 000 vs. 5–10 000/day), cause greater 

blood loss (0.2 vs. 0.02ml/day) and their larvae can 

rest dormant and infect via oral ingestion (unlike 

Necator). 

Life cycle 

The gravid female hookworm produces about 

5000–30 000 eggs/day (60µm long) in feces, which 

require a moist shady environment to hatch into 

Figure 11.2 Necator americanus hookworm. Courtesy of 

UK Tropical International Health.

habditiform larvae (300µm long) which grow to 

become infective larvae (600µm) and enter the 

host’s venules or lymphatics, usually when walked 

upon with bare feet. The larvae then migrate into 

the lungs and ascend up the respiratory tract and 

descend to the small intestine, where they attach 

and mature in the jejunum. The time from infection 

to egg production is almost 2 months. 

Epidemiology 

Hookworm is probably the second most prevalent 

intestinal parasite after ascariasis, with 1200 

million people infected worldwide (two-thirds by 

Necator), including 90–130 million with morbidity. 

Necator predominates in Central and South 

America (New World), and Ancylostoma in India, 

China, North Africa and tropical Australia, but 

mixed infections occur in many regions of Asia, 

Africa, Central America and the South Pacific. 

Ancylostoma extends into more temperate regions 

than Necator (e.g. North Africa, China and Europe) 

because its ova are more resistant to cold. In an 

urban Nigerian study of 862 schoolchildren with 

hookworm, 72.0% had Necator alone, 4.5% 

Ancylostoma alone and 23.4% both species of 

hookworm, but with Necator in higher numbers. 60 

Unlike Ascaris and Trichuris, hookworm transmission 

is closely associated with rural farming rather 

than urban slums. There are several other species 

of dog and cat helminths (e.g. Toxocara species) 

which can cause eosinophilic enteritis, cutaneous 

larva migrans or viscera larva migrans in humans. 

For example, studies in tropical Australia have 

described eosinophilic enteritis with abdominal 

pain caused by Ancylostoma caninum, a dog hookworm. 

61 


Hookworms attach to the mucosa with teeth 

(Ancylostoma) or cutting plates (Necator) and 

release anticoagulant polypeptides and neutrophil 

inhibitory factor which down-regulate the inflammatory 

response of the host. They also release 

hydrolytic enzymes which damage mucosal capillaries 

and exacerbate the blood loss. Hookworm 

larvae release Ancylostoma-secreted proteins 

(ASPs) during the early stages of infection, which 

are highly antigenic. The indirect evidence of 

Hookworm 169 

reduced hookworm burdens in adults suggests an 

effect of host immunity, but humoral antibodies 

and cell-mediated immune responses correlate 

poorly with resistance to infection. The possibility 

of a hookworm vaccine to ASPs is under investigation. 

62 


Hookworm larvae entering skin can result in a 

papulovesicular rash at the site of entry (ground 

itch) or cutaneous larvae migrans for animal hookworms. 

Although eosinophilia accompanies the 

larval migration phase, pneumonitis is mild and 

rarely recognized in children. The main morbidity 

from hookworm is iron deficiency anemia, particularly 

with heavy infections. It was not uncommon 

in Caribbean and Pacific islands to have 

school children presenting in congestive heart 

failure with loud hemic murmurs and hemoglobin 

levels of

170 

Prevention 


Measures to prevent hookworm include ceasing 

the use of human feces as fertilizer, use of toilets, 

wearing shoes and generally improving living 

standards. Mass treatment programs with albendazole 

have a transient effect, but need to be 

combined with improved sanitation and health 

education to prevent high reinfection rates. 64 Iron 

supplementation has no effect on either reinfection 

rates or helminth intensities in children. 65 In 

high prevalence areas of hookworm infection and 

schistosomiasis, regular mass deworming 

campaigns with albendazole and praziquantel are 

effective in reducing anemia rates. 66,67 

Trichuriasis 

Introduction 

Trichuris trichiuria, meaning ‘hairy tail’, is actually 

a misnomer, since it is the proximal end that is 

hairlike. The popular name is whipworm, with the 

whip as the long thin pharynx (stichostome) and 

the whip handle as the posterior end with reproductive 

organs and intestine (Figure 11.3). 

Life cycle 

A mature female worm produces up to 20 000 

eggs/day, which are 50 µm long and not infectious 

until the larval stage develops in the soil over 2–4 

weeks. Warm damp soil is ideal for embryonation, 

Figure 11.3 Trichuris trichiura worms attached to the 

colon. Courtesy of UK Tropical International Health. 

and environmental exposure is associated with 

poor hygiene practices. Once ingested, larvae 

penetrate the epithelium of the mucosal crypt in 

the cecum, where they moult and the hair-like 

stichosome remains attached while the broader 

distal end extends into the lumen. The adult worm 

is 4 cm long and survives for 1–2 years in the host. 

Epidemiology 

Trichuriasis is a very common infestation with an 

estimated 1049 million cases worldwide, including 

114 million preschool and 233 million schoolage 

children. 68 Most of these infections are asymptomatic, 

but children suffer greater morbidity than 

adults. There appears to be a genetic or immunological 

predisposition to heavy infection, which 

may be HLA group-mediated. 69 There also appears 

to be some epidemiological ‘synergism’ between 

ascariasis and trichuriasis in that high-intensity 

infections occur together more often than by 

chance. 70 


With severe infection, the cecal mucosa becomes 

inflamed and edematous, but there are only minor 

changes in histology (increased IgM lamina 

propria plasma cells and calprotectin-secreting 

cells, crypt epithelial cell proliferation, distended 

goblet cells). 71 The cytokine response in colonic 

mucosa involves both interferon-γ (Th1) and IL-4 

(Th2), but results in neither worm expulsion nor 

obvious protection from reinfection. There may be 

a protein-losing enteropathy proportional to the 

worm burden. 72 There is an acute-phase response 

with intense trichuriasis, including increases in 

plasma tumor necrosis factor (TNF)-α, C-reactive 

protein (CRP), globulins, viscosity and fibronectin 

with decreased insulin-like growth factor (IGF)- 

I 73–75 . There is also development of an IgEmediated 

immediate hypersensitivity reaction in 

the colon, 76 usually, but not always, with systemic 

eosinophilia. 


Most infections in children are light (< 20 adult 

worms) and asymptomatic, with symptoms developing 

in < 10% of infected children. Occult blood

in feces is uncommon even with heavy infestations, 

although even light infections incite a local 

inflammatory response involving eosinophils and 

neutrophils in the colon. 77,78 With heavy infestations, 

frequent watery or mucous stools occur, 

sometimes with frank blood. Rectal prolapse can 

occur with heavy infestations. 79,80 A very small 

minority of heavily infected children (>200 

worms in the rectum, colon and often terminal 

ileum) develop the Trichuris dysentery 

syndrome, 81,82 characterized by chronic dysentery, 

stunting, anemia and finger clubbing. 

Diagnosis 

The diagnosis is based on finding eggs on stool 

microscopy, with more than 10 000 epg generally 

associated with heavy infection, although there is 

considerable individual variation in eggs to worm 

load. Trichuris dysentery in children must be 

differentiated from amebic and bacilliary causes. 

Most cases of rectal prolapse in malnourished children 

are not due to trichuriasis. 

Prevention 

The use of proper latrines, good hygiene with 

handwashing and washing of vegetables will interrupt 

the life cycle. Overcrowded urban slums with 

limited water supply and heavily fecally contaminated 

soil for growing vegetables place children at 

particular risk. Mass chemotherapy is highly effective, 

but reinfection occurs rapidly in this setting. 

Cryptosporidiosis 

Introduction 

The protozoa Cryptosporidium parvum, Isospora 

belli, Cyclospora cayetanensis and Sarcocystis 

hominis all belong to the group of intestinal 

coccidial infections, which cause diarrhea. They 

have come into prominence in recent years due to 

causing severe and protracted diarrhea in AIDS or 

cell-mediated immune deficiency and infecting 

piped water supplies due to the chlorine resistance 

of oocysts. The opportunistic protozoal infections 

which affect HIV-infected patients include 

Cryptosporidium, Microsporidia, Cyclospora and 

Cryptosporidiosis 171 

Isospora belli. Cryptosporidium also causes persistent 

diarrhea and proximal small-intestinal 

enteropathy in children with normal immune 

function. 10,83 

Life cycle 

Cryptosporidiosis is transmitted by a 3–6µm acidfast 

thick-walled oocyst shed in stool which 

encysts in the lumen of the small bowel after 

ingestion and produces four sporozoites. These 

penetrate the microvillus border and develop into 

trophozoites, which cause disease and can reproduce 

asexually, releasing eight merozoites, which 

invade nearby cells and redevelop into trophozoites 

to continue the infection. The life cycle is 

completed by asexual reproduction of trophozoites 

to schizonts, which develop progressively into 

male microgametes or female macrogametes, 

combining to form zygotes and then oocysts, 

which pass into the stool. After ingestion of 

oocysts, encystation takes place in the upper small 

intestine and sporozoites invade the absorptive 

epithelial cells causing inflammation, partial 

villus atrophy, malabsorption and diarrhea. About 

20% of oocysts are thin-walled and can autoinfect 

the host, which explains how a small number of 

ingested oocysts can cause severe disease, especially 

in immunocompromised patients. Fecal 

oocysts can survive for at least 2 days, and the 

incubation period from cyst ingestion to diarrhea 

in humans is 2–14 days. The major difference from 

Plasmodium species (malaria) is that Cryptosporidium 

completes its life cycle in a single host 

without the mosquito vector. 

Epidemiology 

Cryptosporidium causes diarrheal disease in children 

of developing countries, in travelers and in 

immunocompromised patients; there have been 

waterborne outbreaks in developed countries. 

Transmission is from person to person and from 

animals to people by ingestion of fecally contaminated 

food or water. C. parvum infects numerous 

mammals, including man and cattle, and although 

there is a human-specific form, animal forms may 

also cause disease in humans. Oocysts are highly 

infectious, with ingestion of a median of 132 cysts 

found to be infectious in adult volunteers. Infected

172 


AIDS patients excrete millions of oocysts daily. 

Person-to-person transmission is common, occurring 

in 19% of infected children and is especially 

common in day-care center settings. Oocysts are 

relatively resistant to conventional chlorination 

and filtering, but 1-µm filters, heating (72°C for a 

minute) and freezing are effective. 

Cryptosporium has been reported to occur in 6.1% 

of diarrheal cases vs. 1.5% of controls in developing 

world subjects compared to 2.2% vs. 0.2%, 

respectively, in the developed world. For AIDS 

patients, these rates increase to 24% vs. 5%, 

respectively, in the developing world and 14% vs. 

0% in the developed world. A Peruvian periurban 

study found a peak cryptosporidiosis incidence of 

0.42 episodes/year in 1-year-olds (mean childhood 

incidence of 0.20), with the rainy season and lack 

of toilets as risk factors. 84 In Zambian periurban 

children, cryptosporidial infection appeared to be 

predominantly waterborne with a prevalence 

among diarrheal cases of 18%, and no association 

with home animals, nutritional status or parental 

education. 85 

In community studies of children in Guinea- 

Bissau, Cryptosporidium was found in 5.8–7.4% of 

diarrheal episodes and 2.0% without diarrhea, 

with peak prevalences in the early rainy season 

(17.6% in May), in young children (e.g. 12.6% in 

infants < 6 months) and with persistent diarrhea 

(15%). 86–88 Additional risk factors were pigs and 

dogs in the household, prolonged storage of 

cooked food and male sex, but not impaired immunity. 

89 According to the authors, the epidemiology 

of infection was consistent with a small infective 

dose, airborne transmission and slow development 

of protective immunity. In Kuwait, C. parvum 

oocysts were found in 10% (51 cases) of childhood 

diarrhea, but more older children were affected 

(73% > 2 years). 90 A Gambian study of 1200 children 

documented Cryptosporidium in 8.8% of diarrheal 

cases vs. 2.8% of controls (p < 0.001), with 

peak incidence during the rainy season and among 

infants (6–11 months). 91 A Mexican study of 403 

children with diarrhea had a 6.4% prevalence of 

Cryptosporidium, which was associated with 

young age, malnutrition and lack of breast 

feeding. 92 A Brazilian case–control study showed 

that children who acquired symptomatic cryptosporidiosis 

before 1 year of age had a higher 

burden of subsequent diarrheal disease. 93 

A major waterborne cryptosporidiosis outbreak in 

Milwaukee, USA in 1993 increased IgG antibody 

responses from 15% to 82% over a 5-week period 

in the area served by the water treatment plant, 

demonstrating that C. parvum infection had been 

much more widespread than was previously 

appreciated from stool testing. 94 During this 

outbreak, Cryptosporidium, as the sole pathogen, 

was identified in stools from only 23% of affected 

children suggesting that stool tests for 

Cryptosporidium were insensitive early in the 

course of illness. 95 Although secondary transmission 

undoubtedly took place in child-care facilities, 

the presence of children with asymptomatic 

Cryptosporidium infections did not result in an 

increased risk of diarrhea. 96 


It is paradoxical that Cryptosporidium can produce 

such profound inflammatory mucosal damage 

without invasion. It has no known cytotoxins or 

enterotoxins, but some of the damage may be 

cytokine-mediated (TNF-α, IL-8), contributing to 

the malabsorption. C. parvum sporozoites produce 

a mucin-like surface glycoprotein which may help 

in parasite attachment to enterocytes. 22 Animal 

studies have revealed that cryptosporidiosis 

impairs glucose-stimulated sodium absorption at 

the villus without affecting cyclic AMP-mediated 

chloride secretion by the crypt epithelium. 97,98 

The inflammatory response in the lamina propria 

does not appear to enhance active transport 

processes such as chloride secretion, but diarrhea 

is related to loss of villus epithelium and glucosefacilitated 

sodium transport. 

Severe disease occurs in agammaglobulinemia, so 

humoral immunity provides important protection, 

but cell-mediated immunity is also important in 

clearing infection. An antibody response to 

Cryptosporidium develops in the ileal mucosa 

which is responsible for termination of the infection. 

99 Interferon-γ, produced by the Th1 subset of 

CD4 intraepithelial lymphocytes, is also important 

in combating cryptosporidiosis, as are TNF-α and 

IL-1β but without any synergistic effect. 100,101 The 

mechanisms of action of interferon-γ in vitro are 

prevention of penetration of host enterocytes by 

the parasite and retardation of development of 

intracellular parasites, which were independent of

nitric oxide-mediated killing of parasites, although 

interferon-γ may also up-regulate nitric oxide 

synthesis in enterocytes. 100 

Parasite expulsion and immune-mediated enteropathic 

changes appear to be mediated by T-cell 

function, dependent upon TNF, inducible nitric 

oxide synthase (iNOS) and IL-4 cytokines (Th2 

responses). 102,103 Thus, Th2 cytokines (e.g. IL-4) 

are involved in protection but may also produce a 

pathological response in the intestinal mucosa, 

which had been attributed to Th1 cytokines, and 

does not occur in TNF-α- and interferon-γ-deficient 

subjects. Both severe intestinal inflammation 

with enteropathy and protective immune 

responses to intestinal parasites are dependent 

upon IL-4, but immune protection can be acquired 

without enteropathy. 102 A neonatal mouse model 

of cryptosporidiosis documented increased 

inducible nitric oxide (NO) production with infection, 

which was worsened by NO inhibition and 

antioxidant administration, suggesting a protective 

role for NO. 104,105 The severity of nutrient malabsorption, 

villus atrophy and abnormal intestinal 

permeability with Cryptosporidium infection in 

AIDS is proportional to the number of infecting 

organisms. 106 


Cryptosporidial infection causes watery diarrhea 

with low-grade fever, vomiting and often cramps, 

severe dehydration and hypokalemia. Among 

Aboriginal children in Darwin, it was found in the 

stool of 7.4% of admissions with diarrheal disease 

with a mean age of 12.2 (9.6–15.5) months and 

mean admission serum potassium level of 2.7 

(2.4–3.0) mmol/l. It was associated with the most 

severe and prolonged mucosal damage and inflammation 

on permeability and NO testing, but 

showed less lactose intolerance than rotavirus. 10 A 

retrospective hospital study of 109 cases in 

London, 92% had watery and offensive stools with 

blood and mucus only occasionally, 50% had 

persistent diarrhea (> 14 days, and 33% > 21 

days), 51% had vomiting, 21% had significant 

abdominal pain and 23% were underweight. 83 

Biopsies in nine cases with prolonged diarrhea and 

failure to thrive showed a mild to moderate 

enteropathy with Cryptosporidium adhering to the 

villus epithelium, reduced villus height, reduced 

disaccharidases and increased intraepithelial 

Cryptosporidiosis 173 

lymphocytes. Key risk factors for cryptosporidiosis 

in this European setting were travel to a developing 

country and itinerant parents living in caravan 

sites. There have been two community growth 

studies in Peru and Guinea-Bissau, both suggesting 

an adverse long-term effect of cryptosporidiosis on 

growth. 107,108 

Cryptosporidium causes more prolonged and 

severe diarrhea, which may be fulminant, in 

immunocompromised patients. In an Italian study 

of HIV-infected children with cryptosporidiosis, 

the median duration of diarrhea was 32 days 

compared to only 4 days for other causes. 109 It was 

also associated with loss of 5–30% of body weight. 

A Peruvian hospital case–control study found an 

association between C. parvum infection and 

malnutrition, and high nosocomial spread in the 

hospital context. 110 In a follow-up study, they 

documented that a first symptomatic infection 

resulted in a mean (with 95% CI) of 342 g 

(167–517) weight deficit whereas asymptomatic 

infection (which was twice as common) led to a 

162g (27–297) deficit during the first month of 

infected cases compared to uninfected nondiarrheal 

cases. 111 

Diagnosis 

Cryptosporidiosis is diagnosed by finding oocysts 

in stool using an acid-fast stain. This is sensitive 

with more than 10 000 cysts/g in diarrheal cases, 

but 50 times less sensitive without diarrhea. 

Immunofluorescent and ELISA techniques are 

more sensitive, and PCR may be even more sensitive 

for detecting low numbers of oocysts in stool 

specimens. 92 Serological testing for cryptosporidial 

antibodies is useful for epidemiological 

surveys, but not for clinical diagnosis in endemic 

areas. A Peruvian study has questioned whether 

cryptosporidiosis is caused by a single species by 

identifying both human (in 81% of children) and 

zoonotic genotypes of Cryptosporidium (bovine, 

dog, C. meleagridis and felis) in HIV-negative children, 

with only duration of oocyst shedding longer 

in the human genotype. 112 

Prevention 

The high infectivity and ubiquitous oocysts in the 

environment make prevention by water, hygiene

174 


and sanitation programs very difficult, indeed 

impossible, in the developing world, where up to 

95% of children in some areas have positive serology 

by the age of 2 years. Precautions for travelers 

include washing hands, boiling water, avoiding 

animals, proper cooking of food, peeling fruit and 

avoiding uncooked food in contact with unboiled 

water (e.g. salads). 

Strongyloidiasis 

Introduction 

Although not a major cause of morbidity worldwide, 

the nematode Strongyloides stercoralis is 

unique in its ability to persist indefinitely within 

the host through autoinfection, and cause disseminated 

disease with the prolonged use of corticosteroids 

or other causes of immunosuppression. 

Life cycle 

Adult females are about 2.5mm in length and are 

attached to the lamina propria of the duodenum or 

proximal jejunum (Figure 11.4). Their eggs, which 

hatch into rhabditiform larvae (250µm long) and 

pass via feces into the external environment, 

where they moult into the infective filariform 

larvae (550µm long) which infect by penetrating 

the skin, like hookworms (see above) or become 

tissue-penetrating infective larvae by penetrating 

the colonic wall or perianal skin, becoming reestablished 

as mature female worms in the small 

Figure 11.4 Strongyloides stercoralis lava. Courtesy of 

UK Tropical International Health. 

intestine (autoinfection). Larvae are sensitive to 

drying, excessive heat (> 40°C) and cold (< 8°C), 

but may survive for about 2 weeks in soil. 

Rhabditiform larvae in feces may also moult in 

moist warm soil to form free-living adult males 

and females, who mate. The females produce eggs 

which develop into infective larvae to continue 

their life cycle in man. The time from skin penetration 

to mature worms producing eggs is approximately 

28 days. 

Epidemiology 

S. stercoralis is present in virtually all tropical and 

subtropical regions, but estimates of worldwide 

prevalence vary widely (3–100 million) with the 

best estimate probably around 30 million people in 

70 countries. 113 It is known to be prevalent among 

children in Cambodia, Laos, India (Bihar), Guinea- 

Bissau, Kenya, Sierra Leone, Brazil and the 

Caribbean. A large study in a Peruvian Amazon 

community found a 19.5% prevalence of stool 

larvae, including 25% in preschool children who 

also had high rates of other parasites. 114 

Strongyloidiasis accounted for 7.8% of 269 acute 

diarrheal admissions in Australian Aboriginal children 

in Darwin, with a mean age of 23.3 

(18.1–30.1) months, which was significantly older 

than the mean age of 12.7 (11.8–13.7) months for 

other diarrheal admissions. 10 

Prevalence rates vary with climate, geographical 

region, environmental conditions, soil characteristics 

and socioeconomic status, but also with modifiable 

risk factors such as quality of housing, 

hygiene standards and high population density. In 

endemic areas, most affected individuals have a 

low intensity of infection, but a few are heavily 

infected. Household aggregation of infection has 

been documented in Bangladesh, with risk factors 

being older age (7–10 years), lack of a home latrine 

and low socioeconomic status. 115,116 S. fuelleborni 

is a more virulent infection affecting young children 

in Papua New Guinea, which may be transmitted 

via breast milk. 117 


Malabsorption was recognized as a feature of 

strongyloidiasis in a 1965 Jamaican study using 

iron, folate and xylose absorption tests along with

jejunal biopsies. 118 SBBO and abnormal intestinal 

permeability to 51 Cr-ethylenediaminetetra-acetic 

acid (EDTA) has also been documented in 

Brazilian adults with strongyloidiasis and symptoms 

of abdominal pain, diarrhea and weight 

loss. 119,120 The suggested mechanisms for abnormal 

permeability were enhanced mucus secretion, 

increased enterocyte turnover with impaired paracellular 

barrier function, and protein-losing 

enteropathy. The latter was documented by means 

of increased fecal α1-antitrypsin excretion in 17% 

(5/29) of Gambian children with persistent diarrhea 

and malnutrition, including two of six with 

Strongyloides and two of 17 Giardia cases. 121 

Small-bowel biopsy studies have reported normal 

histology in some mild infections, but most show 

thickening of the bowel wall with edema or fibrosis 

in what has been described as catarrhal, edematous 

or ulcerative enteritis. 122 In severe cases of 

autoinfection, larvae hatching from deposited eggs 

burrow through the lumen causing superficial 

damage to the mucosa with excess mucus production, 

larvae in the lymphatics lead to a granulomatous 

lymphangitis, and parasites in the submucosa 

cause edematous and atrophic changes with fibrosis. 

As with other intestinal nematodes, 

Strongyloides infection elicits Th2-dependent antibodies. 

Immunoglobulin responses to S. stercoralis 

indicate that IgA affects larval output, IgE regulates 

autoinfection and IgG4 blocks IgE 

responses. 123 These immune responses appear to 

offer little protective immunity, and the relative 

contributions of genetic versus environmental 

factors to heavy infections is still unclear. Preexisting 

malnutrition (wasting) is a risk factor for 

hospitalization with the acute diarrheal syndrome 

compared to other causes of diarrhea, increasing 

the risk 6.5-fold even after adjusting for confounding 

factors. 10 


As with hookworm, larval migration may affect the 

lungs (eosinophilic pneumonitis) or skin (‘ground 

itch’ on the foot or ‘larva currens’ on the buttocks) 

but these are not usually recognized in children. 

Larvae from species infecting other mammals may 

penetrate the skin of humans, causing only local 

irritation, but cannot complete their life cycle. The 

most common manifestation of S. stercoralis infec- 

Strongyloidiasis 175 

tion in children is an acute diarrheal illness with 

foul stools with a typical musty odor which can be 

recognized by experienced staff in high-prevalence 

areas. Severe dehydration is uncommon, but 

hypokalemia and malabsorption commonly occur. 

Eosinophilia (5–15% of total white blood cell 

(WBC) count) is a common but not universal 

finding. A syndrome of partial intestinal obstruction 

with strongyloidiasis has been described in 

Aboriginal children in the Northern Territory of 

Australia. 124,125 

S. fuelleborni in infants is associated with abdominal 

swelling, ascites, pleural effusions and a high 

mortality. 126 In contrast to hookworm, with which 

it is commonly associated in infants in Papua New 

Guinea, the intensity of infection peaks by about 

12 months of age. 117,127 A similar S. fuelleborni 

species affects monkeys and humans in central 

Africa, causing less virulent disease with fever, 

lymphadenitis, abdominal pain and eosinophilia. 

41 

Disseminated strongyloidiasis (hyperinfection) 

occurs with impaired cell-mediated immunity, as 

in children treated with prolonged courses of 

steroids (although not from short courses of 

steroids for asthma) or malignancy (e.g. 

lymphoma, leukemia) or on immunosuppressive 

drugs (except cyclosporin, which is antiparasitic). 

Eradication of Strongyloides is essential before 

immunosuppressive therapy is commenced. 

Disseminated infection is always a serious complication 

with high mortality, usually affecting the 

bowel, lungs and central nervous system (CNS) 

and often accompanied by sepsis. Although 

strongyloidiasis is not a common opportunistic 

infection in AIDS, there is an increased frequency 

of larvae with HTLV-I infection, possibly due to 

suppression of the host IgE response. 128 

Diagnosis 

The diagnosis is established by identification of 

larvae on stool microscopy, which is very reliable 

with acute diarrhea, but less reliable with chronic 

or asymptomatic infection, because rhabditiform 

larva excretion is irregular and the parasite load is 

often low. In this situation, a single stool examination 

may detect larvae in only 30% of cases of 

latent infections, although this can be increased to

176 


50% with three stool specimens or various concentration 

techniques. There are a number of culture 

methods which are particularly useful if no larvae 

are found on stool microscopy in the face of clinical 

suspicion. The agar plate technique has a 96% 

sensitivity, which identifies larval tracks 

(Strongyloides larvae lash like a whip, whereas 

hookworm larvae move like a snake). 41,129 In an 

immunocompromised child with suspected overwhelming 

infection, rapid diagnosis can be made 

from a duodenal aspirate, although larvae are 

abundant with hyperinfection so diagnosis is less 

difficult than with latent infection. S. fuelleborni 

infection can be diagnosed from abundant eggs 

shed in the feces. 

Owing to the unreliability of stool microscopy and 

the importance of detecting even low levels of 

infection, various serological tests are available. 

An ELISA test for IgG is available, but there is still 

controversy about its reliability, because of its low 

specificity and positive predictive value. 130,131 The 

main problems with antibody tests are differentiating 

current from past infection, cross-reactivity 

with other helminth infections and false negatives 

on presentation of acute diarrheal disease in children 

(when stool is more reliable). Improved diagnostic 

tests are being developed using more 

specific antigens and specialized techniques, 

which have better potential to detect a risk 

of hyperinfection with immunosuppressive 

therapy. 129 

Prevention 

Disposal of human excreta, wearing of shoes, treatment 

of cases and improved hygiene reduce the 

risk of transmission of strongyloidiasis in communities. 

Regular mass chemotherapy programs 

against all geohelminths (e.g. albendazole) may 

have a modest impact on strongyloidiasis, but less 

than for the other helminths. 

Amebiasis 

Introduction 

Recent molecular and immunological techniques 

have demonstrated two distinct species of 

Entamoeba that are morphologically identical. E. 

histolytica is pathogenic, causing symptomatic 

disease in 10% of infections whereas E. dispar 

causes only asymptomatic colonization. In addition 

to the E. histolytica strain, other risk factors for 

invasive disease are interaction with bacterial 

flora, host genetic susceptibility, malnutrition, 

male sex, young age and immunodeficiency. 

Entamoeba coli and E. hartmanni are also nonpathogenic 

morphologically distinct members of 

the genus. 

Life cycle 

The E. histolytica life cycle consists of an infective 

cyst (10–15µm in diameter) and an invasive 

trophozoite (10–60µm in diameter). Cysts are 

resistant to chlorination, gastric acidity and desiccation 

and can survive in a moist environment for 

several weeks. For transmission of E. histolytica, 

cysts are ingested from fecally contaminated food 

and water and encystation occurs in the intestine, 

transforming the cyst into eight trophozoites. 

Mucosal invasion by trophozoites leads to colonic 

ulcers with migration of parasites to the liver via 

the portal vein. 

Epidemiology 

It is estimated that 500 million people are infected 

with E. histolytica in the world with 50 million per 

year developing invasive disease and 50000– 

100000 deaths. The case/fatality rate is 1 per 

500–1000 diagnosed cases, but in a hospital 

setting, the case/fatality ratio in children is higher, 

with 9% mortality and 27% morbidity. Liver 

abscess and extra-abdominal amebiasis has a 

much higher mortality rate of 10–40% or up to 

90% for cerebral amebiasis. 

The epidemiology of amebiasis has been complicated 

by the difficulty of identifying two genetically 

identical but morphologically distinct 

species, E. histolytica and E. dispar. It is estimated 

that 10% of the population is colonized by 

Entamoeba but 90% of these are with nonpathogenic 

E. dispar. Although E. dispar distribution 

is worldwide, E. histolytica infection occurs 

predominantly in Central and South America, 

Africa and the Indian subcontinent. Prevalence

studies based on stool parasites measure predominantly 

E. dispar, whereas serological surveys 

reflect the incidence of E. histolytica, since E. 

dispar does not cause seroconversion. 

A Bangladeshi study of urban children found the 

prevalence of E. histolytica to be 4.2% compared to 

6.5% for E. dispar with the highest prevalence of E. 

histolytica infection in children with diarrhea aged 

6–14 years. 132 A Mexican national survey reported 

an 8.4% seropositivity to E. histolytica, peaking at 

11% in the 5–9-year-old age group, with 4.2% of 

diarrheal cases due to E. histolytica infection, and 

6.5% with E. dispar. 132 Children 6–14 years of age 

with diarrhea had the highest incidence of E. 

histolytica infection (8%), whereas rural asymptomatic 

children had a 1% prevalence of E. histolytica 

and 7% prevalence of E. dispar. Shigella 

(dysenteriae and flexnerii) were also more frequent 

in children with diarrhea who also had Entamoeba 

infection. A West African study in school children 

found a ratio of E. histolytica : E.dispar of 1 : 46 

(compared to 1 : 3–9 in Asian studies), suggesting 

that the vast majority of Entamoeba infections in 

this region are not pathogenic. 133 A Brazilian study 

documented a 10.6% colonization rate for E. 

histolytica (excluding E. dispar), affecting predominantly 

those of poor socioeconomic status, 

hygiene and nutritional status, but most infections 

were asymptomatic and self-limited (clearing 

within 30–45 days) and reinfection rates were 

low. 134 


Amebic disease occurs when trophozoites invade 

colonic tissue, which is initiated by prior adherence 

to mucins lining the surface of the large 

bowel followed by enzymatic destruction of the 

basement membrane and underlying tissue. The 

resulting inflammatory response contributes 

further to tissue destruction. The stages of amebic 

infection include: adherence to bacteria (especially 

Escherichia coli) and intestinal epithelial 

cells via galactose-binding lectin, which protects 

the parasite by blocking complement; activation of 

virulence factors in parasites such as cysteine 

proteinases; stimulation of intestinal epithelial 

cells to produce cytokines and inflammatory mediators 

by activation of NF-κB; the resulting release 

of chemokines leading to neutrophil influx; medi- 

Amebiasis 177 

ators greatly contributing to the destruction of host 

tissues by lytic necrosis and apoptosis, enabling 

amebic invasion. 135 

Cell-mediated immunity limits the extent of invasive 

amebiasis and protects the host from recurrence, 

including trophozoite killing by activated 

macrophages and cytotoxic lymphocytes. 

Cytokines such as TNF-α and interferon-γ 

contribute to immunocompetent cell activation. 

Innate resistance to infection in children is linked 

to the absence of serum anti-trophozoite IgG, 

which is inherited, whereas acquired resistance is 

linked to intestinal IgA and serum antibodies to a 

parasite lectin. 136,137 

The initial colonic lesion in amebiasis is a small 

intraglandular ulcer of only 1 mm, which extends 

only to the muscularis mucosa. Margins may be 

hyperemic with slight edema of the surrounding 

mucosa. The next stage involves deeper buttonhole 

ulcers which are up to 1 cm in diameter and 

extend into the sub-mucosa. In young children this 

can progress to a fulminant necrotizing colitis 

associated with transmural necrosis. Amebomas 

are uncommon in children but involve the formation 

of granulation tissue with a fibrous outer wall, 

which may result in stricture or obstruction to the 

lumen. Dissemination to the liver occurs in a high 

proportion of patients with fulminant disease. 


The carrier state is the most common form of 

amebic infestation with all E. dispar infections and 

up to 90% of E. histolytica infections remaining 

asymptomatic with only cysts in the feces. Amebic 

dysentery is the most common form of symptomatic 

disease, with gradual onset of symptoms 

over 3 or 4 weeks after infection with increasingly 

severe diarrhea with abdominal pain such that an 

acute abdomen is often suspected. Stools contain 

blood and mucus, fever occurs in about half, and a 

small proportion develop abdominal distension 

with dehydration. Occasionally, young children 

present in a more fulminant manner with intussusception, 

perforation, peritonitis or necrotizing 

colitis. Rarely, children with amebic dysentery 

may present with an abdominal mass that has an 

‘apple-core’ appearance on radiographs, similar to 

colonic carcinoma. Amebic liver abscess and

178 


extra-abdominal amebiasis are much less common 

in children than in adults. 

Diagnosis 

The diagnosis of amebiasis should be considered 

in any child with blood or mucus in the stools, 

particularly if associated with abdominal pain or 

distension. Stool microscopy will yield cysts in 

< 30% of infected individuals, owing to the intermittent 

nature of cyst shedding, although multiple 

examinations increase the diagnostic yield to 

60–70% with amebic colitis but to under half of 

amebic hepatic abscesses. 

Serology can be helpful with invasive amebiasis 

since asymptomatic infections with E. dispar do 

not usually elicit a serological response. The gold 

standard remains culture or iso-enzyme analysis, 

but stool antigen detection tests are now commercially 

available which are more reliable than 

microscopy. A PCR-based amplification technique 

is now available for stool samples; infecting 

isolates are genetically diverse, with differences 

between those associated with intestinal and 

hepatic disease. 138 The major problem with serological 

tests is that they remain positive for years 

after an episode of amebiasis, so they may not be 

useful in endemic areas. 

Wet preparations of material aspirated or scraped 

from the base of ulcers on colonoscopy can be 

examined for motile trophozoites and tested for E. 

histolytica antigen. The appearance of amebic 

colitis resembles inflammatory bowel disease with 

a granular, friable and diffusely ulcerated mucosa. 

It is preferable for biopsy specimens to be taken 

from the edge of ulcers, but the sensitivity of this 

method of diagnosis appears variable. 

Prevention 

Prevention requires interruption of the fecal–oral 

spread of the infectious cyst stage of the parasite 

by improved hygiene, sanitation and water 

treatment. This is of course very difficult in the 

developing world. Current efforts towards a 

vaccine are focusing on the adherence lectin, 

which may prevent colonization. This would lead 

to elimination of the parasites if effective, since 

humans are the only significant reservoir of E. 

histolytica infection. 

Other parasites 

Hymenolepiasis 

Hymenolepis nana is the dwarf tapeworm and the 

only human tapeworm that does not require an 

intermediate host. Nevertheless, rodent strains for 

H. nana are infectious for humans including pet 

rodents such as rats, mice and hamsters. It occurs 

worldwide, with high childhood prevalences 

(> 10%) reported from Argentina, Peru, Brazil, 

Egypt, Pakistan and Zimbabwe. 41 Transmission is 

mostly fecal–oral, either from person to person or 

in food and water, with high rates in children from 

orphanages. 139 

Adult worms are only 15–45 mm in length with 

the spherical/ovoid eggs measuring 30–45µm in 

diameter, which do not survive beyond 11 days 

and are sensitive to heat and drying. In children 

who ingest eggs, the larval stage develops in the 

intestinal villi in 4–5 days, then break into the 

lumen and develop into adult worms, which 

produce ova in the feces within a month or less. 

The larval stage of H. nana is a cyst-like structure 

about 250 µm in diameter and is called a cysticercoid. 

As for other intestinal parasites, transmission 

is enhanced by poor hygiene and overcrowding, 

but control programs have found mass treatment 

more effective than improved hygiene. 41 

Most infected children are asymptomatic. High 

worm burdens of over 3000 may be associated 

with abdominal pain, loose stools and growth 

retardation. Disseminated larval infection has 

been described but is rare. Diagnosis is based on 

the characteristic eggs in stool. A single dose of 

praziquantel 20mg/kg is effective. Niclosamide 

60–80mg/kg per day for 5 days or paromomycin 

45mg/kg per day for 7 days are alternatives, but 

compliance is more difficult to ensure. Retreatment 

10 days later may be necessary to ensure 

eradication of cysticercoids in tissues. 

Enterobiasis 

Enterobius vermicularis is the common pinworm 

or threadworm of the large bowel. Unlike most 

other helminthic infection, enterobiasis may be 

more common in temperate, developed countries 

than in poor, tropical, developing countries. For 

example, rates in Australian schoolchildren have

een reported as 43% compared to 12% in India. 

However, it is worldwide in distribution and is 

almost exclusively transmitted person to person. 

The organism is a small white roundworm with 

the adult female worm 9–12mm long with the 

male worm only 2.5mm long and rarely observed. 

The worm’s lifespan is 5–13 weeks for females and 

only 7 weeks for males, but reinfection is common. 

The oval eggs laid by the gravid female on the anus 

are 50 x 25µm and the diagnosis is based on observation 

of these typical eggs from sticky tape 

applied to the perianal skin and then examined 

under a microscope. Adult pinworms or their eggs 

are rarely found in the feces, so this tape test for 

demonstrating pinworm eggs on the perianal skin 

is the most reliable technique. 

Humans are the only host for E. vermicularis, and 

worms inhabit the lumen of the cecum and appendix. 

The gravid adult female migrates to the perianal 

skin where she deposits her eggs resulting in 

intense anal pruritus, itching of the perianal skin 

leads to the contamination of the fingernails with 

the infective eggs. Each mature female worm can 

produce up to 11000 eggs. Most infections are 

asymptomatic, but perianal pruritus is the most 

common symptom of enterobiasis. Eosinophilia is 

uncommon, since the organism does not generally 

invade tissues. The incubation period is 3–4 

weeks. 

There is no definitive evidence that pinworms 

cause appendicitis, since most pinworms encountered 

in the appendix are an incidental finding, 

occurring in as many normal as inflamed appendices 

after surgery. However, it is impossible to 

exclude the possibility that chronic inflammatory 

changes due to local pinworm infection may 

contribute to some cases of appendicitis. Large 

numbers of larval pinworms have been shown to 

cause eosinophilic enterocolitis in an adult. 140 The 

most common site of infection (86.5%) is the 

lumen of the appendix, where the worms invoke 

no histological reaction. Other sites of infection 

include the abdominal and pelvic peritoneum and 

female genital tract. 141 Little girls sometimes 

present with ectopic pinworm infection of the 

vagina, which can cause hysterical reactions. 

The treatment of choice is albendazole or mebendazole, 

but ivermectin, pyrantel and levamisole 

are also effective. Since reinfection is very 

common, it is wise to readminister the drugs 2 

Other parasites 179 

weeks later and treat all household members, 

particularly children. Prevention of enterobiasis 

rests largely on treating infected children, keeping 

nails short and possibly improving personal 

hygiene, although infection is not an indicator of 

poor hygiene. 

Schistosomiasis 

There are seven human species of this trematode, 

including S. haematobium which affects the renal 

tract and S. mansoni the gastrointestinal tract. It 

has been estimated that 220 million people in 74 

countries are infected by schistosomiasis, and 20 

million have severe disease. Eggs of S. mansoni are 

passed in the feces, and hatch in warm water; the 

ciliated larvae swim and penetrate fresh-water 

snails (Biomphalaria). After a sporocyst stage, by 

4–5 weeks of infection, the larval phase results in 

thousands of cercariae (300 x 60µm) which penetrate 

human skin in water and enter peripheral 

lymphatics or veins and are carried to the lungs 

and mature in portal vessels. Adult worms migrate 

to the liver and mesenteric veins, where they may 

survive for 2–5 years or longer, producing eggs 

25–28 days after cercarial infection. 

Eggs cause granuloma formation resulting in localized 

colitis and hepatitis. The acute phase of S. 

mansoni infection may cause allergic symptoms 

(Katayama syndrome) which are rarely recognized 

in children. Most chronic infections are light and 

asymptomatic, but with heavy infections up to half 

of the eggs become trapped in the mucosa and 

submucosa of the colon, resulting in granulomatous 

reactions with significant blood loss. The 

host’s inflammatory reaction to eggs carried to the 

liver in the portal veins leads to portal hypertension. 

Severe disease with hepatosplenomegaly 

affects about 10% of S. mansoni cases in endemic 

areas, taking 5–15 years to develop. 

Diagnosis is based on finding eggs in the feces, but 

stool concentration methods and numerous 

immunological techniques (ELISA, immunoblotting) 

are more sensitive for milder infections. 

Treatment is with praziquantel 40 mg/kg as a 

single dose. Prevention involves avoidance of 

water sources containing cercariae and promotion 

of latrine use. Control programs for schistosomiasis 

involve mass chemotherapy, destruction of 

snails, environmental sanitation, prevention of

180 


water contact, health education and the future 

development of vaccines. 

Fasciolopsiasis 

The giant intestinal fluke Fasciolopsis buski is a 

class of flatworm called trematodes, which 

includes schistosomes. It is estimated that more 

than 40 million people have food-borne trematode 

infections. Those affecting the liver and lungs will 

not be considered here. The adult worm of F. buski 

measures up to 7.5cm in length and attaches to the 

mucosa of the proximal small intestine. It has a 

lifespan of about 6 months and begins producing 

eggs about 3 months after infection. These are 

excreted in the stool and measure 130µm in 

length. Up to 25000 eggs may be excreted daily. 

After several weeks in fresh water, the larvae hatch 

from the eggs and penetrate snails, where they 

undergo further development. Cercariae emerge 

from the snail after 1–2 months and encyst on a 

wide variety of aquatic vegetation. When humans 

ingest these raw, they develop infection, which 

lodges in the duodenum. The severity of symptoms 

correlates with the number of parasites, but 

heavy infections may cause nausea, vomiting, 

abdominal pain, edema, eosinophilia and poor 

nutrition. The diagnosis of fasciolopsiasis is based 

upon stool microscopy identifying the eggs. These 

are indistinguishable from those of the liver fluke, 

Fasciola hepatica. However, the intestinal fluke 

has a short lifespan and infection does not persist 

beyond 9 months from the time of departure from 

and endemic area. 

The treatment of choice is praziquantel 25 mg/kg 

three times daily for 1 day. The prognosis is generally 

excellent, except for heavy infection in children 

with intestinal obstruction of edematous 

malnutrition. The infection can be prevented by 

cooking aquatic vegetation or immersing plants or 

nuts in boiling water. The use of human feces as 

fertilizer in aquaculture is a major cause of human 

infection. 

Trichostrongylus 

Species of Trichostrongylus (wireworms) mostly 

affect ruminants, but they affect humans in close 

proximity to cattle, particularly in Africa, 

Australia, India, Iran and South America. The 

small adult worms (5–10 mm long) attach to the 

wall of the duodenum and jejunum after ingestion, 

and excrete eggs similar to those of the hookworm. 

Light infections are asymptomatic, but abdominal 

pain, diarrhea and eosinophilia may occur with 

heavy infections. Treatment is as for hookworm, 

and prevention involves thorough washing or 

cooking of vegetables. 

Parastrongylus costaricensis 

This nematode was discovered in Costa Rica in 

1971 and appears to be mainly confined to Latin 

America and the Caribbean. The natural host is the 

cotton rat but adult worms (20mm long) have been 

found in the cecum of children with appendicitislike 

illnesses with eosinophilia. Infection occurs 

by ingesting infected slugs. Diagnosis before 

surgery is based upon eosinophilia, radiology or 

serology, but larvae are not excreted in stool and 

no chemotherapy is effective. 

Cyclospora cayetanensis 

Cyclospora has emerged recently as an important 

protozoal pathogen causing diarrheal disease. 142 It 

appears to be endemic in most parts of the 

Americas, Africa and Asia, with infections occurring 

in travelers, as well as waterborne and foodborne 

outbreaks. 143–145 Children in tropical areas 

appear to have a high prevalence, and the disease 

peaks in the hot rainy season. 146,147 A Venezuelan 

study documented prevalences in adult AIDS 

patients and children with diarrhea of 9.8% vs. 

5.3%, which was more common than S. stercoralis 

(4.2% vs. 1.5%, respectively) but less common 

than C. parvum (35.2% vs. 9.8%, respectively) and 

had a peak prevalence in children between 2 and 5 

years of age. 148 Other childhood diarrheal prevalences 

have been similar in Nepal and Guatemala, 

but higher in Peru and Haiti (up to 18–20%). The 

incidence in Peruvian periurban children was 

0.21–0.28 episodes/child-years. 84 A Haitian study 

found a prevalence of 11% in AIDS diarrhea, with 

symptoms identical to isosporiasis and cryptosporidiosis. 

149 

Since other pathogens are often found, it is difficult 

to characterize the illness exactly, but 

prolonged watery diarrhea with weight loss is

typical, often associated with fever. Mucosal biopsies 

show inflammatory changes with partial villus 

atrophy with crypt hyperplasia. 150 Stool oocytes 

are sparse in infected immunocompetent children 

with diarrhea (

182 


fumarate reductase. It is poorly soluble in water, 

but well absorbed with a fatty meal. It is rapidly 

metabolized in the liver to the active form, albendazole 

sulfoxide, which has a serum half-life of 

8–9 h, and is excreted by the kidneys. It is usually 

very well tolerated as a single dose or daily for 3 

days, with gastrointestinal symptoms (e.g. pain, 

diarrhea, nausea or vomiting) in only 1.3% of 

courses. 156 Worm migration is uncommon with 

albendazole treatment, but prolonged therapy may 

cause alopecia, reversible marrow suppression or 

hepatocellular damage. Albendazole should be 

avoided in pregnancy and in children under 6 

months of age. 

Albendazole 400mg (200mg if

Levamisole 

Levamisole is an immune stimulant which is effective 

against Ascaris and hookworm, and may be 

more effective for intestinal obstruction from 

roundworms, since it acts by paralyzing the 

myoneural junction of the worm. The dosage is 

3mg/kg as a single dose. 

Ivermectin 

Ivermectin has broad-spectrum activity against 

helminths and filariasis, but is the drug of choice 

against strongyloidiasis. Ivermectin is well 

absorbed orally, accumulating in adipose tissue, 

metabolized in the liver, highly protein bound 

with a serum half-life of 12 h and excreted in stool. 

It is generally well tolerated, with occasional 

abdominal distension, chest tightness or wheezing. 

In a Tanzanian study of children, ivermectin 

was found to be more effective than albendazole 

for curing Strongyloides, equally effective for 

Ascaris, less effective for Trichuris and ineffective 

against hookworm infections. 163 Another African 

study of ivermectin in intestinal nematode infections 

found little effect on either prevalence or 

intensity of N. americanus hookworm or Trichuris, 

and only a modest effect on Ascaris. 164 

Ivermectin 200µg/kg as a single dose has a 

reported cure rate of 83% for Strongyloides. In 

complicated or disseminated infection, ivermectin 

should be repeated on days 2, 15 and 16 to 

decrease relapse. In immunosuppressed patients, 

treatment is not always successful, and may need 

to be repeated at monthly intervals, or a longer 

course given. An adult open-label study of 60 

patients with strongyloidiasis compared singledose 

ivermectin with albendazole for 3 days and 

found higher cure rates with the former (83% vs. 

38%). 165 Another adult study comparing ivermectin 

with thiabendazole documented high cure 

rates for both drugs but the adverse effects were 

much greater for thiabendazole (e.g. disorientation, 

fatigue, nausea and anorexia). 166 A comparative 

trial in 301 children from Zanzibar with S. 

stercoralis larvae in stool had cure rates of 82.9% 

with single-dose ivermectin compared to only 

45.0% with 3 days of albendazole. 163 Disseminated 

disease has a high mortality, so may require ivermectin 

over 3–4 weeks. 

Metronidazole 

Drug treatment 183 

Metronidazole is used for giardiasis and amebiasis. 

It is activated by reduction of its 5-nitro group, is 

concentrated in anaerobic organisms and interacts 

with DNA to cause microbial death. It is not well 

tolerated, with anorexia and gastrointestinal upset 

occurring after several days’ treatment. 167 The 

dose of metronidazole has been controversial, but 

a computer simulation study using the conventional 

30 mg/kg per day regime calculated that 

steady state was reached at 24mg/kg per day in 

rehabilitated children and at 12mg/kg per day in 

severely malnourished children using the twice 

daily dosage. 168 Patients with immunodeficiency 

may require treatment for 6–8 weeks for giardiasis. 

The American Academy of Pediatrics and Centers 

for Disease Control recommend that asymptomatic 

Giardia infections not be treated. 169,170 

Asymptomatic cyst excretors, even at day-care 

centers, do not warrant treatment. 170,171 

Amebic colitis or dysentery should be treated with 

metronidazole plus a luminal agent such as diloxanide 

furoate, paromomycin or iodoquinol. 

Although improvement usually occurs within 3–4 

days of treatment, metronidazole should be 

continued for a minimum of 10 days to eliminate 

intestinal colonization with risk of relapse. 

Treatment of asymptomatic cyst passers is inappropriate 

for E. dispar, but is warranted for E. 

histolytica in developed countries but probably not 

practical in most of the developing world where 

the disease in endemic. The dosage for treatment 

of acute amebic colitis is metronidazole 

35–50mg/kg per day in three divided doses for 10 

days. The intraluminal agents are used for eradicating 

cyst passage. The dosages are: iodoquinol 

30–40mg/kg per day in three divided oral doses for 

20 days, or diloxanide furoate 20mg/kg per day in 

three divided doses, or paromomycin 25–35mg/kg 

per day in three divided doses for 7 days. 

Tinidazole 

Tinidazole is another 5-nitroimidazole with a 

similar mechanism of action to that of metronidazole 

but a convenient single dosage. A Cochrane 

review of 34 trials on drugs for treating giardiasis 

concluded that tinidazole 50mg/kg in a single dose 

had a higher clinical cure rate than a short course

184 


of treatment with metronidazole, albendazole or 

secnidazole. 172 

Nitazoxanide 

Nitazoxanide is a new broad-spectrum antimicrobial 

agent with activity against nematodes, trematodes, 

anaerobic bacteria and protozoal parasites 

such as Cryptosporidium. It is metabolized in 

blood to tizoxanide, which inhibits the key 

enzyme pyruvate ferredoxin oxidoreductase of 

target organisms, and is excreted in urine and 

feces. Adverse effects tend to affect the gastrointestinal 

tract, but appear to be mild and transient. 

173 A 3-day course of 100–200mg 12-hourly 

in children (adults 500mg) is effective against giardiasis, 

amebiasis, Blastocystis hominis, 

Balantidium coli, Isospora belli, Ascaris, Trichuris, 

hookworm and Hymenolepis nana. 168 In view of 

this wide spectrum of action, single-dose therapy 

in combination with other drugs is under investigation 

for community treatment programs. 

Two Egyptian randomized placebo-controlled 

trials of diarrheal subjects have shown that nitazoxanide 

was associated with resolution of the 

diarrhea within 7 days in about 80% of cases of 

giardiasis, amebiasis or cryptosporidiosis 

compared to about 40% in the placebo group. 174,175 

A Mexican study of 275 children with helminth or 

protozoan infections documented a higher (but 

non-significant) parasite eradication rate with 3 

days of nitazoxanide (79%) than with 3 days of 

mebendazole plus quifamide (74%). 176 Another 

Mexican study has documented its in vitro effectiveness 

against trophozoites of E. histolytica and 

Giardia. 177 Nitazoxanide was best for eradication 

of H. nana (90–100%) and worst for giardiasis 

(56–74%). Comparative studies of Peruvian children 

with ascariasis, trichuriasis, hymenolepiasis 

and giardiasis reported cure rates for nitazoxanide 

of 89%, 89%, 82% and 85%, respectively, compared 

with 91%, 58%, 96% and 75–80% for albendazole, 

praziquantel (H. nana) or metronidazole 

(Giardia), respectively. 178,179 A recent Zambian 

trial of 3 days of nitazoxanide (vs. placebo) in 100 

children with cryptosporidiosis showed clinical 

response rates of 56 vs. 23% and parasitological 

response rates of 52 vs. 14% in HIV-seronegative 

children, but no significant response in HIVseropositive 

cases. 180 

Paromomycin 

Paromomycin is a poorly absorbed aminoglycoside 

which reaches high concentrations in the intestine, 

but absorbed drug is excreted renally and is 

potentially ototoxic and nephrotoxic. It has been 

used for cryptosporidial diarrhea in AIDS patients, 

requiring continuous maintenance therapy, but 

appears now to be ineffective. 181,182 

Mass community anthelminthic 

treatment 

UNICEF, the World Bank and WHO have promoted 

routine mass anthelminthic treatment programs as 

a cost-effective intervention, and school-based 

programs are popular. 183–185 Although most 

studies report prevalence, reducing the intensity of 

the worm burden is the major aim of control 

programs in children, who have the highest 

burden. Albendazole and praziquantel have broadspectrum 

anthelminthic activity against ascariasis, 

trichuriasis, enterobiasis, hookworm, giardiasis, 

strongyloidiasis and schistosomiasis at relatively 

low cost and with low rates of resistance to these 

agents. Mass treatment protocols may reduce the 

risk of drug resistance by targeting school-age and 

preschool children, by only repeating treatment at 

intervals greater than the nematode generation 

time, by combining anthelminthic drugs in control 

programs to reduce or delay selection for resistance, 

and by monitoring drug resistance to benzimadoles 

using DNA probes. 2 Deworming programs 

were held back for young children because of 

concerns about their safety in children under 2 

years of age (as well as in pregnancy and lactation). 

However, a recent WHO Informal Consultation 

that children over 12 months of age should be 

included in deworming campaigns using praziquantel 

and albendazole/mebendazole on the basis 

of improved safety data and risk–benefit analysis. 

186 

The impact of helminth infections on growth and 

development is a controversial but important 

issue. A Cochrane systematic review of 30 

randomized trials involving 15000 children on the 

effects of antihelminthic treatment of endemic 

communities on growth and cognitive performance 

was reported in 2000. 187,188 It found only

modest weight gain of 0.1kg (0.04–0.17) after a 

year of follow-up and no differences in cognitive 

performance, so concluded that the evidence for 

routine anthelminthic treatment to improve 

growth and cognitive performance was unconvincing. 

Critics of the review pointed out that poorly 

designed trials may have failed to document an 

effect, that short-term treatment cannot assess the 

long-term benefits of regular treatment and that 

the review hid the greatest effect of anthelminthic 

treatment on growth and development in children 

with heavy parasitic burdens. 

Since the Cochrane review, there has been a study 

of 614 children 12–48 months at baseline, in a 

community of high parasite intensity in Tanzania 

who were randomized to single-dose mebendazole 

500 mg 3-monthly vs. placebo and followed for 12 

months. It reported modest reductions in prevalence 

of Trichuris (75 vs. 58%), Ascaris (49 vs. 27%) 

and hookworm (66 vs. 60%), but the effect on 

worm intensity was more significant, reducing 

Ascaris from 126 to 12 eggs per gram of feces (epg), 

Trichuris from 511 to 88 epg and hookworm from 

198 to 119 epg. 189 A large randomized mass treatment 

trial of school children with albendazole and 

praziquantel in China, Kenya and the Philippines 

documented significant reductions (p < 0.0001) in 

mean egg counts at 45 days for hookworm (97 to 

27), Ascaris (5903 to 626) and Trichuris (233 to 

161), but the effects were limited by rapid reinfection 

(Ascaris) and single-dose albendazole ineffectiveness 

(Trichuris). 190 The most important shortterm 

benefits at 6 months from treatment were 

modest rises in hemoglobin level and reductions 

in hepatomegaly (Kenya only) in the children 

treated with praziquantel, but catch-up growth did 

not occur in treated children compared to controls. 

Another study in the low-intensity setting of 

Bangladesh followed 123 children aged 2–5 years 

for 12 months with 2-monthly mebendazole and 

showed reduced prevalences of Trichuris (65 to 

9%), Ascaris (78 to 8%) and hookworm (4 to 0%) 

while associated with an increase in giardiasis (19 

to 49%), but failed to document improved growth 

or improvements in intermediate variables (intestinal 

permeability, plasma albumin, α1-antichymotrypsin). 

191 The increase in giardiasis with mebendazole 

was found in an earlier Bangladeshi 

study, 192 but could be prevented by substituting 

albendazole, which has anti-giardial activity. 

Mass community anthelminthic treatment 185 

Confirmation of the limited effect of helminths on 

growth has come from indirect calorimetry, which 

showed no treatment effect on energy metabolism 

with low-level hookworm, Ascaris, Trichuris or 

Strongyloides infections. 193 A Malaysian study 

found that intestinal helminths did not contribute 

to poor school attendance. 194 

A 9-year cohort study of 119 children in a 

Brazilian shantytown showed that, in this setting, 

the burden of diarrheal disease and helminth 

infections in children under 2 years were independently 

associated with stunting by 2–7 years of 

age, even controlling for confounders. 195 Thus, 

early childhood helminth infections were associated 

with a 4.6-cm shortfall by age 7 years, 

compared to 3.6cm attributed to the mean 9.1 

episodes of diarrhea before the age of 2 years. 

There is also indirect evidence that intestinal 

nematodes affect productivity in adults through 

both disease-related morbidity and ill-health in 

childhood. 196 A Zairian study of 358 moderately 

malnourished preschool children randomized 

them to either vitamin A, mebendazole 500 mg 

3-monthly or no treatment. 197 The vitamin Adeficient 

children showed significant catch-up 

growth on vitamin A treatment, but deworming 

did not improve growth, because only 12 of 123 in 

the mebendazole group had ascariasis of low 

intensity, making the claim in the title of the 

article misleading. 

A South African randomized trial of 428 schoolchildren 

with a high prevalence of Trichuris, hookworm 

and schistosomiasis found that combination 

treatment with 3 days of albendazole and singledose 

praziquantel 6-monthly and iron supplementation 

weekly for 10 weeks reduced worm prevalence 

and increased hemoglobin levels, but did not 

improve growth. 198 A Kenyan study showed that 

albendazole was more effective than mebendazole 

in reducing worm burdens in schoolchildren. 199 

However, a Tanzanian study of 2294 schoolchildren 

from a very high prevalence setting showed 

that single-dose albendazole vs. mebendazole 

reduced the parasite burden of Ascaris by 97% vs. 

97%, of Trichuris by 73% vs. 82%, and of hookworm 

by 98% vs. 82%, respectively. 200 Moreover, 

the high reinfection rate in this setting meant that 

the impact of chemotherapy was short-lived, so 4monthly 

treatment would be necessary to reduce 

long-term morbidity. 64 In South African school-

186 


children, a single dose of albendazole and praziquantel 

reduced prevalence rates of Ascaris, 

Trichuris and S. haematobium from 29.5 to 4.7%, 

51.9 to 38.0% and 22.3 to 3.3%, respectively. 

Invasive parasites which are known to cause 

malabsorption, weight loss or prolonged diarrhea, 

such as Giardia, Cryptosporidium and 

Strongyloides, are the most likely to affect growth, 

so specific studies have examined this in community 

settings. Giardia is the most prevalent intestinal 

protozoan parasite, and certainly can cause 

persistent diarrhea with malabsorption, weight 

loss and mucosal damage, but the key public 

health question is whether the high rates of infection 

without overt clinical symptoms contribute to 

poor growth of preschool children in the developing 

world. Lunn and colleagues examined this 

question in 60 infants in The Gambia where both 

giardiasis and poor growth are known to be highly 

prevalent. 201,202 Giardia-specific plasma immunoglobulins 

were used for diagnosis and did not 

explain the observed growth faltering. Giardia 

infection was not associated with diarrhea in this 

context, but mild infections may have caused 

minimal abnormalities in intestinal permeability 

and α1-antichymotrypsin, an acute-phase reactant 

protein. They concluded that giardiasis was 

unlikely to be a major cause of the poor growth of 

rural Gambian infants. Rapid reinfection after 

treatment was also documented for giardiasis in 

Egypt and Peru, where 98% of children were reinfected 

within 6 months of tinidazole treatment 

and stool excretion lasted a mean of 3.2 

months. 203,204 

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12 

Post-infectious persistent 

diarrhea in developing 

countries 


Global significance of diarrheal 

disorders and persistent diarrhea 

Despite considerable advances in the understanding 

and management of diarrheal disorders in 

childhood, they are still responsible for a major 

burden of childhood deaths globally, with an estimated 

2.5 million deaths. 1 In an estimate of the 

global burden of diarrheal disorders in 1980 the 

World Health Organization (WHO) calculated that 

there were over 700 million episodes of diarrhea 

annually in children under 5 years of age in developing 

countries (excluding China), with approximately 

4.6 million deaths. 2 Reviews in the early 

1990s suggested that diarrheal disorders still 

accounted for almost a third of all admissions to 

health facilities in developing countries, 3 with an 

estimated incidence of diarrheal disorders at 

around 2.6 episodes/child per year. More recent 

reviews of studies published in the past 10 years 

indicate that, while global mortality may have 

reduced, the incidence remained unchanged at 

about 3.2 episodes/child year. 4,5 These findings 

indicate the continuing need to focus on prevention 

and management of childhood diarrhea in 

developing countries. 

It is recognized that most diarrheal disorders form 

a continuum, with the majority of cases resolving 

within the first week of the illness. However, a 

smaller proportion of diarrheal illnesses fail to 

resolve and may persist for longer than 2 weeks. 

Persistent diarrhea has been defined as an episode 

that begins acutely but lasts for 14 days or longer. 

It has been shown to identify children with a 

substantially increased diarrheal burden and leads 

to the majority of all diarrhea-related deaths. 6 In a 

prospective study of diarrheal disorders in north 

India, persistent diarrhea accounted for only 5% of 

all diarrheal episodes, but the case/fatality rate for 

persistent diarrhea was 14% in comparison with 

0.7% for episodes of shorter duration. 7 In a similar 

prospective study of diarrheal episodes in the 

community in and around Lahore (Pakistan), 

persistent diarrhea accounted for 8–18% of all 

diarrheal episodes but 54% of all diarrheal 

deaths. 8 Figure 12.1 indicates the relative proportion 

of diarrheal episodes from several prospective 

community-based studies in developing countries. 

7,9–11 

It is important to emphasize that the bulk of the 

epidemiological information on the relationship of 

acute diarrheal disorders to persistent diarrhea is 

derived from studies undertaken over 10–15 years 

ago, and that there is a paucity of recent data on 

this subject, especially from areas non-endemic for 

HIV. 5 However, it is evident from studies in HIVendemic 

areas that chronic enteropathy and 

persistent diarrhea is a common manifestation of 

advancing HIV infection and AIDS. 

Pathogenesis of persistent diarrhea 

Although a close relationship between diarrheal 

disease and malnutrition has long been recognized, 

12 this has been challenged. 13 The relationship 

of persistent diarrhea to malnutrition is less 

controversial, as the disorder is commonly seen in 

association with significant malnutrition. In a 

verbal autopsy study of diarrheal deaths in 

Bangladesh, Fauveau et al 14 found that almost half 

the deaths were in malnourished children with 

persistent diarrhea, and the relative risk of dying 

with persistent diarrhea and severe malnutrition 

was 17-fold higher than in children with lower 

degrees of malnutrition. 

There are several reasons for malnutrition both to 

predispose to persistent diarrhea and to follow it. 

193

194 

Post-infectious persistent diarrhea in developing countries 

80 

60 

40 

20 

% of episodes 100 

0 

Figure 12.1 Distribution of diarrheal episodes in community-based studies. From references 7 and 9–11. 

These range from achlorhydria with increased risk 

of small-bowel contamination, systemic immune 

deficiency, intestinal and pancreatic enzyme deficiency 

and altered intestinal mucosal repair mechanisms 

following an infectious insult. An independent 

relationship has also been demonstrated 

between cutaneous anergy and the subsequent risk 

of development of persistent diarrhea. 15 There has 

been much interest in the possibility that such 

transient immune deficiency may also be a marker 

of concomitant micronutrient deficiency. 16–18 The 

most striking example of the critical role that the 

immune system plays in the pathogenesis of 

persistent diarrhea is the relationship between 

HIV/AIDS and persistent diarrhea. This is exemplified 

by the host of studies linking persistent 

diarrhea with cryptosporidiosis 19 and other parasitic 

infections 20,21 in Africa and Asia. 

A clear understanding of alterations in intestinal 

morphology and physiology is crucial towards the 

development of interventional strategies, but there 

has been little progress in our understanding of 

this problem in developing countries. This has 

been largely due to a paucity of studies formally 

evaluating intestinal biopsy findings in representative 

populations. A wide variety of pathological 

changes have been described after persistent diarrhea, 

ranging from near-normal appearance to 

mucosal flattening, crypt hypertrophy and 

lymphocytic infiltration of the mucosa. 22 Recent 

electron microscopic studies of the intestinal 

1–7 days 8–14 days 15–21 days > 22 days 

mucosa in persistent diarrhea have revealed 

patchy villous atrophy and intraepithelial lymphocytic 

infiltration 23 as well as severe mucosal 

damage and villous atrophy. 24 

Poor intestinal repair is regarded as a key component 

of the abnormal mucosal morphology. 

However, the exact factors underlying this ineffective 

repair process and continuing injury are 

poorly understood (Figure 12.2). The end result of 

this mucosal derangement is poor absorption of 

luminal nutrients, as well as increased permeability 

of the bowel to abnormal dietary or microbial 

antigens. 25–27 Alterations of intestinal permeability 

in early childhood may reflect changes in intestinal 

mucosal maturation 28 and may be affected by 

concomitant enteric infections. 29 

Risk factors for persistent diarrhea 

It is important to recognize the major risk factors 

for development of persistent diarrhea, as appropriate 

case management of acute diarrhea is key to 

the prevention of prolonged episodes. 

Specific pathogens 

Peru (1989) 

Bangladesh (1982) 

India (1989) 

Bangladesh (1992) 

Pakistan (1993) 

The association of specific bacterial and viral 

infections with persistent diarrhea has been the 

subject of considerable debate. 30,31 Evidence from

Figure 12.2 Mechanisms and effects of enteropathy of malnutrition and prolonged diarrhea. 

Bangladesh suggests that recurrent bouts of infection 

with pathogens such as Shigella lead to 

prolongation of the duration of successive diarrheal 

episodes. Although several studies have 

identified an association between persistent diarrhea 

and enteroaggregative Escherichia coli in the 

small bowel, this is by no means pathognomonic, 32 

nor is there a particular pattern of small-bowel 

microbial colonization or overgrowth seen in most 

cases. In parts of Africa endemic for HIV an association 

of persistent diarrhea with cryptosporidiosis 

and other pathogens 19–21,33 is well recognized, 

but may represent a manifestation of immunodeficiency. 

Malnutrition 

Increased macromolecular 

absorption and permeability 

Increased protein energy and 

micronutrient requirement for 

repair 

Protein energy malnutrition 

Persistent diarrhea is commonly seen in association 

with significant malnutrition, and the relationship 

may be bi-directional. It is widely recognized 

that diarrheal episodes, especially if 

invasive, may become prolonged in malnourished 

children. The recent evidence of micronutrient 

deficiencies, especially of zinc and vitamin A in 

malnourished children with persistent diarrhea, 

Prolonged small-intestinal mucosal injury 

and ineffective repair 

Risk factors for persistent diarrhea 195 

Immunological and inflammatory 

mucosal reaction (cytokine activation 

and altered growth factors) 

Decreased brush-border enzymes 

and transport 

Nutrient malabsorption 

Bacterial overgrowth, infection and 

possible translocation 

indicates impaired immunological mechanisms for 

clearing infections as well as ineffective mucosal 

repair mechanisms. From initial studies indicating 

the potential benefit of zinc supplementation on 

reducing the risk of prolonged diarrhea, 34 the 

evidence of the benefit of zinc supplements in 

children with persistent diarrhea was equivocal. 

35,36 However, a recent meta-analysis of zinc 

supplementation in diarrheal illnesses indicated a 

significant reduction in duration and severity of 

diarrheal illnesses. 37 Thus, zinc deficiency may 

significantly contribute to the prolongation of 

mucosal injury and delayed intestinal repair 

mechanisms. 

Dietary risk factors 

While many children with persistent diarrhea are 

lactose-intolerant, the role of specific dietary allergies 

in inducing and perpetuating enteropathy of 

malnutrition is unclear. Several studies have highlighted 

the high risk of prolonged diarrhea with 

lactation failure and early introduction of artificial 

feeds in developing countries. In particular, the 

administration of unmodified cow’s or buffalo’s

196 


milk is associated with prolongation of diarrhea, 

suggesting the potential underlying role of milk 

protein enteropathy. 26,38 

Inappropriate management of acute diarrhea 

The association of prolongation of diarrhea with 

starvation and inappropriately prolonged administration 

of parenteral fluids has been recognized 

for over half a century. Continued breast feeding is 

important; unnecessary food withdrawal, and 

replacement of luminal nutrients, especially breast 

milk, with non-nutritive agents is a major factor in 

prolonging mucosal injury after diarrhea. In particular, 

blanket administration of antibiotics and antimotility 

agents and semi-starvation diets should be 

avoided in cases of prolonged diarrhea. 39,40 While 

parenteral nutrition has been occasionally life 

saving in selected cases in developing countries, 41 

it is clearly an impractical option for most of the 

developing world. There is now clear evidence 

supporting the enteral route for nutritional rehabilitation 

of malnourished children with persistent 

diarrhea. 12 Starvation has been shown to 

have deleterious effects on the intestinal mucosa, 42 

with a reduction in the nutritive transporters for 

glutamine and arginine. 43 It is therefore imperative 

that malnourished children with persistent 

diarrhea should receive enteral nutrition during 

their period of rehabilitation. 

The aforementioned risk factors highlight the 

importance of recognizing that optimal management 

of diarrheal episodes is key to the prevention 

of persistent diarrhea. It is thus necessary that, 

given the close relationship between diarrheal 

disorders and malnutrition, persistent diarrhea be 

widely recognized as a nutritional disorder, 44,45 

and optimal nutritional rehabilitation be considered 

as the cornerstone of its management. 12 

Principles of management of 

persistent diarrhea 

In general the management of persistent diarrhea 

in malnourished children represents a blend of the 

principles of management of diarrhea and malnutrition. 

Associated malnutrition may be quite 

severe in affected children, necessitating rapid 

nutritional rehabilitation, often in hospital. Given 

the chronicity of the disorder, prolonged hospitalization 

may be problematic in developing countries 

and, whenever possible, ambulatory or homebased 

therapy must be supported. 

The following represent the basic principles of 

management of persistent diarrhea. A suggested 

therapeutic approach is indicated in Figure 12.3. 

Rapid resuscitation, antibiotic therapy and 

stabilization 

Most children with persistent diarrhea and associated 

malnutrition are not severely dehydrated, 

and oral rehydration may be adequate. However, 

acute exacerbations and associated vomiting may 

require brief periods of intravenous rehydration 

with Ringer’s lactate. Acute electrolyte imbalance 

such as hypokalemia and severe acidosis may 

require correction. More importantly, associated 

systemic infections (bacteremia, pneumonia and 

urinary tract infection) are well recognized in 

severely malnourished children with persistent 

diarrhea and a frequent cause of early mortality. 

Children must be screened for these at admission. 

Almost 30–50% of malnourished children with 

persistent diarrhea may have an associated 

systemic infection requiring resuscitation and 

antimicrobial therapy. 46,47 In severely ill children 

requiring hospitalization, it may be best to cover 

with parenteral antibiotics at admission (usually 

ampicillin and gentamicin) while awaiting the 

results of cultures. It should be emphasized that 

there is little role for oral antibiotics in persistent 

diarrhea, as in most cases the original bacterial 

infection triggering the prolonged diarrhea has 

disappeared by the time the child presents. One 

possible exception may be adjunctive therapy for 

cryptosporidiosis in children with HIV and persistent 

diarrhea. 48 

Oral rehydration therapy 

This is the preferred mode of rehydration and 

replacement of on-going losses. While in general 

the standard WHO oral rehydration solution (ORS) 

is adequate, recent evidence indicates that hypoosmolar 

rehydration fluids 49,50 as well as cerealbased 

oral rehydration fluids may be advantageous 

in malnourished children. In general replacing 

each stool with about 50–100 ml ORS is safe.

Recovery 

Parental guidance to sustain feeding at home 

Follow-up 

Figure 12.3 Therapeutic approach to the management of persistent diarrhea. 

Enteral feeding and diet selection 

Irrespective of the cellular mechanisms and structural 

alterations in malnourished children with 

persistent diarrhea, the end result is one of altered 

brush-border and luminal enzymes, with con- 

Principles of management of persistent diarrhea 197 

Persistent diarrhea 

(diarrhea ≥ 14 days with malnutrition 

Assessment, resuscitation and early stabilization 

Intravenous and/or oral rehydration (hypo-osmolar) 

Treat electrolyte imbalance 

Screen and treat associated systemic infections 

Continued breast feeding 

Reduce lactose load by 

• Milk–cereal (usually rice-based) diet or 

• Replacement of milk with yogurt 

Micronutrient supplementation 

(zinc, vitamin A, folate) 

Growth monitoring Failure to recover 

Continued or recurrent diarrhea 

Poor weight gain 

Reinvestigate for infections 

Comminuted chicken diet or green banana diet 

Elemental feeds 

Continued diarrhea and dehydration 

Reinvestigate in the framework of the so-called 

'intractable diarrhea of infancy' 

Intravenous hyperalimentation 

sequent malabsorption. Despite the aforementioned 

alterations in digestive and absorptive 

mechanisms, analysis of studies of metabolic 

balance in children with persistent diarrhea indicates 

that satisfactory carbohydrate, protein and fat 

absorption can take place on a variety of diets. 12,38

198 


It is exceedingly rare to find persistent diarrhea in 

exclusively breast-fed infants, and with the exception 

of situations where persistent diarrhea accompanies 

perinatally acquired HIV infection, breast 

feeding must be continued. Most children with 

persistent diarrhea are not lactose intolerant, 

although administration of a lactose load exceeding 

5g/kg per day is associated with higher purging 

rates and treatment failure. In general therefore 

withdrawal of milk and replacement with specialized 

(and expensive) lactose-free formulations is 

unnecessary. Alternative strategies for reducing 

the lactose load in malnourished children with 

persistent diarrhea include the addition of milk to 

cereals as well as replacement of milk with 

fermented milk products such as yogurt. These 

dietary interventions have now been extensively 

evaluated in several studies in South Asia, and 

found to be of equivalent efficacy to expensive 

formulations. 51,52 

Rarely, when dietary intolerance precludes the 

administration of cow’s milk-based formulations 

or milk, it may be necessary to administer specialized 

milk-free diets such as a comminuted or 

blenderized chicken-based diet or an elemental 

formulation. 53 It must be pointed out that, 

although effective in some settings, 54 the latter are 

unaffordable in most developing countries. In 

addition to rice–lentil formulations such as 

khitchri, the addition of green banana or pectin to 

the diet 55 has been shown to be effective in the 

treatment of persistent diarrhea. 

The usual energy density of any diet used for the 

therapy of persistent diarrhea should be around 

1kcal/g, aiming to provide an energy intake of a 

minimum of 100kcal/kg per day, and a protein 

intake of 2–3g/kg per day. In selected circumstances 

when adequate intake of energy-dense 

food is problematic, the addition of amylase to the 

diet through germination techniques may also be 

helpful. 

Micronutrient supplementation 

It is now widely recognized that most malnourished 

children with persistent diarrhea have associated 

deficiencies of micronutrients including 

zinc, iron and vitamin A. This may be a consequence 

of poor intake and continued enteral 

losses, and requires replenishment during 

therapy. 56 While the evidence supporting zinc 

administration in children with persistent diarrhea 

is persuasive, it is likely that these children 

have multiple micronutrient deficiencies. 

Concomitant vitamin A administration to children 

with persistent diarrhea has been shown to 

improve outcome 57,58 especially in HIV-endemic 

areas. 59 It is therefore important to ensure that all 

children with persistent diarrhea and malnutrition 

receive an initial dose of 100000U of vitamin A 

and a daily intake of at least 3–5mg/kg per day of 

elemental zinc. While the association of significant 

anemia with persistent diarrhea is well recognized, 

iron replacement therapy is best initiated 

only after recovery from diarrhea has started and 

the diet is well tolerated. 

Follow-up and nutritional rehabilitation in 

community settings 

Given the high rates of relapse in most children 

with persistent diarrhea, it is important to address 

the underlying risk factors and institute preventive 

measures. These include appropriate feeding 

(breast feeding, complementary feeding) and close 

attention to environmental hygiene and sanitation. 

This poses a considerable challenge in communities 

deprived of basic necessities such as clean 

water and sewage disposal. 

In addition to the preventive aspects, the challenge 

in most settings is to develop and sustain a form of 

dietary therapy using inexpensive, home-available 

and culturally acceptable ingredients that can be 

used to manage children with persistent diarrhea. 

Given that the majority of cases of persistent diarrhea 

occur in the community and that parents are 

frequently hesitant to seek institutional help, there 

is a need to develop and implement inexpensive 

and practical home-based therapeutic measures. 12 

Recent data indicate that it may be entirely feasible 

to do so in community settings. 60,61 

Conclusion 

Most of the knowledge and tools needed to prevent 

diarrhea-associated mortality in developing countries 

and especially persistent diarrhea are

available. These require concerted and sustained 

implementation in public health programs. 62 

Given the emerging evidence of the long-term 

impact of childhood diarrhea on developmental 

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13 

Introduction 

Small-bowel bacterial 

overgrowth 

Mauro Batista de Morais and Ulysses Fagundes-Neto 

Small-bowel bacterial overgrowth (SBBO) is characterized 

by the colonization of the small intestine 

by bacteria that are normally found only in the 

colonic microbiota. 

In the literature, SBBO has received many names 

such as ‘the blind loop syndrome’, 1 ‘stagnant loop 

syndrome’, 2 ‘small intestinal stasis syndrome’, 3 

and the ‘contaminated small bowel syndrome’. 4 

Initially, SBBO descriptions predominated in 

patients with surgical or anatomical abnormalities, 

and later SBBO was recognized in children who 

did not present anatomical abnormalities, in situations 

such as protein–energy malnutrition, acute 

diarrhea, persistent diarrhea and environmental 

enteropathy. These findings characterize SBBO as 

an important public health problem, occurring 

especially in the pediatric population in lessdeveloped 

countries. SBBO can cause asymptomatic 

intestinal malabsorption and/or chronic 

diarrhea and may be associated with protein– 

energy malnutrition and stunting. 

Etiology 

SBBO is a syndrome that can cause functional and 

morphological abnormalities of the digestive tract, 

resulting in a disturbance in the homeostasis of the 

bacterial flora in the small intestine and a consequent 

imbalance of the mechanisms that control 

the flora. 5,6 Therefore, for better understanding of 

the development of SBBO, the microflora that is 

normally found in the digestive tract and its regulatory 

mechanisms are briefly described. 

It is generally accepted that the upper digestive 

tract (stomach, duodenum, jejunum) is sterile, as 

found in 70% of the population, or may present a 

scarce microflora made up of facultative microorganisms, 

predominantly Gram-positive bacteria. 

The concentration of bacteria (Streptococcus, 

Lactobacillus, aerobes and diphtheroids) and yeast 

is normally no greater than 10 4 colonies/ml in the 

fluid of the small bowel. These micro-organisms 

come from the oral cavity, colonizing the upper 

small intestine after surviving the gastric juice. 

The terminal portion of the ileum comprises a 

transition zone and the microbiota begins to 

change with the appearance of Gram-negative 

bacteria, such as coliforms and bacteroids. The 

ileocecal valve acts as a true barrier, separating the 

Gram-positive species, which predominate in the 

upper small intestine, from the Gram-negative 

species, which inhabit the colon, where the anaerobic 

bacterial population represents the main 

portion of colonic microflora. Bacteroids, anaerobic 

Lactobacilli and Clostridium spp are the main 

components of the colonic flora and exist in 

concentrations ranging between 10 8 and 10 11 

colonies/ml, surpassing the facultative or aerobic 

microflora in a proportion of 1000–10000:1. Table 

13.1 shows the microflora of various segments of 

the digestive tract. 5–7 

The maintenance of the intestinal microbiota with 

the characteristics mentioned above depends upon 

the action of various regulatory mechanisms, such 

as diet, digestive tube motility, gastric acidity, the 

intestinal immunological system and the integrity 

of the ileocecal valve. 5,6 

Diet type 

Animals raised in sterile environmental conditions, 

including feed, are different from animals 

raised under normal conditions that present digestive 

tract colonization. Animals free of bacteria 

201

202 

Small-bowel bacterial overgrowth 

Table 13.1 Microflora of the digestive tract 

Concentration of 

Site micro-organisms/ml Description 

Stomach, duodenum,

intestinal pseudo-obstruction syndrome, which 

is associated with profound abnormalities of 

intestinal motility, SBBO is frequent. 10 

Intestinal mucosal immunity 

Intestinal mucosal immune responses are different 

from those that occur systemically. One of 

the fundamental differences is the production of 

immunoglobulin A (IgA), which is secreted in 

the intestine. IgA is the main class of antibodies 

produced in the intestine, as illustrated by the 

larger number of IgA-producing cells: a proportion 

of 20 for each IgG-producing cell and three 

for each producing IgM. Secretory IgA differs 

from serum IgA, as it is in dimeric form, created 

by the secretory piece, which confers resistance 

against proteolysis in the intestinal lumen. 

Secretory IgA can impede the adherence of 

micro-organisms to the surface of enterocytes, an 

important control mechanism to prevent SBBO. 

It is important to emphasize that newborns have 

a smaller population of plasma cells in the 

lamina propria, which explains their reduced 

ability to respond to local antigenic stimuli. At 

this stage of life, the colostrum and mother’s 

milk are rich in secretory IgA and play an important 

role in the newborn’s defense mechanism. 

5,7,11 

Ileocecal valve 

This valve acts as a barrier separating Grampositive 

bacteria that inhabit the proximal small 

intestine from the Gram-negative bacteria and 

anaerobes that comprise the colonic bacterial 

flora. In the absence of the ileocecal valve due to 

intestinal resection, a retrograde colonization of 

the small intestine with bacteria that are 

normally found only in the colon is observed. 6 

SBBO develops when an alteration of one or 

more of the intestinal mucosa regulatory mechanisms 

occurs. Theoretically, bacteria responsible 

for SBBO may come either from the environment, 

by the ingestion of contaminated food or 

water, or from the colonic microflora itself, as a 

result of proximal colonization due to intestinal 

motility disturbances or ileocecal valve functional 

insufficiency. 



In patients with SBBO, functional and/or morphological 

alterations can be observed, owing to the 

capacity of these bacteria to promote deconjugation 

of bile salts, such as 7α-dehydroxylation, 

which transforms them into secondary bile salts. 

The deconjugation of bile salts causes a reduction 

in the capacity to form mixed micelle, which is 

important in the process of lipid digestion and 

absorption, because the concentration in the 

intestinal lumen does not achieve a critical micellar 

concentration. Therefore, lower solubility of 

fats in the diet causing steatorrhea is observed. On 

the other hand, the secondary bile acids (deoxycholic 

and lithocholic) have a large capacity to 

provoke lesions in the intestinal mucosa, causing 

partial villous atrophy that may be associated with 

the secretion of electrolytes and malabsorption of 

glucose. 5,12,13 

Patients with SBBO also present reduced absorption 

of carbohydrates from the diet by: 

(1) Metabolism of carbohydrates by the SBBO 

bacteria, which generates short-chain fatty 

acids (acetic, propionic and butyric acids) 

and gases, such as hydrogen, which, after 

diffusion through the intestinal mucosa, pass 

through to the circulatory system and reach 

the lungs, where they are eliminated in 

respiration. 

(2) Reduction in the activity of disaccharidases 

due to alterations in the ultrastructure of the 

small intestine. 

Consequently, the unabsorbed carbohydrates 

remain in the intestinal lumen in their original 

form or in the form of short-chain fatty acids as a 

result of bacterial fermentation, generating 

osmotic pressure that promotes the secretion of 

water into the intestinal lumen. 5,11 

Evidence also exists of a reduction in protein 

digestion and absorption from the diet due to 

intraluminal protein catabolism as well as a reduction 

in the transport and uptake of amino acids by 

the intestinal mucosa. 5,11 

SBBO may also cause malabsorption of liposoluble 

vitamins A and D accompanied by steatorrhea. 

Reduction in the absorption of vitamin B12 may

204 


Table 13.2 Probable effects of bacterial overgrowth 

Intraluminal Mucosal Systemic 

Bile salt deconjugation Deficiency of disaccharidases Absorption of bacterial toxins 

and antigens 

Decrease of the biliary Enterocyte damage Hepatic inflammation 

salt ‘pool’ 

Steatorrhea Inflammation Immune complex formation 

Vitamin B12 malabsorption Protein loss Vasculitis 

Production of short-chain Bleeding Polyarthritis 

fatty acids 

occur, owing to the consumption of vitamins by 

bacteria present in the intestinal lumen, especially 

Bacteroides. 5,11 

Systemic effects of SBBO are associated with the 

absorption of antigens and bacterial products 

through the injured intestinal mucosa. 6 Table 13.2 

lists the effects of an overgrowth of bacteria on its 

host. 

Diagnosis 

Research to characterize the digestive tract 

microflora has developed mainly from the 1960s 

onward. The micro-organisms of the digestive tube 

flora, made up of aerobic and anaerobic bacteria, 

protozoa and even some viruses, form a complex 

ecosystem. The terms ‘indigenous flora’ and 

‘microbiota’ are used as synonyms for normal flora 

and refer to micro-organisms that can be found in 

normal individuals. Therefore, in order to establish 

a diagnosis for SBBO, it is necessary to define 

the location, the count and the type of bacteria 

found. In general, studies regarding normal flora 

have been carried out by analyzing fluid collected 

by intubation of the Treitz angle region. Dickman 

et al 14 studied the intestinal fluid of 22 healthy 

individuals, finding 10 3 bacteria/ml in 16 of them 

and 10 4 bacteria/ml in two individuals. In another 

study, Thadepalli et al 15 found up to 10 4 bacteria/ml 

in six of 28 individuals. Fagundes-Neto et 

al 16 evaluated the small-bowel microflora in chil- 

dren who were not undernourished or presenting 

diarrhea, and found similar numbers of bacteria. 

Many authors 17–27 characterize SBBO based on 

bacterial count, without taking into consideration 

the family or genus of these micro-organisms. 

According to this quantitative principle, various 

cut-off points can be found in the literature: 

(1) ≥ 10 4 bacteria/ml; 17–21 

(2) ≥ 10 5 bacteria/ml; 22–25 

(3) ≥ 10 6 bacteria/ml. 26,27 

Other authors 28,29 have used criteria that take into 

consideration the family as well as the number of 

the bacteria, characterizing SBBO when ≥10 3 

coliforms and aerobic or anaerobic enterobacteria/ml 

are found in the intestinal fluid. 

Finally, there is a group of authors that considers 

SBBO to be the presence, in any concentration, of 

aerobic or anaerobic bacteria of the colonic 

microflora. 16,30–33 

In spite of the lack of consensus on the interpretation 

of results, the intestinal fluid culture is 

considered the gold standard test for the diagnosis 

of SBBO. 6,22,28 However, the invasive character of 

duodenal intubation and the high cost of aerobic 

and anaerobic microbiological study have driven 

research into lower cost, non-invasive methods, of 

which the hydrogen breath test has shown itself to 

be the most important.

The basic principle of the hydrogen breath test is 

the fermentation of carbohydrates by bacteria 

present in the intestinal lumen, which generates, 

among other products, hydrogen. After it diffuses 

through the intestinal mucosa and reaches the 

lungs through the circulatory system, the hydrogen 

is eliminated in exhaled air. Normally, 

fermenting bacteria are found only in the colon: 

so, when an unabsorbed carbohydrate reaches the 

colon, it is fermented and the elimination of 

hydrogen through the breath occurs about 10 min 

after it reaches the large intestine. Under these 

circumstances, the carbohydrate must travel the 

entirety of the small intestine for it to begin to 

produce hydrogen. This orocecal transit time 

varies according to the type of carbohydrate and its 

concentration in the administered solution. The 

lactulose solution employed in the hydrogen 

breath test for SBBO diagnosis presents a mean 

orocecal transit time of approximately 90 min. 

When SBBO is present, bacterial fermentation 

occurs prematurely, while still in the small intestine, 

elevating the concentration of hydrogen in 

the breath in the samples collected in the 60 min 

following the ingestion of the carbohydrate. 

Ideally, when the unabsorbed carbohydrate 

reaches the colon, it will produce a second peak of 

hydrogen corresponding to its fermentation by the 

Hydrogen (ppm) 

35 

30 

25 

20 

15 

10 

5 

0 

Normal 

Diagnosis 205 

colonic flora. Thus, after the ingestion of a carbohydrate 

that is not absorbed, such as lactulose, in 

individuals with bacterial overgrowth, two peaks 

in hydrogen production are expected: the first is an 

early peak, generated by the bacteria of the SBBO, 

while the second is a late peak, due to the normal 

production of hydrogen in the colon, as illustrated 

in Figure 13.1. The other carbohydrate used in the 

hydrogen breath test is glucose. As glucose is, in 

ordinary circumstances, completely absorbed by 

the small intestine, there should be no delayed 

peak, except if the patient presents intestinal 

malabsorption of glucose associated with 

SBBO. 19,34–36 

Most studies relating the hydrogen breath test to 

the culture of intestinal fluid have been carried out 

in adults. However, common criteria were not used 

for the interpretation of intestinal fluid cultures, 

which is considered the gold standard for the characterization 

of SBBO. The main points of these 

studies are summarized in Table 13.3. 22,26,35,37–39 

To our knowledge, only six studies have been 

carried out in children. Davidson et al 40 studied 

nine children aged 2–34 months, and characterized 

SBBO as the presence of more than 10 4 bacteria/ml 

in duodenal fluid. Lactose, sucrose and 

lactulose were used as substrates. SBBO was deter- 

Bacterial overgrowth 

(double peak) 

0 50 100 150 200 250 300 

Time (min) 

Non-producer 

Figure 13.1 Schematic representation of possible results of the hydrogen breath test with lactulose.

206 


Table 13.3 Studies in adults evaluating the diagnostic performance of the hydrogen breath test for 

the diagnosis of small-bowel bacterial overgrowth 

Authors and Number of Criteria for Sensitivity Specificity 

reference patients Probe bacterial overgrowth* (%) (%) 

King and Toskes 26 20 lactulose 10g >10ppm 61 41 

Kerlin and Wong 37 45 glucose 50g >12ppm 93 78 

Corazza et al 35 77 lactulose 12g >10ppm 68 44 

Riordan et al 38 42 lactulose 10g >16ppm 20 75 

Riordan et al 22 28 lactulose 10g >10ppm 16 70 

MacMahon et al 39 30 glucose 50g >10ppm 75 30 

*Increment of breath hydrogen concentration before colonic peak 

mined by the presence of a double peak. Boissieu 

et al 41 studied cultures of intestinal fluid and the 

hydrogen breath test after administering glucose to 

five children. A study carried out by Khin-Maung 

et al, 27 with 19 children aged from 3 to 5 years, 

considered SBBO to be a concentration of more 

than 10 6 bacteria/ml in the enteral fluid. After 

ingestion of 10g of lactulose, an increase of more 

than 10ppm in samples collected after 20, 40 and 

60min was considered indicative of SBBO. Only 

two of the children with positive cultures 

presented a hydrogen breath test indicative of 

SBBO. Furthermore, three of the nine children 

with positive cultures did not present a positive 

hydrogen breath test indicative of SBBO. 

Marcelino 42 carried out a study in our institution 

and observed that only three of 18 unweaned 

infants, with acute or persistent diarrhea and 

SBBO, according to an intestinal fluid culture of 

the small intestine, presented a rise in breath 

hydrogen of more than 20ppm after the ingestion 

of 10g of lactulose. It should be pointed out that 

almost 80% of the unweaned infants studied were 

not hydrogen producers and many presented 

secondary lactose malabsorption. 

Guno et al 43 studied SBBO in 31 infants with ages 

ranging from 2 to 24 months suffering from 

protein–energy malnutrition. The culture of the 

small-bowel fluid revealed that SBBO was present 

in ten of the 31 patients. The sensitivity and specificity 

of the hydrogen breath test using lactulose 

was 72% and 90%, respectively, while the scores 

for the hydrogen breath test using glucose were 

55% and 90%, respectively. The authors did not 

include criteria for interpretation of the breath test. 

Silva 33 compared the results of the culture of 

aerobic and anaerobic organisms in the intestinal 

fluid of 31 children, with ages ranging from 6 

months to 16 years, with the increase in breath 

hydrogen after the ingestion of 10g of lactulose. 

SBBO was characterized by the presence of any 

bacterium from the colonic flora in the duodenum, 

and was found in 16 (51.6%) of the 31 children. 

Given the minimum increase of 10ppm in breath 

hydrogen concentration in the samples collected 

up to 60min, the sensitivity of the hydrogen test 

was 75% and specificity 60%. 

Analysis of the available information shows that 

both in adults and in children, irrespective of the 

carbohydrate that is used – lactulose or glucose – 

the occurrence of false-positive and false-negative 

results in the hydrogen breath test in relation to 

culture requires cautious application of this test in 

researching SBBO in a individual patient. 

Another utilization of the hydrogen breath test is 

the analysis of groups of individuals in order to 

obtain information about the bacterial flora of the

Increment of the concentration of H 2 (ppm) 

70 

60 

50 

40 

30 

20 

10 

0 

0 20 40 60 80 100 120 140 160 180 200 

digestive tract in varying environmental conditions. 

The results obtained by Silva, 33 with two 

groups of children (15 with SBBO and 16 without 

SBBO) can, in this light, be reanalyzed differently. 

Figure 13.2 presents the median values of 

increases in hydrogen on expiration. It can be seen 

that the SBBO groups produced a greater amount 

of hydrogen after 60min, and that there was a 

statistically significant difference in hydrogen 

increases at 120, 150 and 180min of the test. The 

data suggest two possibilities: that individuals 

with SBBO may not present a double peak of 

hydrogen; or that the colonic flora of children with 

SBBO has a greater hydrogen-producing capacity. 

This is based on the observation that, at the beginning 

of the test, the difference in hydrogen production 

in expired breath in SBBO patients was lower 

than after 60min of the test. This second aspect 

was further analyzed using the area under the 

curve as the basis for calculation. In the fasting 

sample until 60min, the 16 patients with SBBO 

presented a median hydrogen production rate 

(720 ppm/min) not statistically different from the 

15 patients without SBBO (923 ppm/min). In turn, 

from 60 to 180min this parameter was signifi- 

Time (min) 

Clinical presentation 207 

Figure 13.2 Median of the increment of the concentration of hydrogen in the expired air of 16 patients with bacterial 

overgrowth (unbroken line) and in 15 patients without bacterial overgrowth (dotted line) according to culture of the intestinal 

fluid. Differences at 15min, p = 0.98; 30 min, p = 0.90; 45min, p = 0.58; 60min, p = 0.26; 90 min, p = 0.075; 120 min, 

p= 0.028; 150min, p = 0.031; 180 min, p =0.007. 

cantly higher (p=0.017) in SBBO patients 

(6943 ppm/min) compared to patients without 

SBBO (3074ppm/min). 

Clinical presentation 

SBBO may be asymptomatic or may present with 

chronic diarrhea associated with malabsorption of 

macronutrients. SBBO may thus lead to or aggravate 

protein–energy malnutrition. 5,6 In children, 

SBBO has also been linked to recurrent abdominal 

pain that responded to antimicrobial treatment. 41 

Several disorders may predispose to the development 

of SBBO (Table 13.4). It is therefore crucial 

that in every child diagnosed with SBBO a careful 

work-up be performed, aimed at ruling out these 

underlying conditions. 

We will focus here on SBBO associated with acute 

or persistent diarrhea and with environmental 

factors, given their high incidence and prevalence, 

particularly in young infants and in children living 

in unfavorable environments.

208 


Table 13.4 Clinical conditions associated 

with small-bowel bacterial overgrowth 

Anatomic abnormalities 

Congenital intestinal obstruction 

Acquired strictures and stenosis 

(e.g. Crohn’s disease) 

Intestinal fistula 

Abnormalities of intestinal motility 

Pseudo-obstruction syndrome 

Scleroderma 

Damage of the myenteric plexus 

Post-surgery complications 

Stasis of the afferent loop 

Gastroenterostomy 

Enteroenterostomy 

Colectomy or jejunoileal anastomosis 

Without anatomic abnormalities 

Carbohydrate malabsorption 

Immunological deficiency 

Giardia infection 

Acute and persistent diarrhea 

Environmental enteropathy 

Small-bowel bacterial overgrowth in acute and 

persistent diarrhea 

In developing countries, these two conditions 

account for a major proportion of deaths in the 

early years of life, and it should be emphasized 

that mortality due to persistent infectious diarrhea 

is much greater than that due to its acute 

phase. 44,45 SBBO does occur in children with acute 

diarrhea and is considered one of the factors 

leading to its perpetuation. In the 1970s, Fagundes- 

Neto et al 46 and Albert et al 47 showed a raised incidence 

of SBBO in children with acute diarrhea. A 

later study by Penny et al 48 showed that SBBO was 

more frequent in children with persistent diarrhea 

(80%) than in acute diarrhea (40%). In a study 

carried out in Cuba, Cristia et al 49 observed a 

similar frequency of SBBO in unweaned infants 

who had been hospitalized with acute and 

persistent diarrhea. From a functional point of 

view, Coello Ramirez and Lifschitz 50 found a 

correlation between SBBO and malabsorption of 

carbohydrates. 

Studies in Brazil 31,32,42 and in other countries 48 

have shown an association between SBBO and 

severe acute diarrhea or persistent diarrhea caused 

by classic enteropathogenic Escherichia coli. 

SBBO can thus be present in both acute and 

persistent diarrhea, aggravating the clinical manifestations 

of patients, and, in conjunction with 

other factors, prolonging its course. Being aware of 

this possibility is obviously necessary for proper 

and timely diagnostic and therapeutic interventions. 

Small-bowel bacterial overgrowth in 

environmental enteropathy 

In the 1960s, several studies in tropical countries 

showed that adults without clinical gastrointestinal 

manifestations presented histological changes 

in the small intestine and reduction of D-xylose 

absorption capacity, compared to healthy adults 

living in developed countries. 51,52 With regard to 

morphology, the abnormalities observed in the 

small intestine were reduced height of the intestinal 

villi and increased lymphoplasmocytic infiltrate 

in the lamina propria. The disorder was 

initially named tropical enteropathy. However, the 

possibility of a spontaneous normalization of the 

defect in D-xylose absorption after a change of 

environment, as observed in Indians and 

Pakistanis who moved to New York, 53 its close link 

with unfavorable environmental conditions, as 

well as the occurrence of this disorder in nontropical 

regions, led in the 1980s to a redefinition 

of this clinical condition as ‘environmental 

enteropathy’ by Fagundes-Neto et al. 54,55 

Environmental enteropathy can thus be defined as 

a set of unspecific morphological and functional 

abnormalities of the small intestine that are potentially 

reversible with a change in environmental 

conditions. From the clinical standpoint, it may be 

asymptomatic or associated with chronic diarrhea 

or with recurrent bouts of diarrhea. Stunted 

growth and protein–energy malnutrition often 

occur, as a result of the combination of malabsorption 

and inadequate nutrition, related to under-

privileged socioeconomic conditions. Environmental 

enteropathy may be associated with. SBBO. 

The high prevalence of SBBO in this disorder was 

confirmed by studies on slum-dwelling infants in 

the city of São Paulo, 56,57 including 40 unweaned 

infants without diarrhea but presenting blunted Dxylose 

absorption and histological abnormalities 

of the small intestinal mucosa. SBBO was found in 

61.2% of such infants. Study of the intestinal ultrastructure 

in these patients showed several abnormalities, 

such as decreased number and fusion of 

microvilli, cytoplasmic vacuolization and derangement 

of the mitochondria and endoplasmic reticulum. 

Taken together, these data 56,57 showed that 

exposure to unsuitable environmental conditions 

can damage the intestinal digestive–absorptive 

functions. 

Use of the hydrogen breath test with lactulose to 

characterize SBBO has enabled research into 

environmental enteropathy in larger numbers of 

children, leading to a social vision of the threat 

that SBBO represents to the infant population. 

Pereira et al 58 studied 340 children under 5 years 

of age and found SBBO in 27.2% of this population 

in a town in Australia. 

In Brazil, several studies have been performed 

using the hydrogen breath test with lactulose to 

characterize SBBO associated with environmental 

enteropathy. One such study 59 involved 83 schoolchildren 

who lived in a rural area, an urban area 

and a slum (favela) area of a city in the interior of 

São Paulo State, south-east Brazil. SBBO was 

detected in 7.2% of the children investigated. In 

the same study, the proportion of SBBO in the 

slum-dwelling children (18.2%) was statistically 

higher than that of the non-slum-dwelling 

children, in whom SBBO was not identified. These 

data thus demonstrated an association between 

unsuitable environmental conditions and SBBO. 39 

Two studies performed in 5–10-year-old children 

are also of interest. The first 60 was carried out in 

Indian children living in a reservation in Mato 

Grosso do Sul and found SBBO in 11.5% of the 252 

children studied. The second 61 compared 50 slumdwelling 

children with 50 control children who 

lived in domiciles with adequate food and 

environmental conditions and came from families 

with a solid socioeconomic background. SBBO 

was investigated by means of the hydrogen breath 

Treatment 209 

test with lactulose (10g) on one day and then with 

glucose (50g) on the next. After excluding nonhydrogen-producing 

children, SBBO (increase of 

20ppm in hydrogen concentration in the first hour 

after ingestion of lactulose) was observed in 50.0% 

(23/46) of slum-dwelling children and in 2.2% 

(1/46) of control children. The hydrogen test with 

glucose did not enable characterization of greater 

frequency of SBBO in slum-dwelling children. 

Figure 13.3 displays the curves based on the 

average concentrations of hydrogen in exhaled air, 

showing that production of hydrogen in slumdwelling 

children was greater than in the control 

group, indirectly indicating a greater quantity of 

lactulose-fermenting bacteria. On the other hand, 

the glucose test did not draw a distinction between 

the groups. The average (±SD) of the z-scores of 

weight for age (-0.45±0.95) and height for age 

(-0.66±1.05) of the slum-dwelling children were 

lower than those of the control group (+0.39 ±0.97 

and +0.18±0.84, respectively); the difference was 

statistically significant and showed an association 

between SBBO and protein–energy malnutrition. 61 

The evidence presented shows that unfavorable 

environmental conditions with lack of basic 

sanitation or inadequate supply of treated water 

can prompt the consumption of contaminated 

water and food that cause episodes of acute 

infectious diarrhea. This chronic state of environmental 

aggression may then cause long-lasting 

abnormalities of intestinal function that by inducing 

environmental enteropathy, ends up by 

negatively impacting the health of a large portion 

of the world population. 

Treatment 

Treatment of SBBO depends fundamentally on the 

patient’s general characteristics, especially on the 

presence of those clinical conditions listed in 

Table 13.3. Obviously, when possible, one should 

treat the predisposing conditions, improving 

factors to control bacterial flora. 

In patients with clinical conditions associated 

with SBBO in whom treatment of the underlying 

disease does not always produce satisfactory 

results, such as in intestinal pseudo-obstruction 

syndrome and ileocecal valve resection, use of 

antibiotics is indicated.

210 


Hydrogen (ppm) 

25 

20 

15 

10 

5 

0 

Figure 13.3 Median of the concentration of hydrogen in the expired air in the children living in a slum (n = 50) and 

controls (n = 50) after the administration of 10 g of lactulose and 50 g of glucose on different days. 

Boissieu et al 41 observed the disappearance of 

symptoms attributed to SBBO, such as chronic 

abdominal pain and chronic diarrhea, after antibiotic 

therapy. 

Lichtman 6 reviewed the literature in 2000 on the 

use of antibiotics in the treatment of SBBO. Most 

reports dealt with small groups of patients, with 

different underlying diseases predisposing 

towards SBBO; there were no controlled studies or 

series with a sufficient number of patients. 

Therefore, based on his own experience and in 

view of the scanty evidence from the literature, 

this author recommended the use of antibiotics 

effective against bacteroids, such as metronidazole, 

chloramphenicol and tetracycline. In children, 

an initial course of metronidazole for 2–4 

weeks is considered the first choice. 

In our practice, we normally prescribe courses of 

metronidazole and trimethoprim–sulfamethoxazole. 

In the case of SBBO associated with severe acute 

diarrhea and with persistent diarrhea, a doubleblind 

placebo-controlled study was carried out by 

our group to assess the effect of oral polymyxin for 

7 days on the clinical course and on the proximal 

0 20 40 60 80 100 120 140 160 180 200 

Time (min) 

lactulose (slum children) 

lactulose (controls) 

glucose (controls) 

glucose (slum children) 

small-intestine fluid culture in 25 hospitalized 

infants. 32 Both groups were on the same basic and 

dietary treatments; pre-treatment rates of SBBO 

were 61.5% in the polymyxin group and 71.4% in 

the placebo group. Both groups had a satisfactory 

clinical course. SBBO, however, persisted after 

treatment in a high proportion of patients: 76.9% 

of those given polymyxin and 57.1% on the 

placebo (NS). However, in the group treated with 

polymyxin a reduced need for other antibiotics for 

suspected systemic infections was found (p 

= 0.08). 

Recently, growing attention has been given to the 

possible use of probiotics in a variety of gastrointestinal 

disorders, including SBBO, and some 

preliminary evidence of possible efficacy is 

beginning to emerge. In fact, the risk of bacterial 

translocation in experimental short-bowel syndrome, 

a condition characterized by frequent 

episodes of SBBO, has been found to be reduced 

by the administration of Bifidobacterium lactis in 

rats. 62 Furthermore, two strains of lactobacilli 

(Lactobacillus casei and L. acidophilus strains 

cerela) have been found useful in the treatment of 

SBBO-related chronic diarrhea. 63

When SBBO is associated with environmental 

enteropathy, there is no evidence that antibiotics 

can help control it; in addition, the chronic nature 

of the process with possible recurrences clearly 

discourages this type of treatment. However, 

environmental enteropathy shows spontaneous 

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15. Thadepalli H, Ann Lou SM, Bach VT et al. Microflora of 

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bacterial flora in normal and in children with acute 

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85: 231–237. 

21. Suarez L, Perdomo M, Escobar H. Microflora bacteriana 

y ecosistema intestinal isiopatologia del intestino 

delgado contaminado. Diarréia aguda. Meio ambiente en 

Espana. GEN 1994; 48: 61–64. 

22. Riordan SM, Mciver CJ, Walker BM et al. The lactulose 

breath hydrogen test and small intestinal bacterial overgrowth. 


23. Bouhnik Y, Alain S, Attar A et al. Bacterial populations 

contaminating the upper gut in patients with small 

intestinal bacterial overgrowth syndrome. Am J 


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in small intestinal bacterial overgrowth-related chronic 

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1999; 117: 794–797. 

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overgrowth. Dig Dis Sci 2000; 45: 474–479. 

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xylose, 10-Gram lactulose-H2, and 80-Gram glucose-H2 

breath test in patients with small intestine bacterial 

overgrowth. Gastroenterology 1986; 91: 1447–1451. 

27. Khin-Maung U, Tin-Ay, Ku-Tin M et al. In vitro 

hydrogen production by enteric bacteria cultured from 

children with small bowel bacterial overgrowth. J 


28. Rumessen JJ, Gudmand-Hoyer E, Bachmann E, Justesen 

T. Diagnosis of bacterial overgrowth of small intestine: 

comparison of the 14 C D-xylose breath test and jejunal 

cultures in 60 patients. Scand J Gastroenterol 1985; 20: 

1267–1275. 

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diarrea cronica: estudo clínico y bacteriológico de 40 

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32. Tahan S. O efeito de um antimicrobiano na microbiota 

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teste do hidrogênio no ar expirado no diagnóstico de 

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Thesis, Universidade Federal de São Paulo, 2001. 

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of intestinal gas. Gastroenterology 1970; 59: 921–929. 

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small-intestinal bacterial overgrowth. Scand J 


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1996; 42: 40–45. 

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contamination of the small intestine as an important 

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229–235. 

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bacterial overgrowth in children with chronic diarrhea, 

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42. Marcelino RT. Teste do hidrogênio no ar expirado no diagnóstico 

do sobrecrescimento bacteriano do intestino 

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bacterial aerobic overgrowth in the small intestine of 

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contamination of the small intestine of infants with 

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Med (Buenos Aires) 2002; 62: 159–163.

14 

Introduction 

Functional abdominal pain 

and other functional bowel 

disorders 

Miguel Saps and Carlo Di Lorenzo 

The classic definition of recurrent abdominal pain 

has been based on the work of Apley and Naish, 1 

who described children who presented with intermittent 

episodes of abdominal pain occurring for 

at least 3 months without any identifiable cause 

and interfering with daily activities. The term 

‘chronic abdominal pain’ is often used interchangeably 

with ‘recurrent abdominal pain’. 

Chronic abdominal pain is abdominal pain that is 

continuous, persistent, or intermittent over a 

period of a few months. The pain may wax and 

wane, with some days being better than others. 2 

On occasions, relatively short asymptomatic 

periods may be interposed with ‘painful periods’, 

but the episodes of wellness rarely last long, generating 

a condition that profoundly distresses the 

daily life of children and their families. It is important 

to emphasize that recurrent abdominal pain 

represents a description and not a diagnosis. Many 

conditions can cause abdominal pain that is recurrent, 

but in clinical practice most children and 

adolescents presenting with this symptom have a 

functional disorder without any evidence of 

organic disease. They are considered to have ‘functional 

abdominal pain’. In this chapter we discuss 

conditions associated with functional alterations 

of the gastrointestinal (GI) system, called functional 

bowel disorders, and we only briefly 

describe those organic diseases causing abdominal 

pain (in the section dedicated to the differential 

diagnosis). 

Epidemiology 

Chronic abdominal pain is one of the most 

common pediatric complaints, 3 accounting for 

2–4% all of pediatric office visits. 4 Symptoms 

consistent with irritable bowel syndrome (IBS), 

one of the most common functional bowel disorders, 

occur in 14% of all high-school students and 

6% of all middle-school students. 5 IBS is more 

prevalent than other medical conditions such as 

hypertension, asthma and diabetes that tend to 

receive greater medical attention. 6 As many 

patients with IBS do not seek medical attention, 

assessing the prevalence of IBS is often difficult. 

Current estimates suggest that only one in four 

patients with symptoms of IBS seek medical care 

for their symptoms. 7 Population-based studies of 

adults have shown IBS-type symptoms in 13–15% 

of adult females, with abdominal pain reported as 

the most common complaint. 8 Reports from Kenya, 

Poland, Russia, India and Pakistan reveal that, 

although the relative frequency of an organic etiology 

for chronic pain may differ in various regions 

of the world, functional abdominal pain is probably 

a universal problem. 9–12 A Malaysian study in 

1500 schoolchildren found evidence of chronic 

abdominal pain in 10% of children, concluding 

that, in spite of differences in diet, customs and 

culture, the overall prevalence of this entity was 

similar across regions. 13 A Danish study also 

demonstrated that 15% of children aged 9–12 

years had recurrent abdominal pain. 14 

Quality of life in patients with IBS is substantially 

poorer than in the general population or in those 

suffering from asthma or migraine. 15 Costs related 

to functional bowel disorders are also enormous, 

with direct and indirect medical expenses associated 

with IBS being estimated as up to US$ 30 

billion a year, comparable to those of asthma, 

stroke, hypertensive disease, migraine and arthritis. 

16–18 IBS also has a high impact on a patient’s 

productivity, as a result of missed working days. 19 

A recent survey of adult patients suffering from 

213

214 

Functional abdominal pain and other functional bowel disorders 

IBS showed that 15% believed that IBS would stop 

them from finding a long-term partner, 16% had 

turned down a date in fear of the embarrassment 

that may result from intimacy, and 17% stated that 

they had a relationship ending as a consequence of 

IBS. 20 The survey also revealed that 12% of 

respondents had to give up working, while 35% of 

employed respondents reported having lost work 

time due to IBS. In addition to the direct and indirect 

costs, IBS patients are affected by intangible 

costs and social stigma. In 14% of cases, IBS symptoms 

were not accepted as a valid reason for 

absence by their employers. One-third of the 

patients with IBS had refrained from applying for 

promotions for positions involving multiple meetings 

and presentations. 20 

Physiology of the gastrointestinal 

pain response 

Visceral pain perception involves a complex 

pathway of peripheral and central nervous structures 

that encode, relay and modify the afferent 

stimulus. 

The enteric nervous system (ENS) is organized 

into two major plexuses providing the intrinsic 

innervation of the gut. The plexuses and the 

nerves connecting them constitute a continuous 

network around the circumference of the GI tract 

and along its length. The myenteric plexus, also 

known as Auerbach’s plexus, is situated between 

the external longitudinal and internal circular 

muscle layers, and the submucosal plexus 

(Meissner’s plexus) lies between the circular 

muscle layer and the mucosa. The myenteric 

plexus is larger and projects fibers primarily to the 

smooth muscle of the gut controlling motility. 

Meanwhile, the submucosal plexus projects into 

the mucosa and submucosa and includes more 

sensory cells and the neurons that control gland 

secretion. Although the two intestinal plexuses are 

separated spatially, interconnections bind the two 

networks into a functionally unified nervous 

system. The characteristics of this mesh of sensory 

fibers, interneurons and motor neurons, enables 

this mini-brain or ‘gut brain’ to integrate the 

sensory information, organize the motor and secretory 

responses and influence the luminal absorption, 

producing a functional state that is adapted to 

the well-being of the individual. Although the ENS 

receives input from the central and autonomic 

nervous systems, it can function independently. 

The ENS performs most of its functions in the 

absence of central nervous system (CNS) control, 

locally integrating the information of intrinsic 

afferent fibers (for example, luminal distension 

and chemical stimuli) with efferent axons, resulting 

in motor reflexes or secretory or absorptive 

responses. 

The extrinsic nervous system consists of afferent 

and efferent fibers connecting the ENS with the 

CNS. This communication allows the CNS continuously 

to integrate the information from the 

gastrointestinal tract with incoming information 

from other organs and from the environment, in 

order to initiate an adequate response. Under 

physiological conditions, most of these processes 

do not reach the level of conscious perception. 21 

However, sensations that trigger a particular 

behavior, including hunger, satiety and need to 

defecate, reach the cortex. The constant influence 

of the CNS on the ENS through activation of a 

subset of vagal and sacral parasympathetic fibers 

is exemplified by the relation between psychological 

stress and gastrointestinal response, manifested 

clinically by the occurrence of vomiting or 

diarrhea in patients experiencing a stressful event. 

The ENS and the brain use multiple neurotransmitters 

for chemical signaling and exchanging of 

inhibitory or excitatory information. They include 

excitatory neurotransmitters such as acetylcholine 

and substance P, and gut inhibitory neurotransmitters 

such as nitric oxide, ATP, vasoactive intestinal 

peptide (VIP), cholecystokinin, enkephalins, calcitonin 

gene-related peptide (CGRP), norepinephrine 

(noradrenaline), epinephrine (adrenaline) and 

others. Other neurotransmitters such as serotonin 

(5-hydroxytryptamine; 5-HT) and histamine have 

more complex effects. Ninety-five per cent of the 

total body 5-HT lies within the gut. Of the total gut 

5-HT, 90% is found in the granules of the enteroendocrine 

cells, and 10% in the neurons of the myenteric 

plexus. 22,23 5-HT plays a role in regulating GI 

motility and intestinal secretion. 22 5-HT receptors 

appear to participate in mucosal sensory processing 

within the gut. Distension and stroking of 

mechanosensitive receptors in the enteroendocrine 

cells triggers the release of 5-HT. 24 There 

are at least seven main classes of 5-HT receptor

and 22 subclasses that can be differentiated on the 

basis of structure and function. Four classes have 

been reported in the human GI tract (5-HT1, 5-HT2, 

5-HT3 and 5-HT4). 25 Serotonin action is complex, 

with mixed effects ranging from smooth muscle 

contraction via cholinergic nerves, to relaxation 

through stimulation of inhibitory nitric oxidereleasing 

neurons. Higher levels of serotonin are 

present in diarrhea-predominant IBS. 26 The ENS 

has the ability to modulate signal transduction by 

enhancing or inhibiting the activation of nociceptors 

through alteration in smooth muscle tone and 

contractile activity. Visceral pain may be modulated 

also at the CNS level by emotional or cognitive 

factors, providing a rationale for the use of 

centrally acting agents or cognitive behavioral 

treatments in functional bowel disorders. 

Neuroimaging studies have provided information 

on differences in brain processing of visceral 

stimuli between normal individuals and those 

suffering from IBS, revealing an increased activity 

at the level of the anterior cingulated cortex, 

prefrontal cortex, insular cortex and thalamus (the 

areas associated with emotional responses) in 

patients with IBS compared to asymptomatic individuals. 

27–29 


Several hypotheses have been put forward to 

explain the cause of functional recurrent abdominal 

pain. We examine them in the following 

sections. 

Visceral hyperalgesia 

The visceral hyperalgesia hypothesis proposes that 

greater sensitivity of visceral afferent pathways or 

central amplification of visceral input lead to an 

enhanced perception of visceral stimuli. There is 

evidence that the pain and discomfort of IBS might 

be due to hyperalgesia and allodynia of the gut. 

While in hyperalgesia a painful stimulus is 

perceived as even more painful, in allodynia a 

non-painful stimulus becomes painful. 30 A 

noxious stimulus applied to a particular area of the 

gut may sensitize primary afferent fibers and nociceptors 

of adjacent areas, causing painful sensations 

with a low-intensity stimulus, resulting in 

primary hyperalgesia. 


Most IBS patients experience rectal discomfort at 

lower intraluminal volumes or pressures 31,32 and 

have diminished tolerance to intestinal gas. 33 

Trimble et al 31 found that patients presenting with 

one functional bowel disorder frequently had 

additional symptoms referable to other parts of the 

digestive system, suggesting that enhanced 

visceral nociception may be a pan-intestinal 

phenomenon. For example, it has been reported 

that in addition to the features of rectal hyperalgesia, 

IBS patients have a decreased sensory threshold 

to balloon distension of the esophagus. 

Children with functional abdominal pain exhibited 

generalized visceral hyperalgesia, whereas 

IBS patients had rectal but not gastric hyperalgesia. 

32 Different GI symptoms were reproduced by 

stimulation of the predominant site of hyperalgesia, 

providing a physiological explanation of symptoms 

in children who have distinct phenotypic 

presentations. 

Dysmotility 

In addition to a greater intestinal sensitivity, 

patients with functional bowel disorders may 

display abnormal motility. Various types of motor 

disturbances have been documented in IBS, apparently 

reflecting dysfunction at one or more levels 

of the brain–gut axis. 34 Although the pathophysiology 

of IBS is commonly attributed to dysfunction 

of the large intestine, evidence exists to incriminate 

the small bowel as well. 35 Postprandial motor 

dysfunction in the small bowel appears to be more 

prevalent among IBS patients who exhibit underlying 

visceral hypersensitivity in the fasting state. 

Abdominal cramping has been associated with the 

passage of high-amplitude contractions through 

the ileocecal region. 36 Bloating has been explained 

by an abnormal transit and pooling of gas in 

conjunction with gut hypersensitivity. 33 

Manometric studies have demonstrated postprandial 

antral hypomotility in children and adults 

with functional dyspepsia. 37 However, not all 

studies have demonstrated differences between 

patients and control subjects. 38,39 Motility changes 

in IBS are neither specific nor predictable and do 

not serve as a diagnostic marker or as an aid to the 

selection of treatment. 40 It has been suggested 

than, rather than having a persistent motility 

abnormality, patients with functional bowel disorders 

exhibit an abnormal motor response to a 

variety of physiological stimuli. 41

216 


Brain–gut interaction 

The shortcomings of isolated experimental or 

observational models in explaining the complex 

nature of functional bowel disorders have led 

research to focus on the alterations in the communications 

between the CNS and the GI tract, hence 

the term ‘brain–gut’ interaction. 6,42 There are 

multiple examples of brain–gut interaction, the 

most common being the subjects who, under 

emotionally stressful situations, develop diarrhea, 

nausea or vomiting. Anger and aggression increase 

colonic motility, while hopelessness results in 

decreased motility. 43 The brain–gut model links 

alterations in peripheral sensory afferent communication 

from the gut (e.g. visceral hyperalgesia) to 

CNS processing of the sensory stimuli and its efferent 

signaling to the gut. In IBS patients multiple 

studies have shown that both gut and brain show 

an exaggerated responsiveness to different stimuli. 

Patients with IBS have significantly greater electroencephalogram 

(EEG) abnormalities than 

controls. 44 Dynamic brain imaging technologies 

such as positron emission tomography (PET) and 

functional magnetic resonance imaging (fMRI) 

have recently been applied to the study of the 

gut–brain axis in order to identify the areas of the 

brain activated by visceral sensations. Studies 

with these techniques have suggested an abnormal 

cerebral processing of visceral stimuli in patients 

with functional bowel disorders. 27,28 

Inflammation 

There is evidence that IBS can occur following a 

gastrointestinal infection resulting in transient 

inflammation. Gwee et al reported that 20–25% of 

patients admitted to the hospital for bacterial 

gastroenteritis developed symptoms consistent 

with IBS in the first 3 months. 45 Rectal biopsies 

prospectively obtained during and after acute 

gastroenteritis from patients who developed postinfectious 

IBS and a control group, showed that 

the former group exhibited significantly greater 

expression of interleukin (IL)-1β mRNA. 46 A recent 

study examining full-thickness biopsies from the 

jejunum of patients with severe IBS revealed 

inflammation and neuronal degeneration in the 

myenteric plexus, suggesting a possible pathogenetic 

role of inflammation. 47 Animal studies also 

seem to indicate that inflammation may produce 

persistent neuromuscular gut dysfunction. 48 Mild 

mucosal inflammation may perturb neuromuscular 

function also at remote non-inflamed sites. The 

gut dysfunction may persist even after reduction of 

the mucosal inflammation. Substances that 

mediate these changes are not fully understood, 

but there is growing recognition of the role of serotonin 

as a sensitizing agent. 

Immunity 

The mucosal immune system mediates the clinical 

impact of stress and other psychological factors on 

the gut. Vagal afferents can be activated by products 

of mast cell degranulation, resulting in sensitization 

of silent nociceptors. Mast cell mediators 

may be released in response to luminal macromolecules, 

a phenomenon that could explain 

brain–immune system interactions within the gut. 

A descending input by the vagus nerve may also 

reciprocally affect mast cell degranulation, resulting 

in local effects on secretomotor activity. 

Stressors 

Stressful events have long been believed to be 

important in the development of symptoms in 

functional bowel disorders. 49 Physiological reactions 

to stressors should be considered as attempts 

by the body to adapt – a natural coping mechanism, 

in which, if stressors are not too extreme or 

long standing, the subject is usually successful in 

reaching a homeostatic state. However, at times 

the body loses the capacity to adapt and deleterious 

behavioral responses may arise. Chronic exposure 

to threat is associated with alterations in the 

autonomic outflow, resulting in activation of the 

hypothalamic–hypopituitary–adrenal axis with 

alteration in pain modulation. Corticotropin 

releasing hormone seems to be the hormonal mediator 

of the stress response. Intracerebroventricular 

injection of corticotropin releasing factor, which 

mimics the responses to stress in animals, exacerbates 

nociceptive responses associated with 

increased release of histamine. 50 In humans, possibly 

as a primitive response to danger, stress 

induces delayed gastric emptying, slower smallbowel 

activity and accelerated colonic transit. 51–54

These alterations may presumably cause diarrhea, 

constipation or abdominal distension depending 

on the predominant abnormality. 

Genetics 

A recent study showed a significant association 

between subjects with abdominal pain or bowel 

disturbances and first-degree relatives with IBS 

and dyspepsia. 55 Twin studies have shown a 17% 

concordance for IBS in monozygotic patients with 

only 8% concordance in dizygotic twins. Although 

these data suggest a specific role for heredity in the 

development of IBS, the same study showed a 

higher correlation of IBS with parental symptoms, 

suggesting that social learning from the patient’s 

environment has an equal or greater influence. 56 

Biopsychosocial model 

The biopsychosocial model 57 provides a framework 

to integrate the biological and psychosocial 

processes, in an attempt to understand the underlying 

pathophysiological mechanisms determining 

disease susceptibility, and to explain the clinical 

variability and outcome among individuals. 

The biopsychosocial model, proposed as an 

alternative to the traditional biomedical model, 

conceptualizes the general state of health as resulting 

from the integration of medical and psychosocial 

factors. To understand this model, one 

should differentiate between disease, which is the 

abnormality of the structure and/or function of 

organs and tissues (physical component), and 

illness, defined as the patient’s perception of 

health and bodily dysfunction (psychological 

component). In Engel’s model, 57 illness and 

disease result from interactions at the cellular, 

tissue, interpersonal and environmental levels 

resulting in a clinical outcome. The biopsychosocial 

model assumes that genetic influences on 

disease susceptibility and behavior result in a 

biological and psychosocial predisposition that 

will influence later psychosocial experiences, 

physiological functioning, or susceptibility to a 

pathological condition. This particular background 

is affected by physical and environmental 

exposures such as infection, food intolerance and 

social exposures including friends, family and 

community to influence the patient’s attitude 


towards illness. 58 Stress acting on a vulnerable GI 

tract leads to an imbalance in the system, resulting 

in an alteration of the brain–gut axis. Multiplicity 

of stressors reinforces and up-regulates the 

response. It is well recognized that some IBS 

patients report initiation or exacerbation of symptoms 

at times of stress, trauma and major loss. 59 

Traumatic early life events such as child abuse may 

predispose to functional bowel disorders. 60 There 

have been reports of a greater prevalence of sexually 

and physically abusive experiences in individuals 

with IBS than in patients with organic 

gastrointestinal disorders and non-patient populations. 

61 The interaction of the previously described 

subsystems with psychosocial modifiers (concurrent 

psychiatric diagnosis, life stress, social 

support, coping mechanisms) affects the behavior 

of the individual, the biological nature of the 

condition and, ultimately, the clinical outcome. 

New or uncontrollable threatening situations may 

result in emotional and physiological arousal. 

Psychosocial factors may affect the end result 

(clinical presentation and outcome) acting on gut 

physiology, modulating symptoms experience, and 

influencing health behavior and therapeutic interventions 

(Figure 14.1). The relative contribution of 

the medical and psychosocial factors varies among 

patients. This model should be considered when 

Figure 14.1 Proposed pathophysiological model for 

functional bowel disorders.

218 


planning therapy, as failure to link the disease and 

illness components will reduce the likelihood of 

an effective treatment. 

Functional bowel disorders 

presenting with abdominal pain 

Irritable bowel syndrome 

IBS is the most common painful functional 

gastrointestinal disorder in children, with symptoms 

arising with similar incidence in both 

genders. 5,62 Because there are no known biochemical 

or structural markers for IBS, the diagnosis is 

based on typical symptoms with the aid of negative 

results of a limited diagnostic evaluation. 

Despite their limited validation, the most widely 

accepted criteria for definition of all functional 

bowel disorders in children are the Rome II criteria 

(Table 14.1). The criteria for IBS require abdominal 

pain associated with bowel movements or 

with change in stool frequency or stool characteristics. 

63,64 Patients with IBS may be classified into 

those with a predominance of diarrhea, those who 

tend to have constipation, and those whose symptoms 

alternate from diarrhea to constipation. 

Functional dyspepsia 

According to Rome II criteria, functional dyspepsia 

is persistent or recurrent pain or discomfort 

centered in the upper abdomen. Functional 

dyspepsia has two presentations – ulcer-like and 

dysmotility-like – although considerable variation 

and overlap occur between the two entities. 

Symptoms include upper abdominal pain or 

discomfort, bloating, belching, early satiety, 

nausea, retching, or vomiting. The diagnosis is 

based on symptoms, as there are no biologic 

markers for this condition. 65 A controversial issue 

is the requirement for a negative esophagogastroduodenoscopy 

to reach the diagnosis (Table 14.1). 

Dyspeptic symptoms are frequent in children. An 

Italian school study in children 6–19 years of age 

revealed symptoms of dyspepsia in 45% of children. 

66 Although the link between Helicobacter 

pylori infection and the development of chronic 

abdominal pain is controversial, there seems to be 

evidence of an increased risk of dyspepsia in adult 

patients infected with H. pylori. 67 This link has not 

been clearly defined in children, where it remains 

unknown whether H. pylori-induced gastritis 

(when not associated with peptic ulcer) is responsible 

for clinical symptoms. 68 

Functional abdominal pain 

Although the terminology seems confusing, it 

should be noted that the term ‘functional abdominal 

pain’ has been considered by the Rome II 

committee members as one of the categories of 

abdominal pain, being an entity by itself (Table 

14.1). This group comprises patients with pain 

that is usually located in the periumbilical region 

and is not consistently related to eating, defecation, 

menses, or exercise. Patients may have associated 

headache, dizziness, light-headedness, 

nausea and vomiting. As with other forms of pain 

of functional origin, the diagnosis is clinical. 

Abdominal migraine 

In some children with a personal and family 

history of migrainous headache, the abdominal 

pain may be acute, severe and non-colicky, and 

often associated with pallor and anorexia. This is 

sometimes referred to as abdominal migraine. 

Children with abdominal migraine are completely 

healthy between attacks, but suffer a feeling of 

intense misery during attacks, interrupting their 

activities, and seeking out a quiet, dark room. Pain 

is usually periumbilical, incapacitating and poorly 

defined. Bouts of pain can last from a few hours up 

to 2–3 days. Peak prevalence is at 10 years of age, 

declining rapidly thereafter, although occasionally 

it may persist into adulthood. 69 

In contrast to children, adults with migraine 

headaches usually do not have abdominal pain. 70 

Follow-up studies have shown an evolution of 

children with abdominal migraine into adults with 

migraine headaches, 71 and the episodes of abdominal 

pain have been considered a prodrome to 

migraine headaches. The clinical features of 

abdominal migraine and cyclic vomiting 

syndrome (recurrent, sudden, self-limiting 

episodes of nausea, vomiting and lethargy) show 

considerable similarity; treatment of the two 

conditions often utilizes similar pharmacological 

agents. 72

Functional bowel disorders presenting with abdominal pain 219 

Table 14.1 Rome II criteria for functional bowel disorders associated with abdominal pain or 

discomfort (from reference 74) 

Functional dyspepsia 

In children mature enough to provide an accurate pain history, at least 12 weeks, which need not be consecutive, 

within the preceding 12 months of: 

(1) Persistent or recurrent pain or discomfort centered in the upper abdomen (above the umbilicus); and 

(2) No evidence (including upper endoscopy) that organic disease is likely to explain the symptoms; and 

(3) No evidence that dyspepsia is exclusively relieved by defecation or associated with the onset of a change in stool 

frequency or stool form. 


In children old enough to provide an accurate pain history, at least 12 weeks, which need not be consecutive, in the 

preceding 12 months of: 

(1) Abdominal discomfort or pain that has two out of three features: 

(a) Relieved with defecation; and/or 

(b) Onset associated with a change in frequency of stool; and/or 

(c) Onset associated with a change in form (appearance) of stool; and 

(2) There are no structural or metabolic abnormalities to explain the symptoms. 

The following symptoms also support a diagnosis of irritable bowel syndrome: 

(a) Abnormal stool frequency defined as more than three bowel movements per day or fewer than three bowel 

movements per week; 

(b) Abnormal stool form (lumpy/hard or loose/watery); 

(c) Abnormal stool passage (straining, urgency, or feeling of incomplete evacuation); 

(d) Passage of mucus with stool; 

(e) Bloating or feeling of abdominal distension. 

Functional abdominal pain: 

At least 12 weeks of: 

(1) Nearly continuous abdominal pain in a school-aged child or adolescent; and 

(2) No or only occasional relation of pain with physiological events (e.g. eating, menses, or defecation); and 

(3) Some loss of daily functioning; and 

(4) The pain is not feigned (e.g. malingering); and 

(5) The patient has insufficient criteria for other functional gastrointestinal disorders that would explain the 

abdominal pain. 

Abdominal migraine: 

In the preceding 12 months: 

(1) Three or more paroxysmal episodes of intense, acute midline, abdominal pain lasting 2 h to several days, with 

intervening symptom-free intervals lasting weeks to months; and 

(2) No evidence of absence of metabolic, gastrointestinal and central nervous system structural or biochemical 

diseases; and 

(3) Two of the following features: 

(a) Headache during episodes; 

(b) Photophobia during episodes; 

(c) Family history of migraines; 

(d) Headache confined to one side only; 

(e) An aura or warning period consisting of either visual disturbances, sensory symptoms, or motor 

abnormalities.

220 


Differential diagnosis 

A number of clinical features (‘red flags’) are 

commonly considered as orienting towards an 

organic etiology, although definitive proof for their 

predictive value is scant. Elements that have been 

classically associated with a greater likelihood of 

an organic condition are listed in Table 14.2. The 

presence of an isolated symptom (such as isolated 

abdominal pain) is usually thought to be consistent 

with a functional disorder, while multiple 

symptoms (such as abdominal pain with weight 

loss, or vomiting, or diarrhea) are more likely to be 

due to an organic condition. There are almost 

endless causes of chronic organic abdominal pain 

in children. The most common are listed in Table 

14.3. 

Peptic disease 

Pain related to peptic ulcer disease is usually 

epigastric and non-radiating, but may also be 

generalized or periumbilical. It occasionally 

Table 14.2 Chronic abdominal pain ‘red 

flags’: signs and symptoms suggesting an 

organic etiology 

Age

Table 14.3 Causes of chronic abdominal pain 

Functional 


Functional abdominal pain syndrome 

Dyspepsia 


Constipation 

Organic 

Gastrointestinal 

esophagitis 

gastritis 

duodenitis 

peptic ulcer 

eosinophilic gastroenteritis 

malrotation 

cysts (duplication or mesenteric) 

celiac disease 

parasites 

hernias 

tumors 

foreign body 

intussusception 

inflammatory bowel disease 

Hepatobiliary 

chronic hepatitis 

cholelithiasis 

cholecystitis 

choledochal cyst 

sphincter of Oddi dysfunction 

Pancreatic 

pancreatitis 

pseudocyst 

Carbohydrate intolerance 

In children with chronic abdominal pain, 

increased flatulence and bloating, the diagnosis of 

carbohydrate intolerance should be considered. 

The breath hydrogen test following a lactose or 

fructose load will confirm the diagnosis. Exclusion 

of these offending agents may improve the symptoms. 

On the other hand, lactose intolerance has a 

very high prevalence in the general population and 

Differential diagnosis 221 

Respiratory 

infection, tumor or inflammation vicinity of 

diaphragm 

Genital 

hematocolpos 

endometriosis 

mittelschmertz 

tumor 

Urinary 

ureteropelvic junction obstruction 

recurrent pyelonephritis 

recurrent cystitis 

hydronephrosis 

nephrolithiasis 

Metabolic 

porphyria 

diabetes 

lead poisoning 

Hematological 

angioedema 

collagen vascular disease 

sickle cell disease 

Musculoskeletal 

trauma 

inflammation 

infection 

tumor 

Psychiatric 

conversion reaction 

symptoms after a lactose load develop in only a 

few of the self-reported milk-intolerant subjects. 79 

In a large sample of American patients, lactose 

malabsorption was found in 21–25% of IBS 

patients, 81 a prevalence considered comparable to 

that in the general American population. 

Lebenthal et al 84 found a similar prevalence of 

lactase deficiency in children with recurrent 

abdominal pain and in children of a control group 

of similar ethnic background. Moreover, a lactose-

222 


free elimination diet resolved symptoms in a 

similar percentage of patients in the lactose 

absorbers and in the lactose malabsorbers. As a 

result of the high independent prevalence of both 

conditions in the general population, the presence 

of chronic abdominal pain and lactose intolerance 

in one patient may be merely coincidental. Thus, 

the recommendation of an exclusion diet should 

be made with reasonable expectations, as it may be 

helpful in the resolution of symptoms in only a 

limited number of patients. 

Inflammatory bowel disease 

Occult IBD was found in 1% of adult patients 80 

and in 3–4% of pediatric patients 62 evaluated for 

IBS. Some patients may complain for months or 

years of vague abdominal pain and intermittent 

diarrhea before being diagnosed as having IBD. 

The presentation of the abdominal pain is variable, 

depending on the site of bowel involvement. 

Terminal ileum and cecal disease in the setting of 

Crohn’s disease is often associated with right lower 

quadrant discomfort and tenderness. Diagnosis is 

frequently delayed, with an average lag in diagnosis 

of approximately 7 months. 82 A decrease in 

growth preceded the onset of any symptoms by at 

least 1 year in 24 of 50 patients with Crohn’s 

disease. 83 

Chronic constipation 

IBS with constipation predominance and chronic 

constipation present many descriptive similarities. 

65 However, constipation in combination with 

abdominal pain has a wide differential diagnosis 

and constipation should not be judged as causing 

abdominal pain without consideration of alternative 

diagnoses. In chronic constipation physical 

examination may reveal a fecal mass in the left 

lower quadrant and suprapubic region. Examination 

of the perineum should include assessment 

of the lower back, sacrum and site of the 

anus. Anal examination may reveal the presence of 

a fissure or a sentinel skin tag indicative of a 

fissure. Rectal examination may reveal the presence 

of a dilated rectum containing a hard fecal 

mass. A flat plate radiograph may help in the diagnosis 

in cases where obesity precludes an appropriate 

abdominal examination. 

Gallstones 

Cholelithiasis is considered uncommon in infancy, 

childhood and adolescence, with a prevalence 

ranging from 0.2 to 0.5%. 84 In older children, 

obesity, ileal disease and a family history of childhood 

gallstones have been associated with 

cholelithiasis. 85 Children with gallstones may 

have colicky or unspecific pain or remain asymptomatic. 

The pain is mostly located in the right 

upper quadrant or in the epigastrium, and may 

radiate to the back or right shoulder. Nausea and 

vomiting are present in more than 50% of cases. 

Fatty food intolerance is not commonly reported in 

children. Other biliary tree pathologies such as 

choledochal cyst may present with abdominal 

pain. Presentation is age dependent, with jaundice 

prevailing in children and abdominal pain in 

adults. 86 

Parasitic infections 

Positive fecal ova and parasite tests were found in 

only 2% of adult patients with IBS. 80 Giardia 

lamblia, Dientamoeba fragilis, Cryptosporidium 

and Blastocystis hominis may be found in patients 

presenting with abdominal pain, often accompanied 

by anorexia, abdominal distension and 

diarrhea. Blastocystis hominis is most likely to be 

non-pathogenic in the immunocompetent human 

host. 87 


Symptoms of IBS may overlap with those of 

small-intestinal bacterial overgrowth (SBBO). 

Pimentel et al, 88 in a prospective study, showed 

that 78% of IBS patients had SBBO diagnosed by 

a lactulose hydrogen breath test, and that the 

eradication of the overgrowth improved diarrhea 

and abdominal pain. A study of IBS patients with 

SBBO demonstrated significant motility abnormalities, 

89 leading the authors to conclude that 

dysmotility was the pathogenic mechanism 

linking SBBO to IBS. Another controlled study 

looking at the effects of antibiotics on IBS 

patients with alterations of the duodenal and 

colonic flora has also shown a significant improvement 

of symptoms in the group of patients 

receiving antibiotics. 90


Patients with celiac disease may present with 

symptoms mimicking other conditions. 91 A recent 

study has shown that celiac disease patients were 

initially diagnosed as having IBS in 37% of cases. 92 

In this study, only 32% of adults with celiac 

disease were underweight, and only 50% reported 

frequent diarrhea and weight loss. Anemia was 

present in 67% of the cases. Patients frequently 

presented with abdominal pain and bloating or gas 

which are common clinical manifestations of functional 

bowel disorder. The Dutch College of 

General Practitioners states that celiac disease 

should be added to the differential diagnosis of 

IBS. 93 A Canadian study revealed that, prior to 

being diagnosed as celiac disease, 37% of respondents 

consulted four or more family doctors. 94 An 

Israeli study in 270 consecutive patients who 

underwent endoscopy for abdominal pain demonstrated 

celiac disease in one out of 23 of the 

patients. 95 

Genitourinary disorders 

Pyelonephritis and obstructive conditions such as 

ureteral or pelviureteric junction obstruction may 

present with recurrent cramping abdominal pain, 

despite normal physical examination and urinalysis. 

96 Hematuria can be present in the setting of 

urinary tract infections, abuse, trauma, Henoch– 

Schönlein purpura, or renal stones. Dysuria associated 

with abdominal pain can represent a sign of 

pyelonephritis, abuse, trauma, or a sexually transmitted 

disease. 97 In adolescent girls, a history of 

mid-lower abdominal pain was found to have low 

sensitivity but high specificity for gynecological 

diseases. 98 Gynecological pathology such as 

ovarian cysts, congenital uterine abnormalities 

and endometriosis should also be considered in 

the differential diagnosis of abdominal pain. 

Hematocolpos 99 due to imperforate hymen may 

present with periodic lower abdominal pain and 

urinary retention. Endometriosis may begin 3–4 

years after menarche. Clinically it may manifest as 

cyclic abdominal pain, nausea, vomiting, constipation 

or diarrhea. 100 

Congenital anomalies 

Malrotation presents usually early in life, with 

85% of all cases of midgut volvulus occurring in 


the first year. In neonates, symptoms are usually 

dramatic with sudden onset of bilious vomiting 

and a visibly seriously ill patient. Older infants 

may present with episodes of colicky abdominal 

pain. In one series, 20% of cases of malrotation in 

patients over 1 year of age presented with chronic 

abdominal pain. 101 These patients often have 

vague, long-standing abdominal complaints with 

or without emesis. The pain is often postprandial 

and may be accompanied by bilious emesis and 

diarrhea or evidence of malabsorption or proteinlosing 

enteropathy associated with bacterial overgrowth. 

Duplications of the alimentary tract are 

uncommon congenital abnormalities. The clinical 

presentations may be vague and diverse, depending 

on the location of the duplication. 102 

Presenting signs and symptoms include abdominal 

mass, vomiting, decreased oral intake, gastrointestinal 

bleeding, periumbilical tenderness and 

abdominal distension. 

Musculoskeletal pain 

Pain related to trauma is usually well localized and 

sharp in nature, and may be exacerbated by movement. 

Patients usually are able to recall a history of 

trauma or strain, but occasionally that history 

cannot be elicited. The diagnosis of costochondritis 

should be considered in adolescent patients 

complaining of chest or upper abdominal pain. 

Costochondritis pain originates in the anterior 

chest wall, from where it may radiate into the 

chest, back, or abdomen. Pain is reproducible by 

palpating the affected costal cartilage. 103 

Miscellaneous 

Familial Mediterranean Fever (FMF) is a hereditary 

disease with an autosomal recessive transmission 

that primarily affects populations of non- 

Ashkenazi Jews, Armenians, Arabs and Turks. 104 A 

typical attack consists of fever and inflammation 

of serous membranes lasting from 1 to 4 days. 

Between attacks, FMF patients are asymptomatic 

and appear healthy. The frequency of the attacks 

varies from weekly to one every 3–4 months or 

less. Severe abdominal pain similar to acute peritonitis 

is present in 95% of patients. Other symptoms 

may include chest pain, arthritis and rash. 

Attacks may be triggered by physical and 

emotional stress, menstruation and a high-fat diet. 

There are no specific laboratory tests for FMF,

224 


although a genetic diagnosis might become available 

in the foreseeable future. During attacks, 

acute-phase reactants may be elevated. 

Diagnostic testing 

In patients with no alarm symptoms, the Rome 

criteria have a positive predictive value of approximately 

98%, with additional diagnostic tests 

providing a yield of 2% or less. 105 When needed, 

the exclusion of an organic condition can be 

accomplished by utilizing inexpensive, non-invasive 

and easily available diagnostic tests such as 

complete blood cell count, erythrocyte sedimentation 

rate, chemistry panel, liver and thyroid function 

studies, urine analysis and stool examination 

for blood, ova and parasites. Need for other diagnostic 

tests should be based on history and physical 

examination findings. The physician should 

avoid the lure of having to ‘rule out’ an organic 

disease at all cost. Performing multiple tests may 

provide results that often are unrelated to the 

presenting symptom or have no clinical relevance 

(such as a mildly elevated sedimentation rate). 

Repeating tests to confirm the serendipitous findings 

may further increase anxiety and undermine 

the clinical diagnosis of functional bowel disorder. 

One could use time as the physician’s ally, assuring 

the patient that no test is necessary at this 

point but if further symptoms present or the 

current symptom worsens the physician will not 

hesitate to proceed with further work-up. 

Blood and stool studies 

Hamm et al 80 studied 1452 patients with an established 

diagnosis of IBS and found that screening 

tests showed a low incidence of thyroid dysfunction, 

ova and parasite infestation, or colonic 

pathology. The authors concluded that limited 

detection rates, added costs and the inconvenience 

of these tests made the routine use of endoscopy, 

radiography, thyroid function tests, fecal ova and 

parasite determination and the lactose hydrogen 

breath test questionable in the diagnostic evaluation 

of established IBS patients. In accordance 

with these results, Tolliver et al 106 performed fecal 

ova and parasite determinations in 196 patients 

with a possible diagnosis of IBS, and found no 

evidence of infection in any of them. In the same 

study, complete blood cell count, sedimentation 

rate, serum chemistries, thyroid profile and urinalysis 

were normal or yielded no useful clinical 

information. 

A study designed to investigate the prevalence of 

elevated antiendomysial antibody titers in children 

with recurrent abdominal pain compared 

with healthy children found no association 

between abdominal pain and celiac disease. 107 The 

study showed that 1% of patients in each group 

had positive celiac disease antibodies. An adult 

investigation studied serum antibody testing for 

celiac disease in patients with IBS symptoms and 

a control group, followed by upper endoscopy in 

positive cases. The study revealed that 4.6% of 

patients in the group with possible IBS had positive 

antibodies in comparison with 0.67% in the 

control group, suggesting that testing for celiac 

disease may be one of the few cost-effective evaluations 

in patients with IBS. 108 

Endoscopic studies 

A study investigating the presence of gastroesophageal 

reflux in children with recurrent 

abdominal pain concluded that pathological 

gastroesophageal reflux is a frequent finding in 

such children. 109 Treatment of gastroesophageal 

reflux in this group of patients resulted in 

resolution or improvement of abdominal pain in 

71% of cases. Another study evaluating findings 

on endoscopic examinations in 62 Indonesian 

children with recurrent abdominal pain revealed 

pathological abnormalities including esophagitis, 

erosions and duodenitis in 50% of the patients. 110 

In the absence of peptic ulcers, it is unclear how 

much these pathological findings contribute to the 

patients’ symptoms. Endoscopy and biopsy 

performed in children evaluated for dyspepsia 

demonstrated that most children did not have 

significant mucosal disease. Inflammation without 

evidence of peptic ulceration was found in 38% of 

the patients with H. pylori being identified in only 

five cases. 111 Follow-up at 6 months to 2 years 

revealed that most subjects improved, regardless 

of the cause of dyspepsia. 

Ultrasound 

The diagnostic yield of a sonographic examination 

of the abdomen in children presenting with func-

tional bowel disorders seems to be extremely low. 

Yip et al, in a retrospective evaluation of 644 ultrasound 

studies performed in children with the diagnosis 

of recurrent abdominal pain found abnormalities 

in only ten children, concluding that only 

children who have abdominal pain with atypical 

clinical features should receive sonographic 

screening. 112 In another study, the evaluation of 57 

patients with chronic abdominal pain by abdominal 

and/or pelvic sonography revealed only one 

case of ovarian cyst that later resolved spontaneously. 

113 Stordal et al 114 studied 44 children 

with recurrent abdominal pain without finding 

any abnormalities on ultrasound that could be 

related to the symptoms. 

Intraesophageal pH monitoring 

The diagnostic yield of esophageal pH monitoring 

in children presenting with chronic abdominal 

pain is controversial. A study of 44 children 

presenting with recurrent abdominal pain demonstrated 

gastroesophageal reflux in 25% of cases. 114 

No studies have compared outcomes between children 

who had pH monitoring studies and those 

who did not. The inconvenience associated with 

this test and its cost preclude its use at least in the 

initial evaluation of chronic abdominal pain. 

Lactose hydrogen breath test 

This test is often used to diagnose lactose intolerance 

in patients with functional bowel disorders, 

but the cause–effect relationship between lactose 

intolerance and symptoms has been questioned. 81 

Lactose intolerance is discussed in more detail in a 

previous section of this chapter. 

Treatment 

There is no uniformly successful treatment or cure 

for functional bowel disorders. Once the diagnosis 

has been made, it is essential to emphasize the 

benign aspects of the history, physical examination 

and laboratory tests in order effectively to 

reassure the patient and the family of their significance. 

Initial treatment of functional pain is based 

on reassurance and establishing an effective 

physician–patient–family relationship. Alleviating 

Treatment 225 

symptoms is one of the main goals of caring for 

patients with functional bowel disorders, but a 

rational management of these disorders is often 

challenging, owing to the lack of objective diagnostic 

criteria and unclear pathogenesis. As a 

consequence, there are no specific, universally 

effective therapies. 115 

Reassurance 

It is of great importance to assure the family and 

the patient that the physician believes that the 

symptoms are ‘real’ and that an organic or progressive 

disease is not present. An extensive explanation 

of the nature of the disorder should be given, 

discussing the problem as a common diagnosis 

and not just an exclusion of an organic disease. A 

comprehensive but easily understandable description 

of the nature of this group of disorders should 

be attempted. Comparisons with other common 

and benign entities such as headaches or muscle 

cramps may help. The family and the patient 

should be encouraged to ask questions and share 

their concerns, which should be addressed in 

depth to avoid fears and misconceptions. 

The main goal of the therapy is to re-establish a 

normal daily life for the patient and the family. 

The family should be discouraged from reinforcing 

the symptoms by allowing the child to miss school 

and leisure activities. Patients with perceived low 

self-worth and academic competence may find the 

relief of responsibility as a benefit of the pain experience; 

116 meanwhile, patients with adequate 

perception of their self-worth may find it discouraging. 

Fordyce and others have suggested that 

positive attention from others may serve as a 

secondary gain, transforming the painful experience 

into a rewarded activity that in turn could 

reinforce symptoms, leading to further disability. 

117,118 However, negative attention to pain in 

children with low self-esteem has been associated 

with increased pain behavior, possibly by creating 

affective distress that may further contribute to 

somatic symptoms. 116 Thus, the parents’ attitude 

towards the pain experience should be balanced, 

showing support and understanding, but being 

aware that excessive attention to the painful experience 

and missing activities may allow some 

patients (especially those with low self-worth) to 

develop a sick role, perpetuating the symptoms.

226 


Behavior alternative to assuming the sick role 

should be encouraged and rewarded. Patients 

should be encouraged to discuss perceived triggering 

factors. Psychosocial stressors at home or 

school should be addressed. At school, strict toilet 

times or issues relating to social embarrassment to 

attend the restrooms should be discussed. It is 

often useful to communicate with the school nurse 

or teacher in order to address these issues. 

Owing to the high index of symptomatic success 

with reassurance, medications are not necessary 

for every patient with functional abdominal pain. 

Drug therapy should be recommended only for 

patients with symptoms interfering with satisfactory 

quality of life. 

Diet 

A detailed dietary history may identify factors that 

patients may feel as aggravating or provoking the 

symptoms. Food intolerance was perceived as a 

problem by 20% in an unselected UK population 

who responded to a questionnaire, but with 

controlled challenge the prevalence was slightly 

higher than 1%. 119 Food-induced symptoms are 

common reports among IBS patients, with 20–65% 

attributing their symptoms to adverse food reactions. 

120,121 In a study of 200 IBS patients, 120 the 

effect of an exclusion diet was evaluated, with a 

symptomatic improvement in almost 50% of 

patients, indicating that a significant proportion of 

IBS patients could benefit from therapeutic dietary 

manipulation. However, such intervention is still 

controversial because the observed response rate 

replicates the average placebo response rate in IBS 

trials. 40 Within IBS patients the subgroup of 

patients with diarrhea-predominant symptoms 

seems to benefit the most by a trial of exclusion 

diet. Among those with abdominal pain with or 

without diarrhea, lactose, or excessive fructose or 

sorbitol intake may induce symptoms. The avoidance 

of gas-forming foods such as legumes, 

complex carbohydrates, lactose and fructose may 

provide symptomatic relief in some patients. 

High-fiber diets have long been used in adult IBS 

patients but the data in children are still preliminary 

and accomplishing a substantial increase in 

fiber consumption may be difficult. 122,123 As fibers 

decrease the whole-gut transit time, fiber-enriched 

diets may be more useful in the subgroup of 

patients with constipation. 124,125 Fiber may also 

decrease intraluminal pressures, reducing wall 

tension and pain. 126 In committed families 

wishing to increase dietary fibers, the change 

should be attempted gradually, as the excess of 

undigested carbohydrates in the colon results in 

fermentation with consequent increase of gas, 

aggravating IBS symptoms. 127 Frequently, nonpharmacological 

strategies alone fail to bring 

complete relief to IBS patients, necessitating 

pharmacotherapy (Table 14.4). 

Laxatives 

Patients with severe constipation may find relief 

by combining fiber with a laxative. It is our preference 

to use polyethylene glycol or a senna derivative, 

but other laxatives may be used according to 

the practitioner’s preference. Lactulose should be 

avoided, as the increase of gas production derived 

from its use may trigger pain. 

Anticholinergic and antidiarrheal medications 

Some patients with diarrhea seem to benefit from 

an antidiarrheal preparation such as loperamide or 

diphenoxylate. Studies in adults 6 and anecdotal 

experience seem to demonstrate that some patients 

find relief by using anticholinergics such as 

hyoscyamine, 128 dicyclomine or others that may 

modify intestinal tone and motility. These agents 

are best used on a sporadic basis, whenever the 

symptoms are present much like analgesics are 

used for headaches. When giving medications for 

pain, the high placebo response rate should be 

considered, as several preparations may work in 

the short term, only to relapse after a variable 

period of time. 129 

Tricyclic antidepressants 

An additional option for treating chronic abdominal 

pain is the use of tricyclic antidepressants 

(TCA). TCA are used at smaller doses 

(0.2–0.4 mg/kg per day, 5–50mg/day) than needed 

for treatment of clinical depression. The analgesic 

effects of TCA and other antidepressants are independent 

of their effects on depression, and this 

information should be shared with the family and 

the patient. The beneficial effect of the TCA starts

Table 14.4 Drugs approved for treatment of IBS and scientific 

evidence 

3–7 days after the beginning of the treatment, 

while it takes 2–3 weeks for the onset of the antidepressant 

effects. 130 Relief of chronic pain with 

the use of antidepressants has been documented in 

the absence of any measurable antidepressant 

response, both in depressed patients 131 and in 

patients without clinical depression. In addition to 

its action on noradrenergic and serotoninergic 

receptors, the TCA have antimuscarinic and antihistaminic 

effects. Thus, these agents are especially 

effective in diarrhea-predominant 

patients 132 and those with disturbed sleep, when 

slowing intestinal transit and the side-effects of 

sleepiness may be of therapeutic value. The 

medication is best administered at bedtime. Other 

side-effects such as undesirable weight gain and 

the possibility of cardiac arrhythmias, although 

rare at such low doses, demand caution when 

prescribing these drugs. Electrocardiogram (EKG) 

monitoring can be performed at the practitioner’s 

discretion. Amitriptyline, although probably more 

effective, has greater sedative and anticholinergic 

effects than imipramine. 133 It is recommended that 

the medication be started at low doses, increasing 

the dose progressively as needed to achieve a full 

dose in weeks. 134 Other antidepressant drugs, such 

as selective serotonin reuptake inhibitors (SSRIs) 

are also being used in the relief of chronic pain. 135 

Selective serotonin re-uptake inhibitors 

Scientific 

USA Canada evidence 

Dicyclomine yes yes 

Propantheline yes 

Hyoscymine yes yes 

Hyoscine/atropine yes yes 

Peppermint oil yes yes 

Tegaserod yes yes yes 

Alosetron yes 

(restricted) 

yes 

Source: physicians’ desk reference 2001 (USA) 

Compendium of Pharmaceuticals and Specialties (Canada) 

SSRIs, such as paroxetine, fluoxetine, or sertraline, 

also seem to have therapeutic value in relieving 

Treatment 227 

symptoms in adult patients with functional bowel 

disorders. 128 SSRIs have become the most 

frequently prescribed antidepressant medications, 

owing to their favorable side-effect profile. 136 

Despite the growing popularity of SSRIs, there are 

few controlled studies of their efficacy in managing 

chronic pain syndromes. The effects of TCAs 

and SSRIs in the GI tract are different, with the 

TCAs slowing intestinal transit and SSRIs increasing 

motility in the small intestine. 39,137 Thus, a 

patient in whom the main symptom is constipation 

may benefit most from an initial trial of an 

SSRI, whereas a patient with increased bowel 

frequency may benefit from an antidepressant 

with anticholinergic properties. Recent reviews 

concluded that, although SSRIs may be effective, 

in most circumstances TCAs should remain the 

first-line antidepressant agents for chronic pain. 131 

Serotonin receptor antagonists 

There has been much recent interest in clinical 

gastrointestinal pharmacology focused on 5-HT3 

and 5-HT4 receptors. Such receptors have been 

shown to be involved in diverse sensory and motor 

regulatory processes in the GI tract. The 5-HT3 

receptor has a role in modulating colonic motility 

and visceral pain, increasing the threshold for 

sensation and discomfort, slowing colonic transit 

and improving stool consistency. 138 A number of 

selective 5-HT3 antagonists have been developed 

including ondansetron, granisetron, tropisetron

228 


renzapride and zacopride. Ondansetron was the 

first 5-HT3 to be evaluated for its effects on the gut. 

It demonstrated some benefits in diarrhea-predominant 

IBS, but no improvement in abdominal 

pain. Similarly, no reduction in pain was seen with 

granisetron. This modest efficacy led to the search 

for a 5-HT3 with greater potency. Alosetron, a 

newer 5-HT3 receptor antagonist, has greater 

potency than ondansetron, and good bioavailability. 

139 Treatment with alosetron has led to 

significant relief of abdominal pain and discomfort 

in women with diarrhea-predominant IBS. Though 

generally safe, its use has been associated with 

severe constipation and ischemic colitis. It is 

currently available in the USA as part of a limited 

access program. 

5-HT4 agonists such as tegaserod and prucalopride, 

have been developed for patients with IBS 

and constipation. Tegaserod has demonstrated efficacy 

in the short-term relief of abdominal pain and 

discomfort in adult women with constipationpredominant 

IBS 140 and is commercially available 

for this indication. Adverse events, particularly 

loose stools, are compatible with an exaggerated 

pharmacological response to tegaserod and are 

most common during the first 2 days of therapy. 

Alternative and complementary therapy 

Despite the interventions described above, some 

patients will continue to experience symptoms, 

suggesting that current treatments that target the 

predominant symptom are only partially effective, 

presumably because they do not resolve the underlying 

cause of functional bowel disorder. 6 The 

large number of patients in whom these therapies 

fail has prompted an interest in alternative therapies 

such as diet supplements, probiotics and 

ancient therapeutic modalities such as Chinese 

medicine. 

Peppermint oil (Mentha piperita), which is 

commonly found in many over-the-counter preparations 

for IBS, has long been recognized as a spasmolytic 

agent that relaxes GI smooth muscle, 

relieving pain. Placebo-controlled studies have 

shown an overall improvement in IBS patients 

who used peppermint oil. 141,142 A double-blind 

clinical trial in Chinese medicine demonstrated 

that herbal therapy was effective in the management 

of symptoms related to IBS. 143 Natural and 

herbal medications are not without adverse effects, 

and patients should not take these products 

without medical supervision. A variety of other 

herbal preparations have been studied with different 

methodologies, resulting in mixed results. 

More well-designed, controlled trials must be 

performed to identify other complementary therapies, 

with validation of the safety and efficacy of 

their use. 73 

Another alternative therapeutic strategy for 

patients with significant pain is to use hypnotherapy 

or psychotherapy. 144–146 Hypnotherapy 

has been shown to be effective in the treatment not 

only of gastrointestinal symptoms but also of 

urological, sexual and psychological symptoms 

that are often associated features of IBS in 

adults. 147 Effective psychological treatments 

include cognitive–behavioral interventions, dynamic 

or interpersonal psychotherapy and stress 

management. In a review of published psychological 

trials, Talley et al found methodological 

problems in all the studies, concluding that the 

efficacy of psychological treatment for IBS could 

not yet be established. 148 

Despite the fact that alterations of enteric flora 

may play a role in IBS, convincing evidence for a 

pathogenic role of bacterial overgrowth or for a 

beneficial effect of probiotic therapy is still scant. 

A review of the therapeutic role of probiotics 

concluded that further studies are needed to identify 

particular subgroups of patients with IBS who 

could benefit from their use. 149 More recently, 

however, a very encouraging randomized, doubleblind 

and placebo-controlled study in adults with 

diarrhea-predominant IBS showed efficacy for the 

probiotic preparation ‘VSL#3’. 150 These findings 

will of course have to be reproduced in children. 

In chronic cases of refractory pain, referral to 

specialized treatment centers for an interdisciplinary 

pain management approach may be the most 

efficient method of treating disability. 

Natural history 

Functional abdominal pain is not always a benign 

condition with a satisfactory outcome. Long-term 

psychiatric disorders have been identified in 

patients suffering from functional abdominal pain 

in childhood. 151 Children with abdominal pain do

not necessarily continue to experience physical 

symptoms in adulthood but may have an increased 

risk of adult psychiatric disorders. 152 

Future trends 

The key to revealing the mechanisms and improving 

therapy of functional bowel disorders lies in 

the collaborative efforts among basic scientists, 

clinical investigators, physicians and behavioralists. 

Progress in better understanding of the 

sensory mediators and the causes of visceral 

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143. Bensoussan A, Talley NJ, Hing M et al. Treatment of irritable 

bowel syndrome with Chinese herbal medicine: a 

randomized controlled trial. JAMA 1998; 280: 

1585–1989. 

144. Whorwell PJ, Prior A, Faragher EB. Controlled trial of 

hypnotherapy in the treatment of severe refractory irritable-bowel 

syndrome. Lancet 1984; 2: 1232–1234. 

145. Lea R, Houghton LA, Calvert EL et al. Gut-focused 

hypnotherapy normalizes disordered rectal sensitivity 

in patients with irritable bowel syndrome. Aliment 


146. Whitehead WE, Crowell MD. Psychologic considerations 

in the irritable bowel syndrome. Gastroenterol Clin 

North Am 1991; 20: 249–267. 

147. Houghton LA, Whorwell PJ. Symptomatology, quality of 

life and economic features of irritable bowel syndrome 

– the effect of hypnotherapy. Aliment Pharmacol Ther 

1996; 10: 91–95. 

148. Talley NJ, Owen BK, Boyce P et al. Psychological treatments 

for irritable bowel syndrome: a critique of 

controlled clinical trials. Am J Gastroenterol 1996; 91: 

277–286. 

149. Gionchetti P, Rizzello F, Campieri M. Probiotics in 

gastroenterology. Curr Opin Gastroenterol 2002; 18: 

235–239. 

150. Kim HJ, Camiller M, McKinzie S et al. A randomized 

controlled trial of a probiotic, VSL#3, on gut transit and 

symptoms in diarrhoea-predominant irritable bowel 

syndrome. Aliment Pharmacol Ther 2003; 17: 895–904. 

151. Campo JV, Di Lorenzo C, Chiappetta L et al. Adult 

outcomes of pediatric recurrent abdominal pain: do 

they just grow out of it? Pediatrics 2001; 108: E1. 

152. Hotopf M, Carr S, Mayou R et al. Why do children have 

chronic abdominal pain, and what happens to them 

when they grow up? Population based cohort study. BMJ 

1998; 316: 1196–1200.

15 

Introduction 

Disorders of sucking and 

swallowing 

Erasmo Miele and Annamaria Staiano 

The development of feeding skills is an extremely 

complex process influenced by multiple anatomic, 

neurophysiological, environmental, social and 

cultural factors. This entire process is dynamic 

because of ongoing growth and development. 

Functional feeding skills, which depend on the 

integrity of anatomic structures, undergo change 

based on neurological maturation and experimental 

learning. 

There are a variety of neurological, neuromuscular 

conditions in children and in infants that can 

impair the physiological phases of sucking and 

swallowing and cause disorders of feeding and 

dysphagia. 

In recent years, there has been an increase in 

infant swallowing disorders as a result of 

improved survival rates for infants born prematurely 

or with life-threatening medical disorders. 

Disorders of feeding and swallowing in children 

are serious and potentially fatal problems. 

Aspiration due to dysphagia may lead to severe 

pulmonary disease, and impaired oral and pharyngeal 

function may rapidly result in failure to 

thrive. Prompt evaluation of swallowing disorders 

is therefore critical. 

The differential diagnosis of dysphagia in children 

is widespread. The diagnostic work-up can be 

extremely difficult and exhaustive in many cases. 

Because of this complexity, multidisciplinary team 

evaluations should be conducted. 

Successful rehabilitation of children with swallowing 

disorders requires knowledge of the parameters 

of normal and abnormal swallowing plus 

skill in the integration of a variety of essential therapeutic 

techniques. 

Epidemiology and etiology 

Data on the incidence of swallowing disorders are 

lacking, because in clinical practice, disorders of 

swallowing are often considered in the general 

context of a feeding disorder. Feeding is a complex 

process that involves a number of phases in addition 

to the act of swallowing, including the recognition 

of hunger (appetite), the acquisition of food 

and the ability to bring the food to the mouth. 1 The 

estimated prevalence of feeding problems in the 

pediatric population ranges from 25 to 35% in 

normally developing children, and from 40 to 93% 

in children with developmental delay. 2,3 

Disorders of sucking and swallowing may be 

caused by multiple etiological factors that may 

interfere with the child’s ability to coordinate 

swallowing and breathing maneuvers and may be 

manifested as a unique set of symptoms. Potential 

causes are in three broad categories: immaturity, 

delay, or a defect in neuromuscular control; an 

anatomic abnormality of the aerodigestive tract; 

and/or systemic illness. The magnitude of the 

dysfunction depends on the balance between the 

extent of the structural or functional abnormality 

and the child’s compensatory adaptations. 4 

Disorders associated with sucking and swallowing 

difficulties are listed in Table 15.1. 5 


The fetus is capable of swallowing amniotic fluid 

in utero, indicating that the motor program for 

swallowing functions before gestation is complete. 

However, oral feeding is not initiated in preterm 

infants before 32 weeks of postconceptional age, 

partly because the coordination of sucking, 

233

234 

Disorders of sucking and swallowing 

Table 15.1 Differential diagnosis in dysphagia (adapted from reference 5) 

Prematurity 

Upper airway obstruction 

Nasal and nasopharyngeal 

cohanal atresia, stenosis, septal deflections and abscess, infections, tumors, sinusitis 

Oropharynx 

defects of lips and alveolar processes, cleft lip or palate, hypopharyngeal stenosis, craniofacial syndromes or 

sequences (e.g. Cruzon, Treacher–Collins syndrome, Pierre Robin sequence) 

Laryngeal 

laryngeal cleft and cyst, laryngomalacia, subglottic stenosis and paralysis 

Congenital defects of the larynx, trachea and esophagus 

Laryngotracheoesophageal cleft 

Tracheoesophageal fistula with associated esophageal atresia 

Esophageal anomalies (e.g. strictures, webs) 

Vascular anomalies 

aberrant right subclavian artery 

double aortic arch 

right aortic arch with left ligamentum 

Acquired anatomic defects 

Trauma 

external trauma, intubation, endoscopic, foreign body 

Chemical ingestion 

Neurological disorders 

Central nervous system 

trauma 

hypoxia and anoxia 

cortical atrophy, hypoplasia, agenesis 

infections (meningitis, brain abscess) 

Peripheral nervous system disease 

Trauma 

Congenital defects 

Neuromuscular disorders 

Guillain–Barré syndrome 

Poliomyelitis (bulbar paralysis) 

Myasthenia gravis 

Myotonic muscular dystrophy 

Anatomic and functional defects 

Crycopharyngeal dysfunction 

Esophageal achalasia 

Esophageal spasm 

Paralysis of the esophagus 

Associated atresia-tracheoesophageal fistula, nerve defect 

Peptic and eosinophilic esophagitis 

Riley-Day syndrome (Dysautonomia) 

Brain stem compression (e.g. Chiari malfomation, tumor)

swallowing and respiration is not established. 6 

Even at 34 weeks, the minute ventilation during 

sucking decreases more than that of infants at 

36–38 weeks. Therefore, the co-ordination 

between swallowing and breathing is not yet fully 

organized at 34 weeks of postconceptional age. 7,8 

Anatomic structures, which are essential to 

competent feeding skills, undergo growth that 

changes their physical relationship to one another 

and consequently affects their function. The swallowing 

mechanism, by which food is transmitted 

to the stomach and digestive organs, is a complex 

action involving 26 muscles and five cranial 

nerves. The neurophysiological control involves 

sensory afferent nerve fibers, motor efferent fibers, 

paired brainstem swallowing centers, and suprabulbar 

neural input. Structural integrity is essential 

to the development of normal feeding and 

swallowing skills. 9 

Deglutition is generally divided into phases of 

swallowing, based on anatomic and functional 

characteristics: pre-oral, pharyngeal and 

esophageal. 10,11 

Anatomic considerations 

An understanding of the anatomy of the pharynx 

is essential to a thorough understanding of the 

swallowing process. The anatomy changes during 

Anatomic considerations 235 

development. The tongue, the soft palate and the 

arytenoid mass (arytenoid cartilage, false vocal 

cords and true vocal cords) are larger relative to 

their surrounding chambers when compared with 

the adult. 12 In the infant, the tongue lies entirely 

within the oral cavity, resulting in a small oropharynx. 

12,13 In addition, a sucking pad, composed of 

densely compacted fatty tissue that further 

reduces the size of the oral cavity, stabilizes the 

lateral walls of the oral cavity. The larynx lies high 

in the infant, and the tip of the epiglottis extends 

to and may overlap the soft palate. These anatomic 

relationships are ideal for the normal infant 

feeding pattern of sucking or suckling feeding a 

breast or a bottle in a recumbent position. 14 In the 

infant, the larynx sits high in the neck at the level 

of vertebrae C1 to C3, allowing for the velum, 

tongue and epiglottis to approximate, thereby 

functionally separating the respiratory and digestive 

tracts. This separation allows the infant to 

breathe and feed safely. By age of 2–3 years, the 

larynx descends, decreasing the separation of the 

swallowing and digestive tracts 2,15 (Figure 15.1). 

Development and normal swallowing 

function 

The newborn infant is reflex bound and automatically 

makes certain oral motor movements. For 

example, the newborn’s automatic-phasic bite 

Figure 15.1 (a) The adult oropharynx. The phases of swallowing are labeled. 1, preparatory phase; 2, oral phase; 3, 

pharyngeal phase; 4, esophageal phase. (b) The infant oropharynx. Note that the infant oral cavity providing little space for 

manipulation of the food bolus. The larynx is elevated so that the epiglottis almost touches the soft palate. The tongue is 

entirely within the oral cavity, with no oral pharynx. Reproduced with permission from reference 15.

236 


pattern, although it may look like chewing, actually 

starts liquid flowing into the mouth with its 

pump-like action. The rooting reflex elicited by 

stroking the side of the mouth and resulting in the 

head turning towards the source of stimulation, is 

a food-seeking response. Over time, these reflexive 

movements of the newborn are gradually refined 

and incorporated into more voluntary feeding 

patterns. 14 

Therefore, by increasing the intraoral space, the 

infant begins to suppress reflexive suckling 

patterns and starts to use voluntary sucking 

patterns. In contrast to suckling, true sucking 

involves a raising and lowering of the body of the 

tongue with increased use of intrinsic musculature. 

Most infants complete the gradual transition 

from suckling to true sucking by 9 months of age. 

This is considered a critical step in the development 

of oral skills that will permit handling of 

thicker textures and spoon-feeding. 16 

As with sucking, chewing patterns emerge gradually 

during infancy. Between birth and 5 months of 

age, a phasic bite-release pattern develops. Jaw 

opening and closing begins as a reflex and evolves 

into a volitionally controlled bite. True chewing 

develops as activity of the tongue, cheeks and jaws 

co-ordinate to participate in the breakdown of 

solid food. The eruption of the deciduous teeth 

between the ages of 6 and 24 months provides a 

Table 15.2 Phases of normal deglutition 

Phase Activities Time 

chewing surface and increased sensory input to 

facilitate the development of chewing. 16 

The concept of a ‘critical period’ is relevant to 

feeding development. A critical period is a fairly 

well-delineated period of the time during which a 

specific stimulus must be applied in order to 

produce a particular action. After such a critical 

period a particular behavior pattern can no longer 

be learned. The ‘sensitive period’ is the optimal 

time for the application of a stimulus. After the 

sensitive period, it is more difficult to learn a 

specific pattern of behavior. 17 

Current knowledge of the swallowing mechanism 

is derived mainly from radiographic studies, 

which have been in use since the early 1900s. 

Plain films of the pharynx were replaced in the 

1930s by cineradiography, which, in the 1970s, 

was subsequently replaced by videofluoroscopy. 

Videofluoroscopy permits instant analysis of bolus 

transport, aspiration and pharyngeal function. 18 

Using this descriptive method deglutition can be 

divided into four phases: the oral preparatory 

phase, oral voluntary phase, pharyngeal phase, 

and esophageal phase (Table 15.2). 19 

The oral preparatory phase occurs after food is 

placed into the mouth. The food is prepared for 

pharyngeal delivery by mastication and mixing 

with saliva. This is a highly co-ordinated activity 

Pre-oral phase food introduced into the oral cavity varies; depends on substance 

(voluntary) 

Oral phase bolus formation and passage to Less than 1s 

(voluntary/involuntary) the pharynx 

Pharyngeal phase respiration ceases; pharyngeal 1s or less 

(involuntary) peristalsis; epiglottis closes; larynx 

closes, elevates and draws forward. 

UES relaxes 

Esophageal phase esophageal peristalsis; opening of 8–20s 

(involuntary) lower esophageal sphincter 

UES, upper esophageal sphincter

that is rhythmic and controlled to prevent injury to 

the tongue. The tongue is elevated towards the 

palate by the combined actions of the digastric, 

genioglossus, geniohyoid and mylohyoid muscles. 

Intrinsic tongue muscles produce both the initial 

depression in the dorsum that receives the food 

and the spreading action that distributes the food 

throughout the oral cavity. The buccinator muscles 

hold food between the teeth in dentulous infants 

and help to generate suction in neonates. In this 

phase, the soft palate is against the tongue base 

secondary to contraction of the palatoglossus 

muscles, which allows nasal breathing to 

continue. 2,20 

During, the oral propulsive phase, the bolus is 

propelled into the oropharynx. The oral phase is 

characterized by elevation of the tongue and a 

posterior sweeping or stripping action produced 

mainly by the action of styloglossus muscles. This 

propels the bolus into the pharynx and triggers the 

‘reflex swallow’. The receptors for this reflex are 

thought to be at the base of the anterior pillars, but 

there is evidence that others exist in the tongue 

base, epiglottis and pyriform fossae. Sensory 

impulses for the reflex are conducted through the 

afferent limbs of cranial nerves V, IX and X to the 

swallowing center. Oral transit time is less than 

1s. 2,21 

The pharyngeal phase of deglutition is the most 

complex and critical. The major component of the 

pharyngeal phase is the reflex swallow. This 

results from motor activity stimulated by cranial 

nerves IX and X. The reflex swallow may be triggered 

by a voluntary oral phase component or any 

stimulation of the afferent receptor in and around 

the anterior pillar. 2 Bolus passage through the 

pharynx is accompanied by soft palate elevation, 

lingual thrust, laryngeal elevation and descent 

upper esophageal sphincter (UES) relaxation and 

pharyngeal constrictor peristalsis. The pharyngeal 

phase commences as the bolus head is propelled 

past the tongue pillars and finishes as the bolus 

tail passes into the esophagus. 21 Once it begins, the 

pharyngeal phase is very quick, (1 s or less). 2 It is 

characterized biomechanically by the operation of 

three valves and several propulsive mechanisms. 

The larynx closes and the palate elevates to 

disconnect the respiratory tract. The UES opens to 

expose the esophagus. At the completion of the 

pharyngeal phase, the airway valves (larynx, 

Development and normal swallowing function 237 

palate) open, and the UES closes so that respiration 

can resume. 21 

Pharyngeal bolus transit occurs in two phases: an 

initial thrust phase and a mucosal clearance 

phase. 22 Bolus thrust, which propels most of the 

bolus into the esophagus, is provided by lingual 

propulsion, laryngeal elevation and gravity. The 

tongue has been linked to a piston, pumping the 

bolus though the pharynx. 23 Patients with tongue 

impairment cannot generate large bolus driving 

forces despite an intact pharyngeal constrictor 

mechanism. 24 Laryngeal elevation creates a negative 

post-crycoid pressure to suck the oncoming 

bolus towards the esophagus, and the elevated 

larynx holds the pharyngeal lumen open to minimize 

pharyngeal resistance. 23 

As the bolus enters the pharynx and is stripped 

inferiorly by the combined effects of gravity, the 

negative pressure mentioned above and the 

sequential contractions of the pharyngeal constrictors, 

the soft palate moves against the posterior 

pharyngeal wall to close off the nasopharyngeal 

port. The bolus divides around the epiglottis, 

combines and passes through the crycopharyngeal 

muscle, or upper esophageal sphincter. 2 

The UES is the high-pressure zone located 

between the pharynx and the cervical esophagus. 

The physiological role of this sphincter is to 

protect against reflux of food into the airways as 

well as to prevent entry of air into the digestive 

tract. 25 Posteriorly and laterally the cricopharyngeus 

muscle is a definitive component of the UES. 

The crycopharyngeus has many unique characteristics: 

it is tonically active, has a high degree of 

elasticity, does not develop maximal tension at 

basal length and is composed of a mixture of slowand 

fast-twitch fibers, with the former predominating. 

These features enable the crycopharyngeus 

to maintain a resting tone and yet be able to stretch 

open by distracting forces, such as a swallowed 

bolus and hyoid and laryngeal excursion. The 

crycopharyngeus muscle, however, constitutes 

only the lower one-third of the entire highpressure 

zone. The thyropharyngeus muscle 

accounts for the remaining upper two-thirds of the 

UES. 

The UES function is controlled by a variety of 

reflexes that involve afferent inputs to the 

motorneurons innervating the sphincter. 25 Based,

238 


on functional studies, it is believed that the major 

motor nerve of the crycopharyngeus muscle is the 

pharyngoesophageal nerve. Vagal efferents probably 

reach the muscle by the pharyngeal plexus, 

using the pharyngeal branch of the vagus. 26 The 

superior laryngeal nerve may also contribute to 

motor control of the crycopharyngeus muscle. 1 

Sensory information from the UES is probably 

provided by the glossopharyngeal nerve and the 

sympathetic nervous system. There is probably 

little or no contribution by the sympathetic 

nervous system to crycopharyngeal control. 26 

The relaxation phase begins as the genioglossus 

and suspensory muscles pulls the larynx anteriorly 

and superiorly. The bolus is carried into the 

esophagus by a series of contraction waves that are 

a continuation of the pharyngeal stripping action. 2 

Proposed functions of the UES include prevention 

of esophageal distension during normal breathing 

and protection of the airway against aspiration 

following an episode of acid reflux. 1,26 Qualitative 

abnormalities of the UES have been documented 

in infants with reflux disease. 27 

The esophageal phase occurs as the bolus is 

pushed through the esophagus to the stomach by 

esophageal peristalsis. Esophageal transit time 

varies from 8 to 20s. 14 

Dysphagia 

Dysphagia is an impairment of swallowing involving 

any structures of the upper gastrointestinal 

tract from the lips to the lower esophageal sphincter. 

28 Dysphagia in children is generally classified 

as either oral dysphagia (abnormal preparatory or 

oral phase) or pharyngeal dysphagia (abnormal 

pharyngeal phase). 

Oral dysphagia is seen most commonly in children 

with neurodevelopmental disorders. Infants with 

oral dysphagia often have an impaired oral 

preparatory phase. These children typically 

demonstrate poor lingual and labial co-ordination, 

resulting in anterior substance loss and a poor 

labial seal for sucking or removing food from a 

spoon. Other abnormal patterns include jaw thrust 

and tongue thrust on presentation of food. Oral 

dysphagia may also involve the oral phase of swallowing. 

Children with impaired oral phase function 

often have difficulty in co-ordinating the 

‘suck, swallow, breathe’ pattern of early oral 

intake, resulting in diminished endurance during 

oral feeds. Apraxia of the oral swallow as well as 

reduction of oral sensation are also common. 

Other deficits include reduced bolus formation 

and transport, abnormal holding patterns, incomplete 

tongue-to-palate contact and repetitive 

lingual pumping. 14 

Oropharyngeal dysphagia results from either 

oropharyngeal swallowing dysfunction or 

perceived difficulty in the process of swallowing. 

Major categories of dysfunction are: an inability or 

excessive delay in initiation of pharyngeal swallowing; 

aspiration of ingestate; nasopharyngeal 

regurgitation; and residue of ingestate within the 

pharyngeal cavity after swallowing. Each of these 

categories of dysfunction can be mechanically 

subcategorized using fluoroscopic and/or manometric 

data. 18 


Clinical signs and symptoms of sucking and swallowing 

disorders in infants and in children are 

listed in Table 15.3. 

Complications 

Malnutrition 

In the severely affected child with impaired swallowing, 

poor oral and/or pharyngeal function may 

lead to decreased energy intake as a consequence 

of prolonged feeding time and the inability to 

ingest adequate volumes, and malnutrition may 

result. 1 Malnutrition has many adverse effects. 

The most significant effects are on behavior and 

immune status. Malnutrition negatively influences 

immune status. This leads to recurrent infections 

that increase caloric requirements but decrease 

intake, leading to a worsening nutritional status. In 

addition, malnutrition causes behavioral apathy, 

weakness and anorexia, which can all profoundly 

affect feeding and secondarily, nutritional status. 

Thus, although malnutrition is often a direct result 

of poor feeding skills, it can also have a 

compounding, and even perpetuating, effect on 

feeding problems in children. 14

Table 15.3 Clinical signs and symptoms of dysfunctional sucking and swallowing 

Clinical signs 

Failure to thrive 

Meal-time distress 

Refusing food 

Nasal regurgitation 

Wet or hoarse voice 

Drooling 

Spitting 

Vomiting 

Gastroesophageal or pharyngeal reflux 

Symptoms 

Oral–tactile hypersensitivity 

Feeling of obstruction 

Sialorrea 

Sialorrea (excessive drooling) is defined as the 

unintentional loss of saliva and other oral contents 

from the mouth. Drooling usually occurs in 

patients with neurological disease complicated by 

abnormalities of the oral phase of deglutition. 

Clinical complications of drooling include soaking 

of clothes, offensive odors, macerated skin and, if 

‘posterior’ drooling occurs, aspiration. 29 

Respiratory complications 

Respiratory complications of swallowing disorders 

include apnea and bradycardia, choking episodes, 

chronic or recurrent pneumonia, bronchitis and 

atelectasis. 30 

Apnea and bradycardia may result from stimulation 

of laryngeal chemoreceptors without evidence 

of aspiration or as a consequence of hypoxemia. 

Hypoxemia may result from the effects of direct 

aspiration on gas exchange, from apnea triggered 

by laryngeal and nasopharyngeal chemoreceptors, 

or in patients with compromised lung function as 

a result of a normal decrease in minute ventilation 

that occurs with suckle feeding. 31–33 Symptoms 

such as chronic recurrent coughing, choking and 

postprandial congestion or wheezing generally 

indicate the occurrence of aspiration. Infants, 

Odynophagia 

Atypical chest pain 


Respiratory manifestations 

Coughing 

Choking 

Stridor 

Change in respiration pattern after swallowing 

Apnea and bradycardia (predominantly in infants) 

Noisy breathing after feeding 

Chronic recurrent wheezing 

Chronic recurrent bronchitis, pneumonia and 

atelectasis 

especially premature infants, appear to be at 

increased risk of respiratory disease from dysfunctional 

swallowing. 4 Clinical manifestations of 

dysfunctional sucking and swallowing in infants 

are primarily apnea and bradycardia during 

feeding, although chronic or recurrent respiratory 

problems (congestion, cough, wheezing) are also 

seen. 30 Congested or noisy breathing during and 

following feeding is also a common complaint of 

parents of infants with dysfunctional swallowing. 

Dysphagia can also be an important but underrecognized 

cause of chronic or recurrent bronchitis, 

asthma and pneumonia in infants. 4 

Respiratory disease secondary to dysphagia in an 

older child is typically seen in a neurologically 

impaired host. 34,35 Apnea and bradycardia are 

uncommon in an older child. Bronchitis, pneumonia, 

atelectasis and recurrent wheezing are more 

likely to be seen in this population. Feeding and 

swallowing evaluation should be considered in 

those with central nervous system (CNS) injury 

affecting cranial nerve function and difficult-tocontrol 

chronic or recurrent bronchitis, wheezing, 

pneumonia, or asthma. Tracheobronchomalacia, a 

complication of chronic inflammation of the major 

airways, occurs commonly. Dysfunctional swallowing 

is also encountered in children with a 

tracheostomy. The tracheostomy may interfere 

with normal laryngeal function during swallowing 

and predispose to aspiration. 28

240 


Aspiration may also occur in children with disorders 

of swallowing after an episode of gastroesophageal 

reflux; also acid reflux may result in 

bronchospasm, pneumonia or apnea. 36,37 The most 

obvious sign that a person may have aspirated is 

the post-swallow cough, but in the swallowingimpaired 

child other more insidious indicators 

may be present. ‘Silent aspiration’ with no clinical 

signs can account for over half of all cases of radiologically 

defined aspiration. 28,38 

Diagnosis 

Feeding disorders and dysphagia in infants and in 

children can be both physiological and behavioral 

in nature. 39 The evaluation of feeding and 

swallowing dysfunction is best performed as a 

multidisciplinary process with co-ordinated input 

from a variety of team members, including 

pediatricians, pediatric gastroenterologists, developmental 

pediatricians, speech–language pathologists, 

occupational therapists, and pediatric 

dietitians. 40 The goals of this evaluation include 

Oropharyngeal 

dysphagia 

Structural Functional 

Videoendoscopic 

swallow study 

Examination under 

anesthesia 

Surgery 

the following: ascertaining whether oropharyngeal 

dysphagia is likely, and identifying the etiology; 

identifying structural etiologies of oropharyngeal 

dysfunction; ascertaining the functional integrity 

of the oropharyngeal swallow; evaluating the risk 

of aspiration pneumonitis; and determining 

whether the pattern of dysphagia is amenable to 

therapy. 41 The investigation and management of 

swallowing disorders are summarized in the 

Figure 15.2. 

History 

History 

Physical Examination 

Clinical swallow 

examination 

Videofluoroscopic 

swallow study Videoendoscopic 

swallow study 

A comprehensive history, obtained from individuals 

directly involved in caring for the child (e.g. 

parents, feeding specialist) is essential in evaluating 

children with swallowing disorders. The evaluation 

begins with a focused feeding history, 

including current diet, textures, route and time of 

administration, modifications and feeding position. 

Medical co-morbidites that may affect swallowing 

need to be investigated. 

Neurological 

evaluation 

Management plan 

Videofluoroscopic 

swallow study 

Esophageal 

dysphagia 

Structural Functional 

Esophageal manometry 

Upper GI series 

Upper GI endoscopy 

Upper GI series 

Upper GI endoscopy 

Reduce risk Optimize hydration/nutrition 

Non-oral feeds Modify consistency Modify posture Supplements and dietary advice 

Figure 15.2 Flow chart for the investigation and management of dysphagia in children. Adapted from reference 28. GI, 

gastrointestinal.

The child’s caregivers should also be questioned 

regarding associated symptoms such as oral aversion, 

weak sucking, irritable behavior, gagging and 

choking, and disruptions in breathing or apnea. 

Postural or positional change during feeding may 

be reported in children with dysphagia. 

Odynophagia and emesis may be related to 

pharyngeal and/or esophageal disorders. A history 

of recurrent pneumonia may indicate chronic aspiration; 

a history of stridor in relation to feeding 

may indicate a glottic or subglottic abnormality 

contributing to feeding disorders. Determining 

whether these symptoms occur before, during or 

after the swallow helps localize the affected 

phase. 16,17 

In addition, nutritional and psychological assessment 

should be evaluated. Many patients with 

swallowing disorders have a concurrent illness 

that may increase metabolic needs. Psychological 

assessments help to identify behavioral and 

parental factors that may be contributing to a 

feeding disorder. Psychosomatic causes of dysphagia 

should be considered in adolescents with 

dysphagia. 2,42,43 

Physical and clinical evaluation 

The aims of physical examination in dysphagic 

patients are: to identify underlying systemic or 

metabolic disease when present; to localize the 

neuroanatomic level and severity of a causative 

neurological lesion when present; and to detect 

adverse sequelae such as aspiration pneumonia or 

nutritional deficiency. 18 

The physical examination views the whole child 

and specifically focuses on the upper aerodigestive 

tract, beginning with an examination for structural 

and functional abnormalities. Oral cavity 

anatomic abnormalities, such as ankyloglossia, 

cleft lip or palate, or macroglossia, need to be 

excluded. 2 The palatal gag is perhaps the most 

commonly assessed reflex and should be evaluated. 

29 A hyperactive gag can result in significant 

feeding difficulties; in the past an absent gag reflex 

was viewed as an indication to stop oral 

feeding. 4,34 

It is critical that observation of the feeding process 

be included. 40 This part of the examination is best 

performed in conjunction with a feeding and swal- 

Diagnosis 241 

lowing specialist, such as a speech–language 

pathologist or an occupational therapist. This 

examination includes assessments of posture, 

positioning, patient motivation, oral function, efficiency 

of oral intake and clinical signs of safety. 

During the feeding trial, the presence of abnormal 

movements such as jaw thrust, tongue thrust, 

tonic bite reflex and jaw clenching are noted. A 

variety of therapeutic positions, techniques and 

adaptive feeding utensils may be used. 1,16 

A variety of assessment scales may be used to 

detail and quantitate results of the swallowing 

evaluation. However, all assessments are based on 

similar observation of feeding structure and function. 

44 

Usually, a careful developmental, medical and 

feeding history provides clues to the diagnosis that 

guide the selection of further diagnostic tests. Only 

after all reasonable physical causes have been 

ruled out should a feeding or swallowing disorder 

be attributed to a purely behavioral cause. 2 

Diagnostic tests 

Radiographic assessment 

Videofluoroscopy represents the gold standard for 

evaluation of children with swallowing disorders. 

A videofluoroscopic swallow study is ideally 

performed by a consultant radiologist and specialist 

speech and language therapist. 45 A series of 

swallows of varied volumes and consistencies of 

contrast material are imaged in a lateral projection, 

and framed to include the oropharynx, palate, 

proximal esophagus and proximal airway. Studies 

are recorded on videotape to permit instant replay, 

in slow motion if necessary, and examination of 

both the presence and mechanism of the swallowing 

dysfunction. The videofluoroscopic study 

provides evidence of all four categories of oropharyngeal 

swallowing disorders: inability or excessive 

delay in initiation of pharyngeal swallowing; 

aspiration of ingestate; nasopharyngeal regurgitation; 

and residue of ingestate within the pharyngeal 

cavity after swallowing. Furthermore, the 

procedure allows for testing of the efficacy of 

compensatory dietary modifications, postures, 

swallowing maneuvers and facilatory techniques 

in correction of observed dysfunction. Generally, 

the videofluoroscopic evaluation is completed by

242 


esophagography to evaluate the esophageal phase 

of deglutition (Figure 15.3). 18 

Ultrasonography 

Ultrasound imaging has been used to a limited 

extent in the assessment of oral phase dysphagia. 

Figure 15.3 Lateral fluoroscopic projection of an infant 

showing contrast material in the valleculas, pyriform 

sinuses, laryngeal vestibule and esophagus. 

Using a transducer positioned in the submental 

region, ultrasonography allows observation of the 

motion of structures in the oral cavity such as the 

tongue and floor of the mouth during feeding and 

deglutition, but lacks sensitivity in visualizing 

pharyngeal motion and for determining whether 

aspiration has occurred. Ultrasonography represents 

the only method of imaging that can study 

infants during breast feeding, and may be particularly 

useful in distinguishing an infant’s inability 

to attach from maternal factors contributing to 

feeding difficulties. 16 Unfortunately, laryngeal 

penetration and aspiration are not easily detected, 

because of the shadows cast by the laryngeal structures 

(Figure 15.4). 4,46,47 

Pharyngeal manometry 

Intraluminal manometry, performed using a 

transnasally positioned manometric assembly, can 

quantify the strength of pharyngeal contraction, 

the completeness of UES relaxation and the relative 

time of these two events. Most studies have 

indicated that manometry of the UES and pharynx 

provides useful information, primarily in patients 

who have symptoms of oropharyngeal dysfunction. 

Figure 15.4 Transverse ultrasound scan of the larynx at the level of the vocal cords. During swallowing the vocal cords 

(white arrow) adduct and the glottis closes (black arrow).

The co-ordination of muscle activity at various 

levels can be obtained by simultaneous recording 

of pressure in the pharynx, at the level of the 

crycopharyngeus, and in the esophagus. 

Anatomical references are not avalaible with this 

technique (Figure 15.5). 27,48 

Fiberoptic endoscopic examination 

Pediatric fiberoptic endoscopic examination is a 

relatively new diagnostic method to complement 

the current armamentarium of techniques for evaluating 

dysphagia and/or aspiration. The procedure 

is performed by passing a flexible laryngoscope 

into the oropharynx after anesthetizing the nares 

and nasopharynx. 49 It provides the ability to diagnose 

many of the laryngeal disorders that may 

affect the child, while at the same time evaluating 

the swallowing mechanism itself. The procedure 

involves five components: assessment of the 

anatomy as it affects swallowing; evaluation of 

movement and sensation of critical structures; 

assessment of secretion management; direct 

assessment of swallowing function for food and for 

liquid; and the patient’s response to therapeutic 

maneuvers. In experienced hands, this test can be 

performed in children with minimal discomfort. 

50,51 

Figure 15.5 Upper esophageal sphincter (UES) motility in 

a control child. The pressure is recorded in the pharynx, in 

the UES, and in the cervical esophagus. Note that the 

onset of UES relaxation precedes pharyngeal contraction, 

which is terminated before the return of UES pressure to 

resting values. UES relaxation is complete to the level of 

the esophageal resting pressure (dashed line). Contraction 

of the UES continues into the cervical esophagus as the 

primary wave (dots) of swallowing. From reference 27. 


Scintigraphy 

Scintigraphy is a radionuclide evaluation using 

technetium-99m-labeled sulfur colloid mixed in 

the infant’s formula. It has been proposed as an 

alternative and perhaps more sensitive way of 

quantifying aspiration, transit times, gastroesophageal 

reflux and pharyngeal residue. Based on 

a case report, the radionuclide salivagram has also 

been used to document aspiration of saliva. The 

major limitations of this technique are the poor 

definition of the anatomy and the poor sensitivity 

for detecting aspiration during swallowing in 

known aspirators. At present, the use of this technique 

in pediatric patients is limited. 51,52 


Optimal management strategies are critical for 

infants and children with feeding and swallowing 

problems. The management of swallowing 

dysfunction involves a team approach. Individuals 

involved in addition to the medical team include a 

swallowing expert (speech–language pathologist or 

occupational therapist), a nutritionist and the 

family. Since swallowing abnormalities arise from 

a diverse group of underlying disorders, management 

techniques must be individualized. This 

heterogeneity is also reflected in the fact that 

patients have different potentials for recovery. 1 

Although total oral feeding may not be a realistic 

goal, it is the universal hope of caregivers. 

Professionals are obliged to point out prerequisites 

for oral feeding and to discuss the probability that 

an individual child may reach the goal. These 

management decisions are typically made on the 

basis of clinical observations and assessments. In 

addition, important information is obtained 

through an instrumental assessment by videofluoroscopic 

swallow study. A methodical videofluoroscopic 

swallowing study defines the anatomy of 

the oropahrynx; detects dysfunction as evident by 

aspiration, poor clearance, or poor control of the 

bolus; determines the mechanism responsible for 

the dysfunction; and examines the short-term 

effects of the therapeutic strategies designed to 

eliminate or compensate for that dysfunction. 53 

Management decisions may incorporate nutritive 

recommendations, medical and surgical decisions, 

position guidelines, oral–motor swallowing practice 

and behavioral intervention. 54

244 


The clinical and instrumental evaluation of children 

with sucking and swallowing disorders 

should allow for the recognition of treatable 

anatomic or inflammatory lesions. 

A child may refuse to eat even if his anatomic 

abnormality has been corrected, because of 

learned aversion to feeding. Behavior therapy can 

often overcome this type of conditioned food 

refusal. 2,55 

Various therapeutic approaches may improve the 

efficiency and safety of feeding. Management techniques 

involve devising compensatory strategies to 

minimize swallowing-related complications. 56 

These include changing the textures of foods; 

pacing of feeding; changing the bottle or utensils; 

and changing the alignment of the head, neck and 

body when feeding (Table 15.4). 49 

Frequently, children with severe anatomic disorders 

but normal neurological function develop 

their own adaptive strategies to allow for safe oral 

feeding. Unfortunately, many children with 

feeding disorders have non-correctable neurological 

or anatomic abnormalities that make oral 

feeding difficult or unsafe. Some patients cannot 

obtain adequate nutrition by mouth because of a 

risk for aspiration. Thus, supplying a portion of 

the patient’s nutrition by nasogastric or gastrostomy 

feeding may be beneficial. 2 For those children 

who have been intubated, management 

includes teaching techniques that will facilitate 

the transition from non-oral to oral feeding. 

However, there is little evidence that non-oral 

feeding reduces or eliminates the risk of aspiration. 

57–59 

The strongest evidence-based recommendation 

that can be made pertains to diet modification. 

Furthermore, the literature provides reasonable 

evidence of the plausibility of swallowing therapy 

but minimal evidence of efficacy. Nonetheless, 

although no hard evidence supports its efficacy, 

the available data are inconclusive and swallowing 

therapy has not been proved to be ineffective. 

Thus, the current weight of opinion, combined 

with the convincing demonstration of biological 

plausibility for specific techniques and the consistency 

of low-grade evidence, is the basis for recommending 

that swallowing therapy should be used. 

Large-scale randomized, controlled trials are 

needed to clarify the current recommendations. 18 

Prognosis 

The prognosis depends on underlying conditions 

that predispose to impaired sucking and swallowing. 

However, the early recognition of feeding 

problems, the diagnosis of underlying disorders 

and appropriate intervention improve outcomes 

for the child and the family. 

Table 15.4 Swallowing strategies for 

pediatric dysphagia 

Behavioral training 

Dietary modification 

thickened liquids 

thin liquids 

Proper intrabolus placement 

modification of feeding utensils and bolus 

presentation 

Swallowing exercises 

supraglottic swallow 

supersupraglottic swallow 

effortful swallow 

Mendelsohn maneuver 

Modification of body tone, posture, seating and 

positioning 

head tilt 

chin tuck 

head rotation 

lying on the side, elevation 

Suckle-feeding-valved feeding bottle 

Crycopharyngeal myotomy 

Facilitatory techniques 

biofeedback 

thermal stimulation 

gustatory stimulation 

Provision of alternative means of enteral nutrition 

nasogastric feeding 

gastrostomy tube (surgical or endoscopic)

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32. Thach BT. Maturation and transformation of reflexes 

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the child with dysfunctional swallowing. Dysphagia 

1989; 3: 111–116. 

35. Rogers BT, Arvedson J, Msall M, Demerath RR. 

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cerebral palsy. Dev Med Child Neurol 1993; 35: 3–10. 

36. Berquist WE, Ament ME. Upper GI function in sleeping 

infants. Am Rev Respir Dis 1985; 131: S26–S29. 

37. Boyle JT, Tuchman DN, Altschuler SM et al. 

Mechanisms for the association of gastroesophageal 

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S16–S20. 

38. Smith CH, Logemann JA, Colangelo LA et al. Incidence 

and patient characteristics associated with silent 

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techniques. J Pediatr Gastroenterol Nutr 1997; 25 (Suppl 

1): S32–S33. 

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Gastroenterological Association Medical Position 

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42. Kovar AJ. Nutrition assessment and management in 

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39–49. 

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assessment and treatment of pediatric feeding disorders. 

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ingestive and oral praxis skills: children with cerebral 

palsy vs. controls. Dysphagia 2000; 15: 236–244. 

45. Ekberg O, Olsson R, Bulow M. Radiologic evaluation of 

dysphagia. Abdom Imag 1999; 24: 444.

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46. Bu’Lock F, Woolridge MW, Baum JD. Development of coordination 

of sucking, swallowing and breathing: 

ultrasound study of term and preterm infants. Dev Med 

Child Neurol 1990; 32: 669–678. 

47. Rudolph CD. Feeding disorders in infants and children. 

Pediatrics 1994; 125: S116–S124. 

48. Hila A, Castell JA, Castell DO. Pharyngeal and upper 

esophageal sphincter manometry in the evaluation of 

dysphagia. J Clin Gastroenterol 2001; 33: 355–361. 

49. Broniatowski M, Sonies BC, Rubin JS et al. Current 

evaluation and treatment of patients with swallowing 

disorders. Otolaryngol Head Neck Surg 1999; 120: 

464–473. 

50. Langmore SE, Schatz K, Olsen N. Fiberoptic endoscopic 

examination of swallowing safety: a new procedure. 

Dysphagia 1988; 2: 216-219. 

51. Hamlet SL, Mutz J, Patterson, R, Jones L. Pharyngeal 

transit time: assessment with videofluoroscopic and 

scintigraphic techniques. Dysphagia 1989; 4: 4–7. 

52. Silver KH, Nostrand DV. Scintigraphic detection of 

salivary aspiration: description of a new diagnostic 

technique and case reports. Dysphagia 1992; 7: 45–49. 

53. Logemann JA. Role of the modified barium swallow in 

management of patients with dysphagia. Otolaryngol 

Head Neck Surg 1997; 116: 335–338. 

54. Arvedson JC. Management of pediatrics dysphagia. 

Otolaryngol Clin North Am 1998; 31: 453–476. 

55. Babbitt RL, Hoch TA, Coe DA et al. Behavioral 

assessment and treatment of pediatric feeding disorders. 

J Dev Behav Pediatr 1994; 15: 278–291. 

56. Helfrich-Miller KR, Rector KL, Straka JA. Dysphagia: its 

treatment in the profoundly retarded patient with 

cerebral palsy. Arch Phys Rehabil 1986; 67: 520–525. 

57. Croghan JE, Burke EM, Caplan S, Denman S. Pilot study 

of 12-month outcomes of nursing home patients with 

aspiration on videofluoroscopy. Dysphagia 1994; 9: 

141–146. 

58. Groher ME. Bolus Management and aspiration 

pneumonia in patient with pseudobulbar dysphagia. 

Dysphagia 1987; 1: 215–216. 

59. Shaker R, Easterling C, Kern M et al. Rehabilitation of 

swallowing by exercise in tube-fed patients with 

pharyngeal dysphagia secondary to abnormal UES 

opening. Gastroenterology 2002; 122: 1314–1321. 

Additional educational resource 

Resource center: resources for normal swallowing and 

swallowing disorders (www.dysphagia.com). This multidisciplinary 

website has a wealth of information on 

dysphagia, references to texts, archives and links to other 

related sites; it is user-friendly and comprehensive.

16 

Epidemiology 

Constipation and encopresis in 

childhood 


Constipation is a common disorder in Western 

societies. Survey estimates of the prevalence of 

constipation in childhood vary between 2 and 

15%. The average prevalence of constipation 

increases from childhood (2%) exponentially to 

15% in adults. It is estimated that a general 

practitioner will see 20–30 children with constipation 

per year in an average practice of 2500 

patients. Around 3% of a pediatrician’s practice 

consists of children with chronic constipation. For 

the pediatric gastroenterologist, consultation rates 

vary between 10 and 20%. Thus, a substantial 

number of children have constipation, 1 and this 

problem is of paramount practical importance for 

physicians. 

Normal physiology 

The Rome II criteria are currently used to define 

childhood constipation based on the presenting 

symptom profile. Two subgroups, namely functional 

constipation and functional fecal retention, 

are distinguished. Functional constipation is 

defined as follows: in infants and children at least 

2 weeks of scybalous, pebble-like hard stools for a 

majority of stools; or firm stools two or fewer 

times/week; and no evidence of structural or metabolic 

disease. 2 

Functional fecal retention in contrast, is defined as 

follows: from infancy to 16 years old, a history of 

at least 12 weeks of passage of large-diameter 

stools at intervals, fewer than two times/week; and 

retentive posturing, avoiding defecation by 

purposefully contracting the pelvic floor. As pelvic 

floor muscles fatigue, the child uses the gluteal 

muscles, squeezing the buttocks together. The 

main difference between functional constipation 

and functional fecal retention is the occurrence of 

retentive posturing in the latter. Retentive posturing 

is the behavioral withholding of stool during 

the sensation of urge, which, according to the 

authors of the Rome II criteria, mostly results from 

painful defecation. 

However, the Rome II criteria exclude a very 

common and major symptom of constipation, 

namely fecal soiling (if substantial called encopresis), 

which is not included in the definition. 

Therefore, to study constipation in children and 

define suitable end-points in pediatric research, a 

different definition of constipation has been used 

in children over 4 years of age. Pediatric constipation 

is thus diagnosed if at least two out of the four 

following criteria are fulfilled two or fewer bowel 

movements/week without laxatives; two or more 

soiling episodes/week; periodic passage of a very 

large amount of stool once every 7–30 days; or 

palpable abdominal or rectal mass on physical 

examination. Using this last definition, a small 

group of children (between 10 and 20%) do not 

fulfill these criteria, but still appear constipated, 

having a low frequency of defecation with production 

of firm hard stools with retentive posturing or 

painful experience. This last group is difficult to 

study, but will usually be included by the consulting 

physician for treatment efforts. 3 

Functional non-retentive fecal soiling 

The Rome II group defined functional nonretentive 

fecal soiling as follows: once a week, or 

more, for the preceding 12 weeks, in a child older 

than 4 years (who failed to be toilet trained), a 

history of defecation into places and at times inappropriate 

to the social contacts; in the absence of 

247

248 

Constipation and encopresis in childhood 

structural or inflammatory disease; and in the 

absence of signs of fecal retention. Many studies 

performed in encopretic children assumed that 

these children were constipated. Therefore, the 

new definition of encopresis or functional nonretentive 

fecal soiling states that this is a separate 

entity. Although in the current literature sometimes 

a difference is made between soiling (loss of 

small amounts of feces due to overflow) and encopresis 

(normal bowel movement) the terms are 

used interchangeably. Sometimes the term solitary 

encopresis is used in a research environment; the 

children who presented for constipation with 

soiling and encopresis (around one in three) 

proved to have solitary encopresis or functional 

non-retentive fecal soiling without any sign of 

constipation, and needed a different treatment 

strategy. 4 


The functional diagnosis of constipation 

Constipation, in approximately 5–10% of the 

patients, is a symptom of an underlying disorder. 

In the remaining 90–95% of the patients constipation 

is idiopathic. This label implies that no clear 

underlying mechanism explains the defecation 

problem. The differential diagnosis is large, but it 

is highly unlikely that one of these diagnoses is 

missed on clinical grounds, and therefore investigations 

should be limited and approached 

cautiously. The main presenting symptoms of 

constipation in children are a combination of a 

low defecation frequency and soiling or encopresis. 

The latter occurs several times a day and, in 

severe fecal retention, also at night. If specifically 

asked, most children will report production of a 

large amount of stools, which might clog the toilet 

with the frequency of once a week or once a month. 

Often, the evacuation of such large amounts of 

stool is preceded by an increase of soiling 

frequency. At physical examination in constipated 

children, the rectal fecal impaction might be 

palpated with firm abdominal scybala, but usually 

manual palpation of a rectal examination with 

abdominal palpation as well identifies the large 

fecal mass. 5 Table 16.1 reports the prevalence of 

symptoms associated with constipation. 

Table 16.I The reported symptomatology of 

childhood constipation 

Clinical features Percentages 

Bowel history 

Infrequent defecation 80–100 

Abdominal pain 10–64 

Vomiting 8–10 

Anorexia or poor appetite 10–47 

Abdominal distension 0–61 

Passage of large stool 45–75 

Passage of hard stool 58–100 

Painful defecation 50–90 

Psychological problems 20–62 

Urinary problems 5–43 

Fecal incontinence 35–96 

Positive family history 9–49 

Physical examination 

Fissures and rectal bleeding 5–55 

Rectal prolapse 0–3 

Abdominal mass 30–71 

Rectal mass 28–100 

Percentages are adapted from references 

Defecation frequency 

The average neonate has a defecation frequency of 

between one and four times daily. Ninety-nine per 

cent of newborns pass the first stool within 48h. 

However, newborns with low birth weights or 

premature infants might have a delayed passage of 

the first stool. Eighty per cent of infants weighing 

less than 2500g pass meconium within the first 

24 h of life. If birth weight declines to 1000–1500 g, 

the first stool will be passed after 48h in 22–60% 

of children. This is still within the physiological 

range. In large cohort studies in normal children, 

the stool frequency varied greatly from once daily 

to once every other day. Therefore, a frequency of 

less than three times a week is considered abnormal, 

but other signs of constipation are necessary

to decide on the clinical symptomatology of constipation. 

6 

Normal anatomy and physiology of 

anorectal function 

The most distal part of the gastrointestinal tube is 

formed by the anal sphincter complex, and is 

responsible for maintaining fecal continence. This 

sphincter complex is embedded in the striated 

pelvic floor, where the puborectalis muscle joins 

the upper end of the external anal sphincter with a 

sling. The anal sphincter complex therefore 

consists of a smooth muscle component of the 

internal anal sphincter and a striated muscle 

component of the external anal sphincter and the 

puborectalis muscle. The internal anal sphincter is 

tonically contracted and generates 85% of the anal 

resting pressure, keeping the anal canal closed at 

rest. It is not under voluntary control, and is innervated 

by the enteric nervous system. Stimulation 

of mechanoreceptors in the rectal wall and the 

sigmoid activates intramural inhibitory neurons, 

leading to relaxation of the internal anal sphincter, 

called the anorectal inhibition reflex. 7 This occurs 

after presentation of stool or gas to the anal canal. 

The external anal sphincter is innervated by the 

pudendal nerve and is under voluntary control. 

This muscle is to some degree contracted, but on 

demand it might be contracted or relaxed upon the 

decision to defecate or to have it postponed. The 

puborectalis muscle ends from the pubic bone, 

loops around the caudal part of the rectum at the 

junction with the anal canal and ends at the os 

pubis. This muscle is tonically contracted, maintains 

and forms the anorectal angle and keeps the 

rectum and anus closed during episodes of 

increased abdominal pressure. The pelvic floor 

and gluteus muscles can assist the anal sphincter 

complex in contraction. Sensation arising from the 

anorectal area is crucial for detecting the presence, 

volume and consistency of feces and gas in the 

rectum. Mucosal and intramuscular receptors are 

involved. These nerve endings detect the nature of 

the anal contents, discriminating between gas, 

liquids and solid feces. Intramural stretch and/or 

pressure receptors detect the degree of rectal filling 

and produce sensations of desire to defecate and 

urgency. Receptors located in the pelvic floor 

Normal anatomy and physiology of anorectal function 249 

and/or the pelvis detect increases in intraabdominal 

pressure, causing changes in the anal 

sphincter complex, leading to expulsion of rectal 

contents. These receptors also activate compensatory 

reflexes to increase anal sphincter pressure 

and ensure fecal continence. Sensations arising 

from the anorectal area are transported by afferent 

neural pathways to the spine via ascending nerves 

in the spinal cord (the spinal thalamic tract). The 

information is transported to the thalamus. This 

sensory information is transferred to the limbic 

and somatosensory areas of the cerebellum, where 

sensations such as flatus and the desire to defecate 

will be perceived. 8 

Normal anorectal function depends on the 

complex interplay between the different anorectal 

and pelvic anatomic structures. The main task of 

the anorectum is to assure continuous fecal continence. 

Defecation might be considered as a controlled 

episode of incontinence at a socially acceptable 

moment. Normal defecation is a complex mechanism 

depending on normal sensation and motility 

of the anorectal area, pelvic floor, sigmoid and 

descending colon, and also involving the 

abdominal and respiratory musculature. Psychological 

factors have a major impact on these 

pathways. 

Fecal continence is produced by different mechanisms. 

9 First, the caudal end of the rectum is 

closed by the anal sphincter complex, creating an 

anal sphincter resting pressure of around 

40 mmHg, to which the internal sphincter 

contributes 85%, and the external anal sphincter 

15%. A reflex of the external anal sphincter 

increases this pressure when the intra-abdominal 

pressure increases acutely and counteracts imminent 

loss of feces. This is probably an important 

mechanism in normal daily life, since coughing, 

laughing, bending, sneezing, etc. instantly 

increase intra-abdominal pressure. This function 

of the anal sphincter for keeping the gate closed is 

supported by rectal motility, which is directed 

antegrade, to keep the rectum empty, transporting 

the feces back to the sigmoid and away from the 

anal canal. A third mechanism takes care of continence 

by a sensation in the cranial part of the anal 

sphincter. These receptors are located in the area 

of the skin close to the surface of the anus.

250 


Transsection studies have shown that sensation is 

not lost, emphasizing the distal location of this 

sensation. Triggering of these receptors in the anal 

canal by feces or gas will result in the sensation of 

imminent loss, and gives the person the ability to 

prevent this loss of feces and gas by contracting 

the pelvic floor muscles. When defecation is not 

desired, the external sphincter complex and the 

pelvic floor muscles remain contracted until the 

rectal wall has adapted to the increased rectal 

volume; when the intrarectal pressure decreases, 

the sensation of urge will disappear. In addition, 

retrograde contraction of the caudal part of the 

rectum starts to occur, and transports the feces 

back into the sigmoid colon. The interplay of all 

these mechanisms starts when feces or gas enters 

the rectum, owing to increased propulsive activity 

of the colon after ingestion of a meal. Filling the 

rectal vault, these feces lead to an increase of 

intrarectal pressure and triggering of receptors 

located in the rectal wall. This induces the inhibition 

reflex, leading to a decrease of anal sphincter 

pressure (internal sphincter), which is more 

pronounced when rectal filling increases. Above a 

certain threshold in rectal pressure, the perception 

of urge occurs. At that time, due to a reflex triggered 

by this sensation of urge, the external anal 

sphincter complex contracts for a short time, 

preventing immediate loss of feces, thus creating 

time to consider whether the pelvic floor has to be 

contracted to stop imminent defecation or to 

permit the defecation process to continue. 

Defecation occurs when there is a difference in 

pressure in the rectum on the one hand (rectal 

contractions and straining), and the pelvic floor on 

the other hand (relaxation of the anal sphincter 

complex and pelvic floor, and flattening of the 

anorectal angle). 10 

Training is essential when a child tries to defecate 

without a sensation of urge (e.g. during toilet training). 

During the process of toilet training the child 

starts to obtain control of these complex mechanisms 

in the defecation process. The will of the 

child seems to be a crucial factor in this process. 

Aberrations in these complex interacting mechanisms 

might lead to clinical signs and symptoms of 

constipation and fecal incontinence. The pathophysiological 

mechanisms of these clinical entities 

are largely unknown. In the past decades, only 

little progress has been made in resolving these 

mechanisms. 11 

Colonic propagated contractions are tonic and 

phasic and propel the luminal contents to the 

distal colon and rectum. Non-propagated contractions 

move fecal material antegrade and retrograde 

and mix a shift of the fecal contents over short 

distances. High-amplitude propagated contractions 

(HAPCs) are a pattern of colonic motility 

originating in the proximal colon and proceeding 

to the distal sigmoid colon, and are associated with 

mass movements. They have an amplitude of at 

least 100mmHg, duration of

muscular (impaired contractility) and neural 

(uncoordinated activity) mechanisms may lead to 

impairment of propulsion of fecal contents leading 

to slow-transit constipation. 12 Mechanisms underlying 

these entities might be an impairment of 

neural transmitter function, such as nitric oxide 

(NO) or substance P, or aberrations in the interstitial 

cells of Cajal. However, this entity remains 

extremely difficult to explain and might be 

secondary to the effect of stasis. 

In addition to neuromuscular dysfunction, constipation 

can also result from massive fecal retention 

in the rectum. It has been shown that voluntary 

retention of feces can cause a delay in colonic 

transit in healthy volunteers. Similarly, massive 

fecal retention in children can also inhibit colonic 

transit and thus indirectly leads to prolonged 

transit time. In several children, slow-transit 

constipation after treatment changes to outlet 

obstruction with only a delay in the rectosigmoid 

region. 

An alternative mechanism leading to constipation 

is the so-called outlet obstruction or abnormalities 

in the dynamics underlying defecation. In these 

children, the delay in colonic transit involves the 

rectum. This mechanism is found in approximately 

40–60% of constipated children. It should be noted 

that 50% of constipated children, all presenting 

with the same symptomatology, have normal 

colonic transit time. 13–15 This observation strongly 

suggests that abnormal transit times are secondary 

events in children with constipation. It is also 

supported by normalization of transit time in slowtransit 

constipation after successful treatment. 

Another alternative mechanism might be abnormal 

sphincter function. 16,17 Under normal circumstances, 

the pressure generated by the anal sphincter 

complex should drop during an attempt to 

defecate, allowing expulsion of fecal contents. As 

stated above, in 40% of children with constipation, 

colonic transit is delayed in the rectum, and it was 

suggested that this abnormal obstruction is the 

result of abnormal defecation dynamics. However, 

using anorectal manometry, a paradox for contraction 

in the anal sphincter complex is observed in 

more than 50% of constipated children. This 

contraction of the anal sphincter complex might 

lead to fecal accumulation and constipation. This 

abnormality might be the underlying pathophysio- 

Pathophysiology of functional constipation 251 

logical mechanism of childhood constipation, 

reflecting the observed stool withholding behavior/retentive 

posturing. Possible suggested causes 

leading to this behavior might be pain, resulting 

from the previous production of a large, hard stool; 

anal fissures; primary behavioral mechanisms; not 

taking time to visit the toilet; and avoiding other 

toilets, mainly at school. However, abnormal defecation 

dynamics have not only been observed in 

fecal retention and constipation, but similarly in 

children with functional non-retentive fecal 

soiling. In addition, a large study, comparing 

conventional treatment with additional biofeedback 

training in constipated children, showed that 

biofeedback training could normalize the aberrant 

sphincter contraction, but, it did not lead to a 

larger success rate in children receiving additional 

biofeedback training. 1 These observations argue 

against a major contribution of abnormal defecation 

dynamics to the development of constipation 

in children. 

As explained previously, different types of nerve 

endings, giving rise to sensations of flatus, urge to 

defecate and pain, sense the arrival of fecal material 

into the rectum. This sensory information is 

important for initiating the defecation process. 

Abnormalities in rectal sensation are believed to 

play an important role in the pathogenesis of 

constipation. Children usually report that they do 

not feel the sensation or urge to defecate. Several 

studies have investigated rectal sensitivity in children 

with constipation. In these studies, rectal 

sensation is determined by inflation of a rectal 

balloon, measuring the volume at which the sensation 

of urge is perceived. These studies showed 

impaired rectal sensation in a subgroup of patients 

with constipation. In the majority of children, 

however, rectal sensation was normal and present 

after insufflation of only 20ml of air in the balloon. 

Rectal volumes are obviously age-dependent, with 

a barostat (an insufflatable rectal balloon that can 

keep the volume constant while varying the pressure, 

or vice versa) showing that one subgroup 

needs higher pressures with a normal volume to 

feel urge, but children in another subgroup need 

higher volumes with a normal pressure to feel 

urge. 

Abnormal rectal sensation does not seem to be an 

important pathophysiological entity. In fact, a

252 


number of studies in children with constipation 

have documented a normal anal resting pressure, 

as well as a normal maximal rectal squeeze pressure. 

To date, no consistent abnormalities in motility 

testing have been recorded in children with constipation. 

There were no differences in motility parameters 

between children with long-standing 

constipation and those who have had constipation 

for only a short period. Furthermore, there were no 

indications of neuromuscular damage due to 

abnormalities caused by constipation or its 

therapy. 

Therefore, it is fair to conclude that, there is no 

current explanation of the cause(s) of constipation 

or suggested pathophysiological mechanisms. All 

assumed mechanisms have been found to be 

normal in the majority of children with constipation 

with a mainly uniform clinical presentation. 

Children with functional non-retentive fecal 

soiling, in studies on its pathophysiology, show 

normal anal sphincter resting pressure, normal 

maximal squeeze pressure and normal rectal 

sensation. Also, colonic transit time measurements 

were normal in all children with this entity. 18–20 

Medical history 

Symptoms of constipation in most children start in 

more than 38–65% before the age of 6 months, and 

some have even described bowel problems in 40% 

of children in the first months of life. Stool habits 

might change, owing to stress factors and change 

in nutrition, for instance change from breast 

feeding to formula feeding. Specific questions 

regarding the presence of soiling and encopresis 

should be asked, and also regarding the frequency 

and whether it is present at night-time. These children 

produce an enormous amount of stool once 

every 7–30 days, which is almost never spontaneously 

presented as a symptom during a first 

doctor’s visit. It must also be asked whether this 

enormous amount of stool has been produced just 

before the visit to the doctor (the rectum might 

then be empty for rectal examination). Questions 

about retentive posturing should be asked, but 

might be difficult to answer; nevertheless, the 

parents might notice whether stools are produced 

with pain and also if any of these symptoms 

started after a period in which defecation and 

stools were completely normal. When the 

frequency is less than three times a week, soiling 

and encopresis are present, and large amounts of 

stool are occasionally produced, the diagnosis of 

functional constipation is likely. When a child has 

a painful stressful production of hard stools 

without soiling and encopresis and retentive 

posturing, even at an almost normal frequency, 

constipation will still be considered probable by 

the physician, and a therapeutic attempt should be 

initiated. 21–23 

In developed societies most children are toilet 

trained by the age of 2–3 years. There is no relation 

between failed toilet training and the development 

of constipation or functional non-retentive fecal 

soiling. Before the age of 4 years, the diagnosis of 

constipation can be made only on low or decreased 

frequency of defecation, production of occasional 

voluminous stools, production of hard stools with 

discomfort, pain and/or retentive posturing. In 

infants, the diagnosis of constipation can be 

inferred when they cry before, during and after 

defecation, and this consists of firm, hard stools. 

Behavioral problems occur often, but they are 

almost invariably secondary to the social consequences 

and depend on individual styles of 

coping. Such problems typically improve considerably 

once the defecation difficulties are successfully 

treated. However, poor social behavior, or an 

inadequate parent–child relationship may be associated 

with the continuation of defecation problems. 

Urinary problems, diurnal and also nocturnal 

enuresis, are secondary to the defecation 

problems and usually improve after successful 

treatment. 


Abdominal masses should be gently looked for by 

palpation in the lower abdominal quadrants and 

suprapubic area. The stool mass might be palpable 

extending from the pelvis, but smaller scybala 

might also be detected. Usually, a bimanual palpation 

through a rectal examination with one hand 

combined with abdominal palpation with the 

other hand, clearly defines the rectal mass of stool 

the best. At the first visit a rectal examination 

should be attempted in all children who present

with constipation or non-functional fecal retention. 

Only in 10–15% of children is the fear of 

examination too high, when this procedure has to 

be omitted. Otherwise, it is well perceived and 

gives the essential information about the rectal 

fecal mass. Anal fissures can be clearly visualized 

by spreading the anus, and during the examination 

anatomical abnormalities should be inspected, 

checking the anal position in the perineum and its 

asymmetry: an ectopic anus can in fact be the 

cause of constipation. The inspection of the lower 

lumbar and sacral spine areas should be focused 

on dimpling, surgical scars and hair tufting. Also, 

tendon reflexes should be evoked. Usually, the 

school-aged child has stools or soiling in his 

underpants and one should be aware of the 

production of a large amount of stool just prior to 

the visit to the physician. That might interfere 

with the examination results. Fissures are considered 

to be related to the initiation of constipation 

only in very young infants; an abdominal and/or 

rectal mass is found in 30–100%, depending on the 

investigator. 24 


Over 90% of pediatric patients with constipation 

have functional constipation or non-retentive 

functional fecal soiling. Only in a very small 

number of children is a distinct etiology established, 

and these cases are not easily overlooked. 

Changed dietary habits might decrease the intake 

of fluids and food. The change from breast milk to 

formula feeding as an initiating point is highly 

suggestive of constipation. 

A careful perianal examination will disclose an 

imperforate anus, or an abnormal anteriorly 

displaced anus, as well as other congenital 

anatomic and structural defects. 

Spinal abnormalities are indicated by abnormalities 

of the skin, and also growth impairment and a 

combination of fecal and urinary incontinence or 

constipation. 

Metabolic disturbances are related to severe dehydration, 

as is seen in diabetes insipidus, hypocalcemia 

and renal tubular acidosis, and are not 

easily overlooked. 

Examinations 253 

Hypothyroidism is screened for in the neonatal 

period and might still occur later, but is not easily 

overlooked as a symptom complex in a child. 

Hirschsprung’s disease is suspected after a delayed 

production of meconium beyond 48h after birth, 

and continuing defecation problems usually with 

distended abdomen and poor appetite, failure to 

gain weight and vomiting. Also, the history would 

often document episodes of acute, severe enterocolitis 

with explosive diarrhea. Clinically, the diagnosis 

is made by insertion of a catheter through the 

anus in the distended part, after which decompression 

follows (see Chapter 17). 

Also, Hirschsprung’s disease might involve a very 

small segment of the anorectum and present as 

constipation. In practice, this is seen only on 

extremely rare occasions. We have not made this 

diagnosis in our practice for decades. 

Recently, magnetic resonance imaging (MRI) of the 

pelvis and distal colon has been proposed in order 

to detect small abnormalities, cysts, tumors or 

tethered cord which may be the basis of constipation 

without any other neurological symptom. 

This approach, however, has not been performed 

in a large population, and is currently awaiting 

some protocol definitions. 25 

Examinations 

Plain abdominal X-ray 

On a plain abdominal radiograph some amount of 

stool is always visible. The simple report of ‘stools 

in the colon’ should therefore not be regarded as 

indicative of constipation. Barr et al tried to 

develop a scoring system to define constipation. 

Although this scoring system is used to diagnose 

constipation in children with chronic abdominal 

pain as the only symptom, the method is subject to 

large intra- and interobserver variability. 26,27 

Colonic transit times are measured by the Metcalf 

method. Swallowed radio-opaque tiny rings allow 

the intestinal transit to be measured. This test 

shows normal transit times in half of the constipated 

children and is therefore only useful to diagnose 

slow-transit constipation, a clinical entity 

usually apparent with night-time soiling and resis

254 


tance to treatment. The upper limit of colonic 

transit is 63h. A colonic transit time delayed to 

more than 100h is defined as slow-transit constipation. 

A palpable rectal mass is always found. 

The method can also be used to support the diagnosis 

of functional non-retentive fecal soiling, but 

it has no place in the general management of children 

with constipation. 

Barium enema 

A barium enema performed in the unprepared 

colon might delineate the transition zone in 

Hirschsprung’s disease in young infants, but is of 

limited value, as the transition zone is often difficult 

to see and might only be of value to the operating 

surgeon preoperatively after the diagnosis 

has been made. 

Defecography 

Defecography uses a relatively high radiation 

exposure and is difficult and unreliable in children. 

Anorectal manometry 

Anorectal manometry is a relatively safe, minor 

invasive technique. With an open perfusion 

system, pressures may be assessed in anal sphincter 

muscles at rest, at squeezing and during straining. 

During defecation, the pelvic pressure or 

rectal pressure increases, owing to abdominal 

muscle contraction, and the anal canal pressure 

decreases, creating a difference to allow defecation. 

A rectal balloon might be inflated to assess 

the rectal anal inhibitory reflex against relaxation 

of the internal anal sphincter. In the clinical 

setting, except for Hirschsprung’s disease, the 

majority of children have normal anorectal pressures. 

Rectal sensitivity after inflation of a balloon is 

normal. Children who have abnormal defecation 

dynamics, in an attempt to defecate the balloon, 

will contract the anal sphincters at the same time 

that they contract the abdominal musculature. 

This can be shown on a screen and children can 

learn to relax instead of having this paradoxical 

contraction during defecation of the anal muscula- 

ture. The training by reinforcement is called 

biofeedback training. 

Anorectal manometry is normal in children with 

functional constipation or functional non-fecal 

retention, and therefore this should not be used. 1 

Colonic manometry 

Colonic manometry 28 requires colonoscopic placement 

of the catheter with motility recordings, 

which are measured the day after placement. 

Colonic motility can be tested over hours, possibly 

with bisacodyl administration to enable propagated 

contractions to be endured. This test is 

reserved for children with intractable constipation. 

Some investigators can differentiate children 

with functional fecal retention from those with no 

neuropathy or myopathy of the colon with this 

technique. The technique is still used in a few 

centers; however, its value in the diagnostic 

process of constipation has to be assessed. 

Treatment 

Only a few studies, most of them with small 

patient numbers, have been performed to evaluate 

treatment for children with defecation disorders. 

Treatment of constipation is mainly based on 

empirical experience, rather than on placebocontrolled, 

randomized studies. The main reason 

for a consultation is interference with social activities 

of the child and its family because of the defecation 

problems (soiling and encopresis). They 

should be educated and the problem should be 

demystified. 29 It should be stressed that the prevalence 

of constipation and soiling is quite common. 

The relationship between fecal impaction and 

overflow diarrhea should be explained with the 

help of drawings, and the involuntary nature of the 

loss of feces in the underwear made clear. The 

objective of this is to make parents start to feel 

more comfortable and decrease the feeling of 

shame in the child. The child and parents almost 

invariably accept a positive non-accusatory 

approach with relief. Organic versus functional 

disease should be explained clearly, once the 

history and physical examination have been evaluated 

and the diagnosis is made with confidence. 

It should be stressed that there is no need for

further investigation. The therapy is stressful and 

might be long lasting. The child is the only one 

who is responsible for completing the treatment. 

Behavioral therapy (see below) is not generally 

recommended; if the treatment is successful, the 

behavior abnormalities usually normalize too. It is 

helpful to advise that a diary is kept to follow and 

gain insight into the therapeutic progress; it might 

also motivate the child. The child has to fill in the 

diary himself, and that enhances responsibility. It 

might also be linked to a reward system. 30–33 

Another simple general measure is toilet training 

to normalize defecation. It should be explained 

that the sensation of defecation must be felt by the 

child and, usually from the age of 4, will be admitted 

by the child when it is explained well. The 

treatment of the child should involve an instruction 

to attempt to defecate three times a day for 

5 min after each meal. This should stimulate 

straining actively and the child should be able to 

place his feet on a footrest or on the ground (the 

younger ones usually need a footrest). This is 

important, to flatten the anorectal angle, facilitating 

fecal expulsion. Using this approach, the child 

will be forced to focus on its bowel function. The 

emptying of the rectum will reduce the risk of fecal 

soiling during the rest of the day. This approach is 

only successful in 50% of children with severe 

constipation referred to a tertiary hospital, without 

any added pharmacological treatment. 

Fluid intake 

Fluid intake of children with constipation has 

been found to be slightly lower than normal, 33 and 

so is energy intake, estimated in a prospective 

study to be around 100kcal/day lower. Fiber intake 

of children with constipation was also slightly 

lower than controls, but in 6 months after reinforcement 

we found that it could be increased in 

some by only around 9g while it was actually 

decreased in others up to 16g. The total amount 

remained less than 20g and no child achieved 

30g/day. There was no relation between fiber 

intake, colonic transit times and success in treatment. 

Therefore, while we would still recommend 

increasing fiber intake in constipated children, one 

might not expect much success in children from 

this intervention alone. 34 

Pharmacotherapy 

Treatment 255 

No double-blind randomized study on oral or 

rectal laxatives has been performed in children 

with constipation, except for the use of cisapride. 35 

The effect of lactulose, one of the most widely 

used stool softeners, has not been investigated. An 

evidence-based treatment cannot be constructed. 

Almost all advice concerning the use of oral or 

rectal laxatives is currently based on clinical 

empirical experience. 

The major aim of medical therapy is two-fold: to 

remove fecal impaction; and to prevent its recurrence 

by avoiding prolonged rectal distension. 

Removing fecal impaction 

The most convenient approach in the majority of 

cases is by daily enemas, better administered after 

returning from school, as it might take some time 

to induce defecation. 36 The effect is mainly due to 

a sudden increase in rectal filling, which leads to a 

strong rectal contraction and reflex relaxation of 

the internal anal sphincter, often followed by a 

bowel movement. The advantage of an enema 

strategy is a direct effect on overflow incontinence 

and relief for the child and parents. Enemas have 

the effect of hyperosmosis and increased fluids in 

the colon; furthermore, they lubricate the feces 

and distend the colon. Enemas used in children 

may contain dioctyl sodium sulfosuccinate and 

sorbitol or phosphate. Also, oil enemas and tap 

water enemas can be used. Hyperphosphate 

enemas in children have some risk when the 

enema administration is not followed by defecation 

and might lead, through retention, to hyperphosphatemia, 

subsequent hypocalcemia, hypokalemia 

and dehydration. 37,38 Also, hypocalcemia 

might lead to tetany and cardiac abnormalities in 

children, which in practice it is mainly seen in 

treatment of Hirschsprung’s disease prior to 

surgery. Enemas should contain a sufficient 

amount of fluid: under 2 years of age around 60ml 

and above 2 years of age 120ml. Usually, evacuation 

is achieved within 3 days with consecutive 

daily enemas. Otherwise, it should be continued 

until the fecal mass has been removed successfully. 

When soiling relapses or the defecation 

frequency does not normalize with adequate treatment 

with oral laxatives, enemas are added to

256 


long-term treatment on an individual basis, 

usually 2–3 times weekly. When this procedure 

for severe fecal impaction is unsuccessful, and 

also in children who are treated for constipation 

and have recurrent large impaction, intermittent 

nasogastric lavage treatment might be tried. A safe 

and efficient method to clean the intestine is the 

balanced electrolyte solution of non-resorbable 

polyethylene glycol. This solution is often well 

taken by the child and, if he cannot swallow the 

required quantity, nasogastric tubes might be used. 

The recommended volume varies between 14 and 

40ml/kg per h, not to exceed 1litre/h, and treatment 

should be continued until clear fluid is 

excreted through the rectum, an effect usually 

reached within 24h. This treatment gives some 

temporary relief, but is not a substitute for other 

treatment protocols. 

Preventing recurrence of fecal impaction 

The remaining initial treatment after desimpaction 

is achieved involves osmotic laxatives (lactulose, 

lactitol) at a dose of 1–6g/kg body weight per day. 

The main function is to loosen stool consistency, 

and enhance the rectal sensation and urge of the 

child to defecate. The dose might be increased 

without any danger up to 20–40g daily. Sideeffects 

are initially bloating, flatulence and 

increase of abdominal pain, but these symptoms 

usually disappear after the first 1–2 weeks. 

Therapy should be continued for at least 3–6 

months until constipation has disappeared; the 

dose should be titrated individually. If this treatment 

is insufficient, recently polyethylene glycol 

has been shown to be effective in treating constipation 

in children at a dose of 0.8g/kg per day. It 

also functions as an osmotic laxative. 39,40 It has 

fewer side-effects in terms of flatulence and 

abdominal pain, and its tasteless nature increases 

compliance. The effects are comparable to those of 

lactulose. 

Another laxative is mineral oil, an emollient agent, 

at a dose of 1–3ml/kg per day, whose main function 

is to keep the rectal walls lubricated. 

Disadvantages are anal oil seepage with coloring of 

the underwear, which is not removable with 

washing, and the risk of aspiration and chemical 

pneumonia in very young children, and in children 

with cerebral palsy or other causes of mental 

retardation. Milk of magnesia is a relatively non- 

absorbable laxative, and can be given at a dose of 

1ml/kg per day. The treatment might be started at 

a higher dose, up to 3ml/kg per day. Prokinetic 

agents, such as cisapride at a dose of 0.2mg/kg 

body weight three times daily, have some transient 

effect on constipation, but this drug is no longer 

available. 

Stimulant laxatives such as bisacodyl, sodium 

picosulfate and senna alkaloids should be used 

with caution and have no advantage over osmotic 

laxatives. Biofeedback training has been shown to 

normalize defecation dynamics, but has no place 

in management, because it does not influence therapeutic 

outcome. Surgical colostomies for antegrade 

enemas have been successfully tried, but 

also have their complications; at present, indications 

are difficult to establish. 

In functional non-retentive fecal soiling, biofeedback 

training showed a minor effect on treatment 

outcome. 41 In this form of constipation, the main 

treatment is laxatives. Daily enemas in the 

morning might help to have a clean day, which 

might stimulate the defecation behavior. Oral laxatives 

usually worsen soiling and encopresis and 

should be avoided in these children with functional 

non-retentive fecal soiling. 

Biofeedback training compared to conventional 

treatment 

In a large cohort of 200 children who had conventional 

treatment and one arm of biofeedback training 

added, they did learn to normalize their defecation 

dynamics, but this normalization had no 

influence on outcome of treatment. Only in functional 

non-retentive fecal soiling did biofeedback 

have a modest effect in a sample of 100 tested children. 

Prognosis 

In a cohort of more than 400 constipated children, 

follow-up was obtained by annual telephone 

contact in more than 95% of children. Mean 

follow-up was 5 years (range 1–8). The cumulative 

percentage of children who were successfully 

treated during follow-up was 60% in 1 year, 

increasing to 80% in 8 years (Figure 16.1). 

Interestingly, successful treatment was more

Figure 16.1 Outcome with and without laxatives. 

frequent in children without encopresis, and in 

children with an age at onset of defecation difficulty 

older than 4 years. In the group of successfully 

treated children, approximately 50% 

remained symptom free during the follow-up 

period, while the other half experienced at least 

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30. Lowery SP, Srour JW, Whitehead WE, Schuster MM. 

Habit training as treatment of encopresis secondary to 

chronic constipation. J Pediatr Gastroenterol Nutr 1985; 

4: 397–401. 

31. Roberson G, Meshkinpour H, Vandenberg K et al. Effects 

of exercise on total and segmental colon transit. J Clin 


32. Levine MD, Mazonson P, Bakow H. Behavioral symptom 

substitution in children cured of encopresis. Am J Dis 

Child 1980; 134: 663–667. 

33. Stark LJ, Spirito A, Lewis AV, Hart KJ. Encopresis: 

behavioral parameters associated with children who fail 

medical management. Child Psychiatry Hum Dev 1990; 

20: 169–179. 

34. Mooren GC, van der Plas RN, Bossuyt PM et al. Het 

verband tussen inname van voedingsvezels en 

chronische obstipatie bij kinderen. Ned Tijdschr 

Geneesk 1996; 140: 2036–2039. 

35. Nurko S, Garcia-Arnada JA, Guerrero VY, Worona LB. 

Treatment of intractable constipation in children: 

experience with cisapride. J Pediatr Gastroenterol Nutr 

1996; 22: 38–44. 

36. Price KJ, Elliott TM. What is the rule of stimulant 

laxatives in the management of childhood constipation 

and soiling? (Cochrane Review). Cochrane Database 

Syst Rev 2001; 3: CD002040. 

37. Martin RR, Lisehora GR, Braxton M Jr, Barcia PJ. Fatal 

poisoning from sodium phosphate enema: case report 

and experimental study. JAMA 1987; 257: 2190–2192. 

38. Sotos JF, Cutler EA, Finkel MA, Doody D. Hypocalcemic 

coma following two pediatric phosphate enemas. 

Pediatrics 1977; 60: 305–307. 

39. Loening-Baucke V. Polyethylene glycol without electrolytes 

for children with constipation and encopresis. J 

Ped Gastroent Nutr 2002; 34: 372–377. 

40. Youssef NN, Peters JM, Hnederson W et al. Dose 

response of PEG 3350 for the treatment of childhood 

fecal impaction. J Pediatr 2002; 141: 410–415. 

41. van Ginkel R, Benninga MA, Blommaart PJ et al. Lack of 

benefit of laxatives as adjunctive therapy for functional 

nonretentive fecal soiling in children. J Pediatr 2000; 

137: 808–813. 

42. van Ginkel R, Reitsma JB, Buller HA et al. Childhood 

constipation: longitudinal follow-up beyond puberty. 

Gastroenterology 2003; 125: 357–363.

17 

Introduction 

Hirschsprung’s disease and 

intestinal neuronal dysplasias 

Annamaria Staiano, Lucia Quaglietta and Renata Auricchio 

Hirschsprung’s disease is a heterogeneous genetic 

disorder, resulting from an anomaly of the enteric 

nervous system of neural crest cell origin, characterized 

by the absence of parasympathetic intrinsic 

ganglionic cells in the submucosal and myenteric 

plexuses. It is regarded as the consequence of the 

premature arrest of the craniocaudal migration of 

vagal neural crest cells in the hindgut, between the 

5th and 12th weeks of gestation, to form the 

enteric nervous system, and is therefore considered 

a neurocristopathy. 1 

Epidemiology 

Hirschsprung’s disease occurs in approximately 1 

of 5000 live births, and with a male predominance 

of 4 : 1. It is generally sporadic, although in 3–7% 

of cases a genetic transmission has been reported. 1 

The risk for short-segment disease is 5% in brothers 

and 1% in sisters of index cases; for longsegment 

disease the risk is 10%, regardless of sex. 2 

Etiology 

Hirschsprung’s disease is characterized by the 

congenital absence of ganglionic cells in the submucosal 

and myenteric plexuses in the distal bowel, 

and variable proportion of the colon proximally. The 

embryonic disorder is a lack of the craniocaudal 

migration, differentiation and maturation of neuroblasts 

from the neural crests. The earlier the migration 

ceases, the longer the aganglionic segment will be. 

The aganglionic segment is permanently contracted, 

causing dilatation of its proximal tract. 3 

Hirschsprung’s disease may be classified according 

to the length of the aganglionic segment: the 

classic form (short segment in 70–75% of cases) is 

limited to the rectum and sigmoid colon; the long 

segment, or subtotal colonic disease (10–15%), 

generally involves the bowel up to the splenic 

flexure; total colonic aganglionosis (TCA; 3–6%) 

may extend to involve a variable amount of the 

short bowel; and total intestinal aganglionosis is 

sometimes associated with intestinal malrotation 

or volvulus. 4 Ultrashort-segment aganglionosis is 

considered a functional alteration, without any 

detectable histological finding. Although longer 

aganglionic segments tend to produce more 

dramatic symptoms, some patients with even 

short-segment disease deteriorate rapidly. 5 


The hallmark of diagnosis is the absence of 

ganglionic cells from the myenteric and submucosal 

plexuses, as seen on a full-thickness or 

suction (mucosal–submucosal) biopsy of the 

rectum. Proximal contents fail to enter the unrelaxed, 

aganglionic segment. The lack of nonadrenergic–non 

cholinergic (NANC) inhibitory 

innervation is responsible for a tonic contraction 

of the affected segment, with absence of peristalsis 

and proximal dilatation of the gut. 6 

Morphologically, ganglionic cells are absent from 

the narrowed segment and for some distance 

(usually 1–5cm) into the dilated segment. The 

pattern of nerve fibers is also abnormal; they are 

hypertrophic with abundant, thickened bundles. 

Specific stains for acetylcholinesterase are used to 

highlight the abnormal morphology. 7,8 

259

260 

Hirschsprung’s disease and intestinal neuronal dysplasias 

In recent years, new insights into the pathophysiology 

of Hirschsprung’s disease have been gained. 

There is growing evidence suggesting that the 

disease might be the expression of a genetic alteration, 

as reported in the genetic section of this 

chapter. 

It has also been suggested that abnormal expression 

of the muscular neural cell adhesion molecule 

is likely to be associated with an arrest in the 

craniocaudal migration of neural cells to their 

most distal location. 9 Furthermore, the lack of 

nitric oxide (NO)-producing nerve fibers in the 

aganglionic intestine probably contributes to the 

inability of the smooth muscle to relax, thereby 

causing lack of peristalsis. 10 In addition, in the 

aganglionic segments, interstitial cells of Cajal are 

scarce and their network appears to be disrupted. 11 

Clinical signs/symptoms 

In the newborn, symptoms may appear during the 

first hours of life with failure to pass meconium, or 

in the first week with a picture of intestinal 

obstruction. However, the delay in passage of 

meconium is not constant, and a percentage of 

children still presents late or with complications 

despite a history of problems since birth. 

Enterocolitis, the most common complication, is 

always severe and is an important cause of mortality 

in these young patients. 

In infants and children, the presentation is often 

less dramatic and may not mimic acute intestinal 

obstruction (Figure 17.1). Severe constipation and 

recurrent fecal impaction are more common. 

Physical examination reveals a distended 

abdomen and a contracted anal sphincter and 

rectum in most children. The rectum is devoid of 

stools, except in cases of short-segment aganglionosis. 

As the finger is withdrawn, there may be 

an explosive discharge of foul-smelling liquid 

stools, with decompression of the proximal normal 

bowel. 

Complications 

Over the past four decades, enterocolitis has been 

a major cause of morbidity and mortality in infants 

and children with Hirschsprung’s disease. The 

mean incidence is 25%, but the range is great 

(from 17 to 50%) and may be differently estimated, 

depending on the manner in which it is diagnosed. 

Mortality rates range from 0 to 33%, probably 

reflecting differences in the diagnostic criteria. 12 

Mortality also appears to be associated with other 

factors, such as trisomy 21. The classic clinical 

manifestations described for enterocolitis include 

abdominal distension, explosive diarrhea, vomiting, 

fever, lethargy, rectal bleeding and shock. 13 

Abdominal radiographs show the intestinal ‘cutoff’ 

sign in the rectosigmoidal region with absence 

of air distally. Other common findings are smallbowel 

dilatation in 74% of patients and multiple 

air–fluid levels. 14 Because of the risk of perforation, 

contrast enema should not be performed in 

the presence of clinical enterocolitis. 

Postoperative enterocolitis has been associated 

with a fairly high rate of mortality in several series. 

In fact, when examining the deaths related to 

Figure 17.1 Severe abdominal distension in an infant 

with Hirschsprung’s disease.

Hirschsprung’s disease, several groups found that 

approximately 50% of deaths resulted from 

complications directly related to an enterocolitis 

episode. 15,16 

Rectal washouts should be the initial approach in 

the care of a child, regardless of age, who presents 

with enterocolitis. Along with washouts, intravenous 

antibiotics or oral metronidazole (in mild 

cases) should be used. Should the disease process 

fail to improve, or the infant’s condition deteriorate, 

the performance of a leveling colostomy 

should be considered. 15,16 


For the diagnosis of Hirschsprung’s disease, the 

subject’s history is very important. The crucial 

elements to obtain are: the age of the appearance of 

symptoms; whether the passage of meconium has 

been normal or delayed; and whether the child 

presented with episodes of functional intestinal 

obstruction. In addition, a functional (idiopathic) 

megacolon must be ruled out. A clinical comparison 

between functional and congenital megacolon 

is shown in Table 17.1. When the history (early 

onset of constipation, absence of fecal soiling) 

and/or the physical examination (empty rectal 

ampulla) suggests an organic cause, anorectal 

manometry should be performed. 

Table 17.1 Differentiating types of megacolon in children 

Functional Colonic 

fecal neuromuscular 

Signs and symptoms retention disorders 

Soiling common rare 

Obstructive symptoms rare common 

Large-caliber stools common rare 

Stool-withholding behavior common rare 

Enterocolitis never possible 

Associated upper-gastrointestinal symptoms never common 

Symptoms from birth rare common 

Localization of stools rectum rectal and 

extrarectal 

Diagnosis with differential 261 

Anorectal manometry evaluates the response of 

the internal anal sphincter to inflation of a balloon 

in the rectal ampulla. 17 When the rectal balloon is 

inflated, there is normally a reflex relaxation of the 

sphincter. The rectoanal inhibitory reflex is absent 

in patients with Hirschsprung’s disease; there is no 

relaxation, or there may even be paradoxical 

contraction of the internal anal sphincter (Figure 

17.2). Anorectal manometry is particularly useful 

when the aganglionic segment is short and the 

results of radiological or pathological studies are 

equivocal. 

Barium enema is helpful in the assessment of a 

transition zone between aganglionic and 

ganglionic bowel, and in giving an estimation of 

the length of an aganglionic segment. Demonstration 

of the transition zone is easier if no effort 

is made to cleanse the bowel (Figure 17.3). In the 

newborn, dilatation of the proximal ganglionic 

bowel may not have developed and radiological 

diagnosis may be more difficult. The sensitivity 

and specificity for recognition of a transition zone 

have been reported to be 80% and 76%, respectively. 

18 The barium enema may not show a transition 

zone in cases of total colonic Hirschsprung’s 

disease, or may be indistinguishable from cases of 

functional constipation when ultrashort-segment 

Hirschsprung’s disease is present. 

Nevertheless, the diagnosis is based on 

histological evidence. Since the mid-1970s,

262 


(a) (b) 

Figure 17.2 Anorectal manometry in a 2-month-old boy with functional constipation (a). Note that the distension of a 

rectal balloon with air for 1s produces a decrease of anal pressure (rectosphincter reflex). (b) Anorectal manometry in a 

3-month-old boy with Hirschsprung’s disease. Distension of a rectal balloon with air for 1s produces no decrease of anal 

pressure. 

Figure 17.3 Barium enema showing a long, narrowed 

segment in a child with Hirschsprung’s disease. 

demonstration of acetylcholinesterase activity in 

mucosal biopsies has allowed the non-invasive 

suction rectal biopsy technique to become the 

most reliable diagnostic method for 

aganglionosis. 7,8 The histological diagnosis is 

based on the demonstration of the total absence of 

ganglionic cells in the affected segment of the 

intestine, with an overgrowth of large nerve trunks 

in the intermuscular and submucosal zones 

(Figures 17.4 and 17.5). 19 Two small samples of 

rectal mucosa and submucosa, taken using the 

suction rectal biopsy technique, are sufficient for 

diagnosis. The two pieces must be taken not less 

than 2cm above the dentate line, to avoid the 

physiological hypoganglionic zone, and not more 

than 5cm above the dentate line, to avoid missing 

the diagnosis of a short-segment disease. Acetylcholinesterase 

activity in the normal colon shows 

only a few fibers in the lamina propria and muscularis 

mucosae; in Hirschsprung’s disease there is 

an increase in thick, knotted acetylcholinesterasepositive 

nerve fibers in the muscularis mucosae 

and lamina propria, and hypertrophied nerve 

trunks in the submucosa. 

The hyperplastic nerve trunks in the lamina 

propria, submucosa and muscularis propria are 

both adrenergic and cholinergic. Thus, these are 

extrinsic nerve fibers that are hyperplastic, owing

Figure 17.4 Rectal suction biopsy in a child with 

functional constipation. Note the presence of clusters of 

neurons in the submucosa and acetylcholinesterase 

activity showing only a few wispy fibers. 

Figure 17.5 Intense acetylcholinesterase activity in a 

patient with Hirschsprung’s disease. Note the absence of 

neurons and the increase in thick knotted nerve fibers in 

the muscularis mucosae and lamina propria. In addition, 

hypertrophied nerve trunks are visible in the submucosa. 

to the lack of intrinsic nerve cell bodies with 

which they can synapse. There is evidence that the 

obstruction can be explained on the ground of loss 

of NANC nerves, especially vasoactive intestinal 

polypeptide (VIP)-storing nerves, and an increase 

in sympathetic nerves containing neuropeptide 

Y. 20 Neuropeptide Y exerts strong contractile 

effects on the rectum. 21 These effects, together 

with the loss of VIP, are a more convincing expla- 


nation for the loss of peristaltic activity and the 

contracted segment in Hirschsprung’s disease. 


Treatment of Hirschsprung’s disease consists of 

resecting the aganglionic segment of the rectum 

and colon, pulling down normally innervated 

bowel and anastomosing this bowel at the anorectal 

region, while preserving the sphincter muscle. 

The past decade has seen an evolution in the surgical 

management of Hirschsprung’s disease. The 

previous gold standard of two- or three-stage pullthrough 

with a preliminary stoma has slowly been 

replaced by a one-stage approach in many 

centers. 22–24 More recently, minimally invasive 

approaches to the one-stage pull-through have 

become popular. These consist of pull-throughs 

utilizing laparoscopic abdominal and pelvic mobilization 

of the rectum and the transanal Soave 

procedure, which does not include any intraabdominal 

dissection. 25–30 The one-stage approach, 

either by laparotomy or by combined 

laparoscopy and transanal dissection, has been 

advocated even in the newborn period. 

The results of the one-stage approach in small 

infants appear to be at least as favorable as those in 

which a staged procedure with a colostomy was 

used. Recently, the use of the one-stage definitive 

procedure for small infants with Hirschsprung’s 

disease has increased. One-stage pull-through 

procedures using laparoscopy appear to be associated 

with shorter hospital stays, shorter time until 

full feeding is reached and superior cosmetic 

results. 31–32 

Follow-up 

Some patients with Hirschsprung’s disease 

continue to have problems postoperatively; this 

may be because of residual disease or association 

with neuronal dysplasia. Investigations include 

barium studies to delineate strictures or leaks, and 

further biopsy to exclude residual aganglionic 

bowel. If the definitive operation fails because of 

an impassable stricture, disruption or residual 

disease, further secondary surgery may be necessary 

and a different operation may then lead to an 

acceptable result.

264 



Data are accumulating to indicate that 

Hirschsprung’s disease, a disorder once known 

exclusively to involve an aganglionic segment of 

distal colon, also affects motor function in other 

parts of the gut. The variability in manifestations 

could reflect the heterogeneity of basic genetic 

defects now recognized as being responsible for 

the phenotypic expression of Hirschsprung’s 

disease. Abnormalities in esophageal motility are 

common, and duodenal motor dysfunction is 

present in 48% of patients. 5 

Miele et al have reported a systematic study of 

various aspects of gastrointestinal motor function 

in children with Hirschsprung’s disease long after 

removal of the aganglionic colonic segment, 

observing gastrointestinal symptoms, including 

vomiting, distension and poor growth, long after 

surgery. 33 Abnormalities in duodenal motor activity 

have also been observed in these children 

shortly after operation. 34 

Intestinal neuronal dysplasia 

Intestinal neuronal dysplasia (IND) or hyperganglionosis, 

a condition that clinically resembles 

Hirschsprung’s disease, was first described by 

Meier-Ruge in 1971. 7 It is often associated with 

Hirschsprung’s disease and may cause failure of 

clinical improvement after resectional pullthrough 

surgery. In 1983, Fadda et al classified IND 

into two clinically and histologically distinguished 

subtypes, called types A and B. Type A occurs in 

less than 5% of cases and is characterized by 

congenital aplasia or hypoplasia of the sympathetic 

innervation, presenting acutely in the 

neonatal period with episodes of intestinal 

obstruction, diarrhea and bloody stools. Type B is 

clinically indistinguishable from Hirschsprung’s 

disease: it is characterized by a malformation of 

the parasympathetic submucous plexus, and 

accounts for more than 95% of cases of isolated 

IND. 35 

The incidence of isolated IND varies from 0.3 to 

40% of all suction rectal biopsies. 36 The incidence 

varies considerably among different countries; 

some investigators have reported that 25–35% of 

patients with Hirschsprung’s disease have associ- 

ated IND. 35,37 However, others have rarely encountered 

IND in association with Hirschsprung’s 

disease. 38 Part of this discrepancy may be due to 

the persisting confusion over the essential diagnostic 

criteria. 

For a long time, IND has been diagnosed on the 

basis of four histological criteria applied to acetylcholinesterase-stained 

suction rectal biopsies. In 

1991, on the recommendations of a working party 

(the Consensus of German Pathologists), Borchard 

et al published diagnostic criteria for IND using a 

suction rectal biopsy specimen. These comprised 

two obligatory criteria: hyperplasia of the submucosal 

plexus and an increase in acetylcholinesterase-positive 

nerve fibers in the adventitia 

around submucosal blood vessels. Two 

additional criteria might be used: neuronal heterotopia 

and increased acetylcholinesterase-positive 

nerve fibers in the lamina propria. 39 However, 

concern has been expressed about whether intestinal 

neuronal dysplasia can be safely diagnosed by 

mucosal and submucosal alterations alone, 

without myenteric plexus abnormalities. 

Submucosal hyperganglionosis may reflect a 

normal age-related phenomenon due to immaturity, 

with clinical and histochemical normalization 

after the first year of life. Furthermore, it has been 

reported that most of the patients with submucosal 

IND have a spontaneous clinical improvement, 

which is sometimes associated with histological 

normalization. 40,41 

To date, submucosal intestinal neuronal dysplasia 

has been reported in several disorders such as 

intestinal malformations, meconium plug 

syndrome, cystic fibrosis, gastroschisis, pyloric 

stenosis and inflammatory processes involving the 

gut. The high frequency of histological ‘abnormalities’ 

in young infants may represent a normal 

variant of postnatal development rather than a 

pathological process. Investigations using more 

refined and morphometric methods in rectal specimens 

from infants and children without bowel 

disease are needed to define the normal range for 

different ages. 41 

Patients with IND have been subjected to multiple 

types of treatment; however, the majority of 

patients with IND can be treated conservatively. If 

bowel symptoms persist after at least 6 months of 

conservative treatment, internal sphincter myectomy 

should be considered. The rapid acetyl-

cholinesterase technique has been found to be of 

great value in determining the extent of IND intraoperatively. 

42 

Genetic aspects 

Hirschsprung’s disease 

HSCR occurs as an isolated trait in 70% of 

patients, and is associated with chromosomal 

abnormality in 12% of cases, trisomy 21 being by 

far the most frequent (>90%). Additional congenital 

anomalies are found in 18% of cases, and 

include gastrointestinal malformation, cleft palate, 

polydactyly, cardiac septal defects and craniofacial 

anomalies. The higher rate of associated anomalies 

in familial cases than in isolated cases (39% vs. 

21%) strongly suggests syndromes with Mendelian 

inheritance. 43 Isolated HSCR appears to be a multifactorial 

malformation with low, sex-dependent 

penetrance, variable expression according to the 

length of the aganglionic segment, and a suggestion 

of involvement of one or more gene(s) with 

low penetrance. 44 These parameters must be taken 

into account for accurate evaluation of the recurrence 

risk in relatives. Segregation analyses 

suggested an oligogenic mode of inheritance in 

isolated HSCR. With a relative risk as high as 200, 

HSCR is an excellent model for the approach to 

common multifactorial diseases. 

A large number of chromosomal anomalies have 

been described in HSCR patients. Free trisomy 21 

(Down’s syndrome) is by far the most frequent, 

involving 2–10% of ascertained HSCR cases. 

Syndromes associated with HSCR can be classified 

as: pleiotropic neurocristopathies; syndromes with 

HSCR as a mandatory feature; and occasional association 

with recognizable syndromes. The neural 

crest is a transient and multipotent embryonic 

structure that gives rise to neuronal, endocrine and 

paraendocrine, craniofacial, conotruncal heart and 

pigmentary tissues. Neurocristopathies encompass 

tumors, malformations and single or multifocal 

abnormalities of the tissues mentioned above in 

various combinations. Multiple endocrine neoplasia 

type 2 (MEN 2) and Waardenburg syndrome are 

the most frequent neurocristopathies associated 

with HSCR. 45 

Waardenburg syndrome, an autosomal dominant 

condition, is by far the most frequent condition 

Genetic aspects 265 

combining pigmentary anomalies and sensorineural 

deafness, resulting from the absence of 

melanocytes of the skin and the stria vascularis of 

the cochlea. The combination of HSCR with 

Waardenburg syndrome defines the WS4 type 

(Shah–Waardenburg syndrome). Indeed, homozygous 

mutations of the endothelin pathway and 

heterozygous SOX10 mutations have been identified 

in WS4 patients with central nervous system 

involvement including seizures, ataxia and 

demyelinating peripheral and central neuropathies. 

46 

A wide spectrum of additional isolated anomalies 

have been described among HSCR cases with an 

incidence of sporadic types varying from 5 to 

30%. 47,48 No constant pattern is observed. These 

anomalies include distal limb, sensorineural, skin, 

gastrointestinal, central nervous system, genital, 

kidney and cardiac malformations, and facial 

dysmorphic features. 

These data highlight the importance of a careful 

assessment by a clinician trained in dysmorphology 

for all newborns diagnosed with HSCR. 

Skeletal X-ray and cardiac and urogenital echographic 

survey should be systematically performed. 

The observation of one additional 

anomaly to HSCR should prompt chromosomal 

studies. 

Molecular genetics 

Eight genes are known to be involved in HSCR in 

humans, namely the proto-oncogene RET (RET), 

glial cell line-derived neurotrophic factor (GDNF), 

neurturin (NTN), endothelin B receptor (EDNRB), 

endothelin 3 (EDN3), endothelin converting 

enzyme 1 (ECE1), SOX10 and SIP1 genes. RET and 

EDNRB signaling pathways were considered 

biochemically independent. However, an HSCR 

patient heterozygous for weak hypomorphic mutations 

in both RET and EDNRB has recently been 

reported. 49 Each mutation was inherited from a 

healthy parent. Sox10, otherwise, is involved in 

cell lineage determination and could be responsible 

of the reduced expression of EDNRB in the 

dom mouse. 

The RET signaling pathway 

The first observation was about an interstitial deletion 

of chromosome 10q11.2 in patients with TCA

266 


and mental retardation. 50 The proto-oncogene RET, 

identified as disease-causing in MEN 2 and 

mapping to 10q11.2, was regarded as a good candidate 

gene, owing to the concurrence of MEN 2A 

and HSCR in some families and the expression in 

neural crest-derived cells. Consequently, RET gene 

mutations were identified in HSCR patients. 51 

Expression and penetrance of a RET mutation is 

variable and sex dependent within HSCR families 

(72% males and 51% females). Over 80 mutations 

have been identified including large deletions 

encompassing the RET gene, microdeletions and 

insertions, nonsense, missense and splicing mutations. 

52,53 Haploinsufficiency is the most likely 

mechanism for HSCR mutations. Biochemical 

studies showed variable consequences of some 

HSCR mutations (misfolding, failure to transport 

the protein to the cell surface, abolished biological 

activity). 

Despite extensive mutation screening, a RET mutation 

is identified in only 50% of familial and 

15–20% of sporadic HSCR cases. 54 However, most 

families, with a few exceptions, are compatible 

with linkage at the RET locus. 55 

Mutations in the RET ligand, such as GDNF, 

GFRA1-4, NTN, persephin (PSPN) and artemin 

(ARTN), may occur, but are not sufficient to lead to 

HSCR. 

The endothelin signaling pathway 

A susceptibility locus for HSCR in 13q22 was 

suggested for three main reasons: a significant lod 

score at 13q22 in a large inbred Old Order 

Mennonite community with multiple cases of 

HSCR; de novo interstitial deletion of 13q22 in 

several patients with HSCR; and synteny between 

the murine locus for piebald-lethal, a model of 

aganglionosis, and 13q22 in humans. Subsequently, 

an EDNRB missense mutation was identified 

in the Mennonite kindred. 56,57 Both EDNRB 

and EDN3 were screened in a large series of 

isolated HSCR patients, and EDNRB mutations 

were identified in approximately 5% of the 

patients. It is worth mentioning that the penetrance 

of EDN3 and EDNRB heterozygous mutations 

was incomplete in those HSCR patients, de novo 

mutations have not hitherto been observed and 

short HSCR (S-HSCR) is largely predominant. 58 

SOX10 

The last de novo mouse model for WS4 in humans 

is dominant megalon (Dom). The Dom gene is 

SOX10, a member of the sex-determining factor 

(SRY)-like, high mobility group (HMG) DNA 

binding proteins. Subsequently, heterozygous 

SOX10 mutations have been identified in familial 

and isolated patients with WS4 (including de novo 

mutation) with high penetrance. 59 


Studies have been performed to investigate the 

potential role of HSCR-associated RET, GDNF, 

EDNRB and EDN3 genes in the development of 

IND. They demonstrated that only three RET 

mutation were detected in patients with HSCR, no 

mutation in this gene was observed in IND and 

mixed HSCR/IND patients, HSCR and HSCR/IND 

patients showed over-representation of a specific 

RET polymorphism in exon 2, while IND patients 

exhibited a significantly lower frequency of the 

same polymorphism comparable with that of 

controls. These findings may suggest that IND is 

genetically different from HSCR. 

A homozygous mutation of the EDNRB gene in spotting 

lethal (sl/sl) rats leads to the HSCR phenotype 

with long segmented aganglionosis. The heterozygous 

(+/sl) EDNRB-deficient rats revealed more 

subtle abnormalities of the enteric nervous system: 

the submucous plexus was characterized by a significantly 

increased ganglionic size and density, and 

the presence of hypertrophied nerve fiber strands, 

resembling the histopathological criteria for IND. 

Other animal models, such as Ncx/Hox11L.1-deficient 

mice, suggest that many other genes could be 

involved in the pathogenesis of IND. 60

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48 Auricchio A, Griseri P, Carpentieri ML et al. Double 

heterozygosity for a RET substitution interfering with 

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Hirschsprung disease. Am J Hum Genet 1999; 64: 

1216–1221. 

49. Martucciello G, Biocchini M, Dodero P et al. Total 

colonic aganglionosis associated with interstitial 

deletion of the long arm of chromosome 10. Pediatr Surg 

Int 1992; 7: 308. 

50. Edery P, Lyonnet S, Mulligan LM et al. Mutations of the 

RET proto-oncogene in Hirschsprung’s disease. Nature 

1994; 367: 378–380. 

51. Angrist M, Bolk S, Thiel B et al. Mutation analysis of 

the RET receptor tyrosine kinase in Hirschsprung 

disease. Hum Mol Genet 1995; 4: 821–830. 

52. Seri M, Yin L, Barone V et al. Frequency of RET 

mutations in long- and short-segment Hirschsprung 

disease. Hum Mutat 1997; 9: 243–249. 

53. Attie T, Pelet A, Edery P et al. Diversity of RET protooncogene 

mutations in familial and sporadic 

Hirschsprung disease. Hum Mol Genet 1995; 4: 

1381–1386. 

54. Bolk S, Pelet A, Hofstra RM et al. A human model for 

multigenic inheritance: phenotypic expression in 

Hirschsprung disease requires both the RET gene and a 

new 9q31 locus. Proc Natl Acad Sci USA 2000; 97: 

268–273. 

55. Borrego S, Ruiz A, Saez ME et al. RET genotypes 

comprising specific haplotypes of polymorphic variants 

predispose to isolated Hirschsprung disease. J Med 

Genet 2000; 37: 572–578. 

56. Kiss P, Orsztovics M. Association of 13q deletion and 

Hirschsprung’s disease. J Med Genet 1989; 26: 793–794. 

57. Puffenberger EG, Hosoda K, Washington SS et al. A 

missense mutation of endothelin-B receptor gene in 

multigenic Hirschsprung’s disease. Cell 1994; 30: 

1257–1266. 

58. Auricchio A, Casari G, Staiano A, Ballabio A. 

Endothelin-B receptor mutations in patients with 

isolated Hirschsprung disease from a non-inbred 

population. Hum Mol Genet 1996; 5: 351–354. 

59. Southard-Smith EM, Angrist M, Eleison JS et al. The 

Sox10 (Dom) mouse: modeling the genetic variation of 

Waardenburg–Shah (WS4) syndrome. Genom Res 1999; 

9: 215–225. 

60. Yamataka A, Datano M, Kobayashi H et al. Intestinal 

neuronal displasia-like pathology in Ncx/Hox11L.1 

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Additional educational resources 

www.1uphealth.com/health/hirschsprung_disease_info.htm 

www.bdid.com/cam.htm 

www.anatomy.med.unsw.edu.au/ebl/embryo/OMIM

18 

Introduction 

Chronic intestinal 

pseudo-obstruction in 

childhood 

Peter J Milla 

Chronic intestinal pseudo-obstruction (CIP) is a 

clinical syndrome characterized by signs of intestinal 

obstruction without mechanical occlusion of 

the gut. A number of other names have been used 

to described the disorder, including adynamic 

bowel, Hirschsprung’s disease, megacystis, microcolon 

hypoperistalsis syndrome, visceral neuropathies 

and visceral myopathies. Initially, it was 

thought that CIP was a single disease entity 

without clearly defined pathology. Over the past 

20 years, however, numerous reports have 

appeared which show that this is not the case. 1–4 

CIP is a heterogeneous disorder associated with a 

wide variety of pathologies, some intrinsic to the 

gut, others multisystem disorders involving the gut 

or altering the environment within which the gut 

operates. The conditions cause disordered intestinal 

motor activity and may present acutely or 

chronically. The most common forms of pseudoobstruction 

are acute in nature and occur as postoperative 

ileus or the ileus that is associated with 

electrolyte imbalance and metabolic disorder. 

Acute pseudo-obstruction episodes have also been 

reported in association with food-sensitive intestinal 

disease such as celiac disease and cow’s milk 

protein intolerance, together with drugs such as 

vincristine. CIP was originally thought to involve 

only the small intestine, but it is now realized that 

it may be restricted to one region of the gut, such 

as in achalasia or Hirschsprung’s disease, or it may 

be present diffusely throughout the gastrointestinal 

tract. 


A child may present with either the primary or the 

secondary effects of the underlying disease. 

However, the clinical symptoms are variable and 

often non-specific. The location of the affected 

bowel, diffuse or regional, seems a more important 

determinant of the clinical presentation than 

the underlying disease. A child may be obstructed 

or complain of severe constipation depending 

upon whether the small intestine and colon or just 

the colon is affected. In addition, those with 

urinary tract involvement may initially present 

with acute or chronic urinary retention. These 

effects quite clearly are the result of the ability of 

the underlying disease of the neuromusculature of 

the gut to produce ordered motor activity. 

However, the effects of the underlying disease 

may also be secondary, such as the consequences 

of bacterial overgrowth, fecal impaction or adhesional 

obstruction associated with previous 

surgery. In neuropathic disorders the consequences 

of denervation may not only be on motor 

activity but also on secretomotor control and 

sensation. These effects may result in diarrhea or 

visceral hyperalgesia. 

Although initial reports of CIP were in adults, it is 

now apparent that it probably occurs more 

commonly in infants. Indeed, when the presentation 

and mortality of cases published in the literature 

are considered, it is found to occur most 

commonly in children, with high morbidity and 

mortality. Considering these data 5 together with a 

large series from one center, 1 the conditions in 

childhood present most commonly during infancy, 

either in the neonatal period, or under the age of 1 

year, during which time the highest mortality rates 

are suffered. In most cases an underlying abnormality 

of either smooth muscle or of enteric nerves 

is found when adequately sought. The clinical 

manifestation at presentation depends on both age 

and the type and extent of the condition affecting 

the neuromusculature of the gut. 

269

270 

Chronic intestinal pseudo-obstruction in childhood 

Before birth 

CIP may first be recognized before birth, either as 

part of a routine antenatal ultrasound scan or in 

the investigation of a mother with polyhydramnios. 

On abdominal ultrasound examination the 

fetus may have either dilated loops of bowel or a 

distended bladder, or both. 

Birth and the neonatal period 

The majority of children with CIP present either at 

birth or in the neonatal period. 1 In all series 

approximately half the infants have symptoms at 

birth or within the first few days of life. In those 

who present at birth, the labor and delivery are 

frequently difficult, owing to an already distended 

abdomen. After birth there is abdominal distension, 

failure to pass meconium and bilious 

vomiting. The abdominal distension is due to 

swallowed air, which distends and dilates the 

small bowel, but is not passed further through the 

gut. Contrast studies may show the presence of a 

microcolon or a short small intestine or, in approximately 

34%, a malrotation. In some there may be 

a specific clinical syndrome of a congenitally short 

small intestine, pyloric stenosis and a malrotation. 

6,7 In addition to gastrointestinal symptoms, 

there may also be failure to pass urine, megacystis 

and hydroureter or hydronephrosis. 

Incomplete bladder emptying often results in 

recurrent urinary tract infection, and this may 

completely overshadow the gastrointestinal 

symptoms. 

Later infancy 

After the neonatal period, although infants may 

present with an acute obstruction, the symptoms 

are often intermittent or slowly progressive. 

Initially some infants may appear completely 

healthy, taking breast feeds normally, but then 

suddenly develop an episode of obstruction 

following what appears to be an intercurrent 

enteric infection. In these infants persistence of 

vomiting for more than 7 days warrants further 

investigation in a patient who has been thought to 

have had acute gastroenteritis, as they may have 

developed an acute myositis, which is potentially 

treatable. 8 In other such infants, who have fed 

normally from birth, episodes of obstruction begin 

only when more complex foods are introduced 

into the diet and attempts are made at weaning. 

Urinary symptoms due to involvement of the 

urinary tract may continue to present for the first 

time during infancy. 

Childhood 

In later childhood the initial presentation may 

continue to indicate obstruction, but may simply 

be constipation, which becomes intractable. 

Severe abdominal pain may also occur, owing to 

distension of the bowel or as part of visceral hyperalgesia. 

In those with a distended abdomen, bowel 

sounds may be totally absent or very markedly 

reduced. If high-pitched bowel sounds are present, 

or if there is visible peristalsis, the distension of 

the gut is more likely to be secondary to a mechanical 

rather than a functional obstruction. 

Investigation 

In order to understand the pseudo-obstructive 

disorder and plan rational treatment, there are 

three steps in diagnosis: definition of the presence 

of functional obstruction. definition of the areas 

involved and the physiology of the affected areas; 

and delineating the disease process causing the 

functional obstruction. 

CIP is due to disordered motor activity, and this 

results from disturbance of the control mechanisms 

of motor activity and disease of the smooth 

muscle coats. This may occur as a consequence of 

primary disease of the gut motor apparatus or 

because of involvement of the neuromusculature 

of the gut secondary to disease, which either 

affects the gut as part of a multisystem disease or 

is primarily elsewhere. It is useful to consider that 

the obstruction may be caused at different levels of 

control of gut motor activity: the end-organ smooth 

muscle; the enteric nervous system; the humoral 

environment provided by gut endocrine cells 

or immunocytes; or the extrinsic innervation. 

Disruption at one or all of these levels results in 

the lack of effective co-ordinated propulsive 

movement. Initial investigations were designed to 

demonstrate this.

Radiology and transit studies 

Plain abdominal X-rays and abdominal ultrasound 

examinations may show the presence of large 

distended loops of gut, but it is difficult using such 

studies to define the area of the gut involved. 

Conventional contrast radiography will delineate 

anatomical abnormalities and together with 

studies by radioisotope and computed tomography 

(CT) scanning, may provide a measure of transit 

time and/or demonstrate disordered peristalsis. 

Limited descriptions of transit can be obtained 

using breath hydrogen or radio-opaque pellets and 

plain abdominal X-ray for whole bowel transit 

times. All of these methods provide a limited 

description of the disease but no clues to the 

nature of the disorder. 

Surface electrogastrography 

Electrogastrography (EGG) is defined as the 

recording of myoelectric activity of the smooth 

muscle of the stomach by means of electrodes 

attached to the abdominal skin surface. EGG was 

first devised by Alvarez in the 1920s using 

mechanical means of recording from a string 

galvanometer. The advent of powerful personal 

computers and the development of signal processing 

algorithms has allowed such data to be objectively 

analyzed. A great advantage of the methodology 

is that it is non-invasive and readily detects 

disturbance of gastric antral slow waves and, by 

suitable positioning, duodenal slow waves. This 

method has been used in patients with diffuse CIP 

to detect abnormal myoelectric activity. Persistent 

entral dysrhythmias have been found in the fasting 

state in both myopathic and neuropathic disorders. 

9 

Manometry 

Motor activity may be studied by measurement of 

intraluminal pressure changes and known 

manometry. This is helpful in delineating both the 

extent of the disordered motility and possibly the 

disease processes causing the disorder. In patients 

with suspected functional obstruction at least 

three areas of the gastrointestinal tract should be 

studied: the esophagus, the upper small intestine 

and the left colon, as the disease process may not 

Investigation 271 

be restricted to any one of these areas. In these 

areas swallow-induced peristalsis, fasting small 

intestinal motor activity and the gastrocolonic 

response to food or the induction of highamplitude 

propagated contraction by bisacodyl 

can be used as tests of the integrity of the enteric 

nervous system and of the contractile activity of 

the smooth muscle. 

Esophagus 

Swallow-induced peristalsis and the associated 

relaxation of the lower esophageal sphincter can 

be studied using a Dent sleeve assembly modified 

for use in infants or young children. 10 Particular 

attention should be paid to the nature of the 

primary peristaltic sequence and whether 

secondary peristalsis occurs in response to reflux. 

The presence of tertiary contractions and the 

amplitude and form of the contractile waves 

should also be noted, as should the behavior of the 

lower esophageal sphincter. 

Small intestine 

Most studies of intestinal motor activity in children 

with CIP have utilized small intestinal 

manometry. The cyclical nature of fasting small 

intestinal motor activity is determined by the 

inherent activity of the enteric nervous system. 

This intrinsic property can be used to test the 

integrity of the enteric nervous system and 

whether extrinsic nervous modulation is present. 

Disruption of fasting activity and the establishment 

of postprandial activity results from the 

humorally mediated responses to food and clarifies 

whether enteroenteric responses are intact. In 

addition, these responses can be further tested by 

utilizing the motilin agonists erythromycin and 

somatostatin. The algorithm that the author uses to 

test motor functioning in pseudo-obstruction is 

shown in Figure 18.1. Some studies have shown 

that myopathic processes produce low-amplitude 

poorly propagated contractions5,11 whereas neuropathic 

processes are associated with contractions 

of normal amplitude which are bizarre in wave 

form, abnormally propagated and, in phase 3 activity 

ill formed. 11,12 In addition, clustered phasic 

activity in phase 2 is often present. Disturbance of 

the neuroendocrine environment can also be 

shown where there are changes in frequency of

272 


Radiology 

Transit study 

Rectal suction biopsy 

Electrogastrography 

Antroduodenal manometry 

+ve 

+ve 

Figure 18.1 Investigation of intestinal pseudo-obstruction. 

slow-wave activity and in frequency of phase 3 

contractions. In conditions where there is 

increased secretion of catecholamines such as 

hyperthyroidism, ganglioneuroma and pheochromocytoma 

there is increased frequency of slowwave 

rhythm; in preterm infants and hypothyroidism, 

there is decreased slow-wave 

frequency. 

Colon 

It is often useful to record simultaneously leftsided 

colonic motor activity and post-prandial 

small intestinal motility as a feed will also induce 

increased rectosigmoid contractions. In addition, 

the response of the descending colon to bisacodyl 

Plain abdominal X-ray 

Contrast study 

Hirschsprung's disease surgery 

Ileostomy and 

histology 

Antroduodenal manometry 

-ve 

Radio-opaque pellet transit study 

Rectal biopsy 

Full thickness 

-ve +ve 

Colonic Ileostomy 

manometry or colostomy 

Ileostomy and histology 

in inducing a high-amplitude propagated contraction 

can be demonstrated, and also whether this 

propagated contraction halts in the sigmoid colon. 

Thus, information regarding smooth muscle, local 

enteric nerves and those involved in the gastrocolonic 

response and colocolonic reflexes can be 

obtained. 13 

Etiology 

The disease processes, which result in CIP, affect 

the control mechanisms of intestinal motility. The 

disorders and disease may primarily be of the 

intrinsic enteric nerves with or without involvement 

of the extrinsic autonomic nerves, the

smooth muscle cells themselves or of the tumoral 

and endocrine environment. Good examples of the 

effect of disturbance of the endocrine environment 

are the ileus associated with vasoactive intestinal 

polypeptide-secreting tumors such as ganglioneuromas, 

and the constipation caused by 

hypothyroidism. These conditions will not be 

considered further here. A variety of diseases and 

drugs, which are listed in Table 18.1, may secondarily 

cause CIP. Such secondary disorders are 

much more common in adult life than in childhood. 

Primary disease of the gut neuromusculature 

may be due to disease of the enteric nerves or 

the smooth muscle cells or, at least theoretically, of 

the interstitial cells of Cajal. Surprisingly, there are 

virtually no descriptions of the primary pathology 

of interstitial cells of Cajal, which is said to occur 

in piebaldism, but there have been descriptions of 

alterations of these cells in hypertrophic pyloric 

stenosis and Hirschsprung’s disease. 14,15 Definite 

diagnosis of neuromuscular disease requires 

careful study of the full thickness of the gastrointestinal 

wall in optimally orientated pieces of gut. 

Table 18.1 Miscellaneous conditions 

causing intestinal pseudo-obstruction 

Endocrine disorders 

Hypothyroidism 

Hypoparathyroidism 

Pheochromocytoma 

Carcinoid 

Ganglioneuroblastoma/neuroma 

Metabolic disorders 

Uremia 

Porphyria 

Amyloidosis 

Drugs 

Antidepressants and anti-anxiety drugs 

Anticholinergic agents 

Opiates 

Anticonvulsive cytotoxic drugs 

Toxic agents 

Alcohol in fetal alcohol syndrome 

Irradiation 

Etiology 273 

It is best carried out in centers that have experience 

of both the disease and the histopathological 

techniques required. 

Primary visceral myopathies 

Primary disorders of the intestinal smooth muscle 

coats may represent abnormalities in morphogenesis 

or intrinsic myocyte defects. 4 Abnormalities of 

morphogenesis of the muscle coats may result in 

the presence of an additional muscle coat or the 

absence of a muscle layer. This may occur 

diffusely throughout the gut or may only involve 

only a segment of the gut. Clinically, primary 

visceral myopathies occur as either familial 

genetic diseases with a defined mode of inheritance 

or, more often, as sporadic cases. Three types 

of familial visceral myopathy have been described 

in adults, which all initially presented in the 

second decade and should therefore be considered 

when symptoms begin during adolescence. 

Familial visceral myopathy with diffuse 

abnormal muscle layering 

This condition usually presents at birth, or shortly 

after, with functional obstruction. Investigation 

shows the presence of a short gut and a mid-gut 

malrotation. Three related males have been 

described with this condition (the index case, his 

half brother from the same mother, and his maternal 

uncle), suggesting an X-linked mode of inheritance. 

4,6 The most striking histological finding was 

an extra circular muscle layer with the myenteric 

enteric plexus embedded within it. None of the 

patients tolerated enteral feeding, all required 

long-term parenteral nutrition and all died with 

septic complications of parenteral nutrition. One 

further sporadic case has since been described, 

also in a male child, aged 5 years, who has done 

well since birth with a decompression ileostomy 

and mixed enteral and parenteral nutrition. 

Infantile visceral myopathy 

Most cases occur sporadically but some families 

have been described with either a dominant gene 

with variable expressivity or autosomal recessive 

mode of inheritance. Most affected children 

develop symptoms at birth or within the first year

274 


of life often with severe constipation and 

abdominal distension. Failure to thrive and malnutrition 

are common. When recurrent episodes of 

functional obstruction occur, long-term parenteral 

nutrition is necessary. Usually the entire gastrointestinal 

tract is affected, and almost all patients 

have involvement of the urinary tract with megaureter 

and megacystis. 

Smith and Milla, 4 studying 27 patients with 

smooth muscle disease, identified five histological 

phenotypes in full-thickness biopsies from such 

children using routine microscopy, histochemistry, 

immunocytochemistry (with monoclonal antibodies 

against different neural and smooth muscle 

markers) and electron microscopy. In two of the 27 

patients, a severe myositis was found. This is 

considered separately. Twenty-five had a primary 

myopathic disorder which, on routine microscopy 

of paraffin sections of the smooth muscle, was 

abnormal in only 15. In the remaining patients 

myopathic changes would have been missed 

without application of other techniques, particularly 

electron microscopy. 

These authors, like others, found the presence of 

gross fibrosis of the muscle layers and profound 

atrophy of the smooth muscle cells similar to that 

seen in adults with familial and sporadic forms of 

visceral myopathy. They were able to relate these 

changes to intrinsic myocyte defects or changes in 

the extracellular matrix. A myopathy with 

increased autophagic activity could sometimes be 

detected using histochemistry with increased acid 

phosphatase activity in the smooth muscle cells 

due to active lysozymes. However, but often electron 

microscopy was required, as the condition 

appeared to be active only in the central portions 

of the smooth muscle cells. A further and distinct 

myopathic subtype was found where there was a 

so-called pink blush in the circular muscle layer 

with nuclear crowding, possibly due to a disorganization 

of the muscle cells. On electron 

microscopy, the smooth muscle cells appeared to 

be separated from each other by material secreted 

either by the muscle cells themselves or the extracellular 

matrix. In patients with diffuse disease the 

prognosis is poor, with about 40% of them dying 

during childhood from the complications of 

malnutrition or long-term parenteral nutrition. 1 

Those who tolerate some oral feeding generally 

survive into adult life. 

Megacystis microcolon hypoperistalsis 

syndrome 

This condition causes severe CIP and affects 

predominantly female infants. 5,16 Most cases 

present antenatally. Ultrasound scans show the 

presence of megacystis hydronephrosis and 

distended bowel. In addition, the proximal small 

bowel is often short and there is a malrotated midgut 

with microcolon located entirely on the left 

side of the abdomen. The myopathy causing the 

problem appears to be a degenerative condition of 

smooth muscle cells. Whilst most cases are 

sporadic, others appear to have been inherited in 

an autosomal recessive mode. 

After birth, the affected infants develop massive 

abdominal distension, which is partly due to 

distended bowel and partly due to a distended 

bladder. Patients require a decompression 

ileostomy and either a vesicostomy or frequent 

catheterization to ensure that the urinary tract is 

decompressed. Almost all children require longterm 

parenteral nutrition for survival and, if this 

becomes problematic, small intestinal transplantation. 

Megacystis microcolon hypoperistalsis 

syndrome must be differentiated from prune belly 

syndrome, which is due to early intrauterine 

urethral obstruction and affects predominantly 

male infants. They present with a dilated 

abdomen, constipation, megacystis and hydronephrosis. 

Sometimes there is an intestinal malrotation 

present, but there is no hypoperistalsis and 

no microcolon. 

Familial visceral myopathies types 1, 2 and 3 

These conditions usually present in later childhood 

and have a number of distinctive features. 

Familial visceral myopathy type 1 presents as a 

megaduodenum and is inherited as an autosomal 

dominant trait with a female predominance in 

frequency and severity. 17 The disease is characterized 

by foregut functional obstruction, although 

gastric emptying is often normal, and an elongated, 

redundant, usually dilated colon. Barium 

studies show an aperistaltic esophagus, sometimes 

normal gastric emptying but a flaccid and dilated 

duodenum with prolonged retention of barium. 

The bladder is affected in about half the cases, but 

is often asymptomatic. 17 Schuffler and Pope

showed that there was marked thinning of muscle 

coats and degeneration with vacuolation of smooth 

muscle cells and replacement by fibrous tissue. 18 

Some patients appear to be more mildly affected 

than others, and merely require dietary modification 

with either a low-fat, low-fiber, low-lactose 

diet or enteral feeding, together with the intermittent 

use of antibiotics to treat bacterial overgrowth. 

In patients with more severe disease surgical 

decompression of the foregut into the normal 

jejunum appears to be effective. 19 

Familial visceral myopathy type 2 is quite distinct 

and was first reported as oculogastrointestinal 

muscular dystrophy. Recently the mitochondrialdisease 

nature of the condition has resulted in it 

being renamed mitochondrial neurogastrointestinal 

encephalomyopathy. 20 It is inherited as an 

autosomal recessive trait and presents with external 

ophthalmoplegia with ptosis and diplopia, a 

cardiac conduction defect, mild muscular atrophy 

and dilatation of the entire gastrointestinal tract 

with scattered small-bowel diverticulae. Gastrointestinal 

symptoms with dyspepsia, retrosternal 

chest pain and weight loss may start during 

teenage years. In skeletal muscle biopsies a deficiency 

of cytochrome C oxidase has been demonstrated 

which results in the ragged red fibers 

typical of mitochondrial myopathies. Examination 

of the smooth muscle of the gut shows the presence 

of fibrosis and degeneration with vacuolation 

of the smooth muscle cells. Most patients have 

eventually required total parenteral nutrition. 

Familial visceral myopathy type 3 is much less 

well understood. The data are from of one family 

in which there were four siblings who presented 

with dilatation of the entire gastrointestinal tract. 

The condition appeared to be inherited in an autosomal 

recessive fashion. 21 

Systemic disorders involving 

intestinal smooth muscle 

Until recently the majority of myopathies involving 

multisystem disorders have been described in 

adults, but in whom the disease process has been 

in place for a number of years resulting in obvious 

damage to the intestinal smooth muscle coats, 

mostly with increased fibrosis. With modern physiological 

recording methods and histological 

Systemic disorders involving intestinal smooth muscle 275 

techniques available in young children, myopathies 

associated with systemic disorders have 

been increasingly recognized. It is important to 

identify these conditions, as medical treatment 

may be available for them which can result in 

symptomatic improvement and even prevention of 

progression of the disease process, if it is put in 

place before fibrosis of the muscle coat has 

occurred. 

Connective tissues disorders 

Scleroderma, systemic lupus erythematosus and 

even dermatomyositis may all affect the muscle 

coats of the bowel. However, the best understood 

of these is scleroderma, a systemic disease characterized 

by the excessive deposition of collagen by 

fibroblasts in the skin and in many internal organs. 

It is associated with prominent and often severe 

alteration of the microvasculature, the autonomic 

nervous system and the immune system. 22 

Gastrointestinal involvement with symptoms of 

clinical relevance occur in approximately 50% of 

patients with the systemic form of scleroderma. 

The esophagus is the most commonly affected part 

of the gastrointestinal tract, followed by the 

rectum and then the small intestine. The lesions of 

the muscle coat are similar throughout the gut 

with atrophy and fragmentation of the muscle 

coats, collagen infiltration and fibrosis in a later 

stage of the disease. 

Enteric myositis 

In Crohn’s disease, infiltration of the smooth 

muscle layer with lymphocytes has been found, 

but no clue as to whether this is part of the Crohn’s 

disease or an autoimmune phenomenon. Acquired 

myositis has been described in children in a 

number of reports. Two have presented with 

functional intestinal obstruction at 1 and 2.5 years 

of age. In these patients a dense lymphocyte infiltrate 

mainly of T cells was found along the large 

and small intestine. Both responded to immunosuppressive 

treatment. A further child with similar 

histological findings but in whom there was clear 

evidence of an autoimmune process has more 

recently been described. 8 In this patient features 

were noted that suggested that the intestinal 

muscle cells themselves were taking part in the

276 


inflammatory response. The patient responded to 

prednisolone, azathioprine and cyclophosphamide, 

but was dependent upon steroids. 

A similar inflammatory cell infiltrate was described 

in 12 of 27 Bantu children from South Africa who 

had some sporadic form of an acquired degenerative 

enteric myopathy (V.V. Smith, personal communication). 

However, no information was given as to 

whether the children suffered from other autoimmune 

diseases or had autoantibodies present. Nor 

was there information about response to immunosuppressive 

treatment. 

Muscular dystrophy 

Gastrointestinal involvement may occur in a 

number of forms of muscular dystrophy including 

myotome muscular dystrophy and the dystrophinopathies 

Duchenne and Becker muscular 

dystrophy. Involvement of the smooth muscle of 

the gastrointestinal tract and bladder is well 

described in myotonic muscular dystrophy, and 

seemingly motor abnormalities can be found 

throughout the whole gastrointestinal tract. 23 

Duchenne and the milder variety Becker muscular 

dystrophy are due to abnormalities of dysrophin. 24 

The predominant effects are on skeletal and 

cardiac muscle. Abnormality of particularly the 

smooth muscle of the foregut also occurs, with 

impairment of gastric emptying and disordered 

proximal small intestinal motor activity demonstrable 

on manometry. Histological studies show 

that the intestinal smooth muscle cells become 

swollen, then destroyed, and progressively 

replaced by fat. 25 

Disorders of the enteric nervous 

system 

The enteric nervous system is arranged in the form 

of two major plexuses: the myenteric plexus, 

which is located between the longitudinal and 

circular muscle layers and primarily provides 

motor innervation to the muscle coats; and the 

submucous plexus, which lies in the submucosa 

between the circular muscle layer and the muscularis 

mucosae. 26 The submucous plexus is important 

in regulating secretion by the mucosa and 

providing sensory innervation of the mucosa. As a 

whole it is a collection of neurons derived from 

neural crest cells and has been referred to as the 

‘brain of the gut’ or the ‘little brain’. Whilst there is 

a two-way flow of information between the central 

nervous system and the enteric nervous system, 

often referred to as the ‘big brain’ and ‘little brain’, 

respectively, the little brain can function independently 

of the big brain. 27 The neurons of the 

enteric nervous system are grouped into small 

ganglia that are connected by bundles of nerve 

processes forming the two major nerve plexuses. 

Ganglia consist of tightly packed neurons, terminal 

bundles of nerve fibers and glial cells, which 

usually outnumber the enteric neurons. 26 

Normally, there are between five and seven 

neurons in a ganglion. There are numerous 

interneurons between the two plexuses and within 

the plexuses. Both are connected to the central 

autonomic neural network by parasympathetic 

and sympathetic nerves. Throughout the gastrointestinal 

tract there are also non-neural cells 

derived from the mesenchyme, the interstitial cells 

of Cajal, that generate and propagate slow waves. 28 

The interstitial cells are important modulators of 

communication between nerves and muscle. The 

enteric nervous system is particularly concerned 

with the propulsion of the gut contents in an 

ordered physiologically effective fashion, and the 

control of secretion by the gut. Both quantitative 

and qualitative changes in the enteric nervous 

system have been identified and these are 

described below. 

Primary visceral neuropathies 

Primary visceral neuropathies can be subdivided 

into familial neuropathies, where a distinct pattern 

of inheritance is known, and sporadic cases, in 

which there are distinctive clinical and morphological 

findings. In this chapter, Hirschsprung’s 

disease, which is clearly a primary visceral neuropathy, 

will not be discussed. A number of neuropathic 

motility disorders, including those that 

present with slow-transit constipation, remain 

unclassified, although most frequently degenerative 

changes are found in the enteric neurons. 

Familial visceral neuropathy without extraintestinal 

manifestations 

In this disorder it is mainly the colon and distal 

small intestine that are affected, and it is inherited

as an autosomal dominant trait. 39 The age of onset 

may differ within the same family, but in general 

symptoms develop after infancy. Most patients 

present with severe slow-transit constipation associated 

with abdominal distension and colicky 

pain. In about half of the patients severe episodes 

of functional obstruction have occurred which 

have required decompression. To date, there have 

been no descriptions of any associated abnormalities, 

such as extrinsic autonomic dysfunction. Fullthickness 

biopsies of the affected parts of the 

bowel have shown evidence of degeneration, both 

on silver staining and on routine hematoxylin-andeosin 

staining. No other abnormalities have been 

observed. 

Familial visceral neuropathy with pyloric stenosis, a 

short small intestine and malrotation 

This syndrome has been described in several families. 

An extended kindred from Sicily and 

Southern Italy has shown that it is inherited as an 

X-linked recessive trait through four generations. 

Linkage analysis assigns the genetic defect to a 

locus at XQ28. To date, the gene involved has not 

been identified. Affected infant boys usually 

present with functional obstruction in the neonatal 

period and most have died during the first year 

of life. Histology of the nerve plexuses has shown 

the presence of shrunken neurons with particular 

loss of argyrophilic neurons. However, apparent 

loss of argyrophilic neurons may be a normal 

finding at this age, as the acquisition of argyrophilia 

is associated with changes in the neurofilamentous 

content of the neuron and this occurs 

progressively during the first year of life. 

Familial visceral neuropathy with neuronal 

intranuclear inclusions 

This condition may be inherited as an autosomal 

dominant trait, as it was described in three siblings 

(two female, one male) and their father. 30 The 

patients developed symptoms during childhood 

and, in addition to pseud-obstruction, suffered 

from dysphagia, diarrhea and constipation. They 

became developmentally delayed, had autonomic 

dysfunction and ataxia, and developed dementia. 

A characteristic feature of the condition is the 

presence of eosinophilic intranuclear inclusions in 

the neurons of the myenteric plexus and in the 

central nervous system. 3 In some of the patients 

Disorders of the enteric nervous system 277 

the intranuclear inclusions could be seen within 

the ganglion cells of the submucous plexus on 

suction rectal biopsy. This appears to be a progressive 

degenerative condition affecting a widespread 

class of neurons in both the enteric and the central 

nervous systems. 

Familial visceral neuropathy with neurological 

involvement 

A number of families have been described in which 

there are least two affected siblings. The condition 

is probably inherited as an autosomal recessive 

disorder. The symptoms start in early childhood, 

with neuropathic dysmotility of the gut and 

involvement of the central nervous system. The 

central nervous system disorder appears to consist 

of progressive sensory and motor peripheral 

neuropathies, ophthalmoplegia and hearing loss. 31 

It seems highly likely that this is a mitochondrial 

disorder. On full-thickness biopsy, neurons in the 

myenteric plexus appear normal on conventional 

staining, but there is evidence of degeneration of 

argyrophobic C cells. 

Familial visceral neuropathy associated with 

multiple endocrine neoplasia 

The multiple endocrine neoplasia type 2 

syndromes may be associated with involvement of 

the gastrointestinal tract. These include multiple 

endocrine neoplasia (MEN) 2A, MEN 2B and 

isolated medullary thyroid carcinoma. These 

conditions are inherited as autosomal dominant 

traits and are as a consequence of mutation of the 

gene encoding the RET tyrosine kinase receptor. It 

is extremely important in the development of the 

enteric nervous system as RET null knockout mice 

do not develop neurons within the gut. 32 There is 

now good evidence to show that RET is important 

not only for colonization of the primitive gastrointestinal 

tract by neural crest cells but also for 

their migration down the length of the gut and their 

further differentiation. In MEN 2A and isolated 

medullary thyroid carcinoma, there is an abnormality 

of the RET gene between codons 619 and 

638, the cysteine-rich region of the gene, which 

results in the development of medullary thyroid 

carcinoma with or without pheochromocytoma. In 

about 5% of patients with MEN 2A, Hirschsprung’s 

disease is also present with pheochromocytoma. 33

278 


In MEN 2B there is always involvement of the 

gastrointestinal tract, with transmural intestinal 

ganglioneuromatosis. In most patients, disorders 

of gastrointestinal motility are the first manifestations 

of the disease, but the presentation is variable 

both in severity and in time. Some patients 

present in early infancy, similarly to 

Hirschsprung’s disease, but others not until adult 

life. 34 There is nearly always colonic dysfunction 

present and the most usual presentations are 

either with chronic constipation, episodes of functional 

obstruction or as if this were Hirschsprung’s 

disease. In all the patients that the author has 

studied, evidence of medullary thyroid carcinoma 

has been present from very early on, either as 

clumps of malignant cells in situ within the 

thyroid gland or as an overt tumor. Frequently in 

those patients in whom there are only collections 

of cells in situ within the gland, screening investigations 

such as CT scanning of the thyroid and 

calcitonin determinations have not been helpful. It 

is only when there is a considerable mass of C cells 

present that the normal screening investigations 

become positive. It is for this reason, together with 

the fact that there is no satisfactory radiotherapeutic 

or chemotherapeutic treatment available, that 

prophylactic thyroidectomy is recommended. 35 

The characteristic histopathological findings are 

an increased density of nerve fibers and possibly 

ganglion cells in the submucosa and myenteric 

plexus with penetration of the hyperplastic nerve 

fibers into the mucosal area. The hyperplastic 

nerve fibers are accompanied by large ganglionic 

nodes containing numerous glial cells, with a 

normal to increased quantity of neurons. This 

abnormality of the enteric nervous system is 

present along the entire gastrointestinal tract and 

the hyperplastic neurons may be seen within the 

mouth or anal canal. 35 

Sporadic visceral neuropathies 

Neuropathic dysmotility may also be produced by 

having too few neurons within the enteric nervous 

systems (hypoganglionosis) as well too many 

(hyperganglionosis) or none at all (aganglionosis). 

The conditions that cause these states are nearly 

always congenital, although both hypoganglionosis 

and aganglionosis may result from acquired 

disorders in which there is destruction of neurons. 

As these conditions are defined by the numbers of 

neurons present, it is clear that a reliable means of 

assessing neuronal density is required. 36 Neuronal 

density is affected by the age of the patient, tissue 

freshness and intestinal dilatation as well as by the 

disease process. It is therefore important that a 

standardized technique for assessing neuronal 

density be used. A full-thickness sample of intestine 

at an appropriate site, needing to be greater 

than 1 cm in length, is required. Preferably 

neurons should be counted in sections cut longitudinally 

along the long axis of the bowel rather 

than transversely. 36 If sections are cut transversely 

they should be at least 30 µm apart to avoid counting 

each neuron more than once. There are few 

published studies, especially in children, but 

Smith reported a mean neuronal density of 

3.6 neurons/mm for the jejunum, 4.3/mm for the 

ileum and 7.7/mm for the colon, with no significant 

difference between transverse and longitudinal 

sections. 36 

Hypoganglionosis 

A reduced number of neurons in the myenteric 

plexus, so-called hypoganglionosis, is perhaps the 

most frequent diagnosis in children who present 

with functional obstruction due to a visceral 

neuropathy. Hypoganglionosis also occurs 

commonly in children with severe slow-transit 

constipation. Navarro et al3 reported hypoganglionosis 

of the myenteric plexus in 13 of 26 

patients who presented with functional obstruction. 

Most commonly the hypoganglionosis was 

confined to the distal segment of the colon, and 

diffuse disease was uncommon. Histologically the 

ganglia were smaller than normal, often infiltrated 

with collagen, and there was a paucity of neurons 

within the ganglia. Between the ganglia there were 

numerous thickened nerve fibers that stained 

strongly with acetylcholinesterase. Krishnamurthy 

et al described a further series of patients with 

hypoganglionosis37 in four of 26 children, but 

unlike those described by Navarro et al the nerve 

tracts did not strongly stain with cholinesterase. 

As in both of these series the majority of the children 

presented as infants, care must be taken in 

the interpretation of silver staining as during the 

first year of life there may be absence of silver

staining. In the Krishnamurthy group 37 there were 

19 children with a deficiency of argyrophilic 

neurons. When argyrophilic neurons were present, 

they were small and had few processes. It was 

suggested that these patients suffered from a defect 

in differentiation and maturation of neurons from 

primitive neuroblasts. As these processes continue 

after birth, this would explain why some infants 

during the first year of life may have apparent 

abnormalities of the myenteric plexus which are 

not the case. 38 

The problem of the diagnosis of hypoganglionosis 

is emphasized by the marked variability of the 

clinical course of such patients. Most will present 

in the newborn period with symptoms suggestive 

of Hirschsprung’s disease, but others become 

symptomatic only during their preschool years. In 

those in which the disorder is restricted to the 

colon, ileostomy or colonic resection and the pullthrough 

procedure relieves their symptoms, but 

those in whom the disease is diffuse remain 

dependent on parenteral nutrition for their 

survival. 

Hyperganglionosis 

Hyperganglionosis is characterized by an excess of 

intestinal neurons in the myenteric plexus with or 

without hyperplasia of nerve fibers. The condition 

may also affect the submucous plexus, but in 

some, the submucous plexus will be normal. 

Hyperganglionosis requires the presence of large 

ganglia containing more than seven ganglion cells 

at a greater density than the normal range for the 

region. There is also some evidence that infants, 

especially those during the neonatal period, have a 

higher neuronal density than that in older children. 

38,39 Therefore, the finding of hyperganglionosis 

in a very small infant with dysmotility 

requires caution in its interpretation. 

Marked hyperganglionosis is the hallmark of 

intestinal ganglioneuromatosis and MEN 2B. This 

is dealt with above and will not be considered 

further here. In view of the implications of MEN 

2B in those with severe hyperganglionosis and 

ganglioneuromatosis, mutations of the RET gene 

should be sought in all patients who have severe 

hyperganglionosis even if only the submucous 

plexus is involved. 

Disorders of the enteric nervous system 279 


Those with mild submucous hyperganglionosis 

have sometimes been reported to suffer from 

intestinal neuronal dysplasia, a term that has been 

used over the past 30 years to describe quantitative 

and qualitative abnormalities of enteric ganglia. 

The term was originally used to describe abnormalities 

of both the myenteric and submucous 

plexus. 40 However, over the past 20 years, diagnosis 

has largely been dependent on suction rectal 

biopsy and thus on changes in the submucous 

plexus and the mucosal innervation. The term has 

raised confusion and controversy among clinicians 

and pathologists. It appears to affect all age groups, 

although it is mostly seen in infants with chronic 

constipation and was first considered to be a 

developmental defect of the submucous plexus. 41 

Part of the problem has been the lack of agreed 

criteria, and the confusion has been further 

compounded by the use of the histological description 

as a clinical diagnosis. No studies have shown 

a correlation between morphological features of 

intestinal neuronal dysplasia and symptoms or 

long-term outcome. 42,43 Nevertheless, surgical 

procedures have been recommended on the basis 

of the histological diagnosis. In one prospective 

study of rectal biopsies, the interobserver variation 

between centers was enormous and close to that 

which that might occur by chance. In this study, 43 

377 biopsies from 108 children aged 4–15 years 

were assessed by three experienced pathologists 

for a number of agreed histological features and a 

final diagnosis. Complete concordance was 

obtained for the diagnosis of Hirschsprung’s 

disease, but in only 14% of the remainder was 

there concordance. Assessment of the clinical 

symptoms 1 year after biopsy, demonstrated that 

the diagnosis of intestinal neuronal dysplasia had 

no prognostic value for the outcome in these individuals. 

It seems, therefore, that intestinal 

neuronal dysplasia describes neither a specific 

histological nor a clinical entity, and remains 

controversial. This author can see very little use 

for the term until it is better defined. It should at 

the present time be avoided and certainly not used 

as a criterion for individual treatments. 

Acquired visceral neuropathies 

Damage to the enteric nervous system may occur 

from a variety of agents as well as being secondary

280 


to a systemic disease. Secondary visceral 

neuropathies may occur at any age, before or after 

birth, but most often occur in adults compared to 

children. 

Infectious agents 

Infectious agents may damage enteric neurons 

either by direct invasion of the neuron or by 

involvement in an inflammatory process, often 

autoimmune, that the infectious agent provokes. 

The best example of this is Chagas’ disease, caused 

by infection with Trypanosoma cruzi, in which the 

inflammatory response to the parasite results in an 

autoimmune response in which antibodies to the 

muscarinic receptors on neurons is produced. 

Whilst the most common clinical presentation 

following such an infection is achalasia, other 

areas of the bowel may be affected, including the 

small and large intestines. 

Functional obstructive episodes have also been 

observed with a variety of other infectious agents, 

including acute Lyme disease and the 

neurotrophic viruses from the herpes virus family, 

including cytomegalovirus, varicella zoster virus, 

Epstein–Barr virus and herpes simplex virus type 

1. 44–46 

Chronic inflammation and autoimmune disease 

A number of patients have been reported with 

different non-infectious inflammatory diseases. 

Clearly, classical mucosal inflammatory conditions 

such as Crohn’s disease and necrotizing enterocolitis 

may result in damage to both enteric 

nerves and muscular structures of the bowel. 

However, other autoimmune diseases affecting the 

gut, such as celiac disease and ulcerative colitis, 

may also result in severe dysmotility. It is becoming 

apparent that the neuromusculature of the 

bowel may become involved in the inflammatory 

process. 

Lymphocytic ganglionitis associated with the presence 

of circulating enteric neuronal antibodies has 

been described both in association with small 

round cell carcinoma as a paraneoplastic 

syndrome and in isolation. 47 In both settings 

acquired progressive aganglionosis occurs as a 

result of a severe T-cell-mediated inflammatory 

ganglionitis of both enteric plexuses. In the 

isolated form of the disease the antibody produced 

is similar to the Hu-protein antibody found in the 

paraneoplastic syndrome, but instead of antibody 

staining being restricted to the nucleus, it is 

present in the cytoplasm. In both forms of the 

disease, episodes of functional obstruction are 

responsive to immunosuppressive treatment, with 

a consequent fall in the titers of antibodies 

produced. 

The enteric neuromusculature may also become 

involved in a variety of connective tissues disorders 

including systemic sclerosis, systemic lupus 

erythematosus and dermatomyositis. 

Miscellaneous conditions 

The enteric neuromusculature can be affected by a 

wide variety of other conditions or affected by 

toxic agents, drugs and irradiation. These are listed 

in Table 18.1. 

Treatment 

In all the primary and many of the secondary 

causes of functional obstruction, treatment is 

symptomatic and supportive unless the underlying 

disease process can be corrected by specific 

therapy. For example, celiac disease presenting 

with functional obstruction can be treated acutely 

with immunosuppression and then by a glutenfree 

diet. The slow-transit constipation that occurs 

with hypothyroidism will respond to thyroxin 

replacement therapy. Similarly, other forms of 

autoimmune disease which affect specifically the 

nerves and muscle of the bowel can be treated by 

appropriate immunosuppressive treatment. Where 

an isolated obstructing segment of gut can be 

discerned, surgery may bring very real benefit. 

This will be discussed further below. 

Nutritional therapy plays an important role, as the 

majority of children die either as a consequence of 

malnutrition or of sepsis associated with 

parenteral nutrition. Wherever possible the enteral 

route should be used in preference to parenteral 

nutrition, and even if parenteral nutrition is 

required it is beneficial if small volumes of enteral 

feed can be maintained. In small infants, human 

milk is the preferred milk source, but if this is not 

available a whey protein hydrolysate formula

should be used in preference to whole-proteinbased 

cow’s milk formula, as this empties faster 

from the stomach. In older children episodes of 

functional obstruction can often be managed with 

enteral feeding of protein hydrolysates where they 

have previously tolerated a low-fiber diet. If 

enteral feeding cannot provide sufficient nutrients 

for normal growth and development, then 

parenteral nutrition should be initiated before 

malnutrition develops. Experience of over 40 

patients with severe recurrent episodes of pseudoobstruction 

has shown that approximately half 

will require parenteral nutrition at some time 

during the course of their illness and, in a proportion, 

home parenteral nutrition may be required. 

As a consequence of bowel dilatation and the 

development of blind loop syndromes, bacterial 

overgrowth frequently develops and will further 

enhance malabsorption due to fermentation of 

nutrients. Intermittent treatment with appropriate 

antibiotics is the recommended course of action, 

and this often improves symptoms. 

The use of pharmaceutical agents to improve 

intestinal motility can be expected to be successful 

only if there is remaining function of enteric 

nerves and muscles for the drugs to have a beneficial 

effect. In general, in those with severe and 

recurrent episodes of functional obstruction, 

pharmaceutical agents play little role. Agents that 

have been tried include cisapride, domperidone, 

metoclopramide, erythromycin and octreotide. 

Ondansetron, a 5-hydroxytryptamine3 antagonist, 

may be helpful in those cases in which the emetic 

reflex is activated, but it does not appear to affect 

episodes of obstruction. 

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19 

Introduction 

Gastrointestinal and nutritional 

problems in the neurologically 

handicapped child 


The neurologically handicapped child almost 

invariably experiences nutritional problems. 1 

They more commonly present as malnutrition, but 

obesity and overnutrition can also be found. 

Parameters to assess malnutrition and overnutrition 

in the handicapped child have to be 

adjusted. Height is a proper parameter for growth 

and nutritional status, but difficult in children 

with malformations and spasticity. 2–4 Also, disproportionate 

development of the head, rump and 

extremities makes assessment of height as a parameter 

of nutritional status difficult. 5–7 Therefore, 

crown–rump length, width, crown–heel length, 

distal femoral length and distal arm length 

(Spender growth curve) have been developed to 

assess growth and to relate height to developmental 

abnormalities or to nutrition. 8 It is clear 

that the Quetelet index or body mass index (BMI) 

have to be used with care in these children. 

Different etiologies result in different growth 

abnormalities during development in childhood. 9 

Children with Down’s syndrome, which is a 

genetic chromosomal disorder, have height and 

bone development retardation from birth. The 

rump or sitting height is normal in these children. 

The height development becomes relatively 

shorter each year up to the age of 15. The skull 

development stops at the age of 3. The growth 

deficit is more pronounced in height than in width 

and they appear microcephalic when they get 

older. 

Children with multiple congenital anomalies, with 

specific histories of drug therapy, irradiation and 

viral infections early in gestation, and which could 

be considered as an environmental insult, have 

height curves that are normal until the age of 5 for 

both sexes, and then start to lag behind. By the age 

of 10, they slow down and seem to miss their 

adolescent growth spurt. Many children in this 

group become microcephalic, and usually there 

are more deficits in width than height. 

In children with hypoxia, severe or prolonged 

deprivation of oxygen at the time of birth, in 

essence cerebral palsy with motor function impairment, 

height and trunk measurements are normal 

for 10 years and then slow down, perhaps reflecting 

a failure of the adolescent growth spurt. Head 

circumferences lag behind over all ages. On the 

other hand, children whose neurological deficit is 

minimal brain damage (attention deficit hyperactivity 

disorder, children with school and learning 

problems and no definite impairment of motor 

function), have their heights and weights within 

normal ranges. Therefore, body weight and BMI 

(kg/m 2 ) are more appropriate for evaluation of 

malnutrition in these children. 

In a study on more than 2000 institutionalized 

children with a handicap in Tokyo, Japan, 3 height 

and weight were measured in four distinct groups. 

Groups were divided into deaf children; blind 

children; mentally retarded children, some of 

whom were completely ambulatory and 15% of 

whom needed crutches; and physically handicapped 

children, of whom 65% were non-ambulatory. 

Height more than 3 standard deviations 

below the mean was present in 2% of deaf children, 

10% of blind children, 15% of children with 

mental retardation and 45% of physically handicapped 

children. Underweight more than 2 standard 

deviations below the mean was present in 1% 

of deaf children, 4% of blind children, 5% of children 

with mental retardation and 24% of physically 

handicapped children. Overweight more 

than 2 standard deviations above the mean was 

present in 8% of deaf children, 7.5% of blind 

283

284 

Gastrointestinal and nutritional problems 

children, 17% of mentally retarded children and 

9% of physically handicapped children. 10 In a 

Finnish study of patients up to the age of 20, the 

BMI showed that underweight (BMI 32 kg/m 2 ). 11 Also, more 

than 20% of children being overweight was found 

in another survey of more than 1100 children. 12,13 

Although the studies report height and weight 

reduction of almost 1 standard deviation in large 

cohorts of handicapped children, it seems more 

appropriate to relate the chance of malnutrition to 

mental retardation (5%) or physical handicap 

(25%). A height reduction of more than 3 standard 

deviations occurs in 1% of deaf children, 5% of 

blind children, 2% of mentally retarded children 

and 6% of physically handicapped children. This 

proportion of stagnation in height development in 

chromosomal, toxic and hypoxic disorders was not 

easily explained by nutritional depletion. Also, 

disproportionate development in the head, trunk 

and extremities were not in keeping with nutritional 

problems. 

In the normal child, undernutrition or overnutrition 

is obviously undesirable. In the handicapped 

child, however, a proper nutritional status is of 

crucial importance, as it supports the ability to 

employ all nutrients necessary for normal body 

functions in biological, physiological and psychological 

ways. Undernourished handicapped children 

might not respond properly to intercurrent 

diseases and suffer unnecessarily. On the other 

hand, restoring a normal nutritional status results 

in a better quality of life in many. 

Assessment of nutritional status requires a proper 

follow-up of height, body weight and assessment 

of the standard deviation score. By so doing, negative 

changes are easily discovered and appropriate 

nutritional intervention can be initiated. Spender 

et al 8 showed that upper arm length and lower leg 

length were as appropriate as height measurements 

in these children and had the same technical 

intra- and interobserver errors as the measurements 

of height, usually difficult to obtain in these 

children. In practice, they are easier to perform 

and have a better compliance for regular follow-up 

measurements. Triceps skin fold as indication of 

body fat and arm circumference as indication of 

muscle mass, should be measured in conjunction 

with height and body weight with the highly 

variable muscle mass in these children. 14 

Appetite 

Undernutrition in children with a neurological 

handicap is mostly caused by a decreased appetite 

or intake. Increased requirements or increased 

losses are not reported. Eating problems or difficulties 

in chewing, swallowing disturbances, 

absent swallowing reflex, no co-ordination of oral 

and esophageal phases and choking of food into 

the nose are implicated. Also, rumination, hypersensitivity 

in the mouth area, food refusal or aversion 

contribute to eating disorders. 

Nutrition is further influenced negatively by 

changes in taste, dry mouth, epigastric pain, 

nausea, sedation and hypersalivation. Specifically, 

anti-epileptics cause gingival hyperplasia and 

anorexia; antidepressants such as lithium increase 

thirst and appetite; mental stimulants such as 

Ritalin ® decrease appetite; antacids might cause 

constipation; and aspirin and non-steroidal antiinflammatory 

drugs (NSAIDs) cause pyrosis and 

nausea and may lead to ulcerations in the gastrointestinal 

tract. In the Institutional Tokyo Study it 

was shown that around 10% of the blind needed 

assistance with eating, mostly because of some 

chewing problems, and around 20% had poor 

appetite. In the mentally retarded, around 25% 

needed assistance during eating, 2% had swallowing 

disorders, around 35% had chewing disorders 

and 20% had poor appetite. In the physically 

handicapped, around 65% needed assistance with 

eating, 20% had swallowing disorders, 40% had 

chewing disorders and 30% had poor appetite. 

Four per cent of the mentally retarded children 

had a voracious appetite, which was in keeping 

with their overweight tendency. 15,16 

Nutrient deficiencies 

Nutrient deficiencies further show a relationship 

between undernutrition and nutritional intake, 

supported by several studies. 17–20 The undernourished 

had a lower intake of energy, protein, fat, 

fiber and water. In general, the linoleic acid intake 

was insufficient in 39% and fiber intake overall 

was insufficient in 59%. The micronutrient intake 

showed deficiencies in vitamin B6 (32%), vitamin 

C (18%), nicotinic acid (71%), sodium (61%) and 

iron (84%). Deficient intake of vitamins A, B1, B2 

and B6 was related to the undernourished group;

nicotinic acid and vitamin C were deficient in the 

whole group. In the undernourished, low sodium 

intake was more pronounced and that was also 

seen to a minor extent in the whole group. 

Sodium, potassium, calcium and phosphate intake 

were deficient only in the undernourished. Interestingly, 

iron intake was not different between 

the undernourished and the well-nourished group, 

in keeping with the laboratory assessments. Iron 

intake did not correlate with serum hemoglobin, 

serum iron and vitamin C intake. Calcium intake 

and milk intake showed no correlation with serum 

iron level. Low use of antacids was not correlated 

with serum iron level. Despite iron supplementation, 

serum iron remained deficient. Anemia 

occurred in 9% and, low serum iron in 24%. 

Anemia was more common in the undernourished 

(83% vs. 50%) as was the use of iron medication 

(67% vs. 22%) and also medication for gastroesophageal 

reflux (25% versus 16%). The iron 

resorption was not influenced by low levels of 

vitamin C, or high levels calcium, milk or antacid 

intake. The more severe the anemia, the more 

reflux medication was given. It is suggested that 

the anemia and low iron level were more related to 

intestinal blood loss due to reflux esophagitis than 

to the nutritional variations. 

Nutritional intervention 

In this last study a nutritional intervention was 

undertaken; in the well-nourished group, the nutritional 

intervention was compared and followed. The 

multiply handicapped children had spastic tetraplegia 

(75%), epilepsy (84%), disturbed chewing (84%), 

regurgitation (50%) and choking (50%). The nutritional 

intervention consisted more in a team 

approach than in taking measures specifically 

directed to individual needs. Milk products were 

maximized to 750 ml a day and were taken with 

meals. In between snacks, the emphasis was more 

on fruit and vegetable mixtures and fruit mixtures. 

Fiber was added to cereals in the order of 30 g a day. 

Those who refused bread were given porridge based 

on a mixture of tube feeding powder (1kcal/ml), 

water and cereals. Special considerations to drinks 

were given: drinks were enriched with nutritional 

supplements. If necessary, tube feeding was added; 

30% needed additional tube feeding. 

Nutritional intervention 285 

This multidisciplinary approach and intervention 

lasted for 1 year and resulted in an increase of energy 

intake from 1349 kcal to 1598 kcal. The normally fed 

group changed from 1673 to 1683 kcal/day. Protein 

intake increased from 50 to 67 g and in the normally 

fed from 73 to 79 g/day. Carbohydrates increased in 

the undernourished from 170 to 212 g/day, and in 

the well nourished from 189 to 208 g/day. Fat 

increased from 52 to 54 g/day, in the well nourished 

it declined from 70 to 60 g/day. Linoleic acid went 

from 6 to 10 g/day, and in the well nourished 8 to 

9 g/day. Fiber increased from 11 to 26 g/day and in 

the well nourished from 18 to 31 g/day. Water 

increased from 1077 to 1167 ml/day, and in the well 

nourished from 1401 to 1437 ml/day. After 1 year, 

the BMI improved from 18.8 to 19.3 kg/m 2 , triceps 

skin fold did not change, 0.98 to 1.03 cm, and the 

upper arm muscle circumference increased from 19 

to 20.1 cm. Nutritional deficiencies (in percentage 

less than two-thirds of the daily recommended 

allowance) declined in vitamin B6 of 32 to 2%, 

nicotinic acid of 77 to 34%, vitamin C of 18 to 0%, 

sodium of 61 to 39%, and iron of 84 to 11%). The 

normalization of fiber intake reduced the necessity 

for stimulant suppositories for constipation by 

56%. 

Thus, nutritional intervention by a team approach 

seems to be beneficial in the majority, showing 

that appropriate feeding is helpful in overcoming 

nutritional problems. When tube feeding is necessary 

for longer periods, percutaneous endoscopic 

gastrostomy (PEG) has become a fashionable 

approach. In a 1.5-year prospective study, the 

change of nasogastric tube feeding to PEG tube 

feeding had an unsuspected side-effect in reducing 

nutritional problems, vomiting and respiratory 

infections between 30 and 40%. 21 Also, well-being 

was improved in 40%. Interestingly, vomiting, 

airway infections and also irritability diminished. 

The standard deviation score of weight for height 

improved from -3.8 to -1.8. An easier access via 

PEG tube feeding, as compared to the irritating 

tube in the nose, resulted in better daily nutrient 

intake than more traditional nasogastric tube 

feeding. 

These observations are in keeping with studies in 

energy expenditure of children or adolescents with 

severe disabilities. In a study in children with 

cerebral palsy, 19 Stallings et al measured basic

286 


energy expenditure by indirect calorimetry and 

total energy expenditure by the doubly labeled 

water method. Physical activity including chronic 

spasticity of children with spastic quadriplegic 

cerebral palsy was estimated from the ratio of total 

energy expenditure to resting energy expenditure. 

Control children were those children with 

adequate weight, adequate fat-free mass and fat 

mass, as well as children with a lower fat-free mass 

and a lower body fat mass. Measurements were 

made by triceps skin folds and arm circumference. 

An interesting observation in children with severe 

quadriplegic cerebral palsy who were expected to 

have extra energy demands for involuntary muscular 

work showed lower total energy expenditure 

and lower resting energy expenditure compared to 

well-nourished children with this handicap and to 

controls. Resting energy expenditure and activity 

energy expenditure (estimated as total minus 

resting energy expenditure) were both diminished, 

thus not supporting the commonly held view that 

spastic children expend more energy because of 

their involuntary movements. In this study, 

reported dietary intake was compared to total 

energy expenditure measured by the doubly 

labeled water method. With this method, body 

weight before and after the test period measures 

exactly the number of calories expended and this 

can be compared with the intake. It was thus 

shown that the dietary intake reported was overestimated 

by 50% compared to the actual intake 

measured exactly by the total energy expenditure. 

This finding underlines the problems that these 

children face with feedings: meal duration is 

longer, frequently exceeding 45 min, exceeding the 

tolerance attention span of the patient and the 

available time of the caregiver. Oral motor abnormalities 

of varying degrees are observed in these 

patients. They often contribute to the symptoms 

and may lead to food loss. In all these children 

with growth failure and abnormal body composition, 

it was shown that the resting energy expenditure 

adjusted for fat-free mass was lower in the 

poorly nourished than in the adequately nourished 

group of children with severe spasticity. This 

suggested a basic metabolic response or adaptation 

to the poorly nourished condition. 

Gastroesophageal reflux (GER) symptoms such as 

vomiting, rumination and regurgitations are found 

in 20–30% of the intellectually disabled popula- 

tion. GER-related iron deficiency anemia and 

hematemesis are noted in 10–20% of patients. In 

the Netherlands and Belgium in a large cohort of 

more then 1500 patients, a randomly selected 

intellectually disabled population was tested with 

pH-metry during 24 h. A pathological pH test 

(defined as a duration of a pH of < 4 for more than 

4% of the measured time) was seen in 48% of 

cases. 22 These patients were subjected to 

endoscopy and reflux esophagitis was found in 

96%: 14% had grade I esophagitis, 33% had grade 

II, 39% had grade III and 13% had grade IV (Savary 

Miller classification). Barrett’s esophagus was 

found in 14% and peptic strictures in 4% of cases. 

This study was repeated for the group under the 

age of 14, and similar findings were seen. In fact, 

GER disease was found even in the absence of 

overt symptomatology. 

A possible explanation for the high prevalence of 

GER disease is the increased prevalence of hiatal 

hernia, found in 50% of elderly patients and 76% 

of intellectually disabled children. In the Dutch 

study, 46% had hiatal hernia and no relationship 

with rumination. There was some association with 

cerebral palsy, use of anticonvulsant drugs, scoliosis 

and restlessness. Anticholinergics and sedatives 

do decrease the lower esophageal sphincter 

pressure, which in turn might trigger more 

episodes of GER. Interestingly, dental erosions 

were seen more frequently in individuals with a 

pH lower than 4 for more than 6.3% of the 

measured time and with an IQ of less than 35. 

For the whole Dutch and Belgian group, the standardized 

morbidity ratio for esophageal carcinoma 

was 2.9; there is thus an increased risk of developing 

esophageal cancer, probably related to chronic 

GER disease and Barrett’s dysplasia. For the 

patients who underwent anti-reflux surgery, this 

was found to be effective in 38%, while no 

symptom relief was seen in the remaining 62%. 

H2-blockers were effective in 60% of patients and 

proton pump inhibitors were effective in 69% of 

patients. Surgery for the neurologically impaired 

children is known to have a significantly higher 

incidence of major complications than in intellectually 

normal patients with GER. It is in fact, a 

common notion that re-operation and relapses of 

GER are frequent. The mortality rate was 

8.8–9.4%. The postoperative complication rate was 

12–15%. In this large Dutch and Belgian cohort,

omeprazole was used in a dose of 40 mg once daily 

and was effective in 88% independently of the 

severity of the esophagitis. Ten per cent of patients 

had symptomatic relapse after decreasing the dose 

to 20 mg daily as maintenance treatment; however, 

all these patients became symptom-free again after 

increasing the dose to 40 mg daily. Endoscopically, 

the esophagus was healed at the end of the study. 23 

The occasional patient may need up to 60 mg of 

omeprazole: Hassal et al found that a dose of 

1–4 mg/kg per day was needed in a variety of 

esophagitis patients with hiatal hernia, mental 

retardation, repaired esophageal atresia and even 

in apparently healthy children with esophagitis. 24 

Keeping these children on a maintenance of 

omeprazole 20 mg daily resulted in a marked 

improvement of persistent vomiting, hematemesis, 

regurgitation, food refusal and iron deficiency 

anemia. The prevalence of Helicobacter pylori 

infections was also tested and found to be around 

50% of children, and up to 83% in adults. No clear 

correlation (either direct or inverse) between H. 

pylori infection and GER symptoms was found. 

Gastroesophageal reflux and 

percutaneus endoscopic gastrostomy 

GER and aspiration in patients fed via a gastrostomy 

tube may be caused by relaxation of the 

lower esophageal sphincter (LES) secondary to 

gastric distension caused by rapid intragastric 

bolus feeding. When feeding rate was slowed, LES 

pressure did not diminish to incompetent levels of 

2 mmHg. In general, prospective studies have 

shown reduction of vomiting, pneumonia, restlessness 

and pain in more then 60% of patients. After 

PEG placement, 24-h pH monitoring improved, 

and histological reflux esophagitis normalized in 

these children. Anti-reflux surgery for PEG placement 

considerably increased the complications 

and failed to improve symptomatology. Thus, there 

does not seem to be a place for anti-reflux surgery 

unless symptoms progress after PEG placement, in 

GER and PEG 287 

spite of concomitant treatment with proton pump 

inhibitors. 

The improvement in nutritional status obtained 

through PEG feeding induced further improvement 

in reflux, as judged by 24-h pH studies, 

suggesting a relation between malnourishment 

and reflux symptoms. 25 

Constipation in mentally 

handicapped children 

The incidence of constipation was around 61% in 

a large cohort of mentally handicapped children 

in Dutch and Belgian institutions. Constipation 

was defined as bowel movements less than 3 

times a week. Eighty-eight per cent of the constipated, 

mentally handicapped, children used laxatives, 

in comparison to 40% of constipated 

controls whose constipation was easily 

controlled. A significant correlation was found 

between non-ambulancy, cerebral palsy, use of 

anticonvulsive medication or benzodiazepines on 

the one hand and use of H2-receptor antagonists 

or proton pump inhibitors on the other. Also, an 

IQ of less than 50 correlated with food refusal, 

while there was no correlation with age, gender, 

use of cisapride, motilium, untreated GER disease 

or vomiting. Laxatives used were contact laxatives 

in 45%, and osmotic agents such as lactulose and 

enemas in 14%. Manual evacuation of feces was 

necessary in 7% of patients. In patients with cerebral 

palsy, anal sphincter pressures were normal. 

Rectal sensation was reduced and rectal size was 

increased, possibly contributing to the constipation 

so commonly seen in these children. 

Cisapride did not influence colonic transit time, 

but slightly and non-significantly increased the 

frequency of defecation from 2.5 to four times 

weekly. Thus, in summary, constipation in 

mentally handicapped children is frequently 

encountered, but seems to respond to laxative 

treatment without major sequelae. 26,27

288 


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26. Staiano A, del Giudice E, Simeone D et al. Cisapride in 

neurologically impaired children with chronic constipation. 

Dig Dis Sci 1996; 41; 870–874. 

27. Böhmer CJ, Taminiau JA, Klinkenberg-Knol EC, 

Meuwissen SG. The prevalence of constipation in institutionalized 

people with intellectual disability. J 

Intellect Disabil Res 2001; 45: 212–218.

20 

Introduction 

Cyclic vomiting syndrome 

Bhanu Sunku and B UK Li 

Cyclic vomiting syndrome (CVS) is a disorder of 

unknown etiology and pathogenesis characterized 

by recurrent, stereotypical episodes of vomiting 

with varying intervals of baseline or normal health 

in between. 1 Various recent articles and proceedings 

of two international conferences on CVS 

published in the past decade have defined this 

disorder in detail and proposed potential mechanisms 

and treatment. These publications and 

symposia have provided critical steps in recognizing 

and understanding a disorder that has been 

poorly recognized and commonly misdiagnosed. 

Typical misdiagnoses include gastroenteritis, 

gastroesophageal reflux, food poisoning, recurrent 

‘flu’ and eating disorders. 2 Although CVS can 

begin in infancy, the median age of onset in our 

cohort is 4.8 years of age. As a measure of misdiagnosis, 

the median interval from onset of symptoms 

to the proper recognition is 1.9 years, during 

which time the child has suffered through about 

15 or so episodes. Although the prevalence and 

incidence of CVS are unknown, current estimates 

in a school-based survey of Caucasian children 

5–15 years of age report a prevalence of 2%. 3 

Although CVS is clearly misdiagnosed, in our 

experience this figure appears to be excessive, 

perhaps because the study was based on a questionnaire 

that did not involve exclusionary testing 

and because milder cases that did not require 

medical intervention were detected. In any case, in 

our reported pediatric gastroenterology experience, 

CVS was second only to gastroesophageal 

reflux disease as a cause of recurrent vomiting. 4 

Similar to the gender profile in migraine 

headaches, there is a slight predominance of girls 

over boys (57:43). 5 

Although cyclic vomiting was first reported in 

France by Heberden in 1806, 6 Samuel Gee in 

England in 1882 is credited with the most accurate 

‘modern’ description. 7 In the past decade, greater 

recognition and mechanistic understanding of this 

disorder have been achieved. Prior to this recent 

period, an association with migraine headaches 

was noted as early as 1898 by Whitney 8 and in 

1904 by Rachford. 9 Recently, pathophysiological 

connections have been made with mitochondrial 

disease, autonomic dysfunction and the stress 

response. Current research, including our own, is 

focused on the identification of neuroendocrine 

mechanisms mediating vomiting in these patients, 

with a specific emphasis on the role of hypothalamic 

corticotropin releasing factor (CRF). 

Clinical patterns 

CVS is distinguished by recurrent, severe, discrete 

episodes of vomiting. Episodes are stereotypical in 

regards to time of onset, duration and symptomatology. 

This disorder is also distinguished by an 

on–off pattern with intervals of returning to 

completely normal or baseline health between 

episodes. 2 The duration of episodes is generally 

from hours to days, with a median duration of 

27 h. The median frequency of episodes is 4 

weeks. Because nearly 47% of all patients have 

regular intervals and the remaining have sporadic 

attacks at unpredictable intervals, ‘cyclic’ is a 

slight misnomer. 

The most common time of onset is during nighttime 

or early morning hours with 42% of patients 

having onset from 01.00 to 07.00. 10 Of patients, 

67% have a well-described prodrome that precedes 

the episodes of vomiting. The parents often 

characterize both the onset and the resolution as 

sudden. The warning period typically lasts a 

median of 0.5–1.5 h. Despite the similarities to 

migraines, these prodromes rarely have visual 

289

290 


disturbances and are characterized by pre-vomiting 

autonomic symptoms of pallor, nausea, 

abdominal pain and lethargy. Many parents have 

noted a rapid ‘shut-off’ of symptoms from the end 

of vomiting to the point of resuming oral intake 

and near-normal function that generally lasts a 

median of 8h with a range of 0h to 1 week. 

The vomiting itself has been described as rapidfire 

in nature, peaking at an average of six times 

per hour or once every 10min during the worst 

episode. 4 The vomiting is typically projectile, and 

contains bile, mucus and occasionally blood. The 

latter generally occurs late in the episode as a 

result of prolapse gastropathy from repetitive 

vomiting which can also produce epigastric pain. 11 

Although a threshold of more than four emeses per 

hour at the peak originally identified 92% of those 

with CVS, we have detected increasing numbers 

who fit the consensus historical criteria with a 

lower intensity of vomiting of two to four times per 

hour. 4 These children can appear remarkably 

debilitated during episodes. They are often curled 

up into the fetal position from pain, which is often 

accompanied by pallor, listlessness and unresponsiveness, 

and therefore appear much more ill than 

children with gastroenteritis. 2 

Even though children return to baseline health 

between episodes and are well about 90% of the 

time, CVS can have a significant impact on the 

quality of life of affected children. 10 Over half 

(58%) of all affected patients require intravenous 

hydration during episodes and 19% require this 

with every episode. School-age children miss an 

Table 20.1 Clinical features 

average of 24 days of school per year, owing to 

episodes of vomiting. The high medical morbidity 

is reflected by the average annualized cost of 

management of $17000, including doctor visits, 

emergency department visits, in-patient hospitalizations, 

biochemical, radiographic, endoscopic 

testing and missed work by the parents. 12 

There are many symptoms that typically accompany 

vomiting during CVS episodes (Table 20.1). 

Abdominal pain, retching, anorexia and nausea 

are the most common gastrointestinal symptoms. 

The abdominal pain can be excruciating occasionally 

to the point of requiring narcotics and/or 

laparotomy. 

By the patient’s report, nausea is generally the 

most persistent and distressing symptom: it is 

minimally relieved by vomiting, often receding 

only while sleeping or with sedation. Typical 

behaviors (assuming a fetal position, social withdrawal, 

compulsive drinking, and avoiding lights 

and sounds) represent attempts to alleviate the 

nausea. 10 

The most common autonomic symptoms are 

lethargy and pallor. Other autonomic symptoms 

include fever, flushing, drooling, diarrhea, 

hypothermia and hypertension. Less than half of 

the patients have migraine features including 

headache (42%), photophobia (38%) and phonophobia 

(30%). However, these numbers are significantly 

higher than in those with the chronic 

vomiting pattern who primarily have upper 

gastrointestinal tract disorders. 13 Other symptoms 

• Median age of onset: 4.8 years 

• Female/male: 57/43 

• Vomiting: 6 emesis/h at peak, with bile (81%), mucus (68.6%) and blood (34%) 

• Average emesis per episode: 31 

• Duration of episodes: 27h 

• Typical time of onset: 01.00–07.00 

• Median interval between episodes: 4 weeks 

• Associated symptoms: lethargy (93%), nausea (82%), abdominal pain (81%), anorexia (81%), retching (79%), 

headache (42%), photophobia (38%), phonophobia (30%) 

• Associated signs: pallor (91%), social withdrawal (54%), fever (30%), diarrhea (30%), drooling (27%)

during episodes include sensory hypersensitivity 

and vertigo. 

The largest fraction (32%) have a seasonal clustering 

of episodes with more during the winter and 

fewer during the summer. Although this pattern 

correlates with the school year, we can only speculate 

that less school-related stress and less exposure 

to infections trigger fewer episodes. Winter 

holidays including Thanksgiving, Christmas and 

New Year can serve as a positive stress for some. 

Various stressors have been noted to precipitate 

episodes of CVS. In 76% of patients, the parents 

can identify a recurring trigger preceding the 

vomiting episodes. These triggers consist of 

psychological, infectious and physical stressors 

(Table 20.2). Stress and infections are the most 

common triggers (44% and 31%, respectively). 

Interestingly, two-thirds of the stress is positive 

rather than negative. Various infections can trigger 

episodes, especially chronic sinusitis. Other 

triggers include dietary (23%), physical exhaustion 

(24%), atopic symptoms (6%), motion sickness 

(12%) and menses (22% of menstruating girls). 

Evaluating the family history of patients with CVS 

is helpful in diagnosis because of the much higher 

rate of positive migraines (82%) compared to that 

obtained in those with chronic vomiting due to 

gastrointestinal disorders or to the general population 

(15%). 5 Also, a family history of food allergies 

or atopy can be a clue for food triggers of 

Table 20.2 Common triggers for episodes of cyclic vomiting syndrome 

Infections (urinary tract infection, streptococcal throat, flu, sinusitis, gastroenteritis) 

Positive stress (birthdays, holidays, vacations) 

Negative stress (school, family, deaths) 

Dietary intake (cheese, chocolate, caffeine, monosodium glutamate) 

Physical exhaustion (lack of sleep) 

Motion sickness (car rides, roller-coasters, air travel) 

Asthma 

Allergies (seasonal, inhalants, foods) 

Menses 

Surgery/anesthesia 

Weather (temperature or pressure changes) 

Clinical patterns 291 

attacks. In our series, we have found an unusually 

high percentage of patients with a family history of 

depression (40%) compared to the general population. 

How this plays a role in possible susceptibility 

to CVS of patients is currently unknown. 

Cyclic versus chronic patterns of vomiting 

An important clinical clue to the diagnosis of CVS 

is the pattern of vomiting. Based on a temporal 

pattern, children with recurrent vomiting can be 

delineated into cyclic and chronic groups (Figure 

20.1). The cyclic group has an intense, but 

intermittent pattern of vomiting with peak emeses 

of ≥ 4/h and 2 episodes per week. 13 The chronic 

group has a low-grade, daily pattern of emeses 

with 2 episodes per week 13 

(Table 20.3). These criteria are 92% sensitive and 

100% specific for identifying children with CVS. 2 

Two-thirds of all children with recurrent vomiting 

fit into the chronic or continuous pattern of vomiting. 

These children rarely appear acutely ill or 

become dehydrated. Conversely, the cyclical 

pattern is associated with more intense vomiting 

and affected children more often require intravenous 

hydration (62% vs. 18%) compared with 

the chronic group. 4 

These two patterns are important because both of 

these groups differ in symptom and diagnostic 

profile. In those with the cyclical vomiting pattern,

292 


non-gastrointestinal disorders including neurological 

(including abdominal migraine), renal, 

endocrine and metabolic disorders predominate 

over gastrointestinal disorders by a ratio of 5 : 1. 2,13 

In contrast, in the chronic group, gastrointestinal 

disorders (mostly peptic disease) predominate 

over non-gastrointestinal causes of vomiting by a 

ratio of 7 : 1. 2,13 This implies the need to center the 

Emeses/day 

30 

20 

10 

0 0 30 60 

Days 

Figure 20.1 Temporal patterns of vomiting: cyclic versus 

chronic. The number of emeses is plotted over a 2-month 

period. The chronic pattern represented by a dashed line 

has low-grade, nearly daily episodes, whereas the cyclic 

pattern represented by the solid line has many emeses 

over a 1–2-day period that recurs every few weeks. 

(Adapted from reference 46). 

Table 20.3 Characteristics of chronic and cyclic vomiting 

diagnostic work-up on extraintestinal disorders in 

cyclic vomiting, and on upper gastrointestinal 

tract disorders in chronic vomiting. Consistent 

with proposed migraine association with CVS, the 

cyclic pattern of vomiting has a higher prevalence 

of family members with migraine headache (72% 

vs. 14%), associated headache (41% vs. 19%) and 

photophobia (18% vs. 4%). 4 


Differentiating a cyclic versus a chronic pattern of 

vomiting is the first step in narrowing the differential 

diagnosis (Table 20.4). Although the majority 

of patients (88%) with a cyclical pattern ultimately 

are diagnosed with CVS, the remaining 

12% have specific causes for vomiting found on 

diagnostic testing. The majority of disorders that 

can mimic CVS include non-gastrointestinal as 

well as gastrointestinal disorders. 

Of the gastrointestinal disorders, the most serious 

are anatomic anomalies of the gastrointestinal tract 

including malrotation with intermittent volvulus, 

which can cause ischemic necrosis. Although not 

typically cyclical, we have found a few children 

with eosinophilic esophagitis related to significant 

food allergies to mimic CVS. Lucarelli et al have 

described seven children with a positive radioallergosorbent 

test (RAST) to foods (milk, egg 

Chronic pattern Cyclic pattern 

Time of onset daytime night-time or early morning 

Number of emeses/h 2 episodes/week ≤2 episodes/week, typically 

2–4 weeks 

Family history of migraine uncommon (14%) common (82%) 

Ill-appearing no yes (pale, lethargic) 

Headaches infrequent (19%) frequent (41%) 

Photophobia infrequent (4%) frequent (18%) 

Vertigo infrequent (7%) frequent (24%) 

Intravenous hydration required uncommon (18%) common (62%) 

Esophagitis on EGD common (59%) uncommon (15%) 

EGD, esophagogastroduodenoscopy

Table 20.4 Differential diagnosis of cyclic vomiting 

white and soy) whose episodes diminished after 

specific food elimination. 14 

The most common extraintestinal cause is acute 

hydronephrosis resulting from proximal or distal 

ureteral obstruction. Metabolic causes include 

mitochondrial disorders (disorders of fatty acid 

oxidation, mitochondrial encephalopathy, lactic 

acid and stroke-like syndrome), urea cycle 

defects (partial ornithine transcarbamylase deficiency), 

organic acidurias (proprionic acidemia), 

aminoacidurias and porphyrin degradation 

disorders (acute intermittent porphyria). 15,16 

Chronic pattern Cyclic pattern 


Gastrointestinal peptic injury (GERD esophagitis, anatomic (malrotation, volvulus, 

gastritis, duodenitis) duplication cyst) 

inflammatory bowel disease pseudo-obstruction 

celiac disease cholelithiasis/gallbladder dyskinesia 

chronic appendicitis 

pancreatitis 

eosinophilic gastroenteritis/esophagitis 

Infectious chronic sinusitis sinusitis/other infections may be 

a trigger 

giardiasis 

Genitourinary pyelonephritis, pregnancy acute hydronephrosis due to 

uretopelvic junction obstruction 

or stones 

Metabolic rare mitochondrial disorders (MELAS) 

organic acidemias 

aminoacidurias 

fatty acid oxidation defects 

urea cycle defects 

acute intermittent porphyria 

Endocrine adrenal hyperplasia Addison’s disease 

diabetic ketoacidosis 

pheochromocytoma 

Neurological Chiari malformation migraine (headaches/abdominal) 

subtentorial neoplasm abdominal epilepsy 

familial dysautonomia 

Psychiatric Münchausen-by-proxy Münchausen-by-proxy 

pscyhogenic vomiting anorexia nervosa 

bulimia nervosa 

CVS 

GERD, gastroesophageal reflux disease; CVS, cyclic vomiting syndrome 

Neurosurgical causes include various lesions of 

the subtentorial region including cerebellar 

medulloblastoma, brain stem glioma and Chiari 

malformation. 2 


CVS is considered an idiopathic disorder because 

no etiopathogenesis has been documented. 

However, although no specific cause has been 

identified, several tenable hypotheses and associa-

294 


tions have been raised to explain this unique 

disorder. The current concept is that CVS is a 

functional brain–gut disorder involving central 

neuroendocrine mediation and peripheral 

gastrointestinal manifestations. 

Migraines 

An association with migraines was identified over 

a century ago. 8,9 Previous reports demonstrated the 

association CVS has with migraine headaches, a 

positive family history of migraines, 5 and progression 

of clinical episodes of CVS to migraine 

headaches with advancing age. 5,17 In the absence 

of definitive diagnostic tests for migraines and 

CVS, a putative causal relationship is further 

supported by similar symptomatology (e.g. pallor, 

lethargy, nausea, photophobia, phonophobia) and 

positive responses in both groups to anti-migraine 

therapy. 

Data from our series of over 440 patients show that 

the majority (87%) of patients with CVS do have a 

migraine association based on either a positive 

family history or concomitant or subsequent 

development of migraines in the patient. The 

progression of cyclic vomiting in childhood to 

abdominal migraines and eventually migraine 

headaches in adulthood has been labeled by 

Barlow as the periodic syndrome. 18 Many studies 

have confirmed this observation including reports 

of adults with migraines whose headache symptoms 

started with recurrent vomiting. 19,20 

Compared with the 13% who have non-migraine 

CVS, these migraine-associated CVS patients 

generally have milder episodes with significantly 

fewer emeses/episode, more symptoms of abdominal 

pain, headache, photophobia and social withdrawal, 

a greater association with psychological 

stress and significantly higher response rates to 

anti-migraine therapy (79% vs. 36%). 5,17 

Among the anti-migraine drugs that achieve such 

a positive response is sumatriptan (52%), a selective 

1B/1D serotonin agonist. This action on serotonin 

receptors with similar rates of response to 

patients with migraine headaches suggests a 

central role of action presumably by decreasing 

cerebrovascular dilatation. Since less than half of 

patients with a migraine association actually have 

headaches, a family history of migraines and the 

development of headaches over time are important 

in supporting this etiological linkage. Abdominal 

migraine shares many of the clinical features of 

CVS with midline abdominal pain being the most 

consistent and distressing symptom during 

episodes. 13 Migraine headaches, abdominal 

migraine and CVS differ in their primary symptoms 

but all have similar rates of secondary symptoms 

of pallor, lethargy, anorexia and nausea. 

Recent studies on migraine headaches have identified 

the periaqueductal gray (PAG) matter as a site 

of dysfunction in migraine attacks. Previous work 

with electrode stimulation on PAG, 21 positron 

emission tomography (PET) scan data demonstrating 

increased blood flow, 22 and altered iron homeostasis 

23 all suggest PAG involvement in migraine 

patients. Welch et al have speculated that similar 

mechanisms could be involved in CVS: PAG 

dysfunction may fail to attenuate afferent signals 

for vomiting and other autonomic symptoms 

during attacks. 23 Until we have a clearer delineation 

of mechanisms involved in migraine and 

CVS, we cannot be certain whether the CVS 

patients who do not fit under the migraine 

umbrella have distinct or similar pathophysiologic 

cascades. 

Mitochondrial dysfunction 

An association with mitochondrial DNA (mtDNA) 

mutations has been noted in children with CVS. 

Although the precise functional defects are 

unknown, Boles and Willians have proposed that 

altered mitochondrial metabolism may be 

involved. 16 They reported a large mtDNA 

rearrangement associated with CVS and subsequently 

demonstrated nine mutations in the 

hypervariable region of the D-loop (control region) 

of the mtDNA. 16 Some migraines and cyclic vomiting 

appear to result from disordered energy metabolism 

in mitochondrial encephalopathy lactic 

acidosis and stroke-like (MELAS) syndrome. 24 

Since mtDNA is maternally derived, the findings 

of a matrilineal predominance of migraines (64% 

maternal side only vs. 16% paternal side) in children 

with CVS further suggested an association. 10 

Many of the affected children with identified 

mutations have a clinical presentation with developmental 

delay, poor growth and seizures. 

However, based on non-specific lactate elevations

and organic acid abnormalities (ethylmalonic 

acid), we suspect that there could be subtle underlying 

mitochondrial dysfunction evident during 

CVS episodes even in patients without identified 

mutations. 

Neuroendocrine dysfunction 

Activation of the hypothalamic–pituitary–adrenal 

(HPA) axis was first described in CVS by Wolfe and 

Adler 25 and Sato et al. 25,26 Stressors in the form of 

infectious disorders, psychological perturbations 

and physical triggers have been well documented 

as precipitants of CVS episodes. 2 Sato et al 

described elevated levels of adrenocorticotropic 

hormone (ACTH), antidiuretic hormone (ADH), 

cortisols, prostaglandin E2, and serum and urinary 

catecholamines during episodes of CVS. 27 This 

finding may partially explain the symptoms of 

hypertension and profound lethargy in this subset 

of patients. 

The role of CRF as a brain–gut mediator in foregut 

function has been extensively described in 

animals by Taché et al. 28 In animal models, these 

authors demonstrated convincingly that central 

CRF acting on CRF-R2 receptors stimulated the 

dorsal motor nucleus (proximal end) of the vagus 

and delayed gastric emptying. 28,29 Clinical CVS in 

humans is precipitated by parallel stimuli that 

augment CRF release in animals. Also, the same 

hormones in a subset of Sato’s group reflected a 

stimulated HPA axis presumably initiated by CRF 

release, and appeared to give rise to the prominent 

symptoms of hypertension, anorexia and delayed 

gastric emptying. Our current studies examining 

the role of CRF in CVS may not only elucidate the 

pathophysiological cascade but could also open 

potential therapeutic avenues involving CRF 

antagonists. 

Despite the coherent hypothesis of CRF as a main 

mediator of vomiting, there may be another layer 

of dysfunction needed to explain why CVS 

episodes tend to be prolonged for hours. This 

added dysfunction could explain why most 

stressed individuals simply have ‘butterflies in 

their stomach’ or a single emesis, whereas children 

with CVS vomit for days on end. This could represent 

a dysfunctional PAG area that permits afferent 

autonomic signals to persist unattenuated, or 

Potential subtypes of cyclic vomiting syndrome 295 

augmented HPA axis stimulation or CRF receptor 

sensitivity in CVS patients. 

Autonomic dysfunction 

Symptoms of fever, lethargy, pallor, flushing, 

drooling and diarrhea occur commonly during 

episodes of CVS and are mediated by the autonomic 

nervous system. There are several lines of 

evidence that support the role of autonomic 

dysfunction in CVS, including clinical parallels in 

familial dysautonomia, documented alterations in 

autonomic tone and evidence of dysmotility on 

electrogastrography. Children with familial dysautonomia 

(FD, also known as Riley–Day syndrome), 

can manifest episodes of autonomic crises which 

resemble a sympathetic storm including discrete 

episodes of vomiting associated with tachycardia, 

hypertension, diffuse sweating, and emotional 

lability. Given the similarities, there may be 

commonalities in autonomic dysfunction between 

CVS episodes and FD crises. Studies using single 

photon emission computed tomography (SPECT) 

(cerebral perfusion) have localized enhanced 

temporal lobe perfusion during symptoms of 

nausea and retching that support that region’s 

involvement in ictal vomiting. 30 

To et al have observed heightened sympathetic 

cardiovascular tone and diminished parasympathetic 

vagal modulation via spectral analysis of 

R–R interval variability in CVS patients compared 

to controls. 31 Rashed et al demonstrated similar 

adrenergic autonomic abnormalities between CVS 

and migraine patients by showing lowered 

postural adjustment ratios. 32 Although the significance 

is still controversial, there is some electrogastrographic 

evidence of baseline gastric 

dysmotility in children with CVS that may 

respond to medium-dose erythromycin acting like 

motilin to enhance gastric motility and prevent 

vomiting episodes. 33–35 

Potential subtypes of cyclic vomiting 

syndrome and common associations 

The vast majority (87%) of patients with CVS have 

a migraine association either based most 

commonly on a family history of migraine or, less

296 


frequently, on the subsequent development of 

migraines in the affected child. Because these 

associated symptoms occurred less than half the 

time, we did not use headache, photophobia and 

phonophobia as specific criteria to determine who 

had migraine-associated CVS. When we examined 

the remainder with non-migraine-associated CVS 

(13%), they appeared to have longer episodes, had 

more emeses per episode and were far less likely to 

respond to anti-migraine therapy (79 vs. 36%). 5 At 

present, we cannot determine whether the nonmigraine 

CVS is pathophysiologically distinct or 

simply resides at the severe end of the same mechanistic 

spectrum. 

Are there more subtypes of CVS? Although we 

have been able to differentiate other subgroups 

based on precipitating events, clinical pattern and 

associated symptomatology, there are too few 

subjects in each to know whether there are significant 

differences. In Sato’s subtype, described 

patients have hypertension and profound lethargy 

to the point of inability to walk, talk or respond. 

We have found that these patients generally have 

more prolonged episodes (102h vs. 50h) and 

increased vomiting per episode (75 vs. 31 emeses). 

Several children with developmental and growth 

delay, seizures and mild lactic acidosis are 

suspected of having underlying mitochondrial 

enzymopathy from a mtDNA mutation. Indeed, 

nine patients with this clinical picture have been 

found to have mutations in the D-loop or control 

region of the mtDNA. 36 Others with CVS have 

been found to a have either a large rearrangement 

or a single point mutation (MELAS). 16,24 

There are several other clinical patterns that can 

be identified. Again, it is unclear whether they 

simply represent various inciting stimuli that 

initiate the same pathophysiological cascade, or 

whether they represent distinct effector pathways. 

We hope that delineation of clinical patterns into 

subgroups may ultimately point us towards potential 

treatment approaches. For instance, some 

appear to have episodes that occur after periods of 

fasting, often induced by illness. They appear to 

respond rapidly to intravenous glucose and are 

suspected of being heterozygote carriers of disorders 

of fatty acid oxidation. Others have a stable 

periodicity (e.g. 60 days) to their episodes independent 

of stress or infectious triggers. Stable periodicity 

has been observed in some postmenarchal 

girls who have episodes at the onset of their 

menses and often respond to birth control pills 

with a low estrogen dose. 2 Some respond to prokinetic 

agents, but because of the lack of motility 

studies, it is not known whether they have documented 

gastric dysmotility. 37 Finally, in a group of 

children, dietary triggers of their episodes can be 

identified. Some are initiated by typical migraine 

precipitants including cheese, chocolate and 

monosodium glutamate, whereas others are triggered 

by food allergies identified by RAST 

testing. 14 

Diagnostic evaluation 

At present, there are no specific laboratory 

changes to diagnose CVS, and the diagnosis 

depends on fulfilling key historical criteria (Table 

Table 20.5 Diagnostic criteria (from the First International Symposium on Cyclic Vomiting 

Syndrome) 

Essential criteria 

≥3 recurrent, severe, discrete episodes of vomiting 

Varying intervals of normal or baseline health between episodes 

Duration of episodes from hours to days 

No apparent cause for vomiting (negative laboratory, radiographic and endoscopic testing) 

Supportive criteria 

Stereotypical episodes are similar in regards to time of onset, intensity, duration, frequency and associated symptoms 

and signs 

Self-limited in that episodes will resolve if left untreated 

Associated symptoms and signs

20.5). In the absence of positive laboratory findings, 

most of the testing with recurrent vomiting is 

directed towards excluding other treatable causes. 

Potentially treatable underlying gastrointestinal, 

neurological, renal, metabolic and endocrine 

causes are not rare, and are found in 12% of those 

who present with a cyclic pattern of vomiting. In 

addition, 12% (many overlapping) have an identifiable 

surgical disorder. 2 The challenge is to determine 

what and how much testing should be done, 

because a ‘shot-gun’ approach can be costly, timeconsuming 

and invasive. We conducted a costdecision 

analysis and concluded that an upper 

gastrointestinal tract X-ray with a small bowel 

follow-through followed by 2 months of empiric 

anti-migraine therapy was the most cost-effective 

initial treatment strategy for CVS. 12 If no therapeutic 

response occurs, more systematic testing 

should be performed (Figure 20.2). 

The first step is to identify a recurrent pattern 

versus a single acute vomiting illness typical of 

gastroenteritis. The next is to distinguish between 

a low-grade, nearly daily chronic and explosive, 

intermittent cyclic pattern of vomiting. Once 

identified, the diagnostic evaluation involves 

evaluation for both gastrointestinal and nongastrointestinal 

causes. In our experience, the 

most potentially devastating causes are sought 

including anatomic anomalies of the gastrointestinal 

tract and renal hydronephrosis by upper 

gastrointestinal series with small bowel followthrough 

and renal ultrasound examination, respectively. 

Metabolic and endocrine testing must be 

performed before intravenous glucose and fluids 

are administered, because these can alter respective 

findings on metabolic screening and evaluation 

of the HPA axis metabolites. The endoscopy 

and the head magnetic resonance imaging (MRI) 

are reserved for those in whom therapy has failed 

or who have specific symptoms suggesting peptic 

or allergic gastrointestinal disease or intractable 

headaches, respectively. Laboratory testing and a 

proposed algorithm for evaluation are presented in 

Figure 20.2. 

Natural history and complications 

There are limited data on the natural history of 

CVS. From our data of over 440 patients, the 

median age of resolution of symptoms is 9.9 years 

Natural history and complications 297 

and one-third (28%) of the children have thus far 

undergone the transition from CVS into migraine 

headaches as they reached early adolescence. Our 

projection analysis estimates that 75% of patients 

will develop migraine headaches by the of age 18. 

Other long-term studies have shown that up to half 

of CVS patients will continue with CVS or 

migraine headaches. 17 Several studies have noted 

the mean duration of illness to be around 6 

years, 13,38 but in our cohort, the younger the age of 

onset, the longer the duration. Also, 5% of patients 

will progress through all three phases of periodic 

disease including CVS to abdominal migraine and 

finally to migraine headaches. 13 

Complications and medical morbidity include 

iatrogenic tests and interventions from the misdiagnoses 

that were often applied to recurrent 

vomiting. Most are mislabeled as gastroenteritis, 

gastroesophageal reflux and food poisoning, and 

are treated in urgent care settings. Some with 

severe pain, bilious vomiting and intractability 

have undergone inappropriate laparotomy, appendectomy, 

cholecystectomy and Nissen fundoplication. 

Others have been labeled with psychiatric 

disorders including bulimia and psychogenic 

vomiting, and have been hospitalized on psychiatric 

wards, and a few parents have been 

suspected of Münchausen-by-proxy. 39 

Complications can also occur from the frequent 

and often severe episodes of vomiting that occur 

with CVS. Dehydration and electrolyte disturbances 

are common and intravenous rehydration 

is required in 58% of patients, which can be 

compared to less than 1% in rotavirus infection. 

Hematemesis can occur towards the end of attacks 

and is usually related to prolapse gastropathy or 

Mallory–Weiss tears. 11 Although not common, 

frequent vomiting can lead to secondary peptic 

injury. Aspiration and growth failure fortunately 

seem to be uncommon occurrences. 

Treatment 

Current treatment for CVS can be divided into 

supportive (during episodes), prophylactic (to 

prevent episodes) (Table 20.6) and abortive 

therapy (to stop episodes) (Table 20.7). Other 

strategies for management of CVS include avoidance 

of identified triggers (e.g. dietary cheese),

298 


Figure 20.2 Algorithm for diagnostic evaluation and acute management of recurrent (chronic and cyclic) vomiting.

Table 20.6 Prophylactic therapy 

Drug Side-effects 

Anti-migraine 

Amitryptyline (1–2mg/kg per day) qhs sedation, anticholinergic 

Propranalol (0.5–1mg/kg per day) bid or tid hypotension, bradycardia, fatigue 

Cyproheptadine (0.25–0.5mg/kg per day) bid or tid sedation, weight gain, anticholinergic 

Anticonvulsants 

Phenobarbital (2–3mg/kg per day) qd or bid sedation 

Valproate (500–1000mg ER qhs) somnolence, hepatotoxicity 

Carbamezapine (5–10mg/kg per day) bid sedation, anticholinergic 

Prokinetic 

Erythromycin (10–20mg/kg per day) qid gastric cramps in larger doses 

Treatment 299 

Birth control 

Norethindrone (1.5mg) ethinylestradiol (20–30µg) qd estrogen-related, nausea, abdominal pain 

qhs, at bed-time: bid, twice a day; tid, three times a day; qd, every day 

Table 20.7 Abortive therapy 

Drug Side-effects 

Anti-migraine 

Sumatriptan 20mg NAS and may repeat x1 or 25mg po x1 chest and neck burning (po form), headache 

Frovatriptan 2.5mg po and may repeat x1 coronary vasospasm, dizziness 

Rizatriptan 5–10mg po x1, may repeat q 2h arrythmias, chest pain 

Ketorolac 0.5–1mg/kg per dose q 6h iv/po GI bleeding, dyspepsia 

Antiemetic 

Ondansetron 0.3–0.4mg/kg per dose q 4–6h iv/po headache, drowsiness, dry mouth 

Granisetron 10µg/kg iv q 4–6h pancytopenia, headache 

Sedative 

Lorazepam 0.05–0.1mg/kg per dose q 6 h iv/po sedation, respiratory depression 

(useful adjunct to ondansetron) 

Chlorpromazine 0.5–1mg/kg per dose q 6h iv/po drowsiness, hypotension, seizures 

Diphenhydramine 1.25mg/kg per dose q 6h iv/po hypotension, sedation, dizziness 

(useful adjunct to chlorpromazine) 

NAS, intranasally ; po, orally; q, every; iv, intravenous; GI, gastrointestinal 

psychological interventions (e.g. stress management) 

and supportive care during attacks when all 

else fails. 40 Avoidance of known triggers, 

especially dietary, can reduce the episode 

frequency. In some cases, stress management 

strategies through the aid of a psychologist can 

attenuate the effects of positive or negative stressors. 

41 

Daily use of prophylactic medications is based on 

empiric therapy that is traditionally used to treat 

other disorders, including migraines, epilepsy,

300 


gastrointestinal dysmotility and birth control. 

Although there are no evidence-based guidelines, 

we generally consider prophylaxis in children who 

have either frequent episodes, e.g. more than one 

episode per month, or severe episodes (prolonged 

for more than 3–5 days), debilitating (associated 

with hospitalization) or disabling (e.g. missing 

school days). 2 The goal of prophylaxis is to prevent 

attacks altogether, and if unsuccessful to at least to 

reduce the frequency, duration or intensity 

(number of emeses) of episodes. 

A family history of migraines is a strong indicator 

(79%) of a positive response to anti-migraine 

therapy. 5 In addition, associated symptoms of 

headache, photophobia and phonophobia should 

make one consider starting anti-migraine prophylaxis 

with propranolol, cyproheptadine, or 

amitriptyline with respective efficacy (more than 

50% reduction in frequency or severity of 

episodes) rates of 52%, 39% and 67%, respectively, 

based on our data. Propranolol is contraindicated 

in asthmatics, has side-effects of tiredness and can 

be monitored by a resting pulse decline of 15–20 

beats/min. Cyproheptadine can cause tiredness 

and an increase in appetite and weight. 4 Pizotifen, 

available in Europe, Canada and Australia, acts 

similarly but with fewer side-effects. 42 

Amitriptyline has been the most effective prophylactic 

agent in our experience, but it can cause 

arrhythmias, especially in those with a prolonged 

QTc interval. 43 Based on current recommendations, 

prior to starting amitriptyline, we evaluate 

all candidate patients by checking their QTc interval 

on electrocardiogram. 

Other prophylactic agents that have been used 

include phenobarbital, valproate, gabapentin and 

carbamazepine. 44 Although they are specifically 

indicated when spike and waves are noted on the 

electroencephalogram, they are increasingly used in 

both migraine and CVS prophylaxis. Erythromycin 

has been useful as a prokinetic agent 34 and low-dose 

estrogen birth control can be useful in teenage girls 

who have catemenial CVS. We also note that the 

efficacy rates in the open-label trials above must be 

interpreted cautiously, because of the large placebo 

effect (70%) that has been described from consultation 

alone prior to instituting therapy. 

Abortive therapy is medication taken at the onset 

of an episode or even earlier during the prodromal 

phase, ideally to abort the episode altogether or 

reduce the duration or severity of the episode. 

Abortive therapy should be considered for those 

who have sporadic episodes that occur less than 

once per month and who prefer not taking 

prophylaxis or those who have breakthrough 

episodes while on prophylaxis. 2,40 Because 

patients with intractable emesis are unable to 

tolerate oral medication, these medications 

usually have to be administered parenterally. 

The primary anti-migraine therapy includes 5- 

HT1B/1D agonists commonly used for migraine 

headaches. In our experience, success rates are 

higher in those children with migraine-associated 

CVS, when used early in the episode, and in those 

with episodes less than 24h. In our patients, 

sumatriptan administered via oral, subcutaneous 

or intranasal routes has a 51% efficacy rate, as 

compared with 65% in headaches. The sensation 

of substernal and neck burning rarely occurs with 

intranasal administration. 

Supportive care is used whenever the child is in a 

break-through episode that fails to respond to 

abortive therapy. Supportive care includes intravenous 

fluids, non-stimulating environment, 

antiemetics, sedation and analgesia. 2,40 

Intravenous fluids with high dextrose concentration 

(10%) and electrolytes have a 42% efficacy 

alone in our experience. A quiet, dark single room 

may be helpful. Analgesia is not routinely used in 

our experience but occasionally can include 

narcotic agents. 

Ondansetron, a 5-HT3 antagonist, is primarily 

used as an antiemetic with efficacy rates around 

62%. 45 More effective at the higher dosing of 

0.3–0.4mg/kg per dose, the side-effect profile has 

been excellent with few reports of drowsiness, dry 

mouth and headache. 10 It generally reduces both 

nausea and vomiting, but only rarely aborts the 

episode. The addition of a γ-aminobutyric acid 

(GABA) inhibitor, lorazepam, provides sedation 

that relieves intractable nausea. When all else 

fails, we use a combination of chlorpromazine 

and diphenhydramine primarily to provide sleep 

for relief from symptoms. In our experience, 

phenothiazine antiemetics (D2 antagonists), have 

poor (15%) efficacy in this disorder, even less than 

our placebo responses, suggesting that dopaminergic 

pathways are not involved.

Summary 

Recurrent vomiting is one of the most common 

causes for referral to the pediatric gastroenterologist. 

Improved recognition of CVS as a definable 

disorder with established criteria for diagnosis has 

come with time, and support of two recent scientific 

symposia. The Cyclic Vomiting Syndrome 

Association has been invaluable in providing 

family support for CVS patients as well as supporting 

research efforts in CVS. As work in understanding 

metabolic defects and the pathophysiological 

cascade(s) responsible for brain–gut 

interactions in CVS continues to define this disor- 

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Summary 

301 

der better, greater understanding will no doubt 

result in improved therapeutic strategies for 

patients suffering from CVS. 

Acknowledgments 

We would like to acknowledge Abid Kagalwalla for 

managing our CVS database and providing us with 

the appropriate data for this chapter. Dr Li was 

supported by funding from the Cyclic Vomiting 

Syndrome Association, Grant Healthcare 

Foundation and NINS. 

children: a possible association. Eur J Pediatr 2000; 159: 

360–363. 

15. Rinaldo P. Mitochondrial fatty acid oxidation disorders 

and cyclic vomiting syndrome. Dig Dis Sci 1999; 44: 

97S–102S. 

16. Boles RG, Williams JC. Mitochondrial disease and cyclic 

vomiting syndrome. Dig Dis Sci 1999; 44: 103S–107S. 

17. Symon DNK. Is cyclical vomiting an abdominal form of 

migraine in children? Dig Dis Sci 1999; 44: 23S–25S. 

18. Barlow CF. The periodic syndrome: cyclic vomiting and 

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19. Lance JW, Anthony M. Some clinical aspects of 

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20. Salmon MA. The evolution of adult migraine through 

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1989: 27–32. 

21. Raskin NH, Hosobuchi Y, Lamb S. Headache may arise 

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416–420. 

22. Weiller C, May A, Limmroth V et al. Brain stem 

activation in spontaneous human migraine attacks. Nat 

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matter dysfunction in migraine: cause or the burden of 

illness? Headache 2001; 41: 629–637. 

24. Hirano M, Pavlakis SG. Mitochondrial myopathy: 

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(MELAS): current concepts. J Child Neurol 1994; 9: 

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27. Sato T, Igarashi M, Minami S et al. Recurrent attacks of 

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302 


28. Taché Y, Martinez V, Million M et al. Stress and the 

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2001; 280: G173–G177. 

29. Taché Y. Cyclic vomiting syndrome: the corticotropinreleasing-factor 

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Neurology 2000; 55: 122–125. 

31. To J, Issenman RM, Kamath MV et al. Evaluation of 

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33. Chong SKF. Electrogastrography in cyclic vomiting 

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474–482. 

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social characteristics and precipitants of vomiting in 

children with cyclic vomiting syndrome. Dig Dis Sci 

1999; 44: 19S–22S. 

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pizotifen syrup in the treatment of abdominal migraine. 

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2855–2859. 

44. Gokhale R, Huttenlocher PR, Brady L et al. Use of 

barbiturates in the treatment of cyclic vomiting during 

childhood. J Pediatr Gastroenterol Nutr 1997; 25: 64–67. 

45. Li BUK, Robbins JL, Vu KT et al. Morbidity and 

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of an old disorder. Contemp Pediatr 1996; 13: 49.

21 

Introduction 

Acute and chronic pancreatitis 


Pancreatitis commonly occurs in the pediatric 

population, but it mostly remains undiagnosed. 

The clinician treating acute cases must have a low 

threshold to test for the non-specific and common 

symptoms that occur with this inflammatory 

process. Often, the symptoms are dismissed as 

occurring from an acute gastroenteritis or viral 

infection. 

Pancreatitis can be defined as an inflammatory 

process of the pancreas which occurs in the clinical 

setting of characteristic abdominal and back 

pain, accompanied by elevations of the pancreatic 

enzymes. The different types of pancreatitis can 

be characterized into five main categories according 

to the timing of the illness, clinical symptoms, 

family history and radiographic findings (acute, 

chronic, hereditary, hemorrhagic and necrotic). 

Acute pancreatitis is usually a short, self-limited 

process characterized by the classic symptoms of 

nausea, vomiting, anorexia, epigastric pain and 

back pain. Levels of serum amylase and lipase are 

markedly elevated in the acute inflammatory 

response. Although a child may suffer from 

repeated bouts of acute pancreatitis, the symptoms 

and enzyme elevations should completely resolve 

between attacks. Pancreatic function remains 

intact and the pancreatic morphology is undisturbed. 

If the signs and symptoms of inflammation are 

progressive, this may lead to chronic pancreatitis. 

Chronicity may be accompanied by either temporary 

or permanent loss of both exocrine and 

endocrine function. The severe pain that accompanies 

this condition can be debilitating and lead 

to dependence upon narcotics. Within the gland 

itself, protein plugs may calcify, indicating 

advanced and chronic disease (Figure 21.1). 

Patients with hereditary pancreatitis, by definition, 

will have a family history of the disease. These 

diseases are autosomal dominant; affected family 

members will often present with recurrent bouts of 

acute pancreatitis starting in childhood. 

Hemorrhagic and necrotic pancreatitis are uncommon 

in the pediatric population, but are a significant 

cause of morbidity and mortality from the 

disease. A secondary bacterial infection can occur 

within the gland, leading to bacteremia, shock and 

resultant multi-organ system failure. 

Figure 21.1 Kidney, ureters and bladder radiograph with 

calcified pancreas of a 6-year-old female who presented to 

the emergency department with a 3-month history of 

abdominal pain and distension due to severe pancreatitis. 

Plain film revealed ascites and extensive pancreatic calcifications 

(arrows). Ascitic fluid was markedly hemorrhagic 

and the endoscopic retrograde cholangiopancreatogram 

was normal. Patient was later discovered to have two 

different mutations in the CFTR gene. 

303

304 


Incidence and prevalence 

Although pancreatitis is seen more often in the 

adult rather than the pediatric population, it is 

likely to be underdiagnosed. Its true identification 

requires a high index of suspicion on the part of 

the clinician with a prompt evaluation before its 

resolution. In the literature, most publications on 

this disease in childhood are restricted to reports 

of either an isolated patient or small clusters of 

patients. Because of this, the true incidence and 

prevalence of the disease in this population are 

unknown. The most common pancreatic disorder 

in children is thought to be acute pancreatitis, 

with cystic fibrosis the second most common. 

Etiology and pathophysiology 

The clinical characteristics of acute pancreatitis 

follow a similar pattern, despite its varied causes. 

Damage occurs to the pancreatic acinar cell by an 

inciting event, leading to premature activation of 

the digestive enzymes while still within the cell. 

This inciting event may be infectious, traumatic, 

metabolic, drug-associated or related to an underlying 

anatomic anomaly. An inflammatory 

response occurs to these damaged cells, activating 

platelets and the complement system. Pro-inflammatory 

cytokines are released, which include 

nitric oxide, interleukin-1, platelet activating 

factor and tumor necrosis factor-α. 1 These inflammatory 

mediators, as well as the release of additional 

free radicals and other vasoactive 

substances, damage the gland directly. This can 

lead to edema, ischemia, necrosis and eventual 

loss of glandular tissue and atrophy. Systemic 

shock may occur in severe cases, as demonstrated 

by tachycardia, hypotension, hypoxia and adult 

respiratory distress syndrome (ARDS). 

While the majority of adult cases of pancreatitis 

are related to either alcohol consumption or gallstone 

disease, the causes of pediatric pancreatitis 

are more varied. In adolescent females, gallstone 

pancreatitis is not uncommon. However, young 

children with this disease have often been exposed 

to a recent trauma, infection, or medication as the 

inciting event. Recurrent pancreatitis in childhood 

can be attributed to hereditary pancreatitis, an 

anatomic variant of the pancreatic or biliary tree, 

or an underlying systemic or metabolic disorder. 

Despite exhaustive investigation, up to 25% of 

pediatric patients will not have an attributable 

cause for their acute pancreatitis. The conditions 

associated with acute and chronic pancreatitis in 

childhood are outlined in Table 21.1. 1–17 

Anatomic abnormalities 

Congenital defects in the pancreas are rare, but if 

left uncorrected they can lead to chronic pancreatitis. 

Pancreatic divisum is the most common 

anatomic variant. 18 It occurs when the dorsal and 

ventral pancreatic ducts fail to fuse during fetal 

development, directing flow primarily to the 

dorsal duct. 19 Some believe this variant to be a 

significant cause of recurrent pancreatitis, which 

requires either endoscopic or surgical correction. 

Others think that pancreatic divisum is a variant of 

normal, and that most people with this anatomy 

will not experience pancreatitis. 

Changes in anatomy which result in duodenal 

obstruction can also lead to pancreatitis. Reasons 

for this include strictures, tumors, duplications or 

diverticula of the duodenum or pancreas, and 

duodenal hematoma from either accidental or nonaccidental 

trauma (child abuse). 

Traumatic causes 

Trauma is possibly the most common cause of 

pancreatitis in childhood, and is probably underestimated. 

Motor vehicle and bicycle accidents can 

result in blunt trauma to the pancreas from seatbelts 

and handlebars. Findings on physical examination 

consistent with trauma, in the absence of a 

reliable history, should raise suspicion for child 

abuse. There are often other associated intraabdominal 

injuries in cases of significant blunt 

abdominal trauma. Duodenal hematoma and 

intestinal perforation are not uncommon. 

Infectious causes 

A variety of organisms account for a significant 

number of cases of pancreatitis worldwide, including 

bacteria, viruses and parasites. The Escherichia 

coli strain which produces verotoxin and is associated 

with hemolytic uremic syndrome can also 

cause pancreatitis. Viruses such as varicella and

Etiology and pathophysiology 305 

Table 21.1 Conditions associated with pancreatitis in the pediatric population (from references 1–17) 

Idiopathic 

Up to 25% of cases 

Anatomic 

Ampullary diverticulum 

Ampullary stenosis 

Annular pancreas 

Biliary tract malformations 

Choledochal cyst 

Choledochocele 

Choledochopancreaticoductal junction anomaly 

Cholelithiasis 

Common bile duct: absence or anomalous 

insertion 

Duodenal obstruction from diverticulum, 

hematoma, tumor or stricture 

Duodenal ulcer – perforated 

Duplication cyst of the common bile duct, 

duodenum, gastropancreatic area 

Gastric trichobezoar 

Pancreatic aplasia 

Pancreatic divisum 

Pancreatic duct: absence or anomalous insertion 

Pancreatic dysplasia 

Pancreatic heterotopy 

Pancreatic hypoplasia 

Pancreatic pseudocyst 

Pancreatic tumors 

Sclerosing cholangitis 

Sphincter of Oddi dysfunction 

Traumatic 

Blunt injury to the abdomen 

Burns 

Contrast from ductal imaging (endoscopic 

retrograde cholangiopancreatography, 

percutaneous transhepatic cholangiography) 

Head trauma 

Non-accidental trauma (child abuse) 

Radiation to the abdomen 

Surgical trauma 

Total body cast 

Infectious 

Ascaris lumbricoides (duct obstruction) 

Campylobacter fetus 

Clonorchis sinensis (duct obstruction) 

Coxsackie B virus 

Cryptosporidium 


Echovirus 

Enterovirus 

Escherichia coli (verotoxin-producing) 

Hepatitis A virus 

Hepatitis B virus 

Human immunodeficiency virus (HIV) 

Influenza A virus 

Influenza B virus 

Legionnaire’s disease 

Leptospirosis 

Malaria 

Measles 

Mumps 

Mycobacteria 

Mycoplasma 

Rubella 

Rubeola 

Toxoplasma 

Typhoid fever 

Varicella 

Yersinia 

Hereditary/Metabolic/Systemic 

α1-Antitrypsin deficiency 

Anorexia nervosa 

Autoimmune disease 

Brain tumor 

Bulimia 

Collagen vascular disease 

Congenital partial lipodystrophy 


Cystic fibrosis 

Dehydration 

Dermatomyositis 

Diabetes mellitus (ketoacidosis) 

Glycogen storage disease types Ia and Ib 

Hemochromatosis 

Hemolytic–uremic syndrome 

Honoch–Schönlein purpura 

Hereditary pancreatitis 

Hyperalimentation 

Hypercalcemia 

Hyperlipidemia types I, IV and V 

Hyperparathyroidism 

Hypertriglyceridemia 

Hypothermia 

Hypovolemia 

Inborn errors of metabolism (organic academia, 

cytochrome-C oxidase deficiency) 

Juvenile tropical pancreatitis 

Kawasaki disease 

Liver disease 

Malnutrition 

Organic acidemias (homocystinuria, isovaleric 

acidemia, methylmalonic acidemia, maple 

syrup urine disease) 

Periarteritis nodosa 

Peritonitis 

Refeeding syndrome 

Renal failure with uremia 

Reye’s syndrome 

Sarcoidosis 

Sepsis 

Shock 

Systemic lupus erythematosus 

Transplantation (bone marrow, heart, kidney, liver, 

pancreas) 

Ulcerative colitis 

Vascular diseases 

Uremia 

Wilson’s disease

306 


influenza B, associated with Reye’s syndrome, 

have also been implicated in causing acute pancreatitis 

in childhood. Parasites that are more 

common in developing areas, such as Ascaris and 

Clonorchis, can migrate into the biliary tree, 

leading to obstructive jaundice and pancreatitis. 

Left untreated, this obstruction can lead to severe 

portal hypertension, liver failure and death. 

Children with AIDS are at higher risk for developing 

acute pancreatitis. One Italian study in symptomatic 

HIV-infected children demonstrated 

pancreatic biochemical abnormalities in 15% of 

the patients. 20 However, the elevated enzymes did 

not correlate with clinical evidence of acute 

pancreatitis. Although an adult autopsy series 

showed pancreatic lesions in about 30% of AIDS 

patients, fewer than 10% had clinical symptoms. 21 

In children with HIV at autopsy, pancreatic 

involvement, defined as edema, inflammation, 

fibrosis, inspissated material and enlarged 

Langerhan’s islets, was frequent. 22 However, 

tumors and involvement of opportunistic infectious 

was rare. HIV-positive patients can develop 

elevated enzymes, owing to the HIV infection 

itself, or owing to other co-infections, such as 

cytomegalovirus (CMV), Toxoplasma, mycobacteria 

and Cryptosporidium. 17 Many of the pharmacological 

agents used to inhibit HIV can cause 

pancreatitis (see Medications). Hyperamylasemia 

without pancreatitis can occur from renal failure, 

AIDS-associated nephropathy, or salivary hyperamylasemia 

from parotid gland disease due to 

HIV. 23 Kaposi’s sarcoma and lymphoma can also 

affect the pancreas. 24 

Hereditary, metabolic and systemic diseases 

The most common inherited disease of the 

exocrine pancreas is thought to be cystic fibrosis 

(CF). 25 This autosomal recessive disease is caused 

by mutations in the CF transmembrane conductance 

regulator gene (CFTR). CFTR is located on 

the apical membrane of the epithelial cells that 

line the pancreatic ducts. The transporter 

promotes dilution and alkalinization of the pancreatic 

secretions and they flow through the ductular 

network. CF may be one of the most common 

causes of pancreatitis in childhood, but pancreatitis 

itself is a rare presenting feature of CF. 26 It is 

believed that up to 2% of individuals with CF 

experience pancreatitis as a result of ductal 

plugging due to mutant CFTR. 27 CF is the only 

known hereditary disease in which there can be 

both pancreatitis, and exocrine insufficiency in the 

absence of pancreatic inflammation. 28 However, 

those patients with CF and pancreatic insufficiency 

do not develop acute relapsing pancreatitis, 

presumably because of the loss of functional 

acinar tissue. 7 Even in the absence of lung disease, 

there appears to be a strong correlation between 

specific CFTR mutations and idiopathic and 

chronic pancreatitis. 29–31 Patients with recurrent 

pancreatitis without an obvious cause should be 

screened for CF with a sweat chloride test. CFTR 

mutational analysis is also commercially available. 

The role of CFTR in pancreatitis and other diseases 

of the pancreas is the subject of ongoing research. 

The second most common cause of chronic 

pancreatitis in childhood is believed to be hereditary 

pancreatitis. 32 The gene defects were reported 

in 1996, 33 and help explain some of the pathophysiology 

of the non-hereditary forms of both 

acute and chronic pancreatitis. 34,35 The two 

known types of hereditary pancreatitis are clinically 

similar, and involve different mutations 

within the same gene. Both types are autosomal 

dominant with 80% penetrance. 36 The majority of 

affected patients report symptoms before the age of 

15 years, with some symptomatic even before the 

age of 5 years. The gene involved is located on 

chromosome 7q35, and codes for cationic 

trypsinogen (PRSS1). Both mutations result in a 

form of trypsin that resists degradation by 

mesotrypsin and enzyme Y, 26 allowing trypsinogen 

to become activated to trypsin within the pancreas 

instead of within the duodenum. This leads to 

uncontrolled activation of other pancreatic 

enzymes within the acinar cell, resulting in 

autodigestion and inflammation. The attacks of 

acute pancreatitis are remarkably only intermittent. 

It is thought that this uncontrolled activation 

of other enzymes occurs only when trypsin 

exceeds the capacity of pancreatic secretory 

trypsin inhibitor, the ‘secondary brake’ within the 

pancreatic gland. Identification of those with 

hereditary pancreatitis is critical, as affected 

patients are at increased risk for pseudocysts, 

pancreatic adenocarcinoma, and exocrine and 

endocrine failure. 37 

Since the discovery that hereditary pancreatitis 

can be caused by mutations in PRSS1, researchers 

have been searching for other potential candidate

genes that may predispose patients to chronic 

pancreatitis. Given that the proposed mechanism 

for pancreatitis with PRSS1 mutations is decreased 

inactivation, one candidate gene is that encoding 

for pancreatic secretory trypsin inhibitor or serine 

protease inhibitor, Kazal type 1 (SPINK1). 38 

SPINK1 mutations have been reported in a wide 

phenotype of conditions, including familial, 

hereditary, tropical and idiopathic chronic pancreatitis. 

39–42 Whether or not SPINK1 mutations 

modify an already underlying genetic disease has 

yet to be elucidated. 38 

Pancreatitis has been a reported complication in 

children who have received heart, kidney, liver, 

Etiology and pathophysiology 307 

pancreas or bone marrow transplants. 8 Following 

liver transplantation, it can be life-threatening, 

and is associated with a higher risk for infectious 

peritonitis and emergency retransplantation. 9 As 

with autoimmune and collagen–vascular diseases, 

it is difficult to distinguish between the contributions 

of medications versus the primary disease 

process to the development of the pancreatitis. 

Medications 

Numerous medications and naturally occurring 

toxins have been reported as a cause of pancreatitis 

(Table 21.2). 1–4,6,17,23,43–45 Often, however, the 

Table 21.2 Drugs and toxins associated with pancreatitis (from references 1–4,6,17,23,43–45) 

Acetaminophen overdose 

Alcohol 

Amphetamines 

Anticoagulants 

Asparaginase 

Azathioprine 

Boric acid 

Bumetanide 

Calcium 

Carbamazepine 

Chlorthalidone 

Cholestyramine 

Cimetidine 

Cisplatin 

Clonidine 

Clozapine 


Corticotropin 

Cyclophosphamide 

Cyproheptadine 

Cytarabine 

Cytosine arabinoside 

Diazoxide 

Didanosine 

Dideoxycinosine 

Dideoxycytidine 

Diphenoxylate 

Enalapril 

Erythromycin 

Estrogen 

Ethacrynic acid 

Furadantin 

Furosemide 

Heroin 

Histamine 

Indomethacin 

Isoniazid 

Lamivudine 

Meprobamate 

Mercaptopurine 

Mesalamine 

Methotrexate 

Methyldopa 

Metronidazole 

Non-steroidal anti-inflammatory drugs 

Nitrofurantoin 

Octreotide 

Opiates 

Oxyphenbutazone 

Organophosphates 

Paromomycin 

Penicillin 

Pentamidine 

Phenformin 

Piroxicam 

Procainamide 

Propoxyphene 

Propylthiouracil 

Ranitidine 

Rifampin 

Salicylates 

Scorpion venom 

Spider venom 

Sulfasalazine 

Sulfonamides 

Sulindac 

Tetracycline 

Thiazides 

Tretinoin 

Trimethoprim–sulfamethoxazole 

Valproic acid 

Vincristine 

Vitamin D

308 


relationship between drugs and pancreatitis is 

more of association than causation. Classes of 

medications most likely to cause pancreatitis 

include antibiotics (erythromycin, metronidazole, 

nitrofurantoin, penicillin, rifampin), anticonvulsants 

(carmbamazepine, valproic acid), antihypertensives 

(clonidine, diazoxide, enalapril), antiinflammatories 

(corticosteroids, ibuprofen, 

indomethacin, sulfasalazine and acetaminophen 

when overdosed) and antineoplastic agents 

(asparaginase, azathioprine, mercaptopurine, 

cyclophosphamide, vincristine). Most of the drugs 

mentioned in this chapter have a proposed but 

unproven pathophysiology, and very few documented 

an established causal relationship to 

pancreatitis. 


In the pediatric population, the classic signs of 

acute pancreatitis include nausea, vomiting, 

anorexia and abdominal pain. The pain is classically 

located in the epigastrium, with radiation to 

the back. However, the pain could also be located 

in the periumbilical region, right upper quadrant 

or lower chest. 46,47 Eating usually exacerbates the 

abdominal discomfort and emesis, which may 

progress to biliousness. In the review of systems, 

the physician should inquire about rashes, diarrhea, 

joint pain and other signs of vasculitis. A 

family history of pancreatitis should raise suspicion 

for hereditary and metabolic diseases (see 

Table 21.1). 

More common causes of acute abdominal pain in 

childhood may be differentiated from pancreatitis 

by a thorough physical examination. If fever is 

present, it is usually of low grade. However, tachycardia 

and hypotension may be present early in 

the course of the disease. Tachypnea with hypoxemia 

can indicate developing pulmonary edema. 

The child may be icteric and ill-appearing, with a 

distended abdomen and decreased bowel sounds, 

owing to an ileus, ascites or a mass from a pancreatic 

phlegmon or pseudocyst. While lying supine 

on the examination table, the patient may experience 

some relief of pain when the knees are drawn 

up to a flexed trunk. In advanced disease, where 

there has been pancreatic hemorrhage or necrosis, 

two signs may be present: Grey Turner sign, which 

is a blue discoloration of the flank; and Cullen’s 

sign, where there is blue discoloration around the 

pancreas. The child should be examined for physical 

findings of child abuse, especially if there is an 

unclear history of trauma to the abdomen. 

Evaluation 

Laboratory tests 

Routine blood tests can usually differentiate acute 

pancreatitis from the more common causes of 

abdominal pain in childhood. A complete blood 

cell count with white cell differential usually 

demonstrates leukocytosis with a left shift, and 

hemoconcentration from dehydration. Frequent 

findings in a routine chemistry panel include 

hyperglycemia and elevated levels of total bilirubin, 

alanine aminotransferase and aspartate 

aminotransferase. Anemia, azotemia, hypoalbuminemia, 

hypocalcemia and an elevated lactate 

dehydrogenase level suggest advanced disease 

with hemorrhage and pancreatic damage. 

The most frequently used laboratory tests to screen 

for acute pancreatitis are serum amylase and 

lipase. Amylase levels begin to rise within 2–12h, 

and peak at 12–72h after the initial pancreatic 

insult. 48 However, an isolated serum amylase level 

has a relatively low sensitivity (75–92%) and 

specificity (20–60%). 5 This is because normal 

amylase levels may be seen with pancreatitis, and 

hyperamylasemia can result from many diseases 

that are not of pancreatic origin (Table 

21.3). 5,23,48,49 If the amylase level is three to six 

times above the upper limit of normal for that 

laboratory, the specificity increases for pancreatitis, 

but at the expense of sensitivity. 5 More 

discriminatory are the measurements of serum 

isoamylase levels, which differentiate between 

enzymes of salivary and pancreatic origin. 

Isoamylase levels should be determined if parotitis 

from a viral infection is suspected (such as with 

HIV), in the presence of some cancers, and if 

ovarian disease is present (Table 21.3). 

After serum amylase, serum lipase is the test most 

frequently used to confirm acute pancreatitis. 

Lipase levels begin to increase 4–8h after the onset 

of symptoms, and also peak at about 24h. 50 

However, lipase levels remain elevated for a longer 

period of time than amylase levels, decreasing over

Table 21.3 Conditions other than pancreatitis associated with elevated serum amylase (from 

references 5,23,48,49) 

Abdominal aortic aneurysm (pancreatic amylase 

elevation only) 

Alcoholism 

Anorexia nervosa (salivary amylase elevation only) 

Appendicitis (pancreatic amylase elevation only) 

Biliary duct obstruction (parasite, stone, tumor) 

(pancreatic amylase elevation only) 

Biliary tract disease (pancreatic amylase elevation 

only) 

Bulimia (salivary amylase elevation only) 

Burns 

Cardiopulmonary bypass 

Choledocholithiasis (pancreatic amylase elevation 

only) 

Cirrhosis 


Diabetic ketoacidosis 

Drugs 

Hepatitis 

Heroin addiction 

Intestinal infarction (pancreatic amylase elevation 

only) 

Intestinal obstruction (pancreatic amylase elevation 

only) 

Intestinal perforation (pancreatic amylase elevation 

only) 

8–14 days. Serum lipase levels have a reported 

clinical sensitivity of 86–100% and specificity of 

50–99%. 51 If the serum lipase level is greater than 

three times the upper limit of normal for that laboratory, 

sensitivity and specificity can be increased 

to 99–100%. 5 However, a significantly elevated 

lipase level, in the presence of a normal amylase 

level, has been reported in esophagitis, hypertriglyceridemia, 

renal insufficiency, acute cholecystitis 

and non-pancreatic sources of lipolytic 

enzymes due to malignant tumors. 52 

Clinical sensitivity for the diagnosis of acute 

pancreatitis increases to 94% by using serum 

amylase and lipase level determinations in parallel. 

5,52 It is important to note, however, that the 

degrees of elevation of the amylase and lipase 

levels in the plasma in no way reflect the severity 

of the pancreatic disease process itself. There are 

serum enzymes more sensitive than amylase 

which do correlate with disease severity, such as 

Evaluation 309 

Lung cancer (salivary amylase elevation only) 

Macroamylasemia 

Opiates 

Ovarian cyst (salivary amylase elevation only) 

Ovarian tumor (salivary amylase elevation only) 

Pancreatic duct obstruction (parasite, stone, tumor) 

(pancreatic amylase elevation only) 

Pancreatic tumor (pancreatic amylase elevation 

only) 

Parotitis (salivary amylase elevation only) 

Peptic ulcer – perforated (pancreatic amylase 


Peritonitis (pancreatic amylase elevation only) 

Pneumonia (salivary amylase elevation only) 

Prostate tumors (salivary amylase elevation only) 

Renal insufficiency 

Renal transplant 

Ruptured ectopic pregnancy 

Salivary duct obstruction (salivary amylase 


Salpingitis (salivary amylase elevation only) 

Trauma (to the head or abdomen) 

Viral infections (mumps) (salivary amylase elevation 

only) 

plasma immunoreactive cationic trypsin, pancreatic 

elastase I and phospholipase A2. 5 However, 

these tests are not readily available outside 

research centers. 

The diagnosis of chronic pancreatitis relies not 

only on clinical and radiographic findings (see 

next section), but also on tests of pancreatic function. 

53 The ‘gold standard’ for the assessment of 

pancreatic function involves direct testing for 

pancreatic insufficiency. This is accomplished via 

the administration of intravenous secretin or 

cholecystokinin, and measuring the levels of bicarbonate 

and pancreatic enzymes from the pancreatic 

ductal secretions. To perform this in a pediatric 

patient requires endoscopic intubation of the 

duodenum, with accurate placement of a catheter 

to collect the secretions, under appropriate anesthesia. 

If performed correctly, the sensitivity and 

specificity of this procedure for the diagnosis of 

chronic pancreatitis ranges from 90 to 100%. 54

310 


Because of the challenges in performing and interpreting 

these examinations, they are usually available 

only in tertiary centers. 

Although not as accurate, non-invasive tests of 

pancreatic function are more readily available. 

Chronic pancreatitis can be demonstrated by 

decreased enzymes in the blood (amylase, lipase, 

isoamylase, immunoreactive trypsinogen) or stool 

(trypsin, pancreatic elastase I), or increased 

amounts of malabsorbed food products (primarily 

fat). A recent pediatric study showed that testing 

for fecal pancreatic elastase I compared favorably 

to the secretin–pancreozymin test, reporting 100% 

sensitivity and 96% specificity for pancreatic 

insufficiency due to CF. However, because of the 

generally poor negative predictive value of these 

tests, chronic pancreatitis cannot be excluded with 

certainty. False-positive results can be seen with 

bacterial overgrowth and other mucosal diseases of 

the small bowel. 


Although the study of choice to delineate pancreatic 

changes is abdominal ultrasonography, 55 a 

plain abdominal radiograph (kidney, ureters and 

bladder; KUB) may demonstrate anomalies. Acute 

pancreatitis may result in an ileus, with either 

colonic distension or a ‘sentinel’ loop of dilated 

small bowel. Obscured psoas margins or a radiolu- 

Figure 21.2 Ultrasound demonstrating acute pancreatitis 

in a 9-year-old HIV-positive girl. The head and the body of 

the pancreas are decreased in echogenicity and diffusely 

enlarged. 

cent ‘halo’ around the left kidney are also suggestive 

of pancreatitis. Calcifications can be seen in 

the area of the pancreatic parenchyma and ductal 

system with chronic pancreatitis (Figure 21.1). 

Changes in pancreatic size, contour and texture 

are best appreciated with ultrasound. This modality 

is also excellent at identifying ascites, 

abscesses, pseudocysts, dilated ducts and gallstone 

disease (Figures 21.2–21.5). 

Computed tomography (CT), with oral and intravenous 

contrast, is useful in managing the complications 

of long-standing pancreatitis. 55 CT can 

provide more accurate guidance in the aspiration 

and drainage of an abscess, phlegmon or pseudocyst. 

Prior to any type of surgical intervention, 

such as necrostomy (surgical debridement for 

necrosis), CT may be utilized for further definition 

of the peripancreatic anatomy, and to rule out 

other complications, such as a portal vein thrombosis 

(Figures 21.6–21.15). 

KUB, ultrasound and CT are not adequate in clinical 

circumstances under which a detailed anatomy 

of the pancreatic and biliary tree is necessary, such 

as in chronic pancreatitis and recurrent attacks of 

acute pancreatitis. Cholangiopancreatography may 

be accomplished by endoscopic retrograde cholangiopancreatography 

(ERCP), magnetic resonance 

cholangiopancreatography (MRCP), or via a direct 

cholangiogram performed either percutaneously or 

Figure 21.3 Ultrasound demonstrating sludge in the 

gallbladder of the same patient as in Figure 21.2. There is 

no gallbladder wall thickening or pericholecystic fluid. No 

calculi were identified, but they could be obscured by the 

sludge.

Figure 21.4 Ultrasound demonstrating biliary ductal 

dilatation in a 7-year-old girl with chronic pancreatitis. 

The common bile duct is abnormally dilated, measuring 

1.2cm in diameter. This fusiform enlargement of the 

common bile duct, proximal to its bifurcation just at the 

hilus of the liver, is suggestive of a choledochal cyst. 

Figure 21.6 Computed tomography scan of acute 

pancreatitis in the abdomen of a 4-year-old boy. Fluid 

collections are seen near the pancreatic head and tail 

(arrows), consistent with inflammatory changes. There are 

areas of hypodensity within the pancreas, representative 

of acute pancreatitis. 


Figure 21.5 Ultrasound of a pseudocyst in an 18-yearold 

female with chronic pancreatitis after a severe upper 

gastrointestinal bleed, respiratory failure and septic shock. 

The pancreas was normal in echogenicity, but a pseudocyst 

was seen in the body measuring 

2.8x1.9x1cm. 

Figure 21.7 Computed tomography scan demonstrating 

biliary ductal dilatation in the abdomen of the patient in 

Figure 21.4. There is extrahepatic bile duct and pancreatic 

duct dilatation (arrows). The pancreas has a normal 

density. Intrahepatic ductal dilatation was seen on other 

sections. The differential diagnosis in this patient includes 

choledochal cyst, Caroli’s disease and sclerosing 

cholangitis.

312 


Figure 21.8 Computed tomography scan of the 

abdomen of a 16-year-old morbidly obese male with 

chronic pancreatitis. The pancreas demonstrates enhancements 

with focal lesions. The head was poorly visualized. 

The body and tail are enlarged, consistent with chronic 

pancreatitis. Endoscopic retrograde cholangiopancreatography 

demonstrated pancreatic divisum. 

Figure 21.10 Computed tomography (CT) scan of 

calcified chronic pancreatitis in the abdomen of a 14-yearold 

obese girl. The patient had complained of abdominal 

pain with nausea and vomiting for several months. She 

was found to have a hiatal hernia, and underwent laparoscopic 

fundoplication. The abdominal pain persisted, 

despite a repeat of her ‘slipped’ fundoplication, and this 

CT scan was ordered. There is fatty atrophy of the pancreas 

with multiple punctuate and small calcifications consistent 

with chronic pancreatitis. The pancreatic duct is dilated, 

measuring 1.2cm at the uncinate process. There is a calcification 

in the duct near the ampulla of Vater (arrow), 

which appears to be lodged in the common bile duct, 

causing proximal dilatation. There are several small 

pseudocysts in the upper abdomen. The largest is in the 

lesser sac just inferior to the stomach, measuring 3x4x 

3cm, with inflammation present. This patient remains 

dependent upon parenteral nutrition. 

Figure 21.9 Computed tomography scan of an atrophic 

pancreas in the same patient as in Figure 21.8, 1 year 

later. The pancreas is essentially absent, with only 

minimal tissue identified in the tail. A 4x3.6x3.8cm 

cystic mass is present in the region of the former body of 

the pancreas, consistent with a pseudocyst (arrow). This 

patient went on to develop cirrhosis with portal hypertension 

due to portal vein thrombosis. Esophageal, gastric, 

splenic and retroperitoneal varices were seen on other 

sections. Recanalization of the portal and umbilical veins 

was also visualized. Pancreatic atrophy rendered this 

patient dependent upon insulin and pancreatic enzyme 

replacements. 


abdomen in an 11-year-old girl with chronic pancreatitis 

undergoing treatment for acute lymphoblastic leukemia. A 

massive 19x5.5x8.5cm pseudocyst is seen in the left 

upper quadrant (arrows). There is edema and necrosis 

within the pancreatic tissue, and a smaller pseudocyst 

within the pancreatic head. There is free fluid within the 

abdomen and stranding within the mesentery of the left 

upper quadrant consistent with chronic inflammation. The 

liver shows fatty infiltration with a normal gallbladder. 

This pseudocyst resolved without surgical intervention.


abdomen in a 10-year-old girl with end-stage renal 

disease, found to have bloody drainage from her peritoneal 

dialysis catheter. There are diffuse inflammatory 

changes around the pancreas which extend up and 

around the lateral aspect of the stomach. The pancreas is 

low in attenuation and heterogeneous, suggestive of 

necrosis. There are multiple fluid collections in the region 

of the tail of the pancreas. There is a small amount of 

pericholecystic fluid surrounding the anterior wall of the 

gallbladder (arrow). Other sections delineated superior 

mesenteric and portal vein thrombosis. The kidneys did 

not concentrate or excrete contrast, consistent with the 

patient’s renal failure. 


abdomen of a teenage boy with recurrent pancreatitis. He 

had received high-dose steroids for treatment of non- 

Hodgkin’s lymphoma. The pancreas is edematous and 

there are multiple, small pseudocysts (arrows) which have 

enhancing rims. These findings are consistent with severe 

hemorrhagic pancreatitis. The liver is enlarged with low 

attenuation consistent with fatty infiltration. 


Figure 21.13 Computed tomography scan of chronic 

pancreatitis with cystic changes in the same patient as in 

Figure 21.12, taken 5 months later, demonstrating 

pseudocyst formation with extensive cystic changes within 

the body and tail of the pancreas. Owing to an intracranial 

bleed, the patient’s nutritional status was maintained 

on an elemental liquid diet (appropriate for a patient with 

renal failure) via a gastrostomy tube. 

Figure 21.15 Repeat computed tomography scan of the 

abdomen of the patient in Figure 21.14, performed 8 

months later. There are areas of necrosis within the 

pancreatic body and tail (arrows). A pseudocyst is present 

at the pancreatic tail near the splenic hilum. Bones 

demonstrate osteopenia, also consistent with high-dose 

steroids.

314 


Figure 21.16 Magnetic resonance imaging (MRI) 

demonstrating pancreatitis with ductal dilatation in a 

previously healthy 16-year-old female with a 1-month 

history of nausea and epigastric pain after meals. Initial 

ultrasound examination revealed pancreatic edema and 

ductal dilatation. The patient’s amylase and lipase levels 

continued to rise, despite the pancreatic rest. MRI 

revealed a dilated pancreatic duct (arrow) with increased 

signal intensity at the junction of the body and the tail, 

consistent with edema. 

intraoperatively. These studies may reveal 

cholelithiasis, anatomic malformations or biliary 

strictures. 

ERCP is the study of choice to visualize anatomic 

malformations, such as pancreas divisum or anomalous 

pancreaticobiliary duct junction. 15,18 ERCP 

may be difficult in very small children, owing to 

the large diameter of the endoscope required. 

ERCP, as opposed to MRCP, has the added benefit 

of being a therapeutic modality. Sphincterotomy, 

stent placement and stone removal can all be 

performed at the time of the initial diagnostic evaluation. 

56 Sphincter of Oddi manometry to look for 

elevated basal pressures consistent with dysfunction 

can also be useful, as these patients may 

benefit from endoscopic sphincterotomy. 15 These 

procedures should be undertaken only at centers 

that have significant experience both in performing 

the studies and in managing severe cases of 

childhood pancreatitis. A pediatric surgeon should 

be available at the center, as complications of 

ERCP can include duct perforation or a worsening 

of the pancreatitis from the contrast, leading to 

abscess, phlegmon or pseudocyst formation 

requiring surgical drainage. However, when 

performed by experienced endoscopists, therapeu- 

Figure 21.17 Magnetic resonance cholangiopancreatography 

demonstrating pancreatitis with ductal dilatation in 

the same patient as in Figure 21.16. Dilatation of the 

pancreatic duct (arrow), common bile duct, and the right 

and left main hepatic ducts (arrowheads) are seen, consistent 

with an impacted stone at the ampulla of Vater. 

tic ERCP in selected pediatric patients has been 

reported to have a lower rate of complications than 

in the adult population. 57 

MRCP should be reserved for patients who are too 

small or too clinically unstable to receive general 

anesthesia to undergo ERCP. This modality has 

proved useful in determining the presence of 

pancreaticobiliary disease, the level of biliary 

obstruction, and the presence of malignancy or 

bile duct calculi (Figures 21.16 and 21.17). 58,59 The 

quality of the MRCP images depend upon the 

ability of the patient to remain still (which may 

require light sedation in small children), and 

whether the MRCP equipment and computer 

programs are regularly updated. Interpretation also 

requires a skilled radiologist familiar with the 

various potential pancreaticobiliary tree anomalies. 

If an anatomic variant is suspected, and ERCP or 

MRCP are not possible, the next appropriate step is 

direct imaging of the pancreaticobiliary system 

with contrast, performed either percutaneously or 

intraoperatively. A percutaneous cholangiogram 

may be performed in the presence of dilated ducts, 

or through a biliary drain. Biliary drains may have 

been placed postoperatively from pancreatic surgical 

debridement or orthotopic liver transplant. 

This type of study requires a skilled interventional 

radiologist. In the absence of dilated ducts or a

iliary drain, transduodenal exploration with 

intraoperative pancreatography should be 

performed. Like ERCP, intraoperative imaging can 

likewise be a therapeutic modality at the time of 

initial diagnostic evaluation. If minor or major 

stenosis of papillae is found, surgical sphincteroplasty 

can be performed concurrently. 60 

Treatment 

The management of acute, uncomplicated pancreatitis 

in childhood is mainly supportive. The 

patient should be provided adequate hydration, 

pain relief and pancreatic rest. 55 The child should 

be made nil per os in severe cases, which will 

decrease the cephalic, gastric and intestinal phases 

of pancreatic secretion. Continuous or intermittent 

nasogastric suction may be required in cases with 

ileus or persistent emesis. If the child is expected 

to be without enteral feedings for more than 3 

days, parenteral nutrition should be initiated to 

prevent protein catabolism. Recent studies have 

suggested that nasojejunal feedings with an 

elemental diet, which bypass the duodenum 

completely and therefore do not potently stimulate 

pancreatic secretion, are just as safe as parenteral 

nutrition in adults with severe, acute pancreatitis. 

Nasojejunal feeds are also less costly, have fewer 

metabolic complications, and may shorten the 

length of stay. 61 Antibiotics are not normally indicated, 

unless there are signs of sepsis, necrotic 

pancreatitis, or multiorgan system failure. 

Histamine (H2) receptor antagonists may help to 

prevent stress ulceration by reducing duodenal 

acidification. Current research targeting the 

inflammatory cascade as described in the 

Pathophysiology section of this chapter may also 

lead to therapies that are beneficial for acute 

pancreatitis, regardless of the etiology. 

Adequate treatment of pain in acute, severe 

pancreatitis in childhood can be challenging. It 

may be difficult to relieve a child’s pain 

completely. Opiates have been reported to worsen 

symptoms by increasing spasms of the sphincter of 

Oddi. Meperidine (Demerol ®) is the analgesic of 

choice of all the pure opiate agonists for acute 

pancreatitis, because it produces the least increase 

in enterobiliary pressure. We have also used 

hydromorphone hydrochloride (Dilaudid ® ) as a 

continuous infusion in many children with severe, 

Treatment 315 

acute pancreatitis, as well as in chronic and 

complicated pancreatitis, with excellent pain 

control. 

Complications of chronic pancreatitis include 

pancreatic atrophy with resultant exocrine and/or 

endocrine insufficiency. Severe, prolonged cases 

may require insulin, pancreatic enzyme replacement 

and an elemental or low-fat diet to optimize 

absorption once enteral feedings are reinitiated. 

The major cause of mortality in pediatric patients 

with acute pancreatitis is septic complications. 

These are believed to arise from bacteria that have 

translocated across the intestinal epithelium and 

disseminated systemically via the mesenteric 

lymph nodes and lymphatics. This can result in 

pancreatic abscess, infected pseudocyst, or even 

necrosis of the gland. Evidence of infection within 

a defined area can be obtained with fine-needle 

aspiration under ultrasound or CT guidance. Gram 

stain and culture of the aspirate are clinically 

useful. Often, enteric organisms are recovered, 

such as Escherichia coli, Klebsiella species and 

other Gram-negative rods. 62 In the patient with 

necrotizing pancreatitis and organ failure, it is 

reasonable to initiate treatment with an antibiotic 

that has broad-spectrum activity against both 

aerobic and anaerobic bacteria. 55 

These infections necessitate surgical intervention. 

However, whether a sterile abscess, pseudocyst or 

necrosis requires operative management is still 

controversial. 55 Antibiotics and intensive care 

usually provide adequate support for the patient 

who has sterile necrosis. The presence of persistent 

ileus, bowel perforation, portal vein thrombosis 

and multisystem organ failure are ‘red flags’ 

that indicate urgent surgical intervention. Infected 

pancreatic necrosis is an absolute surgical indication, 

requiring necrosectomy (surgical debridement). 

Necrosectomy is thought to stop the 

progression of the necrotizing process and resultant 

multi-organ failure. Debridement, rather than 

total or partial pancreatic resection, is preferred, as 

it preserves exocrine and endocrine function. It 

may be necessary for the patient to undergo multiple 

reoperations, or continuous lavage with 

catheters left in the retroperitoneum. Necrosectomy 

itself may cause further complications, 

such as sepsis, hemorrhage, wound infection and 

fistulas of the pancreas, intestine and biliary 

system.

316 



Most cases of acute pancreatitis in childhood are 

isolated and uncomplicated, persisting for usually 

less than a week, and rarely progress to chronic 

pancreatitis. The chances of surviving a severe or 

complicated course of pancreatitis are directly 

related to the other organ systems involved. Associated 

complications can affect virtually all organ 

systems (Table 21.4). 2–4,6,15,17–19,21,23,26,34,36,37,45,53,60–63 

The primary morbidity and mortality arise from 

septic shock, renal failure, respiratory failure and 

inflammatory masses of the pancreas. 

The APACHE-II and Ranson criteria, which have 

been developed to predict the outcome from acute 

pancreatitis in adults, are not as reliable in young 

children. Pediatric studies have shown a mortality 

rate of 5–17.5% from an initially mild presentation 

of acute pancreatitis to upwards of 80–100% from 

hemorrhagic pancreatitis or severe multisystem 

disorders. After a bout of necrotizing pancreatitis, 

exocrine and endocrine insufficiency are common. 

The degree of dysfunction correlates directly with 

the extent of parenchymal damage. 

For patients with traumatic pancreatitis, in the 

absence of complete duct transection, nonoperative 

management is believed to be safe, and 

there are usually no long-term complications. 63 

Identification of those with hereditary pancreatitis 

is critical, as affected family members are at 

increased risk for pseudocysts, pancreatic adenocarcinomas, 

and exocrine and endocrine failure. 

Table 21.4 Complications associated with pancreatitis (from references 2–4,6,15,17–19,21,23,26,34, 

36,37,45,53,60–63) 

Pancreatic 

Abscess 

Ascites 

Calculi 

Carcinoma 

Diabetes mellitus 

Duct strictures 

Exocrine insufficiency 

Fibrosis 

Fistula 

Necrosis 

Phlegmon 

Pseudocyst 

Gastrointestinal/hepatic 

Biliary obstruction 

Bowel infarction 

Gastritis 

Gastrointestinal fistula 

Hemorrhage 

Hepatic vein thrombosis 

Hepatorenal syndrome 

Ileus 

Jaundice 

Peptic ulcer 

Portal vein thrombosis 

Splenic vein varices 

Systemic/metabolic 

Acidosis 

Atelectasis 

Adult respiratory distress syndrome 

Disseminated intravascular coagulation 

Electrocardiographic changes 

Encephalopathy 

Fat emboli 

Fat necrosis 

Hyperglycemia 

Hyperkalemia 


Hypoalbuminemia 

Hypocalcemia 

Hypotension 

Mediastinal abscess 

Pericardial effusion 

Pleural effusion 

Pneumonitis 

Psychosis 

Renal failure 

Renal vessel thrombosis 

Respiratory failure 

Sepsis 

Sudden death 

Thrombosis

Conclusion 

The clinician needs to have a high index of 

suspicion for pancreatitis in the child who 

presents with the non-specific but common symptoms 

of nausea, vomiting and abdominal pain. A 

thorough history that emphasizes recent infections, 

medications, trauma and any underlying 

medical condition may make the diagnosis clearer. 

The traditional use of enzyme testing alone (serum 

amylase and lipase) for the diagnosis of both acute 

and chronic pancreatitis may not be adequate, 

since the clinical specificity remains suboptimal. 

Unlike pancreatitis in adults, in which the majority 

of cases are due to either gallstone disease or 

alcoholism, this disease in childhood can be from 

a variety of disparate causes. No identifying factor 

is present in up to 25% of cases. Common known 

etiologies include infection, trauma, medications, 

abnormal anatomy and hereditary or systemic 

diseases. A family history of pancreatitis, espe- 

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6. Weizman Z. Acute pancreatitis. In Wyllie R, Hyams JS, 

eds. Pediatric Gastrointestinal Disease. Philadelphia: WB 

Saunders, 1993: 873–879. 

7. Durie PR. Pancreatitis and mutations of the cystic 

fibrosis gene. N Engl J Med 1998; 339: 687–688. 

8. Werlin SL, Casper J, Antonson D et al. Pancreatitis associated 

with bone marrow transplantation in children. 

Bone Marrow Transplant 1992; 10: 65–69. 

9. Tissieres P, Simon L, Debray D et al. Acute pancreatitis 

after orthotopic liver transplantation in children: incidence, 

contributing factors and outcome. J Pediatr 


Conclusion 317 

cially occurring at a young age, should prompt the 

physician to look for evidence of anatomic abnormalities 

or inherited biochemical defects. 

Ultrasound remains the initial radiographic study 

of choice in acute pancreatitis in childhood, to 

screen for infection, cholelithiasis, congenital 

abnormalities and biliary ductal dilatation. If the 

course of the pancreatitis is complicated or recurrent, 

further detailed imaging of the biliary system 

should be performed with ERCP, MRCP or percutaneous 

or intraoperative cholangiogram. 

Treatment of acute, uncomplicated pancreatitis in 

the pediatric population is basically supportive, 

and most children will recover without sequelae. 

Complications, when they occur, can involve 

every major organ system and be life-threatening. 

Children with severe or complicated pancreatitis 

should be managed at a center with expertise in 

pediatric biliary surgery and non-operative radiological 

and endoscopic interventions. 

10. Collins JE, Brenton DP. Pancreatitis and homocystinuria. 

J Inherit Metab Dis 1990; 13: 232–233. 

11. Kahler SG, Sherwood G, Woolf D et al. Pancreatitis in 

patients with organic acidemias. J Pediatr 1994; 124: 

239–243. 

12. Lévy P, Menzelxhiu A, Paillot B et al. Abdominal radiotherapy 

is a cause for chronic pancreatitis. 


13. Keljo DJ, Sugerman KS. Pancreatitis in patients with 

inflammatory bowel disease. J Pediatr Gastroenterol Nutr 

1997; 25: 108–112. 

14. See Y, Martin K, Rooney M et al. Severe juvenile 

dermatomyositis complicated by pancreatitis. Br J 

Rheumatol 1997; 36: 912–916. 

15. Guelrud M, Morera C, Rodriguez M et al. Sphincter of 

Oddi dysfunction in children with recurrent pancreatitis 

and anomalous pancreaticobiliary union: an etiologic 

concept. Gastrointest Endosc 1999; 50: 194–199. 

16. Mattioli G, Buffa P, Pesce F et al. Pancreatitis caused by 

duodenal duplication. J Pediatr Surg 1999; 34: 645–648. 

17. Dassopoulos T, Ehrenpreis ED. Acute pancreatitis in 

human immunodeficiency virus-infected patients: a 

review. Am J Med 1999; 107: 78–84. 

18. Kamelmaz I, Elitsur Y. Pancreas divisum – the role of 

ERCP in children. W V Med J 1999; 95: 14–16. 

19. Lerner A, Branski D, Lebenthal E. Pancreatic diseases in 

children. Pediatr Clin North Am 1996; 43: 125–156. 

20. Carroccio A, Fontana M, Spagnuolo MI et al. Serum 

pancreatic enzymes in human immunodeficiency virus-

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infected children. A collaborative study of the Italian 

Society of Pediatric Gastroenterology and Hepatology. 

Scand J Gastroenterol 1998; 33: 998–1001. 

21. Brivet FG, Naneau SH, Lemaigre GF et al. Pancreatic 

lesions in HIV-infected patients. Ballières Clin 

Endocrinol Metab 1994; 8: 859–877. 

22. Kahn E, Anderson VM, Greco A et al. Pancreatic disorders 

in pediatric acquired immune deficiency 

syndrome. Hum Pathol 1995; 26: 765–770. 

23. Aboulafia DM. Acute pancreatitis: a fatal complication 

of AIDS therapy. J Clin Gastroenterol 1997; 25: 640–645. 

24. Friedman SL. Kaposi’s sarcoma and lymphoma of the 

gut in AIDS. Ballières Clin Gastroenterol 1990; 4: 

455–475. 

25. Welsh MJ, Tsui LC, Boat TF et al. Cystic fibrosis. In 

Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The 

Metabolic and Molecular Basis of Inherited Disease. New 

York: McGraw-Hill, 1995: 3799–3876. 

26. Dodge JA. Paediatric and hereditary aspects of chronic 

pancreatitis. Digestion 1998; 59 (Suppl 4): 49–59. 

27. Uomo G, Manes G, Rabitti PR. Role of hereditary 

pancreatitis and CFTR gene mutations in the aetiology 

of acute relapsing pancreatitis of unknown origin. How 

are they important? J Pancreas (Online) 2001; 2: 

368–372. 

28. Rosenstein MG, Cutting GR. The diagnosis of cystic 

fibrosis: a consensus statement. J Pediatr 1998; 132: 

589–595. 

29. Cohn JA, Friedman KJ, Noone PG et al. Relation 

between mutations of the cystic fibrosis gene and 

idiopathic pancreatitis. N Engl J Med 1998; 339: 

653–658. 

30. Cohn JA, Jowell PS. Are mutations in the cystic fibrosis 

gene important in chronic pancreatitis? Surg Clin North 

Am 1999; 79: 723–731. 

31. Sharer N, Schwarz M, Malone G et al. Mutations of the 

cystic fibrosis gene in patients with chronic 

pancreatitis. N Engl J Med 1998; 339: 645–652. 

32. Elitsur Y, Chertow BC, Jewell RD et al. Identification of 

a hereditary pancreatitis mutation in four West Virginia 

families. Pediatr Res 1998; 44: 927–930. 

33. Whitcomb DC, Gorry MC, Preston RA et al. A gene for 

hereditary pancreatitis maps to chromosome 7q35. 


34. Gates LK, Ulrich CD II, Whitcomb DC. Hereditary 

pancreatitis. Surg Clin North Am 1999; 79: 711–722. 

35. Whitcomb DC. Hereditary pancreatitis: a model for 

understanding the genetic basis of acute and chronic 

pancreatitis. Pancreatology 2001; 1: 565–570. 

36. Perrault J. Hereditary pancreatitis. Gastroenterol Clin 

North Am 1994; 23: 743–752. 

37. Uretsky G, Goldschmiedt M, James K, Childhood 

pancreatitis. Am Fam Physician 1999; 59: 2507–2512. 

38. Pfützer RH, Whitcomb DC. SPINK1 mutations are 

associated with multiple phenotypes. Pancreatology 

2001; 1: 457–460. 

39. Pfützer RH, Barmada MM, Brunskill APJ et al. 

SPINK1/PSTI polymorphisms act as disease modifiers in 

familial and idiopathic chronic pancreatitis. 


40. Chen JM, Mercier B, Audrezet MP et al. Mutational 

analysis of the human pancreatic secretory trypsin 

inhibitor (PSTI) gene in hereditary and sporadic chronic 

pancreatitis (letter). J Med Genet 2000; 37: 67–69. 

41. Rossi L, Pfützer RH, Parvin S et al. SPINK1/PSTI 

mutations are associated with tropical pancreatitis in 

Bangladesh: a preliminary report. Pancreatology 2001; 1: 

242–245. 

42. Teich N, Ockenga J, Hoffmeister A et al. Chronic 

pancreatitis associated with an activation peptide 

mutation that facilitates trypsin activation. 


43. Sahu S, Saika S, Pai SK et al. L-Asparaginase (Leunase) 

induced pancreatitis in childhood acute lymphoblastic 

leukemia. Pediatr Hematol Oncol 1998; 15: 533–538. 

44. Sammett D, Greben C, Sayeed-Shah U. Acute 

pancreatitis caused by penicillin. Dig Dis Sci 1998; 43: 

1778–1783. 

45. Tobias JD, Capers C, Sims P et al. Necrotizing 

pancreatitis after 10 years of therapy with valproic acid. 

Clin Pediatr 1995; 34: 446–448. 

46. Oberlander TF, Rappaport LA. Recurrent abdominal 

pain during childhood. Pediatr Rev 1993; 14: 313-319. 

47. Stevenson RJ, Ziegler MM. Abdominal pain unrelated to 

trauma. Pediatr Rev 1993; 14: 302–311. 

48. Pieper-Bigelow C, Strocchi A, Levitt MD. Where does 

serum amylase come from and where does it go? 

Gastroenterol Clin North Am 1990; 19: 793–810. 

49. Murthy UK, DeGregorio F, Oates RP et al. 

Hyperamylasemia in patients with the acquired immunodeficiency 

syndrome. Am J Gastroenterol 1992; 87: 

332–336. 

50. Gwodz GP, Steinberg WM, Werner M et al. Comparative 

evaluation of the diagnosis of acute pancreatitis based 

on serum and urine enzyme assays. Clin Chim Acta 

1990; 187: 243–248. 

51. Agarwal N, Pitchumoni CS, Sivaprasad AV. Evaluating 

tests for acute pancreatitis. Am J Gastroenterol 1990; 85: 

356–360. 

52. Frank B, Gottlieb K. Amylase normal, lipase elevated: is 

it pancreatitis? A case series and review of the literature. 


53. Clain JE, Pearson RK. Diagnosis of chronic pancreatitis. 

Surg Clin North Am 1999; 79: 829–845. 

54. Heiji HA, Obertop H, Schmitz PIM et al. Evaluation of 

the secretin–cholecystokinin test for chronic 

pancreatitis by discriminant analysis. Scand J 


55. Banks PA. Practice guidelines in acute pancreatitis. Am J 


56. Samavedy R, Sherman S, Lehman GA. Endoscopic 

therapy in anomalous pancreatobiliary duct junction. 

Gastrointest Endoscop 1999; 50: 623–627. 

57. Guelrud M, Endoscopic therapy of pancreatic disease in 

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58. Fulcher AS, Turner MA, Capps GW et al. Half-Fourier 

RARE MR cholangiopancreatography: experience in 300 

subjects. Radiology 1998; 207: 21–32. 

59. Hirohashi S, Hirohashi R, Uchida H et al. Pancreatitis: 

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60. O’Rourke RW, Harrison MR. Pancreas divisum and 

stenosis of the major and minor papillae in an 8 year 

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Surg 1998; 33: 789–791. 

61. Abou-Assi S, Craig K, O’Keefe SJ. Hypocaloric jejunal 

feeding is better than total parenteral nutrition in acute 

pancreatitis: Results of a randomized, comparative 

study. Am J Gastroenterol 2002; 97: 2255–2262. 

62. Luiten EJ, Hop WC, Lange JF et al. Differential prognosis 

of gram-negative versus gram-positive infected and 

sterile pancreatic necrosis: results of a randomized trial 

in patients with severe, acute pancreatitis treated with 

adjuvant selective decontamination. Clin Infect Dis 

1997; 25: 811–818. 

63. Holland AJ, Davey RB, Sparnon AL et al. Traumatic 

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management in children. Paediatr Child Health 1999; 

35: 78–81.

22 

Introduction 

Food allergies 

Simon Murch 

During the past half century, allergies of all kinds 

have become much more common within the 

developed world. Dietary allergies are no exception, 

and up to 5% of children develop allergy to 

cow’s milk and other proteins (reviewed by 

Walker-Smith and Murch 1 and Wood 2 ). There has 

also been a change in patterns of presentation. As 

dietary exposures in infancy and early childhood 

have altered, previously unusual reactions to antigens 

such as peanut and sesame have become 

much more common. 3–5 There are important 

geographical differences, with different incidence 

of specific allergies varying from country to 

country. 5 This may relate to genetic differences in 

immune responses amongst different ethnic 

groups, or to local dietary customs – exemplified 

most strikingly by reports of anaphylaxis to birds’ 

nest soup in Singaporean infants. 6 However, a 

broader context is provided by recent evidence 

from the direction of basic science, which highlights 

the importance of infectious exposures of 

the innate immune system in early life in inducing 

tolerance to dietary antigens (oral tolerance). This 

chapter attempts to encompass both the clinical 

aspects of food allergy and some of the relevant 

scientific background. 

Early life exposures, possibly even prenatal exposures, 

have changed substantially within countries 

of the developed world, in the past two generations. 

Birth in disadvantaged conditions within the 

developing world is protective against most forms 

of allergy, and predisposition to allergy may manifest 

only once a certain threshold of improved 

material conditions is passed. 7,8 Allergies occur 

because of breakdown of immunological tolerance. 

The immune system must differentiate between all 

foreign molecules, reacting only to potentially 

harmful pathogens while remaining unresponsive 

(tolerant) to the commensal bacterial flora and to 

foods. The role of the bacterial flora in establishing 

immune tolerance has only recently become 

apparent, and will be discussed in more detail 

later, together with evidence that manipulation of 

the bacterial flora may provide a novel approach to 

the management of dietary and other allergies. 8–11 

First, however, it is important to clarify the difference 

between food intolerance and food allergy 

(Table 22.1). As there may however be an overlap 

in the symptomatology, an accurate history and 

Table 22.1 Food intolerance reactions which may be confused with true allergy 

Direct toxic effects 

Bacterial contamination; heavy metals or toxins; some food additives 

Intolerance due to enzyme deficiency 

Inborn metabolic abnormalities (e.g. phenylketonuria, tyrosinemia, galactosemia) inducing adverse responses to 

specific dietary components. Enterocyte gene deficiencies (lactase deficiency, sucrase–isomaltase deficiency or 

glucose–galactose malabsorption) inducing diarrhea after ingestion of relevant sugars. Enteropathy causing downregulated 

expression of lactase and sucrase 

Symptoms due to pharmacological properties of foods 

For example tyramine contained in cheese or red wine; histamine in strawberries 

319

320 


supportive investigations are needed for secure 

diagnosis of true food allergy. 

Food allergies – classification 

There are two major classes of food allergic reactions: 

IgE-mediated and non-IgE-mediated. IgEmediated 

allergies usually present soon after 

ingestion, and thus the causative antigen is often 

readily identifiable. In addition, there are usually 

supportive diagnostic tests such as skin prick tests. 

These reactions are those of type I hypersensitivity 

(Table 22.2). 12,13 They can be very severe, and may 

cause death through anaphylaxis in severe cases. 

Non-IgE-mediated allergies usually present later 

after ingestion, and the causative antigen may be 

more difficult to detect, particularly as tests for 

immediate allergies are often negative. These may 

include type IV hypersensitivity (Table 22.2), or 

may be caused by local eosinophil recruitment. 

They can be an important cause of morbidity, 

which may go unrecognized. The immunological 

basis of such reactions is discussed later. 

Food allergic reactions may also be divided clinically 

into quick-onset reactions, occurring within 

an hour of food ingestion, and slow-onset reac- 

Table 22.2 The classical forms of hypersensitivity (after reference 12) 

tions, taking hours or days. In general, quick onset 

symptoms are IgE-mediated and slow-onset symptoms 

are non-IgE-mediated. However, this is by no 

means invariable, and many children with clear 

quick-onset responses to foods have a low or even 

undetectable serum total IgE level and absent foodspecific 

IgE level. 14 It is also notable that mice 

totally deficient in IgE owing to gene knockout 

may still suffer anaphylaxis, as IgG1 bound to 

FCγRIII on mast cells may induce antigen-specific 

degranulation. 15,16 Such a phenomenon may 

explain why investigations such as skin prick tests 

may be positive in children despite undetectable 

specific IgE for that antigen. 

Differentiation between IgE-mediated and non- 

IgE-mediated reactions may therefore be difficult. 

The Melbourne Milk Allergy Study, conducted by 

Hill and colleagues, 17 identified three types of 

reaction in sensitized children – immediate reactions 

(rapid skin reactions with perioral erythema, 

facial angioedema and urticaria, some developing 

anaphylaxis), intermediate reactions (gastrointestinal 

symptoms such as vomiting or diarrhea occurring 

1–24h after ingestion) and delayed reactions 

(eczema flares or respiratory symptoms such as 

cough and wheeze, occurring between 1 and 5 

days after challenge). The volume of milk required 

Type I: anaphylactic or immediate hypersensitivity 

This occurs within minutes of exposure, as seen in quick-onset food allergy. The allergen binds to, and cross-links IgE 

(occasionally IgG1) on the mast cell surface, inducing its degranulation and release of vasoactive agents (histamine, 

tryptase, etc.) and cytokines (tumor necrosis factor-α). Responses to some antigens (classically peanut) are usually of 

this kind. 

Type II: cytotoxic hypersensitivity 

This reaction occurs when antibody binds to an epitope on the cell surface, then fixes complement, causing 

complement-mediated cell death. This is not a reaction usually described for food allergy, but complement activation 

can be detected in celiac disease. 

Type III: immune complex hypersensitivity 

In this type of reaction, antigen complexes with antibody (IgG or IgM) in the presence of antigen excess, to induce 

complement fixation and a consequent local inflammatory response, several hours after exposure to the antigen. The 

expression of Fc receptors for immunoglobulin appears to determine tissue damage. 13 

Type IV: delayed hypersensitivity or cell-mediated immunity 

This reaction is essentially mediated by T lymphocytes, with tissue damage also caused by macrophages responding 

to T-cell cytokines. The pattern of T-cell responses (Th1 or Th2) may determine overall immunopathology. The classic 

type IV reaction is a Th1 response, as in Crohn’s disease, while both Th1 and Th2 reactions occur in food allergy.

to elicit these symptoms increased between 

groups, and classic allergy tests such as skin prick 

tests were helpful only for the first group of early 

reactors. Knowledge of the time course and likely 

immunopathogenesis indicates that the early reactions 

are due to IgE responses and mast cell 

degranulation, the intermediate reactions follow 

eosinophil recruitment and the delayed responses 

are likely to relate to T-cell responses. 18 These 

concepts will be discussed later, in the sections on 

immunopathogenesis. The Melbourne group have 

also played an important role in the recognition of 

the increasing incidence of multiple food allergies, 

and of the role of food allergy in inducing a spectrum 

of symptoms not previously associated with 

allergy. 5 The role of food allergy in inducing 

visceral dysmotility syndromes such as infant 

colic, gastroesophageal reflux and recurrent 

abdominal pain will be discussed later. 

In a recent study of 121 children with allergy to 

two or more foods, including both those with IgEmediated 

and those with non-IgE-mediated allergies, 

14 children with early-onset symptoms had a 

significant overall increase in serum IgE compared 

to those with late-onset symptoms. However, 30% 

of those with early-onset symptoms had no elevation 

of IgE concentration above the normal range, 

while 10% of those with only delayed symptoms 

did have an elevated IgE concentration. Over 90% 

of those with early-onset symptoms additionally 

demonstrated late-onset symptoms. Although the 

groups differed in IgE responses, they shared, 

regardless of speed of reaction, a pattern of 

immune deviation, with increased serum IgG1 and 

circulating B cells, but reduced IgG2 and IgG4, 

CD8 cells and natural killer cells. IgA concentrations 

were at the low end of the normal range or 

below. This raises the question of whether the 

propensity to sensitize to food antigens is associated 

with minor immunodeficiency, a concept first 

suggested by Soothill, 19 who postulated that 

demonstrated maturational delay in IgA responses 

predisposed to food allergic sensitization. Further 

data in support of a link with a developmental 

delay in IgA maturation was provided by a population 

survey from Iceland, in which an IgA level 

at the lower end of the normal range was more 

predictive of allergic sensitization than was 

elevated IgE concentration, 20 and from other 

studies of food allergic infants, in which increased 

B cells and decreased CD8 cells and decreased IgA, 

Patterns of food allergic responses 321 

IgG2 and IgG4 were associated with milk allergies 

and food-sensitive colitis. 21,22 These data suggest 

that there may be a consistent pattern of minor 

immunodeficiency associated with the process of 

sensitization in early life, and that the manifestation 

of that sensitization (quick- or slow-onset) 

may depend on whether the child has inherited a 

tendency to high IgE production. Thus, a high IgE 

level may not cause food allergy per se, but may 

determine how that allergy is expressed. Most of 

the early literature on food allergy, however, 

understandably focuses on IgE and quick-onset 

responses. 

Later in the chapter, the role of infectious exposures 

in maturation of mucosal immune responses 

and immune tolerance will be explored. Whether 

food allergy can be fully explained by the Clean 

Child Hypothesis 7 remains uncertain, but there is 

substantial circumstantial evidence that these 

infectious exposures are probably an important 

contributory factor in the pathogenesis of allergies. 

Recent recognition of the role of infectious exposures 

in the generation of cells producing the regulatory 

cytokine transforming growth factor (TGF)β, 

and of the central requirement for TGF-β in both 

IgA responses and oral tolerance, may provide 

some explanation for the consistent links with 

slow IgA maturation. 8,19,23 

Patterns of food allergic responses 

Quick-onset symptoms 

These often follow the ingestion of a single food, 

such as egg, peanut or sesame. Within minutes the 

sufferer may notice tingling of the tongue, and 

there may be the rapid development of skin rash, 

urticaria or wheezing. One localized variant, the 

oral allergy syndrome, is often seen in older 

pollen-sensitized individuals and is characterized 

by lip tingling and mouth swelling after ingestion 

of certain fruits and vegetables. 24 More serious 

reactions, however, can occur at any age, and antigens 

such as peanut, tree nuts, fish and shellfish 

can cause exquisite sensitization from early childhood. 

Swelling of the mucous membranes of the 

mouth and upper airway (angioneurotic edema) 

can develop extremely quickly, and the airway 

may become compromised. In cases where

322 


appropriate therapy is not available, life-saving 

tracheostomy has even been performed in the 

presence of gross laryngeal edema. Anaphylactic 

shock may also occur, with dramatic systemic 

hypotension accompanying the airway obstruction. 

A grading system for anaphylaxis has been 

suggested by Sampson, 25 with a severity score 

based on the worst symptom present (Table 22.3). 

Specific therapy for mild cases of immediate 

hypersensitivity would include antihistamines 

such as chlorpheniramine, together with inhaled 

bronchodilators as appropriate. It is notable that 

some patients can have a biphasic response, with 

a relatively modest initial reaction followed 

several hours later by a more profound and potentially 

life-threatening response, and therefore care 

should be taken in the assessment to ensure that 

adequate instructions and therapy are adminis- 

tered before allowing the patient home. There have 

indeed been several cases of anaphylactic death in 

patients discharged home after initial resuscitation, 

up to 6h after food ingestion, and it is therefore 

prudent to maintain observation for several 

hours if there are any clear risk factors, such as 

active asthma or a history of a severe reaction. 25,26 

The presence of wheezing on examination should 

suggest caution; a bronchodilator should certainly 

be prescribed, and in many cases a few days’ 

course of oral prednisolone. 

More severe reactions should be assessed very 

rapidly, and any evidence of airway obstruction or 

systemic hypotension warrants the immediate use 

of intramuscular epinephrine (adrenaline) (Table 

22.3). Use of a preloaded syringe pen, such as a 

pediatric or adult EpiPen ® , prior to transfer to 

hospital, may be life-saving, and avoids potential 

Table 22.3 A grading for anaphylactic reactions, proposed by Sampson. 25 The severity score should 

be based on the most severe symptom in any domain. Symptoms in bold are absolute indications for 

the use of epinephrine (adrenaline) 

Gastrointestinal 

Grade Skin tract Respiratory Cardiovascular Neurological 

1 Localized itching, oral itching or 

flushing, urticaria, tingling, mild 

angioedema lip swelling 

2 Generalized itching, any of the above, nasal congestion change in 

flushing, urticaria, nausea and/or and/or sneezing activity level 

angioedema single vomiting 

episode 

3 Any of the above any of the above rhinorrhea, tachycardia change in 

plus repetitive marked congestion, (increase activity 

vomiting sensation of throat >15 beats/min) level plus 

itching or tightness anxiety 

4 Any of the above any of the above any of the above, any of the above, ‘light 

plus diarrhea hoarseness, ‘barky’ dysrhythmia headedness,’ 

cough, difficulty and/or mild feeling of 

swallowing, hypotension ‘impending 

dyspnea, wheezing, doom’ 

cyanosis 

5 Any of the above any of the above, any of the above, severe loss of 

loss of bowel respiratory arrest bradycardia consciousness 

control and/or hypotension 

or cardiac arrest

dosage errors at such a time of extreme stress. Any 

child thought to be at risk of an anaphylactic reaction 

to food should be prescribed such injection 

devices (at least two or three should be prescribed, 

so that all those caring for the child are equipped), 

and parents and carers should be trained in their 

use. Any severe immediate reaction to foods necessitates 

urgent transfer to an appropriate medical 

setting, such as an Accident and Emergency 

Department. Other treatments that may be needed 

include oxygen, intravenous hydrocortisone, 

chlorpheniramine and inhaled β-adrenergic bronchodilator 

therapy. 25 Supportive treatment for 

hypotension or cardiac dysrrhythmia may be 

required, and in the most severe cases the patient 

may need to be transferred to an intensive therapy 

unit. 

The true incidence of anaphylactic death due to 

food allergy is unknown. A recent UK report 

suggested a low incidence of 0.006 deaths per 

100000 children per year, 27 but this is thought to 

be a significant underestimate, as many cases were 

unlikely to be identified from the study of death 

certificates and clinical reporting alone. 25 

In the follow-up of a patient who has had an 

immediate hypersensitive response to food antigens, 

a decision needs to be taken about the level 

of prophylaxis required, and whether or not to 

prescribe an epinephrine pen. Clearly the severity 

of the first response will inform this decision, and 

it is probably better to err on the side of caution if 

foods such as peanuts are implicated, because of 

Table 22.4 Clinical manifestations in food allergic responses 


their propensity for triggering particularly severe 

episodes. If there is doubt about the food involved, 

both skin prick tests and specific IgE radioallergosorbent 

test (RAST) may be very helpful. 

However, these should be postponed for several 

weeks after an episode of anaphylaxis, as they may 

be artifactually negative in the immediate aftermath 

of a severe reaction. 

Late-onset symptoms 

Slow-onset symptoms may be more insidious and 

their true allergic nature may not be recognized 

(Table 22.4). These may include failure to thrive or 

chronic diarrhea due to enteropathy or colitis, 

eczema, rhinitis, or rectal bleeding. 1,24 As these are 

likely to be mediated by T cells in a delayed hypersensitive 

reaction, they may not be so clearly 

linked to food ingestion. Children may, however, 

manifest both delayed and immediate-onset symptoms. 

Analysis of IgG subclasses and peripheral 

lymphocyte subsets may identify the child at 

increased risk of delayed food allergic reactions. 14 

Certain specific presentations can be recognized, 

as discussed below. 

Food protein-induced enterocolitis 

This disorder is most common in young infants 

below the age of 3 months, and usually presents 

with blood streaking of stools in the absence of 

marked weight loss or systemic upset. Anemia is 

1. Quick onset wheezing, urticaria, angioedema, rashes, vomiting, gastroesophageal reflux, 

anaphylaxis 

2. Late onset diarrhea, abdominal pain, allergic rhinitis, atopic eczema, food-sensitive enteropathy 

or colitis, rectal bleeding, constipation, protein-losing enteropathy 

3. Less clear responses irritable bowel syndrome, chronic fatigue, attention-deficit with hyperactivity, 

autistic symptoms 

4. Secondary general effects eosinophilia, iron deficiency anemia, hypoproteinemia 

For group 3 conditions, there are anecdotal reports of clinical improvement with dietary exclusions. However, there 

are as yet few properly validated studies, and it is likely that only a proportion of such patients will benefit. While 

many maintain an open-minded approach, it is important to ensure that any such diet is nutritionally adequate (joint 

management with dietitians is ideal), and that clinical responses to exclusion and challenge are sufficiently striking 

to justify continuing exclusion diets.

324 


unusual, but an elevated platelet count 

(>450x10 9 /l ) is characteristic. Cow’s milk or soy 

proteins are the most common causative antigens, 

and it is common for such symptoms to occur in 

exclusively breast-fed infants, triggered by milk 

protein in the mother’s diet. 28 It is important to 

recognize that negative skin prick tests do not 

exclude this diagnosis, and indeed most cases are 

negative. 24 If colonoscopy is performed, the colitic 

changes are usually milder than with classic 

inflammatory bowel disease, and the macroscopic 

findings are dominated by loss of vascular pattern, 

prominent lymphoid follicles with a rim of perifol- 

(a) (b) 

(c) (d) 

licular erythema (red halo sign) and an easily traumatized 

mucosa. Histological changes include 

mononuclear cell infiltration, mucosal 

eosinophilia with evidence of degranulation and 

the presence of lymphoid follicles in the majority 

of colonic biopsies. If the ileum is visualized, 

lymphoid hyperplasia is usually seen. Recent data 

suggest a concordance between the endoscopic 

finding of ileocolonic lymphoid hyperplasia and 

food allergies (Figure 22.1), not restricted to those 

infants with allergic enterocolitis alone, 29 which 

may be associated with an increase in mucosal γδ 

T-cell infiltration. 30 See also Chapter 30. 

Figure 22.1 Lymphoid hyperplasia is an important endoscopic feature in food allergies. 29 This ileocolonoscopy was 

performed in a 2-year-old girl with multiple food allergies, and demonstrated ileal lymphonodular hyperplasia (a), with 

prominent reactive germinal centers on histology (b), together with multiple colonic lymphoid follicles (c – a typical follicle 

is arrowed). Histology of each biopsy in her colonic series demonstrated a lymphoid follicle (d).

Some infants manifest a form of food proteininduced 

enterocolitis that is more severe than the 

classic variant, and is less often induced by cow’s 

milk. 24 The histological response is more severe, 

with evidence of frank colitis including crypt 

abscesses, and the response to food challenge may 

include shock. 

Food protein enteropathy 

The most common and best described mucosal 

manifestation of food allergy is food-sensitive 

enteropathy, in which there is an immunologically 

mediated abnormality of the small intestinal 

mucosa, which may include excess lymphocyte 

infiltration, epithelial abnormality or architectural 

disturbance. This may often impair absorption and 

less commonly causes a frank malabsorption 

syndrome. This continues while the food remains 

in the diet and remits on an exclusion diet. This is 

best described for cow’s milk, and cow’s milksensitive 

enteropathy (CMSE) has been recognized 

for over two decades. 32 Enteropathy can also occur 

in response to other antigens, notably soy. The 

lesion is less severe than celiac disease, but is 

characterized by similar findings of crypt elongation 

and villus shortening, giving a reduction of 

overall crypt/villus ratio. There is usually an 

increase of mononuclear cell density within the 

mucosal lamina propria, often including prominent 

eosinophils, and the intraepithelial lymphocyte 

density is often increased (Figures 22.2 and 

22.3). The lesion is not associated directly with 

systemic IgE responses, and skin prick tests are 

often negative. Analysis of mucosal lymphocytes 

confirms excess T-cell activation, with either a Th1 

dominated or mixed Th1/Th2 response. 31,33,34 The 

consequences of this mucosal T-cell activation 

include reduction in brush-border disaccharidase 

expression, leading to impaired carbohydrate 

absorption, and a secondary reduction in pancreatic 

enzyme release, 35 both contributing to malabsorption. 

There is evidence that some children do 

not grow out of CMSE in early childhood, and an 

abnormal mucosa may be seen in later childhood. 

36 

In cases of diagnostic uncertainty, it may be necessary 

to confirm the return of mucosal abnormality 

by food challenge. This was a more common practice 

in the past, when the very existence of foodsensitive 

enteropathies other than celiac disease 


was uncertain. Improvements in infant formulas 

have led to a change in the mucosal appearances of 

CMSE, so that celiac-like villous atrophy is now 

very rare in the developed world. Morphometry of 

recent cases of CMSE confirms a less severe lesion 

than archival biopsies from the 1980s. 14 This 

causes some histopathological difficulty, as there 

is no international consensus in the reporting of 

subtle lesions such as villous blunting or mild 

mucosal eosinophilia. 

Eczema/atopic dermatitis 

There seems little doubt that food-allergic 

responses may contribute to the clinical presentation 

of eczema in infancy, but considerable uncertainty 

about whether adults have anything to gain 

from exclusion diets. 37 There is evidence that children 

with eczema have elevated food-specific IgE 

in serum, and that food challenges of eczematous 

children induce increases in circulating eosinophil 

and mast cell products. 38 There is evidence of 

enhanced intestinal permeability in infants with 

eczema, potentially contributing to sensitization 

through bypass of enterocyte antigen-handling 

mechanisms. 39 The response within the skin is 

dominated by Th2 cytokines, and characterized by 

influx of both T lymphocytes, which express skinhoming 

markers such as the cutaneous lymphocyte 

antigen (CLA), and eosinophils. 37,40 The 

mechanisms by which skin-homing markers 

become expressed on gut sensitized cells remains 

uncertain, as expression of the gut-homing marker 

β7 integrin is likely to have been required for 

initial homing to the intestine. 1 There remains the 

intriguing possibility that bacterial products, 

particularly superantigens from staphylococci and 

streptococci, may specifically up-regulate CLA 

expression in an interleukin (IL)-12-dependent 

fashion, and thus promote skin homing of lymphocytes 

sensitized to dietary antigens. 41 Staphylococcus 

aureus may be an important specific 

complicating factor, as 24 and 28kD proteins 

within the toxins may directly induce an IgE-mediated 

response and thus contribute to allergic 

immunopathology. 42,43 Deficiency in innate 

immune responses, in particular production of βdefensins, 

may contribute to the propensity for 

superinfection with toxin-producing staphylococci 

in children with allergic eczema. 44 Therefore, an 

important consideration in the infant or young 

child with eczema is whether both the diet and the

326 

(a) 


(b) (c) 

Figure 22.2 The relatively subtle appearances of food-sensitive enteropathy. Duodenal biopsy of the same patient as 

shown in Figure 22.1, showing minimal evidence of duodenal blunting, but with a patchy increase in mononuclear cell 

infiltration within the lamina propria (a). High-power views (b, c) show infiltration of eosinophils within the lamina propria 

and epithelium, together with a moderate increase in mononuclear cells. 

bacteriological status of the child have been 

optimized. 

A recent large study of skin prick reactivity to 

dietary antigen in infants with eczema identified 

positive skin prick tests for cow’s milk, egg or 

peanut in 22% of 6-month-old infants with 

eczema, compared to only 5% without eczema. 45 

At 1 year the incidences were 36% and 11%, 

respectively, giving a calculated attributable risk of 

65%. This supports data by Kjellman and 

Hattevig 46 that the development of infantile, but 

not later-onset eczema, is associated with IgE 

antibodies to food antigens. Whether the IgE 

antibodies are directly causative, or alternatively a 

marker of dietary sensitization in infants

(a) (b) 

predisposed to high IgE levels, remains uncertain. 

However, there is clear evidence that manipulation 

of the diet of the eczematous child may be beneficial. 

A double-blind study by Atherton et al in 

1978 47 found that two-thirds of 2–8-year-old children 

with atopic eczema were improved by exclusion 

diets. Subsequent studies have broadly 

confirmed this finding, although in most cases the 

response was not so striking, except in younger 

infants. 37 The dominant inducing antigens of food 

allergy-induced childhood eczema are eggs, milk, 

soy, and peanut in young infants, with the addition 

of wheat, tree nuts and fish in older infants. Most 

children tend to outgrow allergies to eggs, milk, 

wheat and soy, but tend to have persistent reactions 

to peanuts, tree nuts, shellfish and fish. The 

use of skin patch testing has suggested that multiple 

sensitizations are common in affected infants 

below 2 years, and thus exclusion of single antigens 

may not give satisfactory clinical responses. 48 

In addition to antigen exclusion, the use of probiotic 

treatment has been reported to improve the 

symptoms of chronic eczema in food-allergic 

infants. 49 Whether this is because of a direct effect 

on epithelial integrity, or competitive reduction of 

toxin-producing staphylococci is as yet unknown. 

Probiotics are considered in further depth later in 

this chapter, as well as in Chapter 32. For the 


Figure 22.3 There may be an increase of intraepithelial lymphocytes in food-allergic children. This child with cow’s milksensitive 

enteropathy showed normal villous architecture, but increase in CD8 intraepithelial lymphocytes (a). The CD4 

cell population lies essentially within the lamina propria (b). Photomicrographs courtesy of Dr Franco Torrente. 

affected infant who is exclusively breast fed, 

maternal dietary exclusions can improve the 

eczema, but potentially at the cost of maternal 

nutritional inadequacy if multiple exclusions are 

required. 50 In addition, some infants may not 

respond completely to extensively hydrolyzed 

formulas, due to response to the residual milk antigens, 

and these may show improvement only with 

an amino acid formula. 51,52 

Allergic dysmotility 

The concept that food allergies might trigger 

intestinal dysmotility in pediatric patients is relatively 

new, but there is mounting evidence that 

dietary antigens (most commonly cow’s milk, soy 

or wheat) can induce gastroesophageal reflux or 

constipation. 8,53–55 Gastrointestinal investigation 

of children with delayed food allergic responses 

frequently uncovers a history of infant colic, 

gastroesophageal reflux and chronic abdominal 

pain. 5,14,24,51,52 Conversely, amongst infants 

presenting with colic, there is a significant incidence 

of underlying cow’s milk allergy. 56,57 There 

may additionally be evidence of small-intestinal 

enteropathy or allergic colitis. However, it is not 

uncommon for food allergy to be overlooked 

because ‘the investigations are negative’.

328 


In infancy, food allergy-induced gastroesophageal 

reflux is often accompanied by a complex presentation, 

including low-grade enteropathy with 

secondary carbohydrate malabsorption, colic, irritability, 

eczema and prolonged viral infections. 5,8,14 

The infants may fail to thrive, and show foodaversive 

behavior, or weight gain may be acceptable. 

5,14 In many cases, reactions to hydrolysate 

formulas occur, and a therapeutic trial of an amino 

acid formula should be considered. 5,52,58,59 

Dermatographia may be a useful clinical pointer in 

an apparently colicky infant, as is a family history 

of allergies. A distinct pattern on 24-h pH testing 

has been reported to be associated with antigeninduced 

gastroesophageal reflux, in which there is 

gradual reduction in esophageal pH following a 

feed. 53 The frequent finding on esophageal biopsy 

is mucosal eosinophilia, which may be related to 

expression of the chemokine eotaxin in milkinduced 

gastroesophageal reflux. 55 

Even in the older child, milk responses may be a 

cause of continuing symptoms, including chronic 

abdominal pain, with endoscopic findings of 

lymphonodular hyperplasia. 60 There is some evidence 

that delayed allergic responses to milk in 

infancy are not always outgrown, and thus the 

diagnosis should be considered in the older child 

with an atopic history who presents with chronic 

abdominal pain. 36 There is also evidence that 

constipation can be triggered by delayed allergic 

responses to cow’s milk protein in older children. 

54 Once again, mucosal eosinophil infiltration 

was characteristic. Studies using anorectal manometry 

suggested that this pattern of constipation 

was caused by antigen-induced spasm of the anal 

spincter muscles, rather than a more widespread 

colonic dysmotility. 61 The use of radio-opaque 

markers may confirm the pattern of normal colonic 

transit with impaction within the rectum. 

Clinically the children often demonstrate avoidance 

posturing, leaning forward during defecation 

in an attempt to stop the large rectal hard mass 

from bearing down, while passing the softer stool 

from above. Clinical examination may be difficult, 

and even a sizeable acquired megarectum may be 

difficult to palpate. In cases of clinical doubt, a 

plain abdominal X-ray may be helpful (Figure 

22.4). One characteristic pattern is of fecal 

impaction within the rectum, together with abundant 

gas within the small intestine, related to 

malabsorption of carbohydrates plus constipationassociated 

small-bowel bacterial overgrowth. 

Figure 22.4 Plain abdominal X-ray of a child with 

non-IgE-mediated food allergies, demonstrating acquired 

megarectum with fecal impaction. Conventional constipation 

therapy was ineffective, and a cow’s milk- and wheatfree 

diet were required. 

Eosinophilic esophagitis and eosinophilic 

enteropathy 

Eosinophilic esophagitis and eosinophilic enterocolitis 

are emerging clinical entities, which 

overlap with non-IgE-mediated food allergy, but 

which may also occur without recognizable food 

responses. 62 While an apparently increasing cause 

of infant gastroesophageal reflux disease, 

eosinophilic esophagitis is also increasingly seen 

in older children, who often present with abdominal 

pain, dysphagia or vomiting, sometimes with 

associated loose stools. 63,64 In some cases, 

eosinophil recruitment is confined to the serosa, 

and may be missed on mucosal biopsies. In many 

cases, symptoms of esophagitis are severe and 

prolonged.

At endoscopy, the esophagus shows a distinctive 

finding of linear furrows or transverse rings, and 

the mucosa appears granular. 64 The mucosa is 

traumatized unusually easily. 65 Histological diagnosis 

is based on the detection of five or more 

eosinophils per high-powered field. Recent reports 

of endoscopic ultrasound examination show 

increased thickness of the esophageal wall. 66 The 

results of 24-h pH testing are variable, and novel 

techniques such as luminal impedance testing 

suggest that much non-acid reflux may occur. 67 

Skin prick testing is often negative, but a combination 

of skin prick and skin patch testing may be 

helpful in identifying cases of food-induced 

eosinophilic esophagitis. 68 

Later in the chapter, the potential mechanisms of 

eosinophil recruitment within the mucosa will be 

addressed. The eosinophil chemokine eotaxin is 

clearly important in this process, and indeed this 

chemokine was up-regulated within the basal 

esophageal epithelium in infants with milkinduced 

reflux, in comparison to those with 

simple mechanical gastroesophageal reflux. 55 

Management of eosinophilic esophagitis 

Particularly in younger infants, it is important to 

perform adequate dietary exclusions. In a significant 

minority of affected infants, symptoms are not 

adequately relieved using hydrolysate formulas, 

and an amino acid-based formula may be 

required. 58 Effective acid reduction therapy with 

ranitidine or omeprazole, together with a prokinetic 

such as domperidone, are frequently used 

in conjunction. 67 An important clinical finding is 

the rapid symptomatic worsening during viral 

illnesses, which is unresponsive to dietary exclusion. 

This often requires a temporary increase 

in antacid therapy. 

For the older child, dietary exclusions are often 

less helpful, but a therapeutic trial of a ‘few foods’ 

diet may determine whether this is an avenue 

worth exploring. Topical corticosteroids such as 

inhaled fluticasone have proved effective in cases 

where diet has proved ineffective. 69 More recent 

evidence suggests that leukotriene antagonists 

such as montelukast may be helpful in corticosteroid-resistant 

eosinophilic esophagitis. 70 

Respiratory symptoms 

Testing for food allergies 329 

Respiratory allergies, particularly asthma, are 

increasingly common in young children. It is also 

well recognized that the immediate hypersensitive 

response to a food allergen includes respiratory 

symptoms such as wheeze (Table 22.4). What has 

been less clear is whether delayed responses to 

food antigens may include worsening of respiratory 

status in asthma, or can be implicated in 

upper airway disorders such as rhinitis. 71 Foodinduced 

wheezing appears most common in young 

infants. 5,17 The estimated prevalence of foodinduced 

wheezing is under 6% of the total population 

of children with asthma, but it occurs much 

more frequently in children with cow’s milk 

allergy (29%) or atopic dermatitis (17–27% 71 ). 

Whether antigen-induced gastroesophageal reflux 

can contribute to respiratory symptoms is an 

important consideration, and there is potentially 

important recent evidence suggesting that effective 

treatment of gastroesophageal reflux may significantly 

diminish the requirements for bronchodilator 

therapy in an unselected population of childhood 

asthmatics. 72 However, it is not clear how 

many children had straightforward mechanical 

gastroesophageal reflux and how many may have 

had an underlying allergic dysmotility. 

Testing for food allergies 

Food challenge testing 

The essential criterion for diagnosis of food allergy 

is a response to an elimination diet, and other 

diagnostic tests are secondary to this. If there is 

allergy to a single food, exclusion should induce 

relief of all symptoms, and restore normal growth. 

For secure diagnosis, a positive response to challenge 

with the food antigen is strongly supportive 

of the diagnosis of food allergy. This is not always 

practicable in routine practice, if diagnostic tests 

were positive at diagnosis, and many parents may 

refuse challenge if their child has improved 

dramatically. Insurance companies, however, may 

require evidence of positive food challenge for 

reimbursement. 

In addition to initial challenge for first diagnosis, 

subsequent challenge may be performed when it is 

reasonably likely that tolerance has been regained.

330 


This is usually after 2 years, but often later, 

especially in multiply allergic children. The 

European Society for Paediatric Gastroenterology, 

Hepatology and Nutrition 73 made recommendations 

for challenge criteria for children 

with predominant gastrointestinal symptoms, 

suggesting that blinded challenge is not always 

necessary in younger children, but that smallbowel 

biopsy should be performed in cases with 

failure to thrive or diarrhea. Skin prick testing (see 

later) may provide more specific guidance for children 

with immediate reactions. 

In children with multiple food allergies, the 

response to elimination of single antigens is 

incomplete, and lengthy assessment with a very 

restricted diet is often required. Such situations 

may become complicated, particularly since the 

advent of Internet sites that implicate food allergies 

in an unfeasibly broad spectrum of disorders, 

and it may be difficult to persuade some parents to 

broaden their child’s diet. For the child who manifests 

the symptoms of only non-IgE-mediated 

allergy, it may become extraordinarily difficult to 

obtain a clear picture of the true state of current 

true allergy. This situation is complicated by the 

minor immunodeficiency often associated with 

multiple food allergies, and the exacerbating 

effects of intercurrent viral illnesses. 14,19,20 It is 

important not to perform food challenges while a 

child is systemically unwell. For cases of multiple 

sensitization, with delayed responses, it becomes 

logistically difficult to perform lengthy blinded 

challenges. Close teamwork with an experienced 

dietitian is essential in management of any such 

complicated cases. 

The open food challenge is the most common form 

of diagnostic challenge, and is performed either in 

the out-patient clinic or in a day ward, depending 

on the severity and type of reaction expected. 74 

Many centers will use a graded challenge in those 

children who manifest immediate reactions, 

initially placing a single drop of milk or other 

antigen on the skin, then on the lips, and then 

giving increasing amounts by mouth, leaving a 

period of several minutes between each stage. For 

the child with a history of severe reaction, it is 

mandatory that there be adequate medical supervision 

with the presence of appropriate resuscitation 

and drugs. For those with a history of anaphy- 

laxis, an intravenous line is usually inserted prior 

to the procedure. 

For the child who makes delayed reactions only, 

the test may have to be completed at home for 

logistic reasons. False-negative results have been 

reported if late reactions are not taken into 

account. In a study of 370 challenges in 242 children, 

five exhibited mild immediate reactions that 

manifested only on the second day at home. 75 

These reactions were subsequently confirmed by 

skin prick test and double-blind placebocontrolled 

food challenge, and the authors 

suggested supervised feeding of antigen on the 

second day to identify late reactors. Hill et al 17 

identified very late reactions (up to 3 days) which 

required up to 120ml to elicit. Recent data suggest 

that even later reactions may occur during cow’s 

milk challenges, with the onset of gastrointestinal, 

respiratory or cutaneous responses beyond 1 week 

after reintroduction. 76 Therefore, caution and 

judgement are needed to interpret food challenge 

tests, to prevent the missing of true late phenomena, 

but also to exclude over-reporting of symptoms 

by parents convinced that food allergy is 

responsible for all their child’s various symptoms. 

The ‘gold-standard’ challenge test, the doubleblind 

placebo-controlled food challenge is a 

cumbersome and time-consuming intervention, 

but is clearly necessary for assessment of cases 

with genuine uncertainty about sensitization. 

24,73,77 In cases of true uncertainty, the test can 

firmly establish tolerance or persistent reactivity 

in a way that no other test can. Its value is much 

lower when there are large numbers of foods to be 

tested, and the child makes delayed responses 

only. Normal day-to-day variation may then be 

overinterpreted, the situation can become stressed 

if performed on an in-patient basis, or intercurrent 

viral illness induces symptoms interpreted as due 

to the food allergy. This test requires extremely 

good teamwork between pediatrician, dietitian, 

pediatric nursing staff and the child’s family. No 

universally accepted protocol exists, 78 but in 

general the suspected allergen or placebo is given 

in disguised form, either by capsule or hidden in a 

liquid over a period of around 2h. The child 

should not be receiving antihistamines and should 

not have received the antigen for at least 2 weeks, 

and should be well. A total dose of around 10g is 

normally taken as sufficient, although this would

not pick up some of the delayed reactors identified 

by Hill et al, 17 Carroccio et al 76 or Caffarelli and 

Petroccione. 75 Nevertheless, for immediate allergies, 

the test is highly specific and of very high 

prognostic value, with a suggested false-positive 

rate below 1% and false-negative rate below 5%. 78 

Skin prick testing 

The skin prick test remains a cornerstone of the 

diagnosis of immediate allergic reactions, but is 

usually negative in those who manifest delayed 

reactions only. 14,74 This is performed by placing a 

drop of the potential antigen on the skin (usually a 

commercially obtained solution, although some 

units use freshly prepared foods) and introducing 

it into the skin through a puncture device such as 

a lancet. A positive control (histamine) and negative 

control (saline) are used at the same time, and 

the results read at 15–20min. The test is based on 

the induced degranulation of cutaneous mast cells 

by antigen binding and cross-linking of their 

surface IgE molecules. The size of wheal elicited 

determines whether the test is regarded as positive. 

Usually a wheal of 3mm or more is taken as a 

positive reading, although in young infants the test 

can be falsely negative, as the histamine-induced 

positive control is much smaller in infancy than 

later childhood, owing to the smaller numbers of 

cutaneous mast cells. 79 Recent data suggest that 

the size of wheal obtained may be an important 

predictor of reaction, and large wheals (>8mm) 

may be so highly predictive of sensitization that 

unnecessary food challenges can be avoided. 80,81 

The study by Sporik et al, 80 of 467 children aged 

from 1 month to 16 years, correlated the size of the 

wheal elicited to cow’s milk, egg or peanut with 

clinical outcome. Using the traditional cut-off 

value of 3mm was not found to be helpful in 

predicting a response to challenge, and many 

false-positive and false-negative results were 

obtained. However, using a cut-off value of 8mm 

for cow’s milk and peanut and 7mm for egg, they 

found no children with a negative response on 

challenge. Their calculations suggest that they 

could avoid clinical testing of 33% of milk-allergic, 

56% of egg-allergic and 68% of peanut-allergic 

patients. These are potentially very important 

results, but clearly do require local replication, as 

testing solutions and technique will vary from 

center to center, and a negative test will not rule 

Testing for food allergies 331 

out a delayed non-IgE-mediated response to an 

antigen. 

Roberts and Lack 79 have extrapolated from the 

data from Sporik et al to suggest that a more 

precise risk value can be obtained using the Fagan 

likelihood nomogram, 82 in which the risk of true 

reaction based on history is used together with the 

result of the skin prick to determine the overall 

likelihood of true sensitization. They provide an 

example where a child with low pre-test likelihood 

of peanut sensitization (headache and vomiting 4h 

after a peanut butter sandwich) would have a 0.2% 

likelihood of true peanut allergy with a 3mm 

wheal, rising to 5% with a 6mm wheal and >99% 

only at 10mm, in contrast to a child with a high 

pre-test likelihood (urticaria and wheeze on two 

occasions within minutes of accidental peanut 

exposure), who would have a 15% likelihood of 

true peanut allergy with a negative skin prick test, 

rising to 70% with a 3mm reaction and 96% with 

a 6mm reaction. 

Skin patch testing 

The use of the skin patch (atopy patch) test, in 

which the relevant antigen is maintained against 

the skin under a sealed patch for 48h, has been 

suggested to identify cases of non-IgE-mediated 

delayed allergy. A positive test is signaled by the 

finding of erythema and induration at 72h. 

Combination of patch testing with either skin 

prick testing or specific IgE testing has identified 

significant numbers of food-sensitized children 

who may have been negative on classic testing. 83,84 

Of children with delayed reactions to antigen, 89% 

were identified by patch test in one study. 83 This 

test has not become widely used and remains 

under evaluation. Recent reports do, however 

suggest that patch testing may be clinically useful, 

particularly in the presence of eczema. 85,86 There 

are some logistic difficulties, in that the test should 

be read only after 3 days, requiring a second clinic 

visit, and some children will not tolerate an occlusive 

dressing for so long. It is also potentially open 

to artifact due to lack of supervision, and our unit 

has had at least one case of factitious illness, in 

which irritants were introduced beneath the occlusive 

dressing by the mother. However, it appears 

that the test induces a specific T-cell response to 

dietary antigen, 87 and thus a properly performed 

patch test may be helpful in confirming delayed

332 


food allergic responses in cases of diagnostic difficulty. 

Specific IgE testing 

Testing of specific IgE production to individual 

foods can be helpful. Formerly known as RAST 

testing, the technique is now usually based on 

enzyme-linked immunosorbent assay (ELISA) or 

the Pharmacia Cap system. It provides results that 

are complementary to skin prick testing, but at 

greater cost and with more delay. However, there is 

evidence that the information provided can be 

clinically predictive. Using the Pharmacia Cap 

system, positive predictive values of 95% were 

found for egg at 6kUA/l, milk at 32kUA/l, peanut 

at 15kUA/l and fish at 20kUA/l. 88 These tests are 

frequently reported on a semiquantitative scale of 

0 (no specific IgE) to 6 (high titers), with increasing 

likelihood of clinical relevance above level 3. 

However, there is wide variance between centers, 

and it is important to perform local audit to determine 

the clinical relevance of reported specific 

IgE. There is an increased likelihood of longlasting 

allergy in children with higher titers of 

specific IgE for milk, casein or β-lactoglobulin. 89 

Potentially important prognostic information may 

be allowed in future by study of the specific 

sequence of epitopes bound by food-specific IgE. 

Cooke and Sampson 90 identified two forms of IgE 

binding to ovomucoid (the dominant egg allergen). 

Binding to linear peptide sequences within the 

ovomucoid molecule was associated with longlasting 

allergy, whereas binding to discontinuous 

sequences, which are brought into apposition only 

by protein folding, was seen in those who outgrew 

their allergies. This may explain the phenomenon 

whereby some children will be tolerant of cooked 

egg, where the tertiary sequence has been 

disrupted in the cooking process, but still react to 

raw egg white. For cow’s milk, too, IgE reaction to 

linear sequences in casein, rather than the whey 

proteins α-lactalbumin and β-lactoglobulin, 

appears to be predictive of long-lasting milk 

allergy. IgE binding sites in specific sequences of 

αS1-casein, αS2-casein and κ-casein were identified 

in those whose allergy was not outgrown. 91,92 It is 

possible that this may provide the basis for future 

testing of milk-allergic infants, to identify those for 

whom immunotherapy may be necessary to 

prevent lifelong sensitization. 

In vitro testing 

In vitro tests for lymphocyte response remains so 

far a research tool, and simple proliferation assays 

have given quite unreliable results. However, 

analysis of cytokine production patterns, using 

single-cell techniques such as ELISPOT or flow 

cytometry, represents a promising approach for the 

future. Lymphocytes from food-allergic children 

produce a pattern of cytokines associated with Th2 

responses (IL-4, IL-5, IL-13) on antigen challenge, 

whereas those from healthy controls may make a 

more Th1-dominated response, with higher interferon-γ 

production. 93 However, studies have 

reported quite contradictory results when based 

on derived T-cell lines or clones, which may not 

represent true in vivo responses. 

A promising novel technique has recently been 

reported, in which peripheral blood mononuclear 

cells were tagged with a fluorescent molecule 

called carboxyfluorescein succinimidyl ester, 

before stimulation with peanut antigen. 94 This 

allowed simple identification of peanut-responding 

T cells by flow cytometry, and confirmed that 

T-cell responses to peanut in children with active 

allergies are indeed skewed towards Th2 (producing 

IL-4, IL-5 and IL-13, but not interferon-γ or 

TNF-α), in contrast to findings of a Th1-dominated 

response with high interferon-γ and tumor necrosis 

factor (TNF)-α in healthy controls or those who 

had outgrown their allergies. 94 The authors 

reported similar skewing in milk- and egg-allergic 

children compared to controls, suggesting that this 

is likely to be a common mechanism in IgEmediated 

food allergies. These findings imply that 

it is the host immune response, rather than a 

fundamental property of individual food antigens, 

that determines whether a Th2-skewed response 

occurs and allergy is induced. 

It should be noted that mucosal responses appear 

quite different from systemic responses, and there 

are as yet no validated tests that might help in the 

diagnosis of non-IgE-mediated food allergies 

(Figure 22.5). TNF-α production is stimulated 

within the mucosa by milk challenge of allergic 

patients, 38,95 which would not be expected from 

study of circulating T cells, 94 but may reflect its 

release from mucosal mast cells. Studies of 

mucosal T-cell responses agree in showing that 

Th1 responses are maintained in intraepithelial,

(a) (b) 

lamina propria and Peyer’s patch lymphocytes of 

food-allergic children. 23,31,96 

Specific food allergies 

Allergic responses to many food proteins have been 

described. The most common in childhood are to 

cows’ milk, soy, eggs and fish, with peanut allergy 

rapidly becoming more common. 1,3,4,24 However, 

intolerance to fruits, vegetable, meats, chocolate, 

Specific food allergies 333 

Figure 22.5 Mucosal IgE responses may be distinct from those in other sites. (a) IgE immunohistochemistry of the 

duodenal mucosa of a child with milk-induced dysmotility, but negative skin prick testing, a serum IgE below 5 kIU/l and 

no circulating specific IgE. Two types of IgE-positive cell are seen: round cells with a large nucleus and strong surface 

staining (IgE plasma cells) and irregularly shaped cells with intense granular staining (mast cells). (b) Confirmation that 

these granular cells are mast cells, as double staining for mast cell tryptase (red) and IgE (green) gives a resultant yellow 

color. Photomicrographs courtesy of Dr Franco Torrente. 

nuts, shellfish and cereals has been described. In 

adult life there is a different spectrum, with allergy 

to nuts, fruits and fish relatively more common 

than in childhood. However, as the dietary exposures 

of UK children broaden, the range of reported 

allergens also increases: thus sesame, kiwi fruit, 

mango, avocado and other allergies have increased 

in frequency. Such sensitization may depend as 

much on a combination of genetics, infectious 

challenges and timing and dose of exposure as on 

innate antigenicity of individual foodstuffs.

334 


There are no consistent associations between any 

particular food and specific syndromes, although 

some foods are more likely than others to induce 

enteropathy, such as cow’s milk and soy, and 

others usually induce immediate hypersensitivity, 

such as peanut. The incidence of gastrointestinal 

food allergy is greatest in early life and appears to 

decrease with age. However, analogy with celiac 

disease, in which late-onset enteropathy is more 

likely to be clinically subtle, suggests that the 

increase in colonic salvage that occurs with age 

may mask true food-sensitive enteropathy. 

Although enteropathy can cause significant failure 

to thrive, complex multiple allergies may also 

occur in the presence of normal growth. 5 

Cow’s milk 

Cow’s milk allergy may commonly present either 

as an immediate response, including anaphylaxis, 

or with delayed responses within the gut or skin. 

CMSE was frequently diagnosed in the past 

because of failure to thrive following an episode of 

gastroenteritis, 97 and the consequent lactose intolerance 

often inappropriately managed with 

reduced-lactose formulas without cow’s milk 

antigen exclusion (still common practice in some 

developing world countries). Modern adapted 

formulas are now much less sensitizing, and the 

mucosal lesions less severe. While positive skin 

prick tests and milk-specific IgE may be seen in 

some children with enteropathy, they are much 

more frequent in children who have immediate 

reactions to milk. Cow’s milk colitis is most 

common in breast-fed babies, whose mothers are 

consuming milk in their diet, and usually presents 

with low-grade rectal bleeding. For reasons 

unknown, it is unusual for one infant to develop 

both cow’s milk enteropathy and colitis. Milkinduced 

dysmotility is discussed above. 

Egg 

By contrast to cow’s milk, egg allergy usually 

presents either as an acute hypersensitive 

response or with delayed respiratory or cutaneous 

reactions, with worsening of asthma or eczema. 

While vomiting may occur soon after ingestion, or 

diarrhea ensue after a few hours, there is little 

evidence that egg can induce small-intestinal 

enteropathy. 1 Skin prick tests, patch tests and 

specific IgE to egg are more often positive than for 

other antigens, 86 and may be predictive of time 

taken to outgrow egg allergy. About half of under- 

2-year-old children who develop egg allergy will 

tolerate it during 3 years of follow-up, with the size 

of skin prick reaction and specific IgE potentially 

predictive of those children who are unlikely to 

outgrow allergy. 79,98 

Soy 

Soy-based formulas have for some years been used 

in infants with cow’s milk allergy, although more 

commonly by general pediatricians than pediatric 

gastroenterologists. However, recommendation of 

soy milk use by the American Academy of 

Pediatrics Committee on Nutrition 99 may increase 

the use of soy in comparison to hydrolysates. Soybased 

formulas are as antigenic as cow’s milk 

formulas, 100 and the reported reactions span the 

range from anaphylaxis to enteropathy, eczema 

and respiratory symptoms. 1 A 30kD protein in soy 

may induce cross-reactivity to cow’s milk 

caseins, 101 potentially explaining the high incidence 

of soy intolerance in cow’s milk-allergic 

children. An important consideration is that antigenicity 

of soy-derived products is strongly influenced 

by methods of preparation, and thus children 

may react to some soy-based products and 

not others. 102 Unlike in antigens such as peanut 

and egg, skin prick testing is frequently not a good 

predictor of subsequent clinical reactions to soy. 79 

Patch testing may provide more clinically relevant 

information, particularly in a child with eczema. 85 

Wheat 

Acute allergic reactions to wheat are very uncommon, 

although wheat anaphylaxis has been 

described, 103 and an ω-gliadin has been characterized 

as the likely sensitizing antigen in children 

with immediate reactions. 104 By contrast to the 

relative rarity of immediate reactions, delayed 

hypersensitive reactions are common and clinically 

important. Celiac disease is particularly 

important, and affects at least 1% of European and 

North American populations. 105 Celiac disease is 

discussed in Chapter 27 in depth. However, it is 

important to recognize that a low IgA predisposes

to both celiac disease and food allergies. It is thus 

advisable that serological testing for celiac disease 

should be performed in all food-allergic patients at 

some stage during their diagnostic evaluation. 

There is increasing recognition that wheat products 

may play a disproportionate role in inducing 

intestinal dysmotility, such as gastroesophageal 

reflux and constipation. There are also reports that 

wheat and cow’s milk may induce behavioral 

effects, possibly because of their natural content of 

morphine-like exorphins such as β-casomorphine 

and gliadomorphine. 106,107 While this may also 

contribute to constipation, such a response would 

technically be an intolerance rather than a true 

allergy. However, further work is clearly needed in 

what is a poorly understood but potentially important 

area. 

Peanut 

Peanut allergy is concerning, because of its rising 

incidence and its propensity to induce severe 

anaphylaxis. 3,4,24,25 It is particularly important in 

childhood allergy as a cause of fatal anaphylactic 

reaction. 108 Even trace amounts of peanut can 

cause death in those severely sensitized. The surge 

in peanut hypersensitivity may relate to novel 

patterns of exposure, and there is recent evidence 

to suggest that percutaneous sensitization may be 

more important than simple ingestion. 108 Analysis 

of the Avon Longitudinal Study of Parents and 

Children identified that prenatal sensitization was 

extremely uncommon, but that peanut allergy was 

associated with intake of soy milk, rash over joints 

or a crusted oozing rash, and in particular use of 

skin creams for eczema that contained peanut 

oil. 109 In this study, cases were initially identified 

on the basis of a questionnaire, and then subsequently 

the diagnosis was confirmed by doubleblind 

placebo-controlled food challenge. From a 

studied cohort of just under 14000 children, 49 

were identified with a history of peanut allergy 

and the diagnosis confirmed in 23 of 36 children 

tested. 

T-cell responses appear important in determining 

sensitization to peanut, and indeed there has been 

one report of peanut anaphylaxis transferred to the 

recipient of a liver transplant. 110 Intriguingly, 

chimerism was noted in the skin, but not the 

Specific food allergies 335 

blood, of the recipient, which implies that 

lymphocyte homing had occurred. The T-cell 

response of peanut-allergic, but not tolerant, children 

is skewed towards Th2 cytokines, 94 suggesting 

that there is no innate property of peanuts that 

is responsible for allergic sensitization. However, 

the severity of peanut reactions does argue for 

some additional factor beyond simple Th2 

skewing, and it is thus notable that the peanutderived 

lectin peanut agglutinin is used by pathologists 

to identify germinal centers in lymphoid 

follicles. In a rodent model of food allergic sensitization, 

peanut agglutinin was notable amongst 

dietary antigens for its ability to induce high IgE 

responses. 111 Whether the presence of peanut 

agglutinin affects the level of response to the 

recognized sensitizing epitopes for humans is 

currently unknown. Similar evidence from this 

model that a wheat lectin, wheat germ agglutinin, 

has a modulating effect on ovalbumin responses, 

112 suggests that the presence of lectins 

within foods may contribute to immune sensitization 

events. 

In the UK, it is recommended that children from 

an atopic background should not be given peanut 

products until after the age of 6. 3,4 However, as 

most children may be sensitized early in life by 

non-classical routes, 109 this may not be as effective 

as was initially hoped. There is evidence that 

many children may outgrow peanut allergy, and 

that skin prick testing may identify those with a 

good chance of a successful peanut challenge (see 

above). For those with established allergy and a 

history of anaphylaxis, monoclonal anti-IgE 

therapy is a promising option. 113 This is discussed 

in more depth in the section on basic mechanisms 

later in the chapter. 

Multiple food allergy 

Many infants develop gastrointestinal and other 

symptoms related to a wide variety of foods. The 

condition of multiple food allergy 5 provides great 

challenges for the family, the child and the allergist. 

Reactions may be immediate or delayed, and 

do not differ significantly from those described 

above for individual foods. Affected children often 

have a family history of atopy, may have increased 

eosinophils in the peripheral blood, with elevated 

serum IgE and positive specific IgE, and skin tests

336 


to specific foods. 8,14,24,51 Many cases appear to 

sensitize through maternally ingested antigens 

during exclusive breast feeding, with the small 

amounts of dietary proteins either sufficient to 

sensitize or insufficient to tolerize. A specific 

defect in oral tolerance for low-dose antigen has 

been postulated as a cause of this phenomenon, 114 

supported by recent data of a defective generation 

of Th3 cells within the mucosa of affected children. 

34 Affected children may show residual intolerance 

of hydrolysates. 5,14,52 

Recommendations for food allergen 

avoidance 

There remains controversy about the stringency of 

allergen avoidance required in food allergies, 

recently reviewed by Zeiger. 115 Two position statements 

have been published, by the American 

Academy of Pediatrics (AAP) 99 and a joint statement 

by the European Society for Pediatric 

Allergology and Clinical Immunology (ESPACI) 

and the European Society for Pediatric 

Gastroenterology, Hepatology, and Nutrition 

(ESPGHAN). 116 These statements deal with two 

areas of importance: the primary prevention of 

development of food allergies, and the treatment of 

the affected child. 

With respect to primary prevention, there are areas 

of clear concordance, and both statements support 

the limitation of primary prevention to high-risk 

infants only, and the use of hypoallergenic formulas 

(ideally extensively hydrolyzed) but not soy 

milk for bottle-fed high-risk infants. High risk is 

defined on family history grounds rather than any 

perinatal testing, although the AAP defines a positive 

family history as two first-degree relatives 

with atopic disease and the ESPACI/ESPGHAN 

definition requires only one. Neither recommend 

maternal exclusion diets during pregnancy and 

both recommend exclusive breast feeding (AAP 6 

months, ESPACI/ESPGHAN 4–6 months). While 

the European bodies do not recommend a maternal 

exclusion diet during lactation, the American body 

recommends exclusion of peanuts and nuts, and 

consideration of further exclusions. The European 

regulations are also less restrictive about the introduction 

of solid foods, suggesting introduction at 5 

months, rather than the much later introduction of 

cow’s milk and eggs suggested in the AAP report. 

For treatment of established food allergies, both 

statements recommend complete exclusion of the 

causative antigen, and show broad consensus in 

the management of a formula-fed cow’s milksensitized 

infant, with recommendation of an 

extensively hydrolyzed but not partially 

hydrolyzed formula. However, the AAP guidelines 

also suggest that soy is an alternative in this 

circumstance, which is not supported by the 

European guidelines. Both recommend an amino 

acid formula for the infant who is intolerant of 

hydrolysates. Neither support the use of unmodified 

goat’s or sheep’s milk. For the infant who 

becomes sensitized while breast fed, both statements 

concord in support of maternal exclusion of 

the relevant antigen, while the AAP further recommends 

weaning to an extensively hydrolyzed 

formula or soy milk. For the infant with concomitant 

malabsorption due to enteropathy, both 

recommend extensively hydrolyzed or amino acid 

formulas. 

An important recent report from the German 

Infant Nutrition Intervention (GINI) study group 117 

assessed 2252 at-risk infants, who were randomly 

assigned at birth to receive one of four blinded 

formulas, either cow’s milk-based, partially 

hydrolyzed whey, extensively hydrolyzed whey, or 

extensively hydrolyzed casein. The primary endpoint 

at 1 year of age was the presence of one or 

more of atopic dermatitis, gastrointestinal food 

allergy or urticaria. The drop-out rate was high, as 

865 remained exclusively breast fed for 4 months, 

304 left the study and 138 did not comply. Study 

of the 945 remaining treated infants showed a 

significant protective effect of extensively 

hydrolyzed casein compared to unmodified cow’s 

milk (9% vs. 16% had allergies) and atopic 

dermatitis was significantly reduced with extensively 

hydrolyzed casein or partially hydrolyzed 

whey formulas. The protective effect of 

hydrolysates was attenuated in those with a strong 

family history of atopy. 

The basic mechanisms of immune 

response to dietary antigen 

The intestine is an organ that shows the traces of 

evolutionary longevity, and indeed Cambrian 

period fossils from over 600 million years ago

show a recognizable gastrointestinal tract. 118 There 

is much current interest on the links between 

innate and adaptive immune responses, in particular 

pattern receptor molecules such as toll-like 

receptors and nod proteins that induce an immune 

response within innate cells, such as dendritic 

cells, that polarize subsequent T-cell 

responses. 119,120 Evidence that oral tolerance 

cannot be established normally in germ-free mice 

suggests that the normal flora plays an important 

role in the generation of tolorogenic lymphocytes 

and the prevention of food allergies. 121,122 The 

potential role for probiotics in prevention of food 

allergies in susceptible infants is thus likely to be 

based on the role of luminal bacteria in inducing a 

tolerant lymphocyte response. 8,9 Transgenic mice 

whose only T cells responded to ovalbumin were 

in fact entirely tolerant of ovalbumin feeds, unless 

innate immune responses to the flora were blocked 

using cyclo-oxygenase-2 antagonists, when foodsensitive 

enteropathy was induced. 123 Further 

study of dendritic cell populations within the 

intestine is likely to shed light on basic mechanisms 

of tolerance and sensitization. Genetic variation 

in receptors for bacterial products, such as 

toll-like receptors and nod proteins, is known to 

occur, and is likely to be related to allergic sensitizations, 

124 particularly as toll receptors are also 

expressed on mast cells. 125 

In addition to innate immune cells, the intestine 

also contains large numbers of primitive T and B 

cells, such as peritoneal B1 lymphocytes, γδ T 

cells, natural killer T cells and atypical CD8 cells 

with two α and no β chains. 9 Little is known about 

the role of these primitive lymphocyte types in 

food allergies, although it is intriguing that γδ-deficient 

mice have low mucosal IgA levels, 126 while 

their numbers are increased within the mucosa in 

food allergies. 30 There is also evidence that these 

types of T cell can react to lipid and glycolipid 

antigens, presented by non-classical MHC molecules 

such as CD1d, which are expressed by the 

enterocyte. 127–129 It is thus notable that IgE 

responses to β-lactoglobulin in a rodent model of 

sensitization were substantially enhanced when 

the animals were sensitized to whole milk than to 

β-lactoglobulin alone. 130 

The role of extrathymically derived T cells, which 

mature within the gut epithelium, is also unknown 

The basic mechanisms of immune response to dietary antigen 337 

but likely to be significant, particularly in infants 

born preterm. Given the numbers and situation of 

these cells, it is likely that further studies will 

unmask a relevant role in the induction of tolerance 

to dietary antigen. It is probably not coincidence 

that infants with a variety of immunodeficiencies 

have a high incidence of dietary 

sensitizations, chronic enteropathy and failure to 

thrive. 131 It is likely that T-cell responses play a 

large role in determining tolerance or sensitization 

to dietary antigen. There are differences in racial 

susceptibility to sensitization to individual antigens, 

which do not relate to simple early life exposure. 

5 

Antigen presentation by the epithelium 

One cell type that is likely to play a more significant 

role in food allergies than was previously 

recognized is the small-intestinal enterocyte, 

which separates the immune system from both 

dietary antigens and bacteria. Their role in antigen 

presentation and production of an array of 

cytokines has recently been recognized. 32,128,129,132 

An important role in induction of tolerance has 

thus been suggested. Recent data suggest that 

intestinal epithelium may directly induce a regulatory 

phenotype in CD8 cells. 133 Increased paracellular 

permeability, allowing transfer of antigen to 

the immune system without epithelial processing 

and presentation, may underlie the phenomenon 

of sensitization to food antigens during conditions 

such as rotavirus gastroenteritis. 32,97 Formal confirmation 

of the sensitizing role of excess paracellular 

permeability was provided in a transgenic 

mouse model where an intercellular adhesion 

molecule called cadherin was mutated, inducing 

severe enteropathy. 134 

Skewing of B cells towards IgE 

While non-IgE-mediated responses to dietary 

antigen may cause chronic symptomatology, IgEmediated 

mechanisms account for the majority of 

immediate hypersensitive reactions to foods. 

Transient IgE responses to foods are seen in 

normal children, so this is unlikely to be clinically 

relevant. 135 By contrast, high-level IgE responses 

are usually pathological and may be important in 

severe food allergies and anaphylaxis.

338 


Production of IgE is favored by dominance of Th2 

responses, particularly due to IL-4 and IL-13 secretion. 

136 The receptors for IL-4 and IL-13 share a 

common α chain (IL-4Rα), mutations in which 

increased signaling is associated with increased 

atopy. 137,138 Intracellular signaling downstream of 

this receptor is mediated through Stat-6 (signal 

transducer and activator of transcription-6), and 

blockade of either IL-4Rα or Stat-6 appears promising 

as a therapeutic target for IgE-mediated allergic 

reactions. 139,140 

Lineage commitment of B cells towards IgE is 

favored by the presence of IL-4 and IL-13, and 

inhibited by Th1-associated cytokines. 136 This 

may potentially occur within the Peyer’s patches 

in circumstances of Th2-skewed local responses, 

and lead to generation of mucosal IgE-producing 

plasma cells without necessarily affecting the 

commitment of circulating B-cell populations. 

Mucosally produced IgE may also be transported 

into the lumen of the gut or airway by a mechanism 

distinct from secretory component-mediated 

IgA transport. 141,142 It is thus possible that a 

compartmentalized response may occur within the 

intestine, in which mucosal IgE responses may be 

elicited by dietary antigen, even if cutaneous IgE 

responses do not occur, leading to negative skin 

prick tests, and in the absence of circulating 

specific IgE. 

Mast cells and eosinophils in food allergies 

There are undoubted links between intestinal food 

allergic responses and the infiltration of both 

eosinophils and mast cells, which produce a 

variety of vasoactive and neuroactive mediators. 

Both cell types have been particularly implicated 

in dysmotility responses, and it is likely that these 

products may directly affect the function of enteric 

nerves. 143 During the food allergic response, both 

mast cell tryptase and cationic protein (ECP) are 

released into the lumen and may be detected in 

stools. 144–146 However, although mast cells and 

eosinophils produce a similar spectrum of mediators, 

their responses show a different time-course. 

Mast cells induce rapid responses through immediate 

degranulation of mediators stored in intracellular 

granules, whereas eosinophil responses are 

often delayed for several hours, as they are 

recruited from the peripheral circulation into 

tissues. 

Two molecules are very clearly implicated in 

mucosal eosinophilia – the chemokine eotaxin and 

the cytokine IL-5. Important studies by Rothenberg 

et al, using targeted gene deletion in mice, have 

clarified the relative contributions of both mediators. 

Mice were sensitized to ovalbumin, and then 

challenged with oral administration of ovalbumincoated 

beads. 147 Wild-type mice mounted an allergen-specific 

Th2 response, showing mucosal 

eosinophilia with increased circulating IgE and 

IgG1, while eotaxin-deficient mice had preserved 

systemic IgE and IgG1 responses but did not 

recruit eosinophils to the mucosa. By contrast, 

IL5-deficient mice had reduced circulating 

eosinophils. 147 In additional studies of gastric 

eosinophil recruitment, it was possible to confirm 

that antigen-coated beads induced delayed gastric 

emptying, and again eotaxin-deficient mice were 

protected. 148 Further studies from this group have 

identified the esophagus as an apparent target for 

eosinophil recruitment, either as a consequence of 

inhalation of aeroallergens such as aspergillus 149 

or in circumstances of excess systemic IL-5 expression. 

150 This targeting may presumably have some 

as yet unclear evolutionary basis, but these findings 

have potentially important clinical implications. 

First, there may be more than one factor 

inducing esophageal eosinophilia, and there may 

be only a partial response to antigen exclusion if 

the child is also responding to inhaled aspergillus. 

Second, an intercurrent systemic viral illness in an 

allergic child with a Th2-deviated immune response 

may promote esophageal eosinophilia in an 

antigen non-specific manner. The increased 

frequency of viral infections in food-allergic children, 

probably due to low immunoglobulins, CD8 

and natural killer cells, 14 may make this a clinically 

difficult scenario, as appropriate food exclusions 

may give an apparently poor clinical 

response. 

In adults, IL-5 mRNA is increased within the 

small-bowel mucosa of food-allergic patients, but 

not in atopic or non-allergic controls. 151 T cells 

from food antigen sensitized children produce IL- 

5 on food challenge, whereas those from tolerant 

children do not. 93,94 Thus, there is evidence for a 

final common pathway in the mucosal allergic 

response to dietary antigen, which is dependent on

up-regulation of IL-5 production and expression of 

the chemokine eotaxin. 

T-cell responses in oral tolerance 

The phenomenon of oral tolerance lies at the heart 

of food allergy, which by its nature implies a breakdown 

or failure of establishment of oral tolerance 

mechanisms. There has been much recent 

progress in the understanding of oral tolerance 

mechanisms. The dose of ingested antigen appears 

to be particularly important in determining how 

tolerance is established. 152 The bulk of dietary 

antigen is absorbed by enterocytes for nutritional 

purposes, and this antigen is presented by the 

epithelium in such a way that lymphocyte reactivity 

is suppressed and the lymphocytes become 

anergic. 128,129 The absent expression of co-stimulatory 

molecules by enterocytes and production of 

suppressor cytokines may both play a role, 

although little is known about these processes in 

human infancy and childhood. Food antigens have 

also been shown to induce apoptosis of antigenspecific 

lymphocytes in the Peyer’s patches of 

mice, but this has not yet been shown in 

humans. 153 More recent data suggest that a more 

complex state is induced in tolerogenic lymphocytes 

by food administration, in which pro-apoptotic 

and anti-apoptotic factors are simultaneously 

up-regulated while T-cell receptor signaling molecules 

are down-regulated. 154 

In contrast, tolerance to low doses of antigen 

requires uptake by the antigen-sampling M cells 

that overlie Peyer’s patches. This form of tolerance 

requires an active generation of suppressor 

lymphocytes within the Peyer’s patches, and in 

particular Th3 cells that produce the anti-inflammatory 

cytokine TGF-β. 8,155,156 Other regulatory Tcell 

populations that are likely to be very important 

in preventing food allergies include T 

regulator-1 (Tr1) cells, which produce IL-10, and 

CD4+CD25+ cells. 9,129,156 The transcription factor 

Foxp3 appears to be central in the commitment of 

naive T cells towards the regulatory pathway in 

mice. 157 Similar relevance in humans is suggested 

by the development of a multifocal inflammatory 

condition (IPEX syndrome) in infants with mutations 

in Foxp3. 158 Thus, Foxp3 may be a molecule 

that is of critical importance in maintaining oral 

and systemic tolerance. There are currently no 

The basic mechanisms of immune response to dietary antigen 339 

clear data to determine which regulatory cell type 

is most relevant in prevention of childhood food 

allergy. There is certainly evidence that a multiply 

exposed population of elderly circulating CD4 

+CD25+ cells inhibits milk responses in adult 

humans. 159 However, which would be unlikely to 

be the case in early life, when most T cells are 

initially of the naive phenotype? Analysis of circulating 

CD4+CD25+ in adults shows that the 

majority express the skin-homing marker CLA, but 

not the gut-homing β7 integrin, while cord blood 

CD25+CD4+ cells express neither CLA nor β7 

integrin. 160 Evidence of functional immaturity of 

the neonatal CD4+CD25+ cell population, at least 

in mice, is provided by data showing that adult 

CD4+CD25+ cells prevent an autoimmune 

response to the autoantigen myelin oligodendrocyte 

protein, whereas cord blood cells do not. 161 

This is likely to be functionally important in 

responses to ingested antigen, as neonatal animals 

show impaired low-dose oral tolerance and may 

even paradoxically sensitize. 162 

There are now extensive data to suggest that oral 

tolerance is not innate, and that the mechanisms 

are not present at birth but develop postnatally. 

The expression of a specific array of toll receptors 

on CD4+CD25+ regulatory T cells, and increase of 

their suppressor functions by bacterial 

lipopolysaccharide, 163 suggest that the early infectious 

exposures of the young infant are indeed 

likely to be important in the generation of oral 

tolerance and the prevention of allergy. The 

current data on human infants point to a particular 

role for TGF-β rather than IL-10 in the prevention 

of infant allergy. Study of spontaneous and 

cow’s milk-stimulated cytokine production of cord 

blood mononuclear cells identified a reduced TGFβ 

but not IL-10 response in children of allergic 

mothers. 164 The dominant cytokine abnormality in 

the mucosa of food-allergic children does not 

appear to be diminished Th1 or excess Th2 

responses, but reduced numbers of TGF-β secreting 

Th3 cells. 34 Other studies have confirmed that 

Th1 responses are normal or even increased 

within the mucosa in childhood food allergy, 31,33,34 

but that TGF-β responses are impaired: expression 

of TGF-β1 and its receptor are diminished within 

the mucosa in food-allergic enterocolitis, 165 while 

milk-reactive T-cell clones from milk-allergic children 

show a Th2-deviated response but with

340 


minimal TGF-β production. 166 The factors 

involved in early life generation of TGF-β1-producing 

Th3 cells are thus likely to be of great importance 

in determining whether food-allergic sensitization 

occurs. Infectious exposures are certainly 

one such factor, and it is notable that the density of 

TGF-β-producing cells within the duodenal 

mucosa of infants in rural Gambia was an order of 

magnitude higher than in healthy UK infants. 167 It 

is likely that early-life immunomodulation of regulatory 

responses, rather than alteration of dietary 

exposures, will prove the way ahead in childhood 

food allergies. 

Future challenges and opportunities 

in food allergy 

There have been substantial recent advances in 

the basic science of food allergies. There has been 

a broadening of the concepts of food allergy, away 

from simple focus on IgE and towards a consideration 

of overall mucosal tolerance. Could a genetic 

tendency to high IgE responses simply make 

adverse immunological reactions to foods more 

noticeable? As many practitioners are uncomfortable 

without supporting diagnostic tests, non-IgEmediated 

allergy may remain a difficult and 

controversial clinical area. Absence of specific 

tests can also lead to overdiagnosis of allergies, or 

inappropriate blaming of non-specific symptoms 

on food allergy – as can be seen on large numbers 

of Internet sites. 

The advances in basic research, which encompass 

both gut inflammation and allergy because of 

shared tolerance mechanisms, may explain some 

of the recent demographic shifts in allergy. 

Inappropriate infectious priming of the nascent 

mucosal immune system may affect the development 

of normal gut tolerance. Handling of the 

newborn infant has been shown in one study to 

affect allergy in young adulthood. 168 There is also 

clear evidence that the early gut colonization of 

allergic infants differs from those without allergies. 

169 One study which thus demonstrated great 

promise was the recent placebo-controlled trial by 

Isolauri’s group in which neonatal administration 

of a probiotic organism (Lactobacillus GG) led to a 

50% reduction in the later development of eczema, 

although without alteration of systemic IgE 

responses at either 1 year or 4 years. 10,11 The use of 

probiotics at birth may be more effective than later, 

as it may allow stable long-term colonization, 

which does not occur if probiotics are administered 

even at the age of 10 months. 170 As interaction 

between bacterial exposures in early infancy 

and genetically determined responses in innate 

immune cells may determine whether an adequate 

tolerogenic response occurs, probiotics may represent 

an important new class of immunomodulators, 

particularly if used in early infancy. However, 

much work remains to be done to determine the 

dosage, timing and nature of the probiotics to be 

used. 9 An alternative approach to programming a 

Th1 or tolerant response is to use bacterial products, 

such as mycobacterial peptides. A suspension 

made from killed Mycobacterium vaccae 

inhibited airway eosinophilia in a murine model of 

allergy, through the induction of an allergenspecific 

regulatory T-cell response, dependent on 

TGF-β and IL-10. 171 Such therapy may offer a 

refined alternative to probiotic therapy, in which 

regulatory T-cell generation is the therapeutic goal. 

However, much safety information needs to be 

accumulated, and placebo-controlled trials 

completed, before such therapies can become 

more widely used. 

There are other exciting potential therapies for 

food allergies, some of which have been subject to 

clinical trials in humans. 172 The area of 

immunotherapy is well established for systemic 

allergies such as bee-sting allergy, and has 

depended on increasing the dose of antigen gradually 

until an allergy-suppressing Th1 response is 

made. For food allergies, the use of small peptides, 

foods with altered protein sequences, DNA immunizations 

and IgE-blocking agents represent future 

targets for immunotherapy. For small peptide 

vaccines, an antigenic peptide is sequenced and 

synthetic 10–20 amino acid portions are then 

produced, covering the entire protein sequence. 

While able to block IgE binding sites, they are not 

long enough to cross-link IgE on mast cells. Food 

proteins can also be engineered, which are able to 

bind to T cells but not mast cells. In recent studies, 

the major peanut proteins Ara h1, ara h2 and ara 

h3 have been purified, their T-cell and IgE-binding 

domains elicited, and mutations made in the IgEbinding 

domain. 173

While much of the data outlined above suggests 

that IL-5 responses may be critical in food allergies, 

the therapeutic credentials of a highly 

promising anti-IL-5 monoclonal antibody were 

dented by a study in asthmatic patients, in which 

peripheral eosinophilia was reduced, but without 

any significant modulation of the late bronchoconstrictor 

response in asthma. 174 The results of 

clinical trials in severe food allergy will be 

extremely interesting, provided that such agents 

remain in clinical development after such a 

setback. Similarly, a monoclonal antibody that 

blocks eotaxin chemoattraction may prevent the 

migration of eosinophils into the mucosa in 

response to food allergens. 

Relevant therapeutic antibodies that have reached 

clinical trials include two anti-IgE monoclonals. 

The humanized monoclonal anti-IgE rhu Mab E- 

25, which binds to the constant region of IgE, and 

thus prevents IgE binding to its high- or low-affinity 

receptors, has shown promising effects in allergic 

asthma. 175 In a potentially very important 

study, the humanized IgG1 anti-IgE monoclonal 

TNX-901 showed clear promise in the treatment of 

established peanut allergy. 113 Using a dose of 

450mg, given subcutaneously at 4-weekly intervals 

for 16 weeks, treated patients showed an 

increase in reaction threshold to peanut from 178 

to 2805g, essentially the difference between half a 

peanut and nine peanuts. A dose-dependent 

increase in reaction threshold was seen from 

150–450mg doses. This represents a clinically 

worthwhile increase in reaction threshold, and 

would substantially reduce the chances of inadvertent 

consumption of sufficient peanut to trigger 

anaphylaxis. 

In addition to such radical advances in therapy, 

one future challenge in the field of food allergy 

will be provided by the advent of genetically modified 

foods, which have so far an unknown propensity 

for causing allergic reactions. Genes may be 

Future challenges and opportunities in food allergy 341 

introduced into plants either through use of a 

bacterial vector or by direct physical methods, 

while alternatively naturally occurring genes may 

be silenced. 176 Important lessons have already 

been learned. In an attempt to increase the nutritional 

component of cattle feed, the brazil nut 2S 

albumen protein was introduced transgenically 

into soy. Unfortunately, this protein turned out to 

be a major brazil nut allergen, and indeed the 

transgenic soy was able to induce hypersensitivity 

in brazil nut-allergic patients. 177 Therefore, avoidance 

of similar adverse events for the future must 

be minimized by appropriate predictions. 

Recognition of potentially allergic molecules can 

be attempted, on the basis that many are large and 

heavily glycosylated molecules that are resistant to 

breakdown by proteolysis or digestion. 178 

However, some antigens, particularly fruit allergens, 

do not follow these rules. One suggestion has 

thus been to test proteins from genes considered 

for transgenic insertion by immunoassay against 

sera from a variety of allergic patients. 179 

Even if genetically modified foods do not reach the 

market place in large amounts, there still remains 

the major challenge of ensuring that modern food 

manufacturing processes do not leave food-allergic 

patients at risk of anaphylaxis. Taylor et al 180 have 

published an important call for the determination 

of the minimal doses of antigen required to trigger 

reactions, and for international legislation to 

ensure that food manufacturers do not exceed 

these doses. The dietary exposure of infants and 

young children have changed out of all recognition 

within developing countries in the past decades, at 

a time when their infectious exposures have also 

been altered in a way that evolution has not 

prepared them for. The challenge of preventing 

food-allergic deaths is one in which food manufacturers 

may have to work together with basic scientists, 

and in which microbiologists may have as 

much to offer as immunologists. These are interesting 

times.

342 


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23 

Introduction 


Qian Yuan and Harland S Winter 

New knowledge continues to impact on the pathogenesis 

and treatment of the chronic inflammatory 

intestinal disorder described by Dr Burrill Bernard 

Crohn in the early 1930s. 1 However, for over a 

century prior to this report physicians knew of the 

existence of a non-tuberculous ileitis. Characterized 

by transmural, chronic mucosal inflammation 

involving any portion of the gastrointestinal 

tract from the lips to the perineum, Crohn’s disease 

frequently involves the small intestine, especially 

the terminal ileum. Diarrhea, abdominal pain, 

malnutrition and growth delay are common 

features of disease that involves the small intestine. 

Rectal bleeding and extraintestinal manifestations 

are more commonly associated with colonic 

involvement. Although the clinical features of the 

disease are similar in adults and children, complications 

of chronic inflammation are most frequently 

seen in adults who by nature of their age, 

have had inflammation for a longer period of time. 

Growth retardation and delays in sexual maturation 

are issues faced primarily by children with 

Crohn’s disease. 

The diagnosis of Crohn’s disease remains a clinical–pathological 

diagnosis. Despite the availability 

of new serological tests, radiological and pathological 

features are needed to establish a diagnosis. 

Granulomata or chronic inflammation involving 

the small and large intestine will enable an experienced 

pathologist to establish the diagnosis with 

some certainty. However, if only colonic involvement 

is present, one may have difficulty distinguishing 

Crohn’s colitis from ulcerative colitis. 

The distribution of the inflammation, such as 

rectal sparing or predominantly right-sided 

disease, may favor Crohn’s over ulcerative colitis. 

Inflammatory bowel disease (IBD) is thought to 

result from inappropriate and ongoing activation 

of the mucosal immune system driven by the presence 

of normal luminal flora. 2 Despite many 

advances, the relationship between the environment 

and the immunogenetics of the host remains 

unclear. Crohn’s disease and ulcerative colitis are 

collectively referred to as inflammatory bowel 

diseases, and they are thought to be distinct entities 

with significant overlap in pathogenesis, clinical 

presentation and therapeutic management. 

Understanding the potential mechanism of 

mucosal immune dysregulation and developing 

effective therapies in children will not only 

improve our management of Crohn’s disease, but 

may also prevent the complications of chronic 

inflammation seen in adults with Crohn’s disease. 

This new knowledge will ultimately improve the 

life quality of all patients with Crohn’s disease. 

Epidemiology 

General incidence and prevalence 

A recent systematic review by Loftus et al 3 

analyzed the epidemiology and natural history of 

Crohn’s disease in population-based cohorts from 

North America. The prevalence rates of Crohn’s 

disease ranged from 26.0 to 198.5 cases per 

100000 persons. The incidence rates ranged from 

3.1 to 14.6 cases per 100000 person-years. Based 

on an estimate of 300 million people in North 

America, there are approximately 400000 to 

600000 patients living with Crohn’s disease and 

approximately 9000 to 44000 people are newly 

diagnosed in North America with Crohn’s disease 

each year. 3 There appears to be a slight female 

predominance, with the percentage of females 

with Crohn’s disease ranging from 48% to 66%. 3 

The prevalence and incidence of IBD is higher in 

North America and Northern Europe than in Asia, 

347

348 


Africa and southern Europe. 4–9 This geographic 

difference is also observed within individual 

countries including the USA. 10 Despite the low 

incidence and prevalence of IBD in Africa, 11 

similar rates for Crohn’s disease have been 

observed between African-American and Caucasian 

people. 12 Both Crohn’s disease and ulcerative 

colitis appear to have a higher incidence 

among the Jewish people. 13,14 

Incidence and prevalence in children with 


There is significantly less information about 

prevalence and incidence rates in children with 

Crohn’s disease. From a study in Sweden, 15 the 

incidence of Crohn’s disease in children appears to 

be increasing, from 2.4 per 100000 persons 

between 1990 and 1992 to 5.4 per 100000 persons 

between 1996 and 1998. Similar findings have also 

been observed by other investigators. 15–17 The 

peak incidence occurs between the ages of 15 and 

25 years, and about 25–30% of patients with 

Crohn’s disease develop the illness before the age 

of 20 years. 5 In a recent study performed in 

Wisconsin, 18 the incidence of Crohn’s disease was 

4.56 per 100000 children, more than twice the rate 

of ulcerative colitis (2.14 per 100000 children). An 

equal incidence occurred among all ethnic groups, 

and children from sparsely and densely populated 

counties were equally affected. 18 A report from the 

British Pediatric Surveillance Unit revealed an 

estimated incidence of IBD in the UK of 5.3 per 

100000 children under the age of 16, with Crohn’s 

disease being at least twice as common as ulcerative 

colitis. 19 The mean age at diagnosis was 11.8 

years (median 12.6 years) and 13% of cases 

occurred in children aged less than 10 years of 

age. 19 There was a median delay of 5 months from 

the onset of symptoms to a diagnosis; furthermore, 

25% of children experienced symptoms for more 

than 1 year prior to diagnosis. 19 

Etiology 


Recent studies in identifying susceptibility genes 

for human IBD have supported the hypothesis that 

genetic factors play an important role in the devel- 

opment of IBD. Several clinical observations with 

variations in incidence and prevalence among 

different populations, co-segregation of IBD in rare 

kindreds with various genetic disorders and familial 

aggregation of IBD have suggested that genetic 

factors contribute to an individual’s susceptibility 

to IBD. 2 First-degree relatives of an affected patient 

with IBD are 4–20 times more likely to develop the 

disease than are the background population. 20–23 

The absolute risk of IBD is approximately 7% 

among first-degree family members. 24 In addition, 

a family history of Crohn’s disease is associated 

with an earlier age of diagnosis in affected 

patient. 25–27 Observations in twin studies have 

strongly supported the role of genetic factors in the 

development of Crohn’s disease. 24,28 However, the 

absence of simple Mendelian inheritance suggests 

that multiple gene products contribute to a 

person’s risk of IBD. 2 

DNA linkage analyses have identified an area on 

chromosome 16, designated IBD1, with apparent 

linkage to Crohn’s disease but not ulcerative 

colitis. 29 Several other genomic loci have also been 

identified in patients with both Crohn’s disease 

and ulcerative colitis. 30–32 Detailed mapping analysis 

revealed that the NOD2 gene on chromosome 

16 was linked to Crohn’s disease. 33,34 The NOD2 

gene encodes a cytoplasmic protein expressed in 

macrophages known as CARD 15 (caspase activation 

and recruitment domain). CARD 15 is thought 

to function as a pattern-recognition receptor for 

bacterial lipopolysaccharide and to regulate 

nuclear factor-κB (NFκB) activation and 

macrophage apoptosis. 2 European and North 

American patients with Crohn’s disease, including 

those without a family history of IBD are more 

likely to have a variant of NOD2 than are persons 

without Crohn’s disease; 2 however, the number of 

individuals with Crohn’s disease who also have a 

variant of NOD2 remains very small. A more than 

20-fold increase in susceptibility to Crohn’s 

disease (ileal disease in particular) is observed in 

individuals homozygous for variant NOD2. 35–37 In 

children with Crohn’s disease, not only are 

NOD2/CARD15 variants associated with ileal 

disease, but they are also associated with lower 

weight percentiles at the time of diagnosis. 37 

Another putative locus on chromosome 5 has been 

identified in strong association with early-onset 

Crohn’s disease. 38,39 A list of putative genes identified 

for IBD is given in Table 23.1.

Table 23.1 Putative genes for inflammatory bowel disease (IBD) 

IBD Locus Chromosome Putative genes Reference 

CD 

CD, UC 

UC 


IBD1 16q12 NOD2 29 

IBD4 14q11 TCR α/δ complex 32, 164 

IBD5 5q31-33 IL-3, 4, 5, 13, and CSF-2 38 

IBD6 19p13 ICAM-1, C3, 38 

TBXA2R, LTB4H 

other 1p36 TNF-R family, CASP9 165 

other 7q MUC-3 30 

other 3p HGFR, EGFR, GNAI2 30 

IBD2 12q13 VDR, INF-γ 30 

CD, Crohn’s disease; UC, ulcerative colitis 

Despite the genetic association of Crohn’s disease, 

lack of total concordance among monozygotic 

twins indicates that additional factors may 

contribute to the pathogenesis of Crohn’s disease. 

Multiple environmental factors have been studied, 

but when critically evaluated, many do not 

provide consistent results. The evolving role of 

epigenetics may be significant in explaining some 

of these observations. 

Dietary component 

To date, no specific dietary component has been 

consistently identified as a cause for IBD. Diets 

high in refined sugar appear to be associated with 

the development of Crohn’s disease, 40 but not 

ulcerative colitis. 41 Decreased dietary consumption 

of fruits and vegetables may be associated 

with an increased risk of developing Crohn’s 

disease. 40 Increased dietary n-6 polyunsaturated 

fatty acids relative to n-3 polyunsaturated fatty 

acids also may be associated with Crohn’s 

disease. 42 Dietary components may alter intestinal 

flora, which then may modify the mucosal 

immune response in the susceptible host. 

Modified carbohydrate diets are used by many 

patients with Crohn’s disease and one should not 

disregard patients’ observations about the impact 

of specific foods on disease activity. As long as 

Etiology 349 

dietary restriction does not impact on nutritional 

well-being, patient observation will guide these 

therapies in the absence of randomized controlled 

studies. 

Breast feeding and perinatal exposures 

The data supporting the positive or negative association 

of breast feeding with IBD is not strong. 

Although studies on children with Crohn’s disease 

and their unaffected siblings suggest that children 

with Crohn’s disease are three to four times less 

likely to have been breast fed, 43 no apparent association 

existed between breast feeding and the 

development of ulcerative colitis. 44 Other data do 

not indicate an association between breast feeding 

and Crohn’s disease. 45 The negative association 

between breast feeding and Crohn’s disease may 

be related to early exposure to pathogens. Children 

with Crohn’s disease are three times more likely to 

have had a diarrheal illness in infancy. 43 

Furthermore, in a Swedish study, a four-fold 

increased risk of IBD was observed in patients who 

had a history of illness in early infancy. 46 

Cigarette smoking 

Cigarette smoking appears to have different effects 

on the development of Crohn’s disease and ulcerative 

colitis. Smoking doubles the risk for developing 

Crohn’s disease, 47,48 and cessation of smoking

350 


may decrease the risk of exacerbation in patients 

with established Crohn’s disease. 49 In contrast, 

smoking decreases the risk of developing ulcerative 

colitis. 48,50,51 Although current smokers have 

about a 40% lower risk of developing ulcerative 

colitis than non-smokers, former smokers are 

about 1.5 times more likely to develop ulcerative 

colitis than those individuals who have never 

smoked. 51 

Non-steroidal anti-inflammatory drugs 

Taking non-steroidal anti-inflammatory drugs 

(NSAIDs) has been associated with an increased 

risk for the development and exacerbation of 

IBD. 52–55 A retrospective study by Bonner et al 

failed to demonstrate an association between 

NSAID use and an increased risk for active IBD; 56 

however, there may be subsets of IBD patients who 

can tolerate NSAIDs with less likelihood of an 

exacerbation of disease. 57 Although the mechanisms 

of NSAID-associated gastric toxicity have 

been extensively studied, the mechanisms leading 

to intestinal damage are poorly understood, but 

may be related to damage of enterocyte mitochondria 

causing enhanced intestinal permeability, 58 

inhibition of cyclo-oxygenase (COX), 59 enterohepatic 

recirculation, 60 and formation of drug enterocyte 

adducts. 61,62 

Both COX-1 and COX-2 serve as constitutive and 

inducible enzymes in inflammation and cytoprotection. 

63 Although selective inhibition of COX-1 

or COX-2 is not ulcerogenic, the combined inhibition 

of COX-1 and COX-2 induced severe lesions in 

the stomach and small intestine in rats, suggesting 

an important role for COX-2 in the maintenance of 

gastrointestinal mucosal integrity. 64,65 While COX- 

2 selective inhibitors have been shown to cause 

less gastrointestinal injury than standard NSAIDs 

in healthy animals and humans, 66,67 their effect on 

pre-existing gastrointestinal inflammation is not 

completely clear. COX-1 expression is detected in 

both non-inflamed and inflamed gastrointestinal 

mucosa. In contrast, COX-2 is expressed in epithelial 

cells in the upper portions of the crypts as well 

as on the surface of colonic enterocytes in Crohn’s 

colitis and ulcerative colitis and in villous epithelial 

cells in Crohn’s ileitis. COX-2 is not detectable 

in the epithelium of the normal ileum or colon, 68,69 

but is up-regulated in the colonic mucosa in both 

experimental and human colitis 68 and appears to 

have a beneficial effect in healing experimental 

colitis. On the other hand, COX products are an 

important part of the inflammatory process and 

COX inhibition by agents such as mesalamine 

might be beneficial. 70 

Oral contraceptive drugs 

Data relating oral contraceptive drugs to the development 

of inflammatory bowel disease have been 

inconsistent. In two prospective studies, 47,71 oral 

contraceptive use has been associated with 

increased risk for developing both Crohn’s disease 

and ulcerative colitis. Women who currently use 

oral contraceptives are 2.5 times more likely to 

develop ulcerative colitis and 1.7 times more likely 

to develop Crohn’s disease. 47 Other case–control 

studies have not found a strong association 

between the use of oral contraceptives and the 

development of either Crohn’s disease72 or ulcerative 

colitis. 73 

Infectious agents 

Although available data do not convincingly 

incriminate a single, persistent pathogen as a 

universal cause of IBD, the role of infectious 

agents is still considered a strong possibility as a 

trigger for the development of IBD. Many infectious 

agents including Mycobacterium, Chlamydia, 

Listeria monocytogenes, cell-wall-deficient Pseudomonas 

species and reovirus have been proposed as 

the causative organism of Crohn’s disease. 

Paramyxovirus (measles virus) has been implicated 

etiologically in Crohn’s disease as a cause of 

granulomatous vasculitis and microinfarcts of the 

intestine. 74 However, the tissue evidence for 

persistent measles infection in patients with 

Crohn’s disease remains controversial. 75,76 One 

Swedish study demonstrated an increased incidence 

of Crohn’s disease but not ulcerative colitis 

among individuals born during measles 

epidemics; 77 however, two other studies from the 

UK failed to establish an association between the 

development of Crohn’s disease and birth during 

measles epidemics. 78,79 The relationship between 

measles vaccination and the development of 

Crohn’s disease has evoked even more acrimonious 

discussion. Although one initial study

eported that the relative risk for developing 

Crohn’s disease and ulcerative colitis was 3.0 and 

2.5, respectively, in children who received the 

measles vaccine, 80 subsequent studies failed to 

confirm these findings. 81,82 Mycobacterium paratuberculosis 

has been cultured from the bowel of 

patients with IBD, but definitive evidence to link a 

mycobacterium to Crohn’s disease is lacking. 83–85 

Commensal bacterial flora is an important etiological 

factor in IBD. Bacteria within the enteric 

lumen have a complex ecosystem that is in contact 

with the external environment. There are 10 12 

bacteria/g feces in the colon, of 400 different 

species, with anaerobes predominating. 86 The 

numbers of anaerobic bacteria and Lactobacillus 

are significantly decreased in patients with active, 

but not inactive, IBD. 87 Genetically altered animals 

that are susceptible to acquiring IBD do not 

express the phenotype when raised in a germ-free 

environment. 88,89 Furthermore, experimental 

colitis is attenuated when animals are treated with 

broad-spectrum antibiotics. 90 Further studies by 

Duchmann et al demonstrated that mucosal, but 

not peripheral blood mononuclear cells from 

patients with IBD proliferate when exposed to 

autologous intestinal bacteria. These data support 

the hypothesis that normal flora function as a 

modulator of ‘physiological inflammation’. 91,92 

Patients with IBD have increased numbers of 

surface-adherent and intracellular bacteria in the 

colonic epithelium, 93,94 and these commensal 

organisms may be playing a role in the development 

and maintenance of mucosal inflammation. 

Others factors 

Several studies have suggested that appendectomy 

may protect against the occurrence and severity of 

ulcerative colitis. 95–99 However, appendectomy 

does not affect the disease course of ulcerative 

colitis. 100 The relationship between appendectomy 

and the risk of developing Crohn’s disease is 

controversial. 99,100 In a large, retrospective cohort 

study, Andersson et al demonstrated that an 

increased risk of Crohn’s disease was found for 

more than 20 years after appendectomy. This 

increased risk was dependent on the patient’s 

gender, age and the diagnosis at operation (nonperforated 

vs. perforated appendicitis). 101 In T cell 

receptor (TCR)-α-deficient mice, appendectomy is 

protective against the development of colitis. 102 



Growing evidence suggests that inflammatory 

bowel disease is the result of a dysregulated 

immune response to common luminal flora. The 

intestinal inflammation of IBD may be viewed as 

an exaggeration of the ‘physiological’ inflammatory 

response always present in the normal lamina 

propria of the intestine and colon. 103 An intact 

mucosal barrier and regulatory mechanisms 

normally prevent the immune and inflammatory 

responses from causing tissue injury. 103 A defect in 

either mucosal barrier function, antigen processing 

or immunoregulation could result in a chronic 

inflammation, lymphocyte proliferation, cytokine 

release, neutrophil recruitment and tissue 

damage. 103 The factors that trigger activation of the 

immune system are unclear, but could be related 

to an intrinsic defect (either constitutive activation 

or the failure of down-regulatory mechanisms) or 

ongoing stimulation resulting from a change in the 

epithelial mucosal barrier. 2 

Data from studies on tissue samples from patients 

with IBD and experimental animal models of 

colitis have demonstrated unbalanced Th1 vs. Th2 

responses in the intestinal mucosa. 84,104,105 The 

mucosa of patients with established Crohn’s 

disease is dominated by CD4 + lymphocytes with a 

Th1 phenotype, characterized by the production of 

interferon-γ and interleukin (IL)-2; 2 whereas the 

mucosa in patients with ulcerative colitis may be 

dominated by CD4 + lymphocytes with an atypical 

Th2 phenotype, characterized by the production of 

transforming growth factor (TGF)-β and IL-5, but 

not IL-4. 2 CD4 + lymphocytes clearly play an 

important role in the pathogenesis of tissue 

damage in inflammatory bowel disease, particularly 

in Crohn’s disease. 84,106 Patients with disorders 

such as glycogen storage disease 1b, which 

are associated with abnormalities in neutrophil 

function may exhibit clinical manifestations of 

IBD. These observations suggest that the mechanisms 

leading to mucosal injury are not always 

lymphocyte dependent. 

Loss of tolerance towards the luminal commensal 

bacterial flora appears to be an important factor in 

the pathophysiology of IBD. Concomitant decrease 

of production of TGF-β and IL-10 by regulatory T 

lymphocytes may be partially responsible for the 

loss of tolerance to luminal flora and activation of

352 


Th1 cells. 107–109 Results from murine studies have 

shown that Th1 cytokines activate macrophages, 

which in turn, produce IL-12, IL-18 and macrophage 

migration inhibitor factor, thereby stimulating 

a Th1 response in a self-sustaining cycle. 110,111 

Activated macrophages produce a variety of potent 

proinflammatory cytokines including tumor 

necrosis factor (TNF)-α, IL-1 and IL-6. TNF-α has a 

variety of biological effects, including: 

macrophage activation and induction of protease, 

both of which can play a role in tissue destruction; 

112 up-regulation of adhesion molecule 

expression, facilitating recruitment of monocytes, 

lymphocytes and granulocytes; 113 enhancement of 

chloride secretion from intestinal epithelial 

cells; 114 increase of epithelial cell permeability; 115 

and enhancement of production of acute-phase 

reactants. 112 The inflammatory process and tissue 

destruction of the intestine are further promoted 

by generation of various proinflammatory mediators 

including other cytokines, chemokines, 

growth factors, arachidonic acid metabolites 

(prostaglandins and leukotrienes) and reactive 

oxygen metabolites such as nitric oxide. 2 

Activation of this destructive process results in the 

mucosal injury and clinical manifestations of IBD. 


The initial clinical presentation of Crohn’s disease 

may be subtle, variable, non-specific and easily 

overlooked. Common symptoms include abdominal 

pain, diarrhea and/or weight loss. 103 A plateau 

in linear growth, delayed pubertal development, 

perianal lesions, fever, pallor, hematochezia and 

digital clubbing may also be present. 103 Crohn’s 

disease may affect any area of the gastrointestinal 

tract from the lips to the perianal area. In a study 

on Scottish children and adolescents with Crohn’s 

disease, 116 approximately 30% of patients had 

disease limited to the terminal ileum, 20% of 

patients had exclusive colonic involvement and 

50% of patients had both ileal and colonic involvement. 

In a more recent population-based study in 

Wisconsin, at the time of diagnosis isolated ileal 

disease was identified in 25% and ileocolonic 

involvement was found in 29%. About one-third of 

children had colonic involvement and 14% had 

disease in the upper gastrointestinal tract. 18 The 

inflammation associated with ulcerative colitis is 

limited to the colon, with the exception of mild 

inflammation in the ileum, termed ‘backwash 

ileitis’. 

The constellation of abdominal pain, diarrhea, 

poor appetite and weight loss represents the 

classic presentation of Crohn’s disease in children 

of any age group. 103 Frequently, the onset of pain is 

insidious and intermittent. Families and care 

providers often dismiss the symptoms as an acute 

illness, or a condition related to anxiety. In some 

individuals, anorexia may be the primary manifestation 

prompting an evaluation for anorexia 

nervosa or an eating disorder. Laboratory studies 

may suggest chronic inflammation, but up to 20% 

of children with IBD have a normal erythrocyte 

sedimentation rate. A summary of the prevalence 

of various clinical presentations from two separate 

studies is shown in Table 23.2. Abdominal pain is 

the most common single symptom at presentation, 

and may be periumbilical or localized to the right 

lower quadrant or to the lower abdomen. Grossly 

bloody diarrhea or extraintestinal manifestations 

signify colonic involvement. When diarrhea is 

predominant without visible blood or the patient 

has clubbing, one should suspect small-bowel 

involvement. Uncontrolled gastrointestinal hemorrhage 

is rare in Crohn’s disease, but may occur 

with an ileal ulcer. 

Clinical case 1 

A 6-year-old boy developed swollen lips 

(Figure 23.1) and painful ulcers in his mouth. 

He denied any history of abdominal pain, but 

his weight was decreased. An upper gastrointestinal 

series with small-bowel followthrough 

was normal. He had a history of anal 

fissures in the past and because of hard stools, 

he had been treated with stool softeners. An 

upper endoscopy and colonoscopy did not 

reveal evidence of inflammation, but a biopsy 

of the buccal mucosa demonstrated granulomatous 

cheilitis. He was treated with oral 

prednisone and metronidazole, with an initial 

improvement. He developed hepatitis while 

taking 6-mercaptopurine. Three infusions of 

infliximab were not effective. His perianal 

disease improved with a course of 20 hyperbaric 

oxygen sessions. Nutritional therapy 

with nightly nasogastric tube feedings for 2

Figure 23.1 Swollen lips in a child with Crohn’s disease 

involving the oral mucosa. 

years has contributed to his maintaining his 

weight and growth, but he has been unable to 

tolerate sufficient caloric intake to have catchup 

growth. Five years after his initial presentation, 

he has developed chronic inflammatory 

changes in the colon. 

Points of interest 

Clinical signs and symptoms 353 

(1) Crohn’s disease may present in any region of 

the gastrointestinal tract; 

(2) One-third of patients with Crohn’s disease do 

not respond to infliximab; 

(3) Nutritional therapy is important adjunctive 

therapy. 

Impaired linear growth and concomitant delay in 

sexual maturation are important clinical manifestations 

in children with Crohn’s disease, that may 

precede the onset of intestinal symptoms by 12–18 

months. 103 In a prospective study of children with 

IBD, 117 30% of children with Crohn’s disease had 

growth delay, which was defined as a fall in the 

height centile of more than 0.3 standard deviation 

per year, a growth velocity of less than 5cm per 

year, or a decrease in the growth velocity of ≥ 2cm 

compared with the preceeding year. About 50% of 

children had evidence of decreased height velocity 

prior to the diagnosis of Crohn’s disease. 118 

Delayed linear growth velocity and sexual maturation 

may be related to a chronically insufficient 

dietary intake and/or an increased energy requirements 

related to chronic inflammation or 

fever. 118,119 Anorexia occurs in 30% of children 

with Crohn’s disease and may be related to upper 

gastrointestinal tract involvement. 120 Studies in a 

rat colitis model demonstrated that TNF-α inhibited 

maturation of growth plate chondrocytes, 121 

suggesting that some proinflammatory cytokines 

Table 23.2 Prevalence of clinical presentations in Crohn’s disease from two studies (references 103 

and 166) 

Clinical symptoms Percentage (n=386) 103 Percentage (n=40) 166 

Abdominal pain 86 95 

Weight loss 80 80 

Diarrhea 78 77 

Blood in the stool 49 60 

Perianal lesions 44 * 

Fevers 38 * 

Growth failure * 30 

Mouth ulcers 28 * 

Arthralgia/arthritis 17 * 

Skin lesions 8 * 

*Prevalence was not specified

354 


may be a factor in the growth delay observed in 

children with Crohn’s disease. 

Anemia is present in 25–85% of patients with 

Crohn’s disease, 122 many of whom have anemia of 

chronic disease. Iron deficiency anemia is microcytic 

and may result from gastrointestinal blood 

loss, malabsorption of iron in the duodenum and 

jejunum because of inflammation and/or a lack of 

adequate oral intake. Folate deficiency causes a 

megaloblastic anemia, but frequently folate deficiency 

is associated with iron deficiency as well, 

and the indices may not be macrocytic. Folate 

deficiency is most commonly due to nutritional 

causes, but patients who take sulfasalazine are at 

increased risk for developing folate deficiency. For 

that reason, sulfasalazine is always prescribed 

with folate supplementation. Vitamin B12 is 

absorbed in the ileum; deficiencies are usually 

related to lack of absorption, related to inflammatory 

changes, fibrosis or resection. Because many 

years may be required to deplete vitamin B12 stores 

in an individual who has a normal reserve, the 

development of deficiency is often insidious. 

Children with ileal disease should be monitored 

for vitamin B12 deficiency by measuring serum 

levels. Clinical manifestations of the disease – 

anemia, dermatitis, cheilitis, decreased serum 

transaminases, peripheral neuritis, irritability and 

posterior column signs – do not develop for many 

months. 

Clinical case 2 

A 13-year-old girl was referred for evaluation of 

lower abdominal pain, diarrhea and a perirectal 

abscess. She had had intermittent abdominal 

pain from infancy but about 1 year prior to evaluation 

noted an increase in frequency and 

intensity. Her pediatrician recommended a 

lactose-restricted diet and the pain completely 

resolved. Two months prior to her referral to a 

pediatric gastroenterologist, she developed a 

perirectal abscess that was drained by a 

surgeon. The abscess healed slowly. She 

reported having 4–5 loose stools daily, but 

never noticed any blood. Her appetite was good 

and her rate of growth was not changed. There 

was no family history of IBD but her mother has 

Sjögren’s syndrome, a maternal second cousin 

has juvenile dermatomyositis and her maternal 

grandfather has rheumatoid arthritis. Her physical 

examination was normal with the exception 

of a well-healed surgical incision about 

4cm from the anus. Her weight was 25% for 

age; her height was 50% for age. A complete 

blood count (CBC), erythrocyte sedimentation 

rate (ESR) and liver function tests were normal. 

An upper gastro-intestinal radiograph with 

small-bowel follow-through was read as 

normal. Over the next 10 weeks she continued 

to experience intermittent crampy abdominal 

pain and occasional loose stools. She noted 

some blood on the paper after wiping and the 

perianal abscess would drain intermittently. 

However, over this period of time she continued 

to gain weight. An ileocolonoscopy 

revealed a normal-appearing ileum and right 

colon with multiple aphthoid lesions in the left 

colon and erythema in the rectum. Biopsies 

identified an active and chronic ileitis with 

granulomas but no evidence for ulceration, as 

well as microscopic changes of chronic and 

active inflammatory changes in the left colon 

with erosions. 

She was started on mesalamine and metronidazole. 

She began to feel better after 1 week of 

therapy, but then had recurrence of crampy 

abdominal pain with nausea and increased 

frequency of stooling up to seven loose bowel 

movements daily. Two weeks after starting 

therapy, prednisone 20mg twice a day was 

prescribed. Metronidazole was discontinued 

because of dysesthesia in her hands. After 3 

weeks of taking prednisone, she was quite 

Cushingoid, but she was passing three formed 

bowel movements daily and the perianal 

abscess was not draining. She began to taper 

the dose of prednisone by 5mg/day every week. 

When she reached 30mg of prednisone daily, 

she began to have increased frequency of stooling 

and crampy abdominal pain. Because of 

concerns for steroid dependence, she was 

started on 50mg daily of 6-mercaptopurine 

after it was checked that her thiopurine methyltransferase 

(TPMT) activity was in the normal 

range. A CBC and differential, liver function 

tests and amylase were checked weekly for 3 

weeks and then monthly. She tolerated the 6mercaptopurine 

well and was able to discontinue 

prednisone after 5 months. She was maintained 

on mesalamine and 6-mercaptopurine.

After 18 months of therapy, she began to 

develop intermittent abdominal pain and diarrhea. 

Her symptoms increased despite therapy 

with metronidazole and ciprofloxacin. She 

began to lose weight. Infliximab was started 

and 1 week after the initial infusion, she began 

to improve. She completed a second infusion 2 

weeks after the first and a third infusion 6 

weeks after the second infusion. She is now 

maintained on 6-mercaptopurine and an infliximab 

infusion every 8 weeks and remains 

without gastrointestinal symptoms. 

Points of interest 

(1) The onset of Crohn’s disease is often insidious; 

(2) Radiographic studies in the early stages of 

Crohn’s disease may appear normal; 

(3) Mucosal biopsy of normal-appearing endoscopic 

areas may provide evidence for inflammatory 

bowel disease; 

(4) Mesalamine with or without antibiotics may 

be effective therapy in some children with 

new-onset mild-to-moderate Crohn’s disease, 

but therapy should be changed if there is not 

a response within 2–4 weeks; 

(5) The inability to tolerate a taper of corticosteroids 

is an indication to begin 6-mercaptopurine; 

(6) Therapy with 6-mercaptopurine may take at 

least 3 months to become effective; 

(7) When 6-mercaptopurine fails to control 

symptoms of Crohn’s disease, infliximab 

should be considered. About two-thirds of 

adults will have an initial response to infliximab. 

Perianal lesions may be the first presenting feature 

of Crohn’s disease. Perianal disease associated 

with Crohn’s disease is frequently mild with small 

perianal skin tags or anal fissures, but more severe 

problems such as perianal fistulae and abscesses 

may develop. Fortunately, less than 5% of children 

with Crohn’s disease will develop a highly destructive 

form of perianal disease with recurrent 

abscesses and fistulae (Figure 23.2) involving the 

genitalia, and often resulting in rectal strictures. 

123,124 As illustrated in Case 2, the patient 


was thought to have a perirectal abscess, but after 

surgical intervention, the area did not heal. With 

the exception of the first 2 years of life, children 

with persistent perianal abscess, fissure or fistula 

that does not respond to topical treatment and 

antibiotics should be evaluated for Crohn’s disease 

prior to the initiation of surgical therapy. Approximately 

one-third of children with Crohn’s disease 

can have significant perianal abnormalities during 

the course of their disease. 123 The most common 

perianal problem is skin tags which may become 

quite large. Some may become inflamed and 

painful, but for many adolescents they become a 

source of embarrassment. Perianal inflammatory 

disease may respond to antibiotics that have good 

anaerobic coverage, such as metronidazole, but 

intravenous administration is frequently required 

to achieve maximal healing. Non-inflamed skin 

Figure 23.2 Perianal fistula in a child with Crohn’s 

disease. Arrow marks the opening of the fistula. The 

erythema is commonly seen because of the excoriation to 

the skin caused by the drainage onto the perineum.

356 


tags usually do not resolve with medical treatment, 

and the use of topical tacrolimus or corticosteroids 

has not proved to be beneficial in reducing the size 

of the skin tags. Immunomodulators or corticosteroids 

may be necessary to control mucosal 

inflammation which may be a contributing factor 

to the growth of perianal skin tags. 

Extraintestinal manifestations are usually associated 

with colonic involvement of Crohn’s disease, 

and may precede intestinal symptoms by many 

months. The commonly involved organs are joints, 

skin, liver, eye and bone; the manifestations are 

listed in Table 23.3. 125,126 At least one extraintestinal 

manifestation is present in about 25–35% of 

adults with IBD. 125 

Complications 

Malnutrition 

Weight loss and malnutrition are the most prevalent 

nutritional disturbances in patients with 

IDB. 103 Approximately 85% of children with 

Crohn’s disease have a history of weight loss at 

initial diagnosis. 127 Malnutrition is mainly due to 

decreased intake caused by either primary 

anorexia from proinflammatory cytokines, or 

intestinal inflammation. An active inflammatory 

process, especially associated with fever, may 

further increase the body’s caloric consumption. 

Table 23.3 Extraintestinal manifestations of Crohn’s disease 

Estimates suggest that an increase in 1ºC increases 

the metabolic rate by 7%. For this reason, children 

with Crohn’s disease who experience recurrent 

febrile episodes often need to receive additional 

calories. 

As the result of the location of chronic intestinal 

inflammation in Crohn’s disease, a variety of 

micronutrient deficiencies may occur. These deficiencies 

include water-soluble vitamins (mainly 

folic acid and vitamin B12), fat-soluble vitamin D, 

and minerals (iron, copper and zinc). 103 Deficiency 

of these micronutrients may be subclinical or associated 

with specific clinical signs and symptoms 

(Table 23.4). The following factors may create or 

potentiate specific nutrient deficiencies: inadequate 

intake, the inflammatory/immunological 

response, poor absorption, increased nutrient 

demand for tissue repair or concurrent usage of 

specific medications. The severity of nutrient deficiency 

is often associated with the duration of 

disease and the degree of Crohn’s disease activity. 

Hepatobiliary and pancreatic complications 

Bile salts are absorbed in the distal ileum via an 

enterohepatic circulation. Malabsorption of bile 

salts caused by ileal inflammation or resection 

results in increased colonic bile salts and diarrhea. 

Bile salt malabsorption also may predispose 

towards gallstone formation. Agents that bind bile 

acids may be beneficial in these clinical situations. 

Presentations Percentage Reference 

Joint 

arthritis/arthralgia 2*, 15 (adult data) 126 

Skin 

erythema nodosum 1*, 8–15 (adult data) 18, 125 

pyoderma gangrenosum 0.5*, 1.3 (adult data) 

Eye 

episcleritis 125, 126 

uveitis 

orbital myositis 

Hepatobiliary involvement 3* 18 

PSC

Table 23.4 Micronutrient deficiencies 


Clinical 

Micronutrient Prevalence presentations Laboratory test RDA Reference 

Water-soluble vitamins 

Vitamin B12 20–60% macrocytic plasma vitamin B12 1.5–3µg for 168 

anemia, level children; 169 

neuropathy 3µg for adults 170 

Vitamin C * scurvy (ecchymoses, plasma vitamin C 40–45mg for 171 

gingival bleeding, level children 172 

petechiae, 60–125mg for 173 

hyperkeratosis, 

arthralgia, poor 

wound healing 

adults 174 

Folate 34–54% macrocytic anemia plasma folate level 200–400µg for 127 

children; 168 

400µg for adults 175 

Thiamine * beriberi-like erythrocyte thiamine 0.9–1.5mg for 122 

(vitamin B1) symptoms transketolase (ETKA), children; 169 

(neuropathy, or blood thiamine 1–1.4mg for 

cardiomyopathy, concentration, or adults 

encephalopathy, transketolase urinary 

gastrointestinal 

symptoms) 

thiamine excretion 

Nicotinic acid * pellagra ? plasma nicotinic 12–20mg for 122 

(dermatitis, acid level children and 169 

diarrhea and adults 176 

dementia) 177 

Riboflavin (B2) * photophobia, plasma riboflavin 0.4mg for infants; 122 

angular level 1.1–1.8 mg for 169 

stomatitis, children and adults 177 

dermatitis 178 

Pyridoxine * neuropathy, plasma pyrodoxal-5- 0.9–2mg for 122 

(vitamin B6) glossitis, phophate (PLP) level, children; 169 

dermatitis or erythrocyte 

transaminase activity, 

or urinary 4-pyridoxic 

acid excretion, or 

urinary excretion of 

xanthurenic acid 

2mg for adults 178 

Fat-soluble vitamins 

Vitamin A 11% xerophthalmia plasma retinol level 2500–4000IU 171 

(dry eyes and skin, for children; 172 

blindness) 4000–5000IU 179 

for adults 180 

181 

Vitamin D 75% osteomalacia, rickets plasma vitamin D level 400IU for 122 

children and adults 182 

Vitamin E * neuromuscular plasma vitamin E level 9–15IU for 171 

disorders, hemolysis children and 30IU 172 

and anemia for adults 173 

Vitamin K * bleeding diathesis 20–80µg for 

children; 65–80µg 

for adults 

168 

continued

358 


Table 23.4 continued Micronutrient deficiencies 

Clinical 

Micronutrient Prevalence presentations Laboratory test RDA Reference 

Minerals 

Calcium 13% osteopenia, rickets plasma calcium level 800–1200mg 168 

for children 

and adults 

173 

Copper * skin and hair plasma copper level 0.4–0.6mg for 183 

abnormalities infants; 1.5–3mg 

for children and 

adults 

Iron 39–81% microcytic anemia plasma iron level 10–18mg for 168 

children and adults 184 

Magnesium 14–33% myopathy plasma magnesium 200–400mg for 122 

level children; 168 

300–350mg for 169 

adults 185 

186 

187 

Selenium * cardiomyopathy, plasma selenium level 20-50 µg for 173 

encephalopathy, children; 188 

immune dysfunction 55–70 µg for 189 

adults 190 

191 

Zinc 40–50% growth retardation, plasma zinc level 10–15 µg 122 

alopecia, dysgeusia, for children; 168 

acrodermatitis, 15mg for adults 192 

impaired wound 

healing 

193 

* Not specified 

RDA, recommended daily allowance 

Pancreatitis can occur as a result of inflammation 

in the duodenum or by medications such as 

azathioprine, 6-mercaptopurine or 5-aminosalicylic 

acid. 103 In some patients, the cause of pancreatitis 

is unknown and may be recurrent. Pancreatic 

insufficiency and carbohydrate intolerance are 

rare in Crohn’s disease, but a trial of pancreatic 

enzyme supplementation may be beneficial in 

treating inflammation. 

Nephrolithiasis 

Patients with Crohn’s disease have an increased 

risk of developing calcium oxalate and uric acid 

renal stones as a result of chronic steatorrhea and 

diarrhea. Under normal circumstances, free 

dietary calcium binds to oxalate in the intestinal 

lumen and is eliminated in the stool. In patients 

with steatorrhea, increased luminal fatty acids 

competitively bind free dietary calcium and leave 

oxalate free to be absorbed. The increased oxalate 

absorption results in hyperoxaluria. Dehydration 

and metabolic acidosis potentiate the formation of 

uric acid stones. 

Thromboembolic events 

Venous and arterial thromboembolism can result 

from hypercoaguability caused by thrombocytosis, 

hyperfibrinogenemia, elevated factor V and factor 

VII, and depression of antithrombin III. 128,129 A 

retrospective study by Talbot et al in 7199 adult 

patients with either chronic ulcerative colitis or 

Crohn’s disease demonstrated that thrombo-

embolic complications developed in 92 (1.3%) of 

these patients. 130 An additional four patients had 

cutaneous vasculitis, and 17 had an arteritis-associated 

diagnosis. Of the thromboembolic complications, 

61 were deep vein thromboses or 

pulmonary emboli. 130 Peripheral arterial thrombosis, 

coronary thrombosis, and mesenteric and 

portal vein thrombosis were predominantly postsurgical 

complications, but 77% of peripheral 

venous thromboses occurred spontaneously. 130,131 

In isolated case reports, cerebrovascular accidents 

have occurred in children with Crohn’s disease 

with seizures being the primary presenting 

symptom. 132–134 Retinal vascular disease can also 

occur in patients with Crohn’s disease. 129,135,136 

Children with clinical evidence of a hypercoaguable 

state should be evaluated for underlying 

causes. Dehydration and indwelling catheters are 

the main risk factors that should be avoided. 

Metabolic bone disease 

Decreased bone density is an important and probably 

underdiagnosed complication in children with 

Crohn’s disease. Multiple factors, including inflammatory 

cytokines that inhibit osteoclast activity, 

vitamin D deficiency and chronic systemic steroid 

therapy, may contribute to osteopenia or osteoporosis. 

Therefore, in children with Crohn’s 

disease, it is crucial to assess bone density and 

Table 23.5 Bisphosphonate preparations 


decrease the risk factors for osteoporosis such as 

lack of physical exercise, chronic steroid use, lack 

of hormonal therapy of chronic secondary amenorrhea 

in adolescent girls, and deficient calcium and 

vitamin D supplementation. 103 Bisphosphonates 

are synthetic analogs of inorganic pyrophosphate 

that inhibit bone resorption (Table 23.5). In a recent 

randomized study of 84 adult patients with Crohn’s 

disease and osteopenia/osteoporosis, the efficacy of 

ibandronate and sodium fluoride as adjuncts to 

calcium and vitamin D treatment was evaluated. 137 

The results showed that both ibandronate and 

sodium fluoride were effective, safe and well tolerated 

in inducing an increase in lumbar bone 

density. 137 Experience is very limited with bisphosphonate 

therapy in children who have metabolic 

bone disease associated with Crohn’s disease. 

Results from ongoing multicenter trials of bisphosphonate 

in children with Crohn’s disease will 

provide valuable information. 

Local intestinal complications 

Intestinal obstruction, severe hemorrhage, perforation, 

fistulae, intra-abdominal abscesses and toxic 

megacolon can occur as a result of chronic intestinal 

inflammation. Mucosal ulceration may result in 

bleeding and perforation depending on the site and 

size of the ulcer. Fibrosis, a complication of inflammation, 

may result in stricture formation that 

Preparations Potency within generation Potency across generation 

First generation low 

Etidronate 

Second generation high 

Pamidronate 

Clodronate 

Tiludronate low 

Third generation high 

Zolendronate 

Ibandronate 

Risedronate 

Olpadronate 

Alendronate 

Neridronate 

Incadronate low high

360 


predisposes the patient to fistula, abscess, obstruction 

and perforation. In contrast to fibrosis, which 

usually accompanies Crohn’s disease, perforation 

and toxic megacolon are unusual and most 

commonly associated with ulcerative colitis. These 

conditions may require surgical intervention. 

Diagnosis 

The list of conditions that should be considered in 

the differential diagnosis for Crohn’s disease is 

extensive, and is related to the various clinical 

presentations of Crohn’s disease (Table 23.6). A 

high index of clinical suspicion is crucial if the 

clinician is to make a diagnosis in the early phases 

of the illness. Delay in growth is often a clue that 

the presenting symptoms are not caused by an 

acute illness. 

Table 23.6 Differential diagnosis of Crohn’s disease 

Symptoms Differential diagnosis 

Clinical suspicion for Crohn’s disease 

It is important to rule out Crohn’s disease in any 

child with recurrent abdominal pain, chronic 

diarrhea, weight loss, blood in stools, growth delay, 

pubertal delay, unexplained anemia and perianal 

disease. Growth failure can be an important initial 

clue in suspecting Crohn’s disease, since approximately 

half the children with Crohn’s disease have 

a delay in height velocity prior to obvious intestinal 

manifestation. 118 For patients with abdominal pain 

or growth delay, accompanying anorexia, change in 

diet, diarrhea or extraintestinal manifestations 

should raise the possibility of Crohn’s disease. If 

fecal leukocytes are found in a patient with 

hematochezia, inflammatory/infectious causes 

should be considered. Although 20% of patients 

with Crohn’s disease may have a normal ESR, if it 

is abnormal, this non-specific marker of inflammation 

may have relevance. 

Constitutional 

recurrent fever, malaise, pallor collagen vascular disease, infection, malignancy, especially 

lymphoma 

Intestinal 

abdominal pain lactose intolerance, constipation, peptic ulcer disease, Helicobacter 

pylori, irritable bowel syndrome or psychosocial stress 

diarrhea infectious colitis/enteritis (Salmonella, Shigella, Campylobacter, 

Yersinia); immunodeficiency (HIV, primary immune deficiency) 

heme-positive stool/hematochezia ulcerative colitis, infectious colitis including Shigella, Salmonella, 

Campylobacter, Escherichia coli O157:H7 and amebiasis, 

Clostridium difficile colitis, CMV colitis, vasculitis, Henoch– 

Schönlein purpura; juvenile polyp, Meckel’s diverticulum, fissure, 

hemorrhoid 

fever, acute severe abdominal pain appendicitis, diverticulitis, intestinal perforation 

perianal disease histiocytosis, immunodeficiency 

Abnormal liver profile viral hepatitis, toxin, cholelithiasis 

Abnormal pancreatic enzymes idopathic pancreatitis, familial pancreatitis, cystic fibrosis 

Growth failure celiac disease, cystic fibrosis, endocrinopathy (thyroid, adrenal, 

pituitary, especially growth hormone), anorexia nervosa, 

Pubertal delay anorexia nervosa; bulimia; chromosomal abnormality 

Arthritis juvenile rheumatoid arthritis, acute rheumatic fever 

CMV, cytomegalovirus

Findings on physical examination such as pallor 

and abdominal tenderness are most often not 

specific for Crohn’s disease, but abdominal mass, 

aphthoid oral ulcers, erythema nodosum, 

pyoderma gangrenosum, digital clubbing, arthritis, 

or perianal skin tags are highly suggestive of 

Crohn’s disease. 

Laboratory studies 

A number of laboratory tests can offer useful and 

supportive information in facilitating diagnosis, 

although they are generally non-specific. An initial 

screening evaluation with CBC with differential, 

platelet count, ESR, serum albumin, stool hemoccult 

test, and stool culture are often obtained. 

Serum iron studies and serum levels of vitamins A, 

E, B12 and folate can be helpful in assessing specific 

nutritional deficiencies. 

Serological markers 

Several serological markers have been reported to 

facilitate the diagnosis of IBD and in distinguishing 

between Crohn’s disease and ulcerative colitis. 

Although these tests may have benefit in some clinical 

situations, the diagnosis remains to be determined 

by clinical–pathological criteria. Atypical 

perinuclear antineutrophil cytoplasmic antibodies 

(atypical P-ANCA, i.e. not directed against 

myeloperoxidase) can be detected in 60–80% of 

adult patients with ulcerative colitis and 10–20% of 

adult patients with Crohn’s disease. 138–140 In children 

with IBD, a positive test for P-ANCA and a 

negative test for anti-Saccharomyces cerevisiae 

antibody (ASCA) are indicative of increased likelihood 

of ulcerative colitis rather than Crohn’s 

disease (sensitivity 57%, specificity 97%). 139 

Conversely, a negative P-ANCA test and a positive 

ASCA test in children with IBD are suggestive of 

Crohn’s disease (sensitivity 49%, specificity 97%). 

The relatively low sensitivities of these serological 

markers for establishing a diagnosis of Crohn’s 

disease and ulcerative colitis limit their widespread 

clinical utility. 103 Antibody against Escherichia coli 

outer membrane porin (anti-OmpC antibody) has 

been reported as a potential serological marker for 

Crohn’s disease. It is a curious finding that the 

markers that are associated with Crohn’s disease 

are related to a host response to luminal organisms 

Diagnosis 361 

(i.e. yeast and bacteria). As experience increases in 

the pediatric population with the relationship 

between phenotype and serological markers, they 

may become more clinically relevant. 


Barium upper gastrointestinal series with smallbowel 

follow-through is a useful tool in diagnosing 

gastroduodenal and ileal involvement of Crohn’s 

disease (Figure 23.3). Radiographic features in 

patients with Crohn’s disease include narrowing of 

the lumen of the small intestine or colon with 

nodularity and ulceration, a ‘string’ sign when 

luminal narrowing becomes more advanced or 

with severe spasm, a cobblestone appearance, fistulae 

and abscess formation, and separation of bowel 

loops, a manifestation reflecting the transmural 

inflammation and bowel wall thickening. Antral 

narrowing and segmental structuring of the duodenum 

can be seen with gastroduodenal Crohn’s 

disease. 

Air-contrast barium enema may be helpful in 

detecting colonic lesions such as ulcers, strictures 

and fistulae, but these colonic radiographs have 

been largely replaced by colonoscopy. In specific 

clinical situations, such as a distal stricture that 

does not permit visual inspection of the more proximal 

colon, virtual colonoscopy may be of benefit. 

Inflammation limited to the colon may make it 

difficult to distinguish ulcerative colitis from 

Crohn’s colitis; however, radiographic disease in 

the small intestine, stomach or esophagus strongly 

supports a diagnosis of Crohn’s disease. 

Computerized tomography (CT) scans have become 

extremely valuable in the assessment of the child 

with established Crohn’s disease who presents with 

abdominal pain or fever. The use of oral, rectal and 

or intravenous contrast increases the likelihood of 

finding a fistula, stricture or abscess. For the child 

with perianal disease, a careful CT scan with 

narrow cuts may identify a small perirectal abscess. 

Scintigraphy 

Scintigraphy with the 99mTc hexamethyl, propylene 

amino oxime (HMPAO)-labeled leukocyte scan 

(99mTc white blood cell (WBC) scan) has been

362 


(a) (b) 

(c) 

(d) 

Figure 23.3 (a) Axial computerized tomography (CT) 

images with intravenous and oral contrast revealing 

abnormal mucosal thickening of the cecum with 

abnormal enhancement. Numerous enlarged mesenteric 

lymph nodes are present (arrow). (b) This 15-year-old 

child with Crohn’s disease developed a large abscess in 

the anterior abdominal wall (arrow).(c) Markedly 

narrowed terminal ileum with ulcerations seen on a 

barium study (arrowhead). The same small bowel loop is 

seen on a coronal reformatted CT image (white arrow). 

(d) Small fistula tracks are seen extending from a 

thickened, inflamed terminal ileum to the ascending 

colon (arrow). (Courtesy of Dr Sudha Anupindi).

used as an alternative, non-invasive diagnostic test 

to determine the extent and distribution of inflammation 

in children with IBD. 142–144 In one study, 141 

the result of the 99mTc WBC scan correlated with 

histological findings on endoscopic and colonoscopic 

biopsies in 128 of 137 children. The sensitivity 

and specificity were 90% and 97%, respectively. 

141 Nevertheless, the value of this study for 

diagnosis is limited. 

Endoscopic studies and histologic features 

Compared with the continuous distribution of 

ulcerative colitis, Crohn’s disease is characteristically 

segmental, with areas of sparing 

throughout the intestinal tract; the terminal ileum 

is the most commonly affected site. 103 Data from a 

study in 389 children and adolescents with Crohn’s 

disease 103 revealed that 29% of patients had 

involvement of the terminal ileum with or without 

cecal disease, 9% had more isolated proximal (ileal 

or jejunal) disease, 42% had ileocolonic inflammation 

and 20% had only colonic involvement. 

Endoscopic examination is an important diagnostic 

tool for Crohn’s disease and colonoscopy is the 

most effective test to determine whether the colon 

is affected. Crohn’s disease often spares the 

rectosigmoid region, but this pattern of involvement 

may also be seen in early ulcerative colitis, 

especially in young patients. The colonoscopic 

features of Crohn’s disease range from subtle focal 

aphthoid ulcerations adjacent to areas of normal 

appearing mucosa (Figure 23.4) to diffuse areas of 

edema and ulceration that create a polypoid 

mucosa and give a cobblestone appearance (Figure 

23.5). Discontinuous colonic involvement with 

intervening normal appearing mucosa, often 

referred to as skip areas, is a key feature of Crohn’s 

disease. Deep linear ulcerations may evolve into 

mucosal bridges with relatively normal-appearing 

mucosa traversing ulcers (Figure 23.6). Nonspecific 

gastritis and duodenitis may be seen in 

patients with Crohn’s disease on esophagogastroduodenoscopy, 

but histological findings are often 

most helpful in establishing a diagnosis. 

Mucosa that appears grossly normal may reveal abnormalities 

on histological examination. Edema and 

an increase in mononuclear cell density in the 

lamina propria are relatively non-specific findings. 103 

Diagnosis 363 

Figure 23.4 Focal aphthous lesion in Crohn’s disease 

with surrounding area of erythema (arrow). 

Figure 23.5 Cobblestone appearance (arrow) and 

mucosal ulcerations with mucopurulent exudate of the 

colon in Crohn’s disease. (Courtesy of Dr Esther J. Israel). 

In the early phases of Crohn’s disease, microscopic 

changes may resemble an infectious colitis with 

infiltration of the crypts by polymorphonuclear 

leukocytes (cryptitis or crypt abscesses), and distortion 

of crypt architecture 103 (Figure 23.7). Focal

364 


Figure 23.6 Ulceration with mucosal bridging (arrows) 

caused by undermining ulcerations of the colon in 

Crohn’s disease. (Courtesy of Dr Esther J. Israel). 

(a) 

Figure 23.8 (a) Focal ileitis in Crohn’s disease (arrow) 

(low-power view). (b) Ileitis in Crohn’s disease (highpower 

view) demonstrating neutrophilic infiltrate into the 

mucosa (arrow). (Courtesy of Dr Gregory Lauwers). 

ileitis is characteristic of Crohn’s disease (Figure 

23.8). The presence of fibrosis and histiocytic 

proliferation in the submucosa suggests Crohn’s 

disease. The pathological hallmark of Crohn’s 

inflammation is focal inflammation or transmural 

extension involving all layers of the bowel wall. 

Non-necrotizing granulomas are seen in 60% of 

Figure 23.7 Active colitis in Crohn’s disease (arrow) with 

area of relatively preserved mucosa without mucin depletion. 

(Courtesy of Dr Gregory Lauwers). 

(b) 

surgical specimens and 20–40% of mucosal biopsies 

145,146 (Figure 23.9). Microscopic focal enhancing 

lesions in the stomach (Figure 23.10) were 

thought to be indicative of Crohn’s disease, but 

they can be seen in ulcerative colitis as well. 

However, they are supportive of a chronic inflammatory 

process.

Figure 23.9 Focal granuloma (arrow) in the colon of a 

child with Crohn’s disease. (Courtesy of Dr Gregory 

Lauwers). 

Treatment 

Management of children with Crohn’s disease 

includes medical therapy, potential surgical intervention 

as well as nutritional and psychiatric 

support. Education of the patient and the family is 

a critical aspect of care that should not be overlooked. 

The IBD Notebook that is available through 

the North American Society for Pediatric 

Gastroenterology, Hepatology and Nutrition is a 

valuable resource empowering patients to understand 

and control their disease. The general 

guiding principles for treatment are to control 

inflammation and achieve normal growth while 

maintaining a high quality of life. For patients with 

mild-to-moderate disease, initial therapy with 5aminosalicylic 

acid (5-ASA) and antibiotics may 

induce remission. For patients with more active 

disease, corticosteroids may provide a more rapid 

response. Initial treatment with 6-mercaptopurine 

seems to decrease steroid dependency, but most 

clinicians reserve immunomodulator therapy for 

patients who fail to maintain a remission. 

Nutrition support 

Nutritional therapy is a necessary and essential 

aspect of therapy for all children with Crohn’s 

disease; achieving normal growth potential is one 

of the major therapeutic challenges. Nutrition has 

been used as a primary therapy for children with 

Treatment 365 

Figure 23.10 Focal enhancing lesions of the stomach in 

a patient with Crohn’s disease. (Courtesy of Dr Gregory 

Lauwers). 

Crohn’s disease, but when compared to corticosteroids, 

children treated with nutritional therapy 

relapsed sooner. Although the impact on linear 

growth was less in the nutrition group, compliance 

with nutritional regimens is more difficult. 

Suboptimal intake related to anorexia or fear of 

symptoms with eating, stool losses of nutrients 

caused by inflammation, ulceration or resection, 

increased nutritional requirements secondary to 

fever or increased metabolic requirements, treatment 

with corticosteroids that inhibit insulin-like 

growth factor-1, or circulating cytokines that delay 

linear growth are all relevant factors that impair 

growth. Medical or surgical therapy may correct or 

in some situations exacerbate some of the causes of 

undernutrition, but finding a tolerable nutritional 

supplement is the key to successful nutritional 

therapy. 

Careful plotting of weight, height and rate of 

growth, and calculation of the body mass index 

(BMI) (weight in kg/(height in m) 2 ) is a critical part 

of the evaluation that enables one to assess when 

growth delay began. Anthropometric measurements 

such as triceps skin-fold thickness and midarm 

circumference provide an estimation of body 

fat and muscle mass. CT scans and magnetic resonance 

imaging (MRI) may also be beneficial in 

assessing body composition. Bioelectric impedance 

analysis (BIA) and total body electrical 

conductance (TOBEC) assess total body water and 

fat mass, but have not been validated in the

366 


pediatric IBD population. Dual energy X-ray 

absorptiometry (DEXA) scanning of the spine is a 

valuable tool to assess bone mineralization. 

Daily energy requirements are increased in children 

with Crohn’s disease, and during a flare of 

disease energy requirements increase while energy 

generation decreases. Catch-up growth is possible, 

but may require daily dietary energy intakes over 

130% of the recommended values for ideal body 

weight. In practical terms, this corresponds to 

intakes ranging between 60 and 75kcal/kg per day. 

Daily protein intake should approximate 3g/kg, 

but the requirements of specific proteins such as 

glutamine is not substantiated. Amino acid-based, 

hydrolyzed or intact protein diets appear to be 

equally beneficial although there is a theoretical 

immunological benefit to giving protein that is less 

antigenic. In practice this does not seem to be 

beneficial for most patients. Total amount of 

protein rather than composition appears most relevant. 

Growing children with Crohn’s disease who are 

treated with corticosteroids stimulate osteoclastic 

bone resorption, inhibit osteoblast proliferation, 

decrease calcitriol synthesis and do not absorb 

calcium efficiently. These processes result in 

decreased bone mineralization. Patients who are at 

greatest risk for decreased bone mineralization 

seem to be those who take more than 7.5mg/day, 

have a greater than 5g lifetime cumulative dose or 

more than 1 year lifetime exposure. For a growing 

adolescent 1300mg/day of calcium is recommended 

along with 400IU/day of vitamin D. 

Other minerals and vitamins should be replaced if 

deficient. Zinc is decreased with inflammation 

and serum zinc may not reflect intracellular stores. 

Many patients with Crohn’s disease take zinc along 

with selenium and vitamin E as an antioxidant 

cocktail without strong supportive evidence for 

efficacy. Folate requirements may increase in 

active Crohn’s disease, but the folic acid requirement 

for children with Crohn’s disease is not 

known. Many clinicians recommend a dose of 

1mg daily, but the dose is not based on sound 

evidence. Vitamin B12 deficiency may need to be 

treated with subcutaneous injections as ileal 

absorption is often impaired. Release in 2003 of a 

nasal form of vitamin B12 may permit children 

who require vitamin B12 to avoid painful injections. 

5-Aminosalicylic acid drugs 

The anti-inflammatory effects of this class of 

medication results from the inhibitory effect of 5- 

ASA on leukotriene biosynthesis. Effective delivery 

of these drugs is achieved by various structural 

modifications that permit the medication to reach 

the area of inflamed mucosa. Sulfasalazine, a 

prototype of this class of drug, consists of 5-ASA 

linked to sulfapyridine via an azo bond. The sulfa 

moiety serves as a carrier to facilitate delivery of 

therapeutically active 5-ASA to the colon, which is 

achieved by bacterial cleavage of the diazo bond 

and release of the 5-ASA in the intestinal lumen. A 

number of different 5-ASA preparations have been 

developed based on a similar strategy. A summary 

of the different chemical modifications of 5-ASA 

preparations, and their release mechanisms are 

listed in Table 23.7. The dosage and site of effect as 

well as side-effects are listed in Tables 23.8 and 

23.9, respectively. A profile of release within the 

gastrointestinal tract of the different 5-ASA preparations 

is shown in Figure 23.11. The medication 

should be selected that targets the areas of inflammation. 

The dose ranges between 30–60 mg/kg per 

day, but some clinicians use higher doses. 

Pediatric dosing should not exceed the adult 

recommended dose. Topical 5-ASA preparations 

(enema or suppository) are used more commonly 

in ulcerative colitis or in those patients with 

Crohn’s disease who do not have rectal sparing. 


Systemic corticosteroid treatment remains an 

important and effective therapy for children with 

Crohn’s disease, but side-effects often limit their 

use. The anti-inflammatory effect of corticosteroids 

is related to inhibition of cell-mediated 

immunity, decreased cytokine production, 

decreased capillary permeability, impaired 

neutrophil and monocyte chemotaxis and stabilization 

of lysosomal membranes. 147,148 Prednisone 

or prednisolone is commonly used in children 

with Crohn’s disease who have active mucosal 

inflammation that does not respond to initial 

therapy with 5-ASA and antibiotics. Prednisone is 

a synthetic glucocorticoid of intermediate potency, 

and is converted to its active form, prednisolone, 

in the liver. 103 Prednisone or prednisolone is 

administrated orally or intravenously at 1–2 mg/kg

Table 23.7 Chemical modification and release mechanisms of 5-aminosalicylic acid (5-ASA) 

preparations 

Preparation Trade name Chemical modification Release mechanism 

Table 23.8 Dosage and site of effect of 5-aminosalicylic acid preparations 

Preparation Trade name Dosage Site of effect 

Sulfasalazine Azulfidine C: 40–60 mg/kg per day ÷ BID. colon 

For maintenance 30mg/kg per day ÷ 

QID (max 2g/day) 

A: 3-4 g/day ÷ QID 

For maintenance 2g/day ÷ QID 

Olsalazine Dipentum C: not available colon 

A: 1.5–3g/day ÷ BID – QID 

Balsalazide Colazal C: not available colon 

A: 6.75g/day ÷ TID. 

For maintenance 3–4 g/day ÷ BID 

Treatment 367 

Sulfasalazine Azulfidine azo bond to sulfapyridine bacterial cleavage 

Olsalazine Dipentum 5-ASA attaches to 5-ASA bacterial cleavage 

Ipsalazide azo bond to inert carrier bacterial cleavage 

Balsalazide Colazal azo bond to inert carrier bacterial cleavage 

Mesalamine/mesalazine Asacol attach to acrylic-based resins pH-dependent release (pH >7) 

Mesalamine/mesalazine Salofalk, Claversal attach to acrylic-based resins pH-dependent release (pH >5.6) 

Mesalamine/mesalazine Pentasa coated with ethyl cellulose time and moisture-dependent 

release 

Mesalamine/mesalazine Rowasa, Canasa uncoated direct local effect (rectum to left 

enema/suppository colon) 

Mesalamine Asacol C: 25–50 mg/kg per day ÷ BID – TID distal ileum or right colon 

A: 2.4–4.8g/day ÷ TID – QID 

Mesalamine Salofalk, C: not available mid- to small bowel 

Claversal A: 2.4–4g/day ÷ TID – QID 

Mesalamine Pentasa C: 25–50mg/kg per day ÷ BID – TID small bowel and colon 

A: 4g/day ÷ TID – QID 

Mesalamine Rowasa enema, C: not available rectum and left colon 

enema/suppository Canasa suppository A: 4g enema nightly; 500mg 

suppository BID 

C, children; A, adults; BID, twice a day; QID, four times a day; TID, three times a day

368 


Table 23.9 Side-effects of 5-aminosalicylic acid preparations 

Preparation Side-effect 

Sulfasalazine (mainly related to sulfa moiety) dose-dependent (nausea, vomiting, headaches, hemolysis) 

hypersensitivity (fever, rashes, Stevens–Johnson syndrome, 

agranulocytosis, pulmonary fibrosis, hepatotoxicity) 

male fertility impairment 

folate deficiency 

Mesalamine/mesalazine acute pancreatitis 

Olsalazine diarrhea 

Figure 23.11 Gastrointestinal release profile of 5-aminosalicylic acid preparations. The 

diagram of gradient indicates increased release. 

per day to a maximum of 40–60 mg/day, and gradually 

tapered after establishment of remission. A 

typical adolescent patient who required corticosteroids 

might start on 40mg of prednisone once 

daily (or 2mg/kg per day, whichever was less). If 

the clinical response is suboptimal, the dose may 

be divided twice a day. Splitting the dose further 

has little proven efficacy and increases adrenal 

suppression. Although some clinicians may 

increase the dose to a maximum of 60 mg/day for 

those patients who do not respond, there is no 

evidence that higher doses are beneficial and they 

are associated with increased untoward events. 

Systemic corticosteroid therapy is generally not 

used as a maintenance regimen. The adverse effects 

of systemic corticosteroid therapy are summarized 

in Table 23.10. Topical intrarectal corticosteroids 

(hydrocortisone enemas or foam) are also available 

for those patients with rectal disease. 

Oral budesonide is designed for release in the 

ileum, cecum and right colon and is usually 

prescribed at 9mg/day initially for an adult for 8 

weeks and then tapered by 3-mg increments. 

Budesonide is not approved by the Food and Drug 

Administration (FDA) for use in children. Because 

of its high first-pass hepatic metabolism, budesonide 

has significant local effect with much less 

systemic effect. 149 The incidence of overall adverse 

effects is less than with prednisolone as noted in 

clinical trials with adult patients with Crohn’s 

disease. 150 However, long-term use of oral budesonide 

may still cause significant systemic glucocorticoid 

effects, since budesonide has an affinity 

for the glucocorticoid receptor 50–100 times more 

than that of prednisone. 2 Experience with pediatric 

patients with Crohn’s disease has demonstrated 

that growth failure remains an active issue 

in long-term treatment with budesonide, because

Table 23.10 Adverse effect of systemic corticosteroid therapy 

Common Rare Long term 

of either direct suppression of linear growth or an 

inability to control disease activity fully. 151 

Immunoregulatory agents 

Azathioprine and 6-mercaptopurine 

Growing evidence supports the use of the 

immunoregulatory agents azathioprine and 6mercaptopurine 

in treating Crohn’s disease as effective 

therapy to maintain control of intestinal 

inflammation. These agents are particularly useful 

in patients who are steroid-dependent. 6- 

Mercaptopurine is a purine analog capable of interfering 

with DNA and RNA synthesis by competing 

with endogenous purines. Azathio-purine is a prodrug 

that exerts its immunosuppressive effect 

through its metabolite 6-mercaptopurine. 6- 

Mercaptopurine undergoes extensive transformations 

to form cytotoxic intracellular metabolites 

responsible for the immunosuppressive effect. 

Studies suggest that the intracellular levels of the 

metabolite 6-thioguanine (6-TG) correlate with efficacy, 

and the intracellular levels of the metabolite 

6-methyl mercaptopurine (6-MMP) with hepatotoxicity. 

152 Genetic polymorphisms of thiopurine 

methyltransferase (TPMT), an enzyme that catabolizes 

6-mercaptopurine to 6-MMP, controls the 

baseline enzymatic activity of TPMT. One in 300 

subjects has very low enzyme activity or none at 

all, and 11% of the population has intermediate 

enzyme activity. Inherited low TPMT activity 

appears to be a risk factor for acute bone marrow 

failure by leaving more 6-mercaptopurine available 

for conversion to cytotoxic 6-TG. 

In a prospective, double-blind, placebo-controlled 

pediatric trial, 55 children (mean age of 13 years) 

Treatment 369 

Acne seizure growth failure 

Moon facies pseudotumor cerebri nephrolithiasis (hypercalciuria) 

Hirsutism psychosis osteopenia 

Cutaneous striae myopathy osteoporosis 

aseptic necrosis of femoral head diabetes 

cataracts 

increased intraocular pressure 

secondary hyperparathyroidism 

with newly diagnosed Crohn’s disease were 

randomly assigned to receive prednisone plus 

either 6-mercaptopurine (1.5mg/kg per day) or 

placebo. 153 Markowitz et al found that the duration 

of steroid use and the cumulative steroid dose was 

significantly decreased in the group that received 

steroids plus 6-mercaptopurine. Although the rate 

of remission achieved in both groups was similar 

(89%), relapse was less frequent in the group that 

received 6-mercaptopurine. 153 Base on these findings, 

6-mercaptopurine should be considered as 

part of the initial treatment prescribed for children 

with newly diagnosed moderate-to-severe Crohn’s 

disease activity who are started on corticosteroids. 

153 The dosages, adverse effects, and monitoring 

parameters for azathioprine and 6-mercaptopurine 

are listed in Table 23.11. The monitoring 

of 6-TG and 6-MMP remains controversial, as 

discussed by Dubinsky and Griffiths. 154 

Methotrexate 

Methotrexate exerts its cytotoxic effect by interfering 

with thymidine synthesis, by inhibiting the 

conversion of the folic acid to its active form 

tetrahydrofolate. Intramuscular administration of 

methotrexate weekly has proved effective in inducing 

and maintaining remission in adult patients 

with Crohn’s disease who are either steroid-refractory 

or -dependent, 155 or in pediatric patients with 

Crohn’s disease intolerant or refractory to azathioprine/6-mercaptopurine 

treatment. 156 Common 

adverse effects of methotrexate include nausea and 

abnormal liver serum transaminase levels. 

Concerns about possible hepatic fibrosis may limit 

the long-term use of methotrexate.

370 


Table 23.11 6-Mercaptopurine and azathioprine therapy 

Dosage 

Azathioprine 6-Mercaptopurine Potential adverse effects Monitoring program 

1.5–2.5mg/kg per day 1–2mg/kg per day fever TPMT level before therapy 

pancreatitis 

rash 

arthralgia weekly for 4 weeks, then 

nausea every 3months: CBC with 

vomiting differential, liver function 

diarrhea, leukopenia tests, amylase, lipase 

thrombocytopenia 

opportunistic infection 

hepatitis consider: monitoring 6-TG 

malignancy and 6-MMP 

TPMT, thiopurine methyltransferase; CBC, complete blood count; 6-TG, 6-thioguanine; 6-MMP, 6-methyl 

mercaptopurine 

Anti-tumor necrosis factor-α agents 

TNF-α is a pro-inflammatory cytokine produced by 

activated macrophages, and is thought to play an 

important role in the pathogenesis and clinical 

manifestations of IBD. Several reagents have been 

developed as antagonists of TNF-α in the treatment 

of Crohn’s disease. Infliximab (Remicade ® ) is a 

chimeric monoclonal antibody composed of a 

complement-fixing ‘human’ IgG1 constant region 

and a mouse-derived antigen-binding variable 

region, and binds directly to soluble TNF-α. 2 

Infliximab is efficacious as therapy in about twothirds 

of adult patients with moderately to 

severely active Crohn’s disease resistant to corticosteroid 

and azathioprine/6-mercaptopurine 

therapy. However, about half of those who respond 

initially will have a sustained response over the 

first year. Infliximab is also effective in patients 

with fistulae that are refractory to antibiotic and/or 

azathioprine/6-mercaptopurine treatment. 157–159 

Infliximab is administered intravenously with a 

recommended regimen for treatment of fistulae of 

three initial doses at 0, 2 and 6 weeks, followed by 

repeat infusions at 2-month intervals, for patients 

who demonstrate response to the initial doses. 160 

Although this regimen is not FDA approved, most 

patients with Crohn’s disease including those 

without fistulae are treated thus. Common sideeffects 

associated with infliximab therapy include 

fever, rash, vomiting and chest pain. 160 Rarely, a 

serious hypersensitivity reaction may also occur 

with repeat infusion. Reactivation of tuberculosis 

associated with infliximab therapy has been 

reported as a potential lethal complication. 160 

Therefore, all patients must receive tuberculosis 

screening prior to initiation of therapy. Lymphoma 

has developed in a small number of patients 

receiving infliximab, although a causal relationship 

has not been established. 2,160 

In a retrospective open-labeled pediatric study, 19 

children with Crohn’s disease (mean age 14.4 

years) received 1–3 infusions of infliximab 

(5mg/kg per dose) over a 12-week period for corticosteroid-resistant 

(n=7) or corticosteroid-dependent 

disease (n=12). 161 Significant initial 

improvement (first 4 weeks after infusion) was 

noted in all subjects, with pediatric Crohn’s 

disease activity index (PCDAI) values decreasing 

significantly (42.1±13.7 to 10.0±5.6, p

with Crohn’s disease (aged 8–17 years) were 

randomized to receive a single infusion of infliximab 

1mg/kg (n=6), 5mg/kg (n=7), or 10mg/kg 

(n=8). 162 Improvement in the PCDAI, ESR and Creactive 

protein (CRP) was observed with all infliximab 

doses, beginning at week 1. All treated 

patients experienced approximately 50% improvement 

in the PCDAI by week 2, and by week 12, the 

PCDAI remained approximately 30% improved 

from baseline. 162 During the study, all 21 patients 

(100%) achieved a clinical response, and ten 

patients (48%) achieved clinical remission; there 

were no infusion reactions in any of the treated 

patients. 162 Appropriately powered pediatric 

studies of infliximab are needed to establish safety 

and efficacy. 163 

Antibiotics 

Antibiotics are often used to treat newly diagnosed 

or relapsed patients with Crohn’s disease or 

patients with perianal fistulae/abscesses. There are 

no randomized clinical trials to support efficacy in 

the pediatric population. Commonly used antibiotics 

and their dosage and side-effects are listed 


Surgery 

The most common reasons for surgery are 

intractable symptoms despite medical therapy, 

obstruction, intra-abdominal abscess, fistula 

refractory to medical therapy, or intractable 

hemorrhage. In patients with a well-defined region 

Table 23.12 Commonly used antibiotics for Crohn’s disease 

Follow-up management 371 

of disease that has not been progressive over time, 

surgical resection can be a highly effective therapy. 

The potential benefits of surgery include rapid 

resolution of symptoms, enhanced growth and 

pubertal development, and improved quality of 

life. Postoperative recurrence of disease is a significant 

risk. Data from adults have indicated that the 

incidence of clinical recurrence following resection 

is about 10% per year. 

Supportive measures 

Antibiotic Dosage Side-effects 

Psychological support and psychiatric counseling 

are important adjunctive therapies to cope with 

chronic disease. Children with Crohn’s disease 

may have to face delayed sexual maturation and 

short stature. Missing school impacts on social 

maturation and relationships. Psychiatric and 

psychological support is a critical aspect of a pediatric 

IBD program; anti-anxiety or antidepressant 

medications may be beneficial. Long-term therapy 

should be considered for any child having difficulty 

in school or with interpersonal relationships. 

Follow-up management 

The PCDAI is a useful monitoring tool for disease 

activity, but it is time-consuming to use in a 

routine clinical setting. 194–198 A numerical score 

(0–100) based on general well-being, clinical 

symptoms and objective measurements of weight, 

height and clinical examination, as well as laboratory 

tests provides an objective means to follow 

disease activity and response to therapy (Table 

Metronidazole 30–50mg/kg per day, TID metallic taste, disulfiram reaction with alcohol, 

peripheral neuropathy, potential birth defect 

Ciprofloxacin 20–30mg/kg per day, BID skin rash, headache, nausea, vomiting, renal 

failure, seizures, arthropathy 

Augmentin 20–40mg/kg per day, TID skin rash, nausea, vomiting, diarrhea, hypersensitivity 

reactions, seizures, interstitial nephritis 

TID, three times a day; BID, twice a day

372 


23.13). A score of 0–10 indicates inactive disease, 

11–30 mild-to-moderate disease, and over 30 moderate-to-severe 

disease. Signs of pubertal development 

and nutritional assessment should be an important 

part of ongoing care. Annual ophthalmological 

examination is important for all patients who have 

been exposed to corticosteroids. In addition to 

dietary supplement of vitamin D and calcium to 

prevent development of osteopenia and osteoporosis, 

regular bone density study using DEXA is recommended 

for patients on prolonged corticosteroid 

therapy. There are no proven therapeutic interventions 

in children with Crohn’s disease that have been 

shown to prevent recurrence of disease or maintain 

remission. Nevertheless, immunomodulator therapy 

and 5-ASA are often used in this role. 

Table 23.13 Pediatric Crohn’s Disease Activity Index (PCDAI) (adapted from reference 194) 

History (recall, 1 week) Score 

Abdominal pain 

None 0 

Mild (brief, does not interfere with activities 5 

Moderate (daily, prolonged, nocturnal, interfering with activities) 

Stools (per day) 

10 

0–1 (liquid, no blood) 0 

1–2 (semi-formed with small amount of blood) 

or 2–5 (liquid) 

5 

≥6 (liquid or gross bleeding or nocturnal diarrhea) 

Patient functioning, general well-being (recall, 1 week) 

10 

No limitation of activities, well 0 

Occasional difficulty in maintaining age-appropriate activities 5 

Frequent limitation of activity 


Hematocrit (%) 

33 0 

28–32 2.5 

34 0 

29–33 2.5 

Prognosis 

Crohn’s disease is a chronic inflammatory process 

that cannot be cured by current medical therapy or 

by resection. Nevertheless, children with Crohn’s 

disease can manage their disease and achieve their 

goals. General Eisenhower had Crohn’s disease 

and he was elected President of the United States. 

Athletes with Crohn’s disease perform effectively 

and children should be encouraged to pursue their 

dreams. Education, recognition of early manifestations 

of disease and compliance will enable chil- 

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189. Hinks LJ, Inwards KD, Lloyd B, Clayton B. Reduced 

concentrations of selenium in mild Crohn’s disease. J 

Clin Pathol 1988; 41: 198–201. 

190. Ringstad J, Kildebo S, Thomassen Y. Serum selenium, 

copper, and zinc concentrations in Crohn’s disease and 

ulcerative colitis. Scand J Gastroenterol 1993; 28: 

605–608. 

191. Rannem T, Ladefoged K, Hylander E et al. Selenium 

status in patients with Crohn’s disease. Am J Clin Nutr 

1992; 56: 933–937. 

192. Kelly DG, Fleming CR. Nutritional considerations in 

inflammatory bowel diseases. Gastroenterol Clin North 

Am 1995; 24: 597–598. 

193. Hendricks KM, Walker WA. Zinc deficiency in inflammatory 

bowel disease. Nutr Rev 1988; 46: 401–408. 

194. Hyams JS, Ferry GD, Mandel FS et al. Development and 

validation of a pediatric Crohn’s disease activity index. J 


195. Hyams JS, Mandel F, Ferry GD et al. Relationship of 

common laboratory parameters to the activity of Crohn’s 

disease in children. J Pediatr Gastroenterol Nutr 1992; 

14: 216–222. 

196. Otley A, Loonen H, Parekh N et al. Assessing activity of 

pediatric Crohn’s disease: which index to use? 


197. Loonen HJ, Griffiths AM, Merkus MP, Derkx HH. A critical 

assessment of items on the Pediatric Crohn’s Disease 

Activity Index. J Pediatr Gastroenterol Nutr 2003; 36: 

90–95. 

198. Kundhal PS, Critch JN, Zachos M et al. Pediatric Crohn 

Disease Activity Index: responsive to short-term change. 

J Pediatr Gastroenterol Nutr 2003; 36: 83–89.

24 

Introduction 

Indeterminate colitis 


The majority of patients with chronic inflammatory 

bowel disease (IBD) are diagnosed with either 

ulcerative colitis or Crohn’s disease on the basis of 

established clinical, endoscopic, histological and 

radiological criteria. 1 However, in 5–23% of 

patients with chronic colitis, a definitive diagnosis 

of ulcerative colitis or Crohn’s disease cannot be 

established because the initial colonoscopic and 

histological features overlap between ulcerative 

colitis and Crohn’s disease. 2–6 While the condition 

of most of these patients eventually evolves into 

patterns consistent with ulcerative colitis or 

Crohn’s disease, approximately 20–60% retain the 

diagnosis of indeterminate colitis over periods as 

long as 5–10 years after the diagnosis. 3,5,7–11 This 

latter observation suggests that indeterminate 

colitis may constitute a separate category within 

the spectrum of IBD. This chapter reviews the clinical 

features of indeterminate colitis, focusing 

primarily on the pediatric population. 

Table 24.1 Prevalence of indeterminate colitis (IC) 

Epidemiological aspects of 

indeterminate colitis 

Most children with indeterminate colitis are evaluated 

because of recurrent abdominal pain and 

diarrhea, with a smaller number noting hematochezia. 

12 In young children (less than 5 years of 

age), failure to thrive is more prominent than seen 

in ulcerative colitis. 13 Hassan et al noted no difference 

in gender, age at diagnosis or types of 

symptom at presentation among the 38 newly 

diagnosed children with ulcerative colitis, indeterminate 

colitis and Crohn’s disease. 14 

The prevalence of indeterminate colitis in reported 

series of patients with IBD varies among centers 

from 5 to 23% 2–6 (Table 24.1). In our pediatric 

population of 428 children actively followed with 

IBD, 49 (11.4%) were diagnosed with indeterminate 

colitis 4 (Table 24.2). In 42.9% of those with 

indeterminate colitis, the histology ‘favored ulcerative 

colitis’ but these patients also had features of 

Total no. of Age Indeterminate Peak age (years) 

IBD patients group colitis patients IC UC 

Gupta et al 4 420 pediatric 51 (11.9%) 10 — 

Heikenen et al 5 91 pediatric 9 (10%) 7.8 9.7 

Hildebrand et al 3 132 pediatric 36 (27%) — — 

Stewenius et al 15 — — — 10–19 20–29 

Meucci et al 10 1113 adult 50 (4.6%) — — 

Shivananda et al 2 2201 adult 116 (5.3%) — — 

IBD, inflammatory bowel disease; UC, ulcerative colitis 

379

380 


Table 24.2 Indeterminate colitis: histological 

features in 49 pediatric patients at the 

University of Chicago (from reference 4) 

‘Favor ulcerative colitis’: 43% – except for the 

presence of: 

Focal colitis 

Colonic granulomas adjacent to ruptured crypts 

Gastroduodenal inflammation (Helicobacter pylori 

negative) 

Anal fissure 

‘Favor Crohn’s disease’: 18% – except for findings 

of: 

Absence of granulomas 

No small-bowel X-ray features of Crohn’s disease 

No distinguishing features: 39% 

Crohn’s disease including areas of focal colitis, 

focal gastric or duodenal inflammation, anal 

fissures or isolated granulomas adjacent to 

ruptured crypts. Features ‘favoring Crohn’s 

disease’ were present in 20.4% of children with 

indeterminate colitis, none of whom had granulomas, 

radiological evidence of small-bowel Crohn’s 

disease or perianal findings. Endoscopic and histological 

findings of IBD without distinguishing 

features of ulcerative colitis or Crohn’s disease 

were present in 36.7% of our patients with indeterminate 

colitis. 

Heikenen et al noted a similar prevalence of indeterminate 

colitis (10%) in a pediatric population 

of IBD. 5 These authors noted that children with 

indeterminate colitis were diagnosed at a younger 

age (7.8 years) than those with either ulcerative 

colitis (9.7 years) or Crohn’s disease (11.4 years). 

Similarly, in Sweden, the peak age range at diagnosis 

was younger (10–19 years) for patients with 

indeterminate colitis in comparison with ulcerative 

colitis (20–29 years). 15 A particularly high 

prevalence of indeterminate colitis (23%) has been 

reported from one pediatric center in Sweden. 3 

Criteria for histological diagnosis 

In establishing the diagnosis of indeterminate 

colitis, it is essential to exclude other causes of 

colitis such as infections (Clostridium difficile, 

Yersinia, Mycobacterium tuberculosis, Entamoeba 

histolytica, Escherichia coli 0157:H7 or other verocytotoxin-producing 

strains), drugs (non-steroidal 

anti-inflammatory drugs (NSAIDs)), Behçet’s 

disease, malignancy, vasculitis and other identifiable 

causes of colitis. 

Riddell stated that to differentiate indeterminate 

colitis lesions from Crohn’s disease lesions such as 

submucosal and subserosal lymphoid aggregates 

away from areas of ulceration, non-necrotizing 

granulomas and skip areas should be absent. 16 

This is particularly true where there is nonspecific 

ileal involvement or gastritis and special 

stains for Helibacter pylori are negative. The most 

frequently used diagnostic study for distinguishing 

indeterminate colitis from Crohn’s disease (in 

addition to ileocolonoscopy with biopsy) is the 

small-bowel X-ray. 

The endoscopic and histological findings differ 

from classic ulcerative colitis in that there may be 

relative rectal sparing, focal inflammation or deep 

fissuring ulceration. The latter is most common in 

patients with fulminant colitis. It is also important 

to recognize that some medications, such as corticosteroids 

or aminosalicylic acid preparations, 

may change the diffuse histological appearance in 

ulcerative colitis to a more focal appearance. 6,16 

Thus, slides from the original or pretreatment 

colonoscopy should be reviewed when considering 

a diagnosis of indeterminate colitis. 

Although the above criteria would appear to allow 

differentiation between Crohn’s disease and ulcerative 

colitis on the basis of pathology, Farmer et al 

documented disparity among pathologists reviewing 

cases of colonic IBD. 17 The diagnoses of 

gastrointestinal pathologists differed from that of 

the referring institution in 45% of surgical 

specimens and 54% of biopsy specimens. Of 70 

cases initially diagnosed with ulcerative colitis, 30 

(43%) were changed to Crohn’s disease or indeterminate 

colitis; in contrast, 17% of cases initially 

diagnosed with Crohn’s disease were changed to 

ulcerative colitis or indeterminate colitis. 

The performance of upper gastrointestinal 

endoscopy and biopsy (EGD) identifies some 

patients with Crohn’s disease whose colonoscopy 

biopsies were indeterminate. 12,18 Kundhal et al 

reported that, while diffuse non-specific gastritis 

occurred with similar frequency in children with

either Crohn’s disease or ulcerative colitis (92% vs. 

75%), focal antral gastritis was significantly more 

common in Crohn’s disease than ulcerative colitis 

(52% vs. 8%). 12 The authors defined focal inflammation 

as ‘localized inflammation of the gastric 

pits, glands, or foveolae by mononuclear and polymorphonuclear 

leukocytes bordering directly on 

uninflamed mucosa’. This is similar to the statements 

previously published by Riddell. 16 

Granulomas in the stomach or duodenum 

provided evidence confirming the diagnosis of 

Crohn’s disease even in endoscopically normalappearing 

mucosa. 12 Hence, performing an EGD 

should be strongly considered during the initial 

evaluation of patients for IBD. In order to further 

categorize our patients with indeterminate colitis 

further, an X-ray study of the upper gastrointestinal 

tract with small-bowel follow-through was 

performed in all patients to exclude the possibility 

of Crohn’s disease. EGD with biopsy may be particularly 

useful in those children whose symptoms 

(such as nausea, vomiting, early satiety) suggest 

gastroduodenal Crohn’s disease. 18 

Serologic markers and defining 


categories 

We are currently evaluating the role of perinuclear 

anti-neutrophil cytoplasmic antibodies (P- 

ANCA) and anti-Saccharomyces cerevisiae antibodies 

(ASCA) in identifying patients with 

ulcerative colitis and Crohn’s disease previously 

diagnosed with indeterminate colitis. 4 While P- 

ANCA was positive in 68% of those favoring ulcerative 

colitis, and ASCA was positive in 37% of 

those favoring Crohn’s disease, 86% of our patients 

with indeterminate colitis were both p-ANCA and 

ASCA negative. 

Recently, Joossens et al correlated serological 

markers with prospective follow-up evaluation in 

97 adult patients with indeterminate colitis. 8 After 

a mean follow-up of 6 years, 32% of the adult 

patients with indeterminate colitis were reclassified 

as having ulcerative colitis or Crohn’s disease, 

half of whom were positive for p-ANCA or ASCA. 

However, almost half of the patients with indeterminate 

colitis (48.5%) remained p-ANCA/ASCA 

negative and continued to have characteristics of 

Serologic markers and defining IBD categories 381 

indeterminate colitis even 10 years after the initial 

diagnosis. 

Radiological imaging 

In a further attempt to distinguish between the 

various forms of pediatric IBD, 99 m-technetium 

white cell scans and magnetic resonance imaging 

have been evaluated in children with indeterminate 

colitis, ulcerative colitis and Crohn’s 

disease. 18–20 The technetium scan had a sensitivity 

of only 76% compared with colonoscopy and 

biopsy. 19 Others found that conventional magnetic 

resonance imaging had a low sensitivity (40%) for 

detecting Crohn’s disease and did not correlate 

with the severity of inflammation. 20 However, 

gadolinium-enhanced magnetic resonance imaging 

in combination with oral polyethylene glycol 

(PEG) solution (used to distend the small bowel) 

may be more discriminating. 21 With the latter technique, 

increased wall thickness was noted in 26/26 

children with Crohn’s disease while those with 

indeterminate colitis and ulcerative colitis showed 

mild parietal contrast enhancement but not bowel 

wall thickening. Further confirmation of these 

observations is needed. 

Natural history 

With time, 50–72% of adult patients and 64% of 

pediatric patients with indeterminate colitis can 

be reclassified as having definite ulcerative colitis 

or Crohn’s disease during subsequent observation 

3–4,9-11,22 (Table 24.3). After a mean follow-up 

period of 14 months, one group reported that 33% 

of 36 patients with indeterminate colitis were 

reclassified as ulcerative colitis and 17% as 

Crohn’s disease. 9 Meucci et al reported that 37 of 

50 patients (74%) changed from indeterminate 

colitis to a definite diagnosis of ulcerative colitis or 

Crohn’s disease during follow-up with a cumulative 

probability of 80% within 8 years of diagnosis. 

10 In contrast, Wells et al followed 16 patients 

with indeterminate colitis for a mean of 10 years 

and observed that three were reclassified with 

ulcerative colitis, one with Crohn’s disease and the 

rest remained indeterminate. 11 The course of indeterminate 

colitis in 36 Swedish children after a 

mean follow-up of 4.6 years was analyzed by 

Hildebrand et al. 3 The findings were similar to

382 


Table 24.3 Indeterminate colitis (IC): changes in diagnosis with time 

those as described above in adults: 21/36 (58%) 

were subsequently categorized as ulcerative 

colitis, 2/36 (6%) as Crohn’s disease and 13/36 

(36%) remaining as indeterminate colitis. In our 

report describing 49 children with indeterminate 

colitis, nine had undergone colectomy at a mean 

of 24 months after diagnosis. During a mean 

follow-up period of 42 months, 6/9 (66%) had a 

subsequent course, including repeat endoscopic 

examination consistent with ulcerative colitis, 

3/9 (33%) as indeterminate colitis and 1/9 (11%) 

as Crohn’s disease. 

Medical therapy 

The observation that the majority of patients 

with indeterminate colitis over time are reclassified 

as ulcerative colitis or Crohn’s disease 

makes it difficult to know whether indeterminate 

colitis represents a separate form of IBD. Perhaps 

because of the small number of patients with 

indeterminate colitis, the response to various 

drug regimens in this population has not been 

specifically addressed. 7 In our program the 

choice of therapeutic intervention is selected 

depending on the severity of symptoms, extent 

and severity of endoscopic and histological findings 

and laboratory parameters 23 (Table 24.4). For 

most patients, drug therapy is similar to that 

indicated for patients with ulcerative colitis of 

Diagnosis 

Initial Final Final Final 

IC IC (%) UC (%) CD (%) 

Hildebrand et al3 36 (pediatric) 36 58 6 

Moum et al9 36 (adult) 50 33 17 

Meucci et al10 50 (adult) 20 34 40 

Kangas et al22 6 (surgery) 50 — 50 

Wells et al11 16 (surgery) 75 19 6 

Gupta et al4 12 (surgery/pediatric) 33 50 17 

UC, ulcerative colitis; CD, Crohn’s disease 

comparable extent and severity. These include 5aminosalicylic 

acid (5-ASA) preparations for 

mild disease and corticosteroids and 

immunomodulatory therapy for moderate and 

severe disease. However, we are more likely to 

use metronidazole in this population, especially 

where there is extensive focal colitis or those 

‘favoring’ Crohn’s disease. Immunomodulatory 

agents, such as azathioprine or 6-mercaptopurine, 

are used in approximately 60% of our 

pediatric population with IBD, owing to the presence 

of steroid dependency, resistance or toxicity. 

24 

Many large series involving clinical trials of 

adult patients with IBD have included small 

numbers of patients with indeterminate colitis, 

although they have not specifically addressed 

the treatment of indeterminate colitis. 7 The 

response of adult patients with refractory ulcerative 

colitis and indeterminate colitis appears to 

show similar improvement to azathioprine/6mercaptopurine 

and cyclo-sporin as well as 

newer immunomodulatory agents such tacrolimus 

and thalidomide. 25–27 The role of infliximab 

in indeterminate colitis is as yet to be 

determined. However, favorable outcomes in 

pediatric patients with ulcerative colitis suggest 

that it could be considered in patients with indeterminate 

colitis who are not responding to 

conventional medications. 28

Table 24.4 Medical approach to the pediatric patient with indeterminate colitis 

5-Aminosalicylic acid preparations for mild disease 

Corticosteroids (moderate-to-severe disease severity) 

Metronidazole if histology favors Crohn’s disease 

Azathioprine (AZA) or 6-mercaptopurine (6-MP) 

Surgical treatment 

Considerable conflicting data have been published 

regarding complication rates following medical 

and surgical intervention in patients with indeterminate 

colitis versus ulcerative colitis. Some 

centers reported that indeterminate colitis was 

more refractory to medical interventions than 

ulcerative colitis, resulting in a greater relapse 

rate 29 and subsequent need for colectomy. 30 

Colectomy rates averaged 36.1/1000 person-years 

in patients with indeterminate colitis versus only 

7.5 for those with definite ulcerative colitis. 30 In 

contrast, Witte et al described similar response 

rates to medical intervention in indeterminate 

colitis and ulcerative colitis. 31 The European 

Collaborative Study on Inflammatory Bowel 

Disease (EC-IBD) reported ‘complete relief of 

complaints’ in 48% of ulcerative colitis patients 

versus 50% of those with indeterminate colitis; in 

addition, 37% of patients with ulcerative colitis 

‘improved’ versus 33% with indeterminate 

colitis. 31 Similarly, higher rates of pouch failure 

after ileal pouch–anal anastomosis (IPPA) 32,33 and 

colorectal cancer 34 have been reported by some 

groups, while others have reported lower rates of 

pouchitis for indeterminate colitis (29%) than 

Surgical treatment 383 

Consider measuring red blood cell 6-thioguanine levels to reduce the risk of toxicity if increasing the dose in 

refractory patients 

Change to AZA from 6-MP (or vice versa) for non-hypersensitivity side-effects (e.g. rash, arthralgia, headache) 

Methotrexate (parenterally) if intolerant or refractory to AZA/6-MP 

Cyclosporin intravenously or micro-emulsified oral formulation 

Tacrolimus (0.1–0.15mg/kg twice a day); monitor blood level 

Thalidomide (50–100mg/day in older children and adolescents) 

Remicade (at conventional dosing) 

ulcerative colitis (58%) and Crohn’s disease (72%). 

However, this latter group observed a greater 

frequency of fistulae after IPAA in patients with 

indeterminate colitis (26%) versus for ulcerative 

colitis (10%). 35 Post-IPAA complications resulting 

in pouch removal were higher for indeterminate 

colitis (19–28%) versus ulcerative colitis (0.4–8%) 

in some studies 32,33 but not in others. 35–37 

It is our practice to repeat colonoscopy, usually 

with concurrent EGD, during selected periods of 

relapse to assess whether histological changes 

consistent with ulcerative colitis or Crohn’s 

disease have developed. This is especially the case 

if colectomy and IPAA are being considered 

because of refractory disease. At this time, repeat 

small-bowel X-ray is usually obtained so that 

patients with ileal Crohn’s disease would be 

excluded and patients with persistent 

indeterminate colitis would be counseled regarding 

the potentially greater risk of pouch complications. 

Often, patients with indeterminate colitis 

undergo a multi-staged operative procedure 

consisting of a subtotal colectomy with temporary 

ileostomy and Hartmann pouch. In this way, the 

entire resected colon can be assessed to exclude 

Crohn’s disease prior to creating the IPAA. 36

384 


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12. Kundhal PS, Stormon MO, Zachos M et al. Gastric antral 

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13. Mamula P, Telega GW, Markowitz JE et al. Inflammatory 

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14. Hassan K, Cowan FJ, Jenkins HR. The incidence of 

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15. Stewenius J, Adnerhill I, Ekelund GR et al. Ulcerative 

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diagnostic accuracy in colonic inflammatory bowel 


18. Lenaerts C, Roy CC, Vaillancourt M et al. High incidence 

of upper gastrointestinal tract involvement in children 

with Crohn disease. Pediatrics 1989; 83: 777–781. 

19. Cucchiara S, Celentano L, deMagistris TM et al. 

Colonoscopy and technetium99m white cell scan in 

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Pediatr 1999; 135: 727–732. 

20. Durno CA, Sherman P, Williams T et al. Magnetic resonance 

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21. Laghi A, Borrelli O, Paolantonio P et al. Contrast 

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25 

Introduction 


Leslie M Higuchi and Athos Bousvaros 

Ulcerative colitis and Crohn’s disease are the two 

most common forms of idiopathic inflammatory 

bowel disease (IBD). Ulcerative colitis differs from 

Crohn’s disease in that the inflammation in ulcerative 

colitis is confined to the mucosal layer of the 

colon. In contrast, Crohn’s disease is characterized 

by transmural inflammation in either a limited 

region or extensively in the bowel, and may 

involve any portion of the gastrointestinal tract 

from the mouth to the anus. The peak incidence of 

IBD occurs between the ages of 15 and 25 years, 

but ulcerative colitis may begin at any age. 1 

Approximately 20% of patients with ulcerative 

colitis present before the age of 20 years. 2 While 

children and adults develop similar symptoms, 

children often present with more extensive 

disease. 3 Clinicians caring for children and adolescents 

with ulcerative colitis must treat both the 

gastrointestinal and extraintestinal complications, 

optimize nutrition and linear growth, and address 

the psychosocial ramifications of the illness. Since 

the majority of the published studies investigating 

the natural history and treatment of ulcerative 

colitis are in adults, we refer primarily to these 

studies, with reference to pediatric studies where 

available. 

Epidemiology 

Most children with ulcerative colitis present 

between the ages of 10 and 18 years. However, 

ulcerative colitis in children under the age of 5 

years is well described. 1,4,5 Epidemiological 

studies primarily conducted in the US, GB, and 

Scandinavian countries, suggest that the incidence 

of ulcerative colitis in children ranges from 1.4 to 

4.3 cases/100000 population per year. 3,6–10 The 

incidence of ulcerative colitis in children has 

remained relatively stable 11 (Table 25.1). The 

majority of incidence data for Crohn’s disease and 

ulcerative colitis in the pediatric population originates 

from geographic regions with higher rates of 

IBD. 

Adult studies demonstrate that ulcerative colitis is 

more prevalent in North America, the UK, and 

Scandinavia and less common in southern Europe, 

Asia and Africa. 2 The data suggest a north–south 

gradient with higher incidence rates of both 

Crohn’s disease and ulcerative colitis in northern 

locations, even within individual countries. 12,13 

Ulcerative colitis is more common among Jewish 

than non-Jewish peoples, 14 but disease rates in 

people of Jewish origin vary by geographic region 

and parallel those of the general population. 15 The 

higher rates of IBD in individuals of Jewish origin 

across different countries support a common 

genetic predisposition; however, the geographic 

variation of IBD rates in Jews emphasizes that 

environmental factors (see below) influence the 

inherited risk. 

Etiology and pathogenesis 

The pathogenesis of ulcerative colitis is unknown. 

A widely accepted hypothesis suggests that, in the 

genetically susceptible individual, a combination 

of host and environmental factors leads to the 

initiation and perpetuation of an abnormal intestinal 

immune response, resulting in ulcerative 

colitis. 16 In support of this theory, colitis in 

animals occurs in a wide variety of genetically 

altered rodents, including: knockout mice for 

interleukin (IL)-2, IL-10 and T-cell receptor; and 

HLA-B27 transgenic rats. 17 Interestingly, most of 

these animal models do not develop colitis in 

385

386 


germ-free environments. These findings suggest 

that multiple genes may contribute to the pathogenesis 

of IBD, and that interaction with the environment 

is essential. 

In humans, ulcerative colitis appears to have a 

non-Mendelian pattern of inheritance. Current 

evidence suggests that genes comntribute less to 

the risk in individuals with ulcerative colitis than 

in those with Crohn’s disease. In a Danish twin 

cohort study and a recently updated Swedish twin 

cohort study, the calculated pair concordance rates 

among monozygotic twins were 14–19% for ulcerative 

colitis and 50% for Crohn’s disease; and 

among dizygotic twins, 0–5% for ulcerative colitis 

and 0–4% for Crohn’s disease. 18,19 Although the 

concordance rates of disease are higher in monozygotic 

twins, the incomplete concordance suggests 

that non-genetic factors also contribute to the 

development of ulcerative colitis. First-degree relatives 

of patients with ulcerative colitis have a 9.5fold 

increase in risk of developing ulcerative 

colitis, compared to the general population. 20 The 

risk of developing Crohn’s disease or ulcerative 

colitis is increased in children of affected parents 

with IBD. In one study, the life-time risks for IBD 

in offspring ranged from 5–8% when one parent 

had Crohn’s disease, and from 2–5% when one 

parent had ulcerative colitis. 21 In another study of 

families with two or more affected family members 

with IBD, there was a high concordance for the 

diagnosis of ulcerative colitis or Crohn’s disease. 22 

Of 83 families in which the proband had ulcerative 

colitis, 72 relatives had ulcerative colitis (81%, 

72/89) and 17 had Crohn’s disease (19%, 17/89). 22 

Family linkage studies suggest that candidate 

genes may be present on chromosomes 3, 7 and 12, 

with the strongest association identified on chromosome 

12. 23 Associations with certain HLA 

alleles (especially DR2) have been described. 16,24,25 

However, no specific gene or protein has been 

identified. 17 

Environmental factors may contribute to the development 

of ulcerative colitis. However, most 

studies examining environmental risk factors have 

the limitations of retrospective, case–control 

methodology. One of the most consistent findings 

in multiple studies is the lower risk of ulcerative 

colitis among current smokers. Current smokers 

have approximately one-half the risk of developing 

ulcerative colitis compared to non-smokers. 26,27 

Table 25.1 Incidence of ulcerative colitis (UC) in children and adolescents (no. of new cases/ 

100000 persons per year) 

First author Location Age range (years) Time period studied Incidence 

Barton, 1989 6 Scotland >5 and ≤ 16 for UC 1968–83 

1968 1.9 

1983 1.6 

Calkins, 1984 7 Baltimore, MD, USA

Several authors have suggested that exposure to 

infections in the perinatal period or early life may 

contribute to the development of ulcerative colitis. 

Individuals with Crohn’s disease or ulcerative 

colitis were more likely to have experienced a diarrheal 

illness during infancy, when compared to 

their unaffected siblings. 28 Appendectomy at a 

young age is associated with a lower risk of ulcerative 

colitis. 29–31 In a population-based study, the 

inverse relation between appendectomy and ulcerative 

colitis was observed only in those individuals 

who underwent surgery before the age of 20 

years. 29 Interestingly, the risk of ulcerative colitis 

was reduced only in patients who had an appendectomy 

performed for inflammatory conditions, 

such as appendicitis or mesenteric lymphadenitis, 

but not in patients who underwent appendectomy 

for non-specific abdominal pain. 29 These findings 

may suggest that the inflammatory condition that 

preceded the appendectomy, rather than the 

appendectomy itself, may be inversely related to 

the development of ulcerative colitis later in life. 29 

Some published reports suggest that non-steroidal 

anti-inflammatory drugs (NSAIDs) may precede 

the onset of IBD, lead to a reactivation of quiescent 

IBD, or exacerbate already active IBD in 

humans. 32–35 In an adult case–control study, 

Felder et al compared the use of NSAIDs in 60 

patients hospitalized for exacerbations of IBD, 

either ulcerative colitis or Crohn’s disease, to that 

of 62 out-patients with irritable bowel 

syndrome. 36 At least 31% of the IBD patients (35% 

of the ulcerative colitis patients) who used 

NSAIDs within 1 month of symptoms developed 

the onset or an exacerbation of IBD, whereas only 

2% of the irritable bowel patients experienced 

aggravation of their symptoms after similar 

NSAID use. In a retrospective review of initial 

office visit records of adult out-patients with 

either Crohn’s disease (112 initial visits) or ulcerative 

colitis (80 initial visits), Bonner et al did not 

find any association between NSAID use and 

active IBD. 37 Also, another short report suggested 

the possible exacerbation of IBD activity associated 

with the use of celecoxib, a selective cyclooxygenase 

(COX)-2 inhibitor, in two patients, one 

with ulcerative colitis and one with Crohn’s 

disease. 35 Studies suggest that both standard 

NSAIDs and selective COX-2 inhibitors can exacerbate 

colitis in animal models of colonic inflammation. 

38,39 It has been postulated that NSAIDs 

Etiology and pathogenesis 387 

may worsen colitis by inhibiting the synthesis of 

colonic prostaglandins that may exert anti-inflammatory 

effects in the setting of colonic inflammation. 

40 Further study is needed to clarify any true 

association of NSAID therapy with the onset of 

ulcerative colitis, to identify those individuals at 

most risk, and to determine the safety profile of 

COX-2 inhibitors in comparison to standard 

NSAIDs in reference to potential colonic mucosal 

injury. In general, given the current data, it is 

advisable for children with ulcerative colitis to 

avoid NSAID therapy if there are other reasonable 

alternatives for pain control (e.g. acetaminophen). 

In patients with arthritis, alternative anti-inflammatory 

medications (e.g. sulfasalazine) should be 

considered. 

Given the constant intestinal exposure to numerous 

luminal dietary antigens, it seems reasonable 

to postulate a relationship between diet and ulcerative 

colitis. The data on the association of breast 

feeding and ulcerative colitis are inconclusive, 

with one published study suggesting a protective 

effect, 41 and two other studies showing no 

effect. 28,42 Ecological and case–control studies 

have examined the association between certain 

foods and ulcerative colitis, 43,44 but at present, 

there is no definitive evidence linking diet to the 

development of ulcerative colitis. Methodological 

issues of these retrospectively designed dietary 

studies, such as the collection of pre-illness 

dietary information, remain a problem in the 

interpretation of findings. As an example, the 

recalled dietary intake may reflect changes in the 

diet secondary to the effects of the disease itself, 

rather than the individual’s dietary habits preceding 

the onset of disease. The association between 

oral contraceptive use and ulcerative colitis 

remains controversial. 26,45 

Current evidence suggests that colitis results 

when the intestinal mucosal immune system in 

patients with inflammatory bowel disease reacts 

inappropriately to intestinal bacteria. Evidence 

supporting this hypothesis includes the fact that 

most animal models of colitis do not develop 

disease in germ-free environments, the reports of 

efficacy of antibiotics in the treatment of colitis 

and pouchitis, and the seasonal variations in the 

onset of ulcerative colitis. However, no specific 

infectious agent has consistently been associated 

with exacerbations of ulcerative colitis. 17,46

388 


Activated cells of the mucosal immune system are 

present in the bowel of both Crohn’s disease and 

ulcerative colitis patients. There is some evidence 

that Crohn’s disease and ulcerative colitis are characterized 

by different mucosal immune responses, 

suggesting that different subsets of T cells may be 

involved. Crohn’s disease is characterized by 

increased secretion of the cytokines IL-2, interferon-γ, 

tumor necrosis factor (TNF)-α, and IL-12, 

suggesting a Th1 pattern of cytokine response. 47,48 

In contrast, in ulcerative colitis, the lamina propria 

T cells secrete increased amounts of IL-5 and 

possibly IL-13 and there is increased production 

by B cells of IgG1, suggesting a Th2 pattern of 

cytokine response. 46,29 Such differences may 

explain why anti-TNF therapies, such as infliximab, 

have thus far failed to show the same degree 

of efficacy in ulcerative colitis as in Crohn’s 

disease. Patients with active ulcerative colitis also 

have increased levels of the chemokine IL-8 in 

biopsy specimens as well as in rectal 

dialysates. 50–52 IL-8 and other chemokines facilitate 

the recruitment and transmigration of 

neutrophils across mucosal surfaces. 53,54 These 

neutrophils in turn produce prostaglandins and 

leukotrienes, which cause pain, diarrhea and 

further intestinal inflammation. 55 Thus, alterations 

in function of immune system cells, particularly 

regulatory CD4 lymphocytes, probably 

result in aberrant responses to bacterial antigens, 

antibody production and cytotoxicity against gut 

epithelium, and recruitment of inflammatory cells 

into the colonic crypts. 


The typical symptoms of ulcerative colitis include 

rectal bleeding, diarrhea and abdominal pain. The 

presentation can vary depending upon the extent 

of colonic involvement and the severity of inflammation. 

The colon in ulcerative colitis is inflamed 

in a diffuse, continuous distribution, extending 

from the rectum proximally. By convention, ulcerative 

colitis is classified according to the extent of 

disease into the following three subgroups: proctitis 

(disease limited to the rectum), left-sided colitis 

(disease extending to the sigmoid or descending 

colon, but not past the splenic flexure) and pancolitis 

(disease extending past the splenic flexure). 

Proctitis may present with tenesmus, urgency and 

the passage of formed or semi-formed stool with 

blood and mucus. 56 In contrast, pancolitis or leftsided 

disease may present with bloody diarrhea 

and significant abdominal pain. The majority of 

patients will present with a history of symptoms 

for several weeks; however, some will present with 

a more acute clinical picture. 

Although adults and children with ulcerative 

colitis can present with similar symptoms, there 

are differences in the clinical presentation of these 

two populations. Studies suggest that children 

with ulcerative colitis present with more extensive 

colonic involvement than adults with ulcerative 

colitis. 3,4,10 In a Danish study of 80 patients aged 

less than 15 years and 1081 patients aged 15 years 

or more with ulcerative colitis, the younger group 

had more extensive disease at diagnosis compared 

to the older group diagnosed with ulcerative 

colitis. 3 Of the ulcerative colitis patients younger 

than 15 years, 29% had pancolitis and 25% had 

proctitis; in contrast, of the ulcerative colitis 

patients 15 years or older, 16% had pancolitis and 

46% had proctitis. 3 Gryboski examined 38 children 

diagnosed with ulcerative colitis at ≤ 10 years 

old and reported 71% with pancolitis, 13% with 

left-sided colitis and 6% with proctitis. 4 

Approximately 5% of children with ulcerative 

colitis have evidence of delayed linear growth 

and/or weight loss at diagnosis, although growth 

failure is much less frequent than in children with 

Crohn’s disease 4,57 (Table 25.2). 

Table 25.2 Symptoms at initial presentation 

of ulcerative colitis in children and 

adolescents (from references 3, 4, 9, 57, 300) 

Clinical symptoms Range (%) 

Rectal bleeding 75–98 

Diarrhea 71–91 

Abdominal pain 44–92 

Weight loss 13–74 

Arthralgia/arthritis 5–9 

Fever 3–34 

Growth restriction 4–5

Children with ulcerative colitis may present with 

varying degrees of disease severity. Approximately 

50% of children with ulcerative colitis will present 

with a mild form of disease, characterized by an 

insidious onset of diarrhea and rectal bleeding, 

without abdominal pain or systemic symptoms 

such as fever. In these patients, disease may be 

confined to the distal colon. 58,59 Disease of moderate 

severity is seen in 30% of children with ulcerative 

colitis and is characterized by a more acute 

presentation with bloody diarrhea, tenesmus and 

urgency; systemic symptoms including low-grade 

fever, abdominal tenderness, weight loss and mild 

anemia may be present. 58,59 Approximately 10% of 

children will present with a severe form of ulcerative 

colitis. 58,59 Characteristic findings in severe 

disease include six or more bloody stools per day, 

fever, weight loss, anemia, hypoalbuminemia and 

diffuse abdominal tenderness on physical examination. 

58–60 A very small percentage of children 

will present initially with extraintestinal symptoms 

or manifestations, without obvious intestinal 

symptoms. 59 These extraintestinal manifestations 

of IBD may include axial or peripheral arthritis, 

erythema nodosum, pyoderma gangrenosum, or 

primary sclerosing cholangitis (see Extraintestinal 

manifestations, p.394). 

Diagnosis and differential 


The diagnosis of ulcerative colitis is established by 

the information gathered from a detailed symptom 

and family history, physical examination, and a 

combination of laboratory, radiological, endoscopic 

and histological findings. It is important to 

exclude other etiologies, such as an infectious 

process, and to distinguish ulcerative colitis from 

Crohn’s disease. Colonic inflammation is typically 

characterized by bloody diarrhea with abdominal 

cramping. The differential diagnosis of colitis 

depends upon the age of the child at the time of 

evaluation. In infancy, necrotizing enterocolitis, 

Hirschsprung’s enterocolitis and allergic colitis are 

common. In contrast, in the older child and 

adolescent, enteric infection and IBD are the most 

common diagnoses. Causes of colitis are listed in 

Table 25.3. In patients with painless rectal bleeding, 

other conditions (Meckel’s diverticulum, 

Diagnosis and differential 389 

Table 25.3 Differential diagnosis of colitis 

Infectious etiologies 

Campylobacter 

Salmonella 

Shigella 

Escherichia coli 0157: H7 and other 

enterohemorrhagic E. coli 

Clostridium difficile 

Aeromonas 

Plesiomonas 

Entamoeba histolytica 


Herpes simplex virus 

Yersinia 

Tuberculosis 

HIV and HIV-related opportunistic infections 

Other 



Henoch–Schönlein purpura 

Hemolytic uremic syndrome 

Intestinal ischemia 

Intussusception 

Allergic colitis (primarily in infancy) 

Hirschsprung’s enterocolitis (primarily in infancy) 

polyp) should be considered. In addition to details 

of the clinical presentation, the history should 

include family history, recent antibiotic therapy, 

infectious exposures, growth and sexual development 

and the presence of extraintestinal manifestations 

of ulcerative colitis. Physical examination 

should include assessment of height, weight and 

body mass index; abdominal distension, tenderness, 

or mass; extraintestinal manifestations (e.g. 

aphthous stomatitis, pyoderma gangrenosum, 

uveitis or arthritis); and fecal blood on rectal 

examination, perianal abnormalities (e.g. fistulae, 

fissures or tags). Findings on physical examination 

may help to distinguish ulcerative colitis from 

Crohn’s disease; for example, pronounced growth 

failure or a perianal abscess strongly suggests the 

diagnosis of Crohn’s disease. A severely ill child 

with ulcerative colitis may have tachycardia, 

orthostatic hypotension, fever, or dehydration.

390 


Such findings in the presence of abdominal distension 

and a concerning abdominal examination, 

may herald a fulminant presentation of ulcerative 

colitis with increased risk of developing toxic 

megacolon. 

Laboratory assessment 

Initial laboratory evaluation should include appropriate 

blood tests, stool for occult blood, Clostridium 

difficile toxin assay and stool cultures. A 

complete blood cell count with differential may 

reveal a leukocytosis with or without left shift, 

anemia, or thrombocytosis. Thrombocytosis, hypoalbuminemia 

and elevated erythrocyte sedimentation 

rate (ESR) or C-reactive protein (CRP) may 

indicate increased disease activity. 61–63 The presence 

of anemia with low mean corpuscular 

volume (MCV), wide red cell distribution width 

(RDW) and low iron levels may indicate an irondeficient 

anemia secondary to ongoing fecal blood 

losses or the anemia of chronic disease. Children 

with significant mucosal inflammation may have 

normal laboratory test results. In a study of children 

with ulcerative colitis or Crohn’s colitis, 13 of 

36 patients with ulcerative colitis (36%) had 

normal blood test results, including seven of 28 

ulcerative colitis patients with macroscopic findings 

(obvious abnormalities) on colonoscopy, and 

12 of 31 ulcerative colitis patients with histological 

moderate or severe chronic inflammation. 63 Stool 

examination should rule out possible enteric infections 

(see Table 25.3). In sexually active patients, 

rectal cultures for gonorrhea should be considered. 

In ulcerative colitis, Gram stain or methylene blue 

stain of stools may identify leukocytes. 

It has been proposed that certain serum antibodies 

may be helpful for screening for IBD and discriminating 

ulcerative colitis from Crohn’s disease. 64,65 

Perinuclear antineutrophil cytoplasmic antibodies 

(P-ANCA) are seen in 60–80% of adults with 

ulcerative colitis compared to 10–27% of 

adults with Crohn’s disease. 64,66,67 Similarly, anti- 

Saccharomyces cerevisiae antibodies (ASCA) are 

commonly found in individuals with Crohn’s 

disease but are rarely seen in ulcerative colitis. In 

a study of 173 children, ASCA yielded a sensitivity 

of 55% and specificity of 95% for Crohn’s 

disease, and ANCA had a sensitivity of 57% and 

specificity of 92% for ulcerative colitis. 64 In a 

study of 128 pediatric patients undergoing evaluation 

for IBD, Dubinsky et al utilized modified cutoff 

values to optimize the sensitivity of the ASCA 

and ANCA assays. For the combination of ASCA 

and P-ANCA, the sensitivity of detecting IBD 

increased to 81% with the modified values 

compared to the 69% with standard cut-off values; 

however, this was accompanied by an increase in 

false-positive rates among the children without 

IBD. 65 An overlap of ASCA and P-ANCA positive 

serology between patients with Crohn’s disease or 

ulcerative colitis remains. In particular, P-ANCA 

tends to test positive in the serum of patients with 

Crohn’s disease who exhibit ulcerative colitis 

features. 64,68 The value of these tests to supplement 

the routine diagnostic tests in IBD is a 

subject under study. 

Endoscopic and radiographic evaluation 

Evaluation with colonoscopy and ileoscopy with 

biopsies and a barium upper gastrointestinal series 

with small-bowel follow-through should be 

performed to diagnose ulcerative colitis, determine 

the extent and severity of ulcerative colitis presentation 

and distinguish ulcerative colitis from 

Crohn’s disease or a non-IBD diagnosis. In patients 

with severe colitis, a limited flexible sigmoidoscopy 

examination with minimal air insufflation 

may be prudent to avoid increased risk of a 

full colonoscopy (perforation, hemorrhage, toxic 

dilatation). In order to establish the extent of 

disease involvement by colonoscopy, we recommend 

biopsies from the terminal ileum and each 

segment of the colon, even if there are no visible 

findings at a particular level of the colon. In ulcerative 

colitis, typical findings seen by the endoscopist 

include a diffuse, continuous process starting 

at the rectum and extending more proximally 

into the colon. However, in children with ulcerative 

colitis, rectal sparing has been reported. 69,70 

The colonic mucosa often appears edematous, 

erythematous and friable, with minute surface 

erosions and ulcerations (Figure 25.1). Larger, 

deeper ulcerations with associated exudate may 

develop in more severe disease. With more chronic 

(longstanding) ulcerative colitis, pseudopolyps 

may be present. (Figure 25.2). In contrast, in 

Crohn’s disease, colonoscopy may reveal focal 

ulcerations (aphthous lesions) with intervening 

areas of normal-appearing mucosa (skip lesions).

Figure 25.1 Severe colitis at initial presentation of ulcerative 

colitis. The colonoscopy demonstrates a featureless 

colon with loss of vascular pattern and hemorrhage. 

In severe or chronic Crohn’s disease, linear ulcerations, 

nodularity (cobblestoning) and strictures or 

stenoses may be present. In general, the ulcerations 

in Crohn’s disease are deeper and focal 

versus the diffuse, superficial ulcerations typical 

of ulcerative colitis (Table 25.4). 64–74 

An upper gastrointestinal series with small-bowel 

follow-through should be performed to look for 

any evidence of abnormality of the terminal ileum 

or more proximal gastrointestinal tract, and the 

presence of fistulae, which would suggest Crohn’s 

disease. The only exception is the finding of ulcerative 

colitis-associated ‘backwash ileitis’, which 

should be distinguished from terminal ileal 

disease of Crohn’s disease. With ‘backwash ileitis’, 

the ileum appears patulous and inflamed, involves 

only the distal ileal segment and is associated with 

pancolitis; there should be no evidence of extensive 

ulcerations or stricturing, as seen with 

Crohn’s disease. 75 

Although by definition, the disease of ulcerative 

colitis is confined to the colon, children with 


Figure 25.2 Colonic pseudopolyps present in a 16-yearold 

girl with an 8-year history of ulcerative colitis. The 

patient had persistent symptoms of diarrhea and rectal 

bleeding despite chronic corticosteroid and 6-mercaptopurine 

therapy, and subsequently underwent colectomy. 

Crohn’s disease or ulcerative colitis can have 

inflammation of the upper gastrointestinal 

tract. 76–79 In a controlled, blinded study of children 

with ulcerative colitis or Crohn’s disease, 

biopsies from the esophagus, gastric antrum and 

duodenum revealed histological evidence of 

esophagitis, gastritis and duodenitis in patients 

with either ulcerative colitis or Crohn’s disease. 

Esophagitis occurred in 50%, gastritis in 69% and 

duodenitis in 23% of patients with ulcerative 

colitis. In contrast to ulcerative colitis patients, 

those with Crohn’s disease had a higher prevalence 

of esophagitis, gastritis and duodenitis (72%, 92% 

and 33%, respectively). 76 Granulomas of the upper 

gastrointestinal tract were seen in 40% of the 

patients with Crohn’s disease and duodenal cryptitis 

was noted in 26% of patients with Crohn’s 

disease; none of these lesions was seen in the biopsies 

of patients with ulcerative colitis. 76 In another 

study, the presence of focally enhanced gastritis in 

children did not reliably differentiate between 

Crohn’s disease and ulcerative colitis. 79 Except for 

the presence of granulomas of Crohn’s disease, it 

may be difficult to distinguish between ulcerative

392 


Table 25.4 Typical endoscopy and histopathology findings – ulcerative colitis (UC) vs. Crohn’s 

disease (from references 69–74, 84) 

Characteristic Ulcerative colitis Crohn’s disease 

Endoscopy findings diffuse continuous involvement focal lesions/disease interspersed 

extending from the rectum with normal-appearing mucosa (skip lesions) 

colitis and Crohn’s disease by the appearance of 

upper gastrointestinal lesions. Some pediatric 

centers routinely perform upper endoscopy in 

addition to colonoscopy under general anesthesia 

in their initial evaluation of children with 

suspected IBD, in order to determine the extent and 

severity of upper gastrointestinal inflammation. 

Evaluation of plain abdominal radiographs and 

abdominal/pelvic computerized tomography (CT) 

scans may aid in the assessment for complications 

of ulcerative colitis, including toxic megacolon, 

perforation or stricture. A plain abdominal radiograph 

may demonstrate thumbprinting, loss of 

haustral patterns, colonic dilatation (i.e. toxic 

megacolon), obstruction, or pneumoperitoneum 

(i.e. perforation of the bowel). 80–82 CT is not typi- 

rectum usually involved* rectal sparing possible 

diffuse, superficial, minute aphthous lesions often surrounded by 

ulcerations; deeper ulcerations normal-appearing mucosa; deep ‘collar button’ 

in severe disease ulcers; linear or serpiginous ulcerations 

strictures very rare strictures, often occurring in terminal ileum 

pseudopolyps 

Histopathology findings no granulomas † granulomas (36%) 

diffuse chronic inflammation focal chronic inflammation, 

limited to the mucosa †† ; crypt transmural inflammation 

abscesses 

with or without architectural 

distortion** 

* In children, ‘rectal sparing’ has been seen in UC69,70 † Giant cell reactions can occur around damaged crypts and spilled mucin. This must be distinguished from ‘true’ 

granulomas, which by definition, are not seen in UC 

†† Deeper layers of the colon may be involved in fulminant UC disease 

** In children with UC, initial colonic biopsies at time of diagnosis are less likely to show architectural distortion 

than biopsies from adults74 cally performed in the initial assessment for ulcerative 

colitis, but may demonstrate diffuse bowel 

wall thickening, marked rectal wall thickening and 

perirectal fibrofatty proliferation. 75 A barium 

enema should not be performed during active 

ulcerative colitis as this predisposes to toxic megacolon. 

83 Prior to the routine use of colonoscopy for 

the diagnosis of ulcerative colitis, published 

barium enema findings of ulcerative colitis 

included mucosal granularity, superficial ulcerations, 

thickened and nodular haustral folds 

(secondary to inflammation and edema) and 

colonic shortening. 81 With longstanding ulcerative 

colitis, the colon becomes featureless and markedly 

shortened 81 and strictures may form, which may 

require colonoscopy for further evaluation for 

possible cancer. 75

(a) (b) 

Pathology of ulcerative colitis 

In active ulcerative colitis, typical findings on 

histopathology include a diffuse inflammatory 

cell infiltrate of the lamina propria mostly with 

plasma cells, lymphocytes and neutrophils, but 

mast cells and eosinophils are also seen 73 (Figure 

25.3a). Neutrophils invade the epithelium of the 

crypts, leading to cryptitis, crypt abscess formation 

and goblet cell mucin depletion (Figure 

25.3b). The inflammatory infiltrate is typically 

confined to the mucosa, but in severe ulcerative 

colitis, ulceration may extend into the submucosa 

and deeper layers. 73 In quiescent (inactive) ulcerative 

colitis, the inflammatory infiltrate may 

diminish, but signs of chronic colitis (architectural 

distortion, crypt branching and shortening, 

reduction in the number of crypts and separation 

of crypts) can persist. 73 In children with ulcerative 

colitis, signs of chronic colitis (e.g. architectural 

distortion) are not always seen. 74 

Histological differentiation of ulcerative colitis 

from Crohn’s disease can be difficult. The histological 

hallmark of Crohn’s disease is the noncaseating 

granuloma, which may be found in up to 

36% of children with Crohn’s disease. 84 However, 

a giant cell reaction mimicking a granuloma can 


Figure 25.3 (a) Low-power view of a colonic biopsy from a patient with active ulcerative colitis. Note the increased 

lamina propria inflammatory infiltrate, crypt abscesses and crypt architectural distortion. The crypts are irregular in shape 

and placement and do not descend to the level of the muscularis mucosae. (b) High-power view of colonic crypts in a 

patient with active ulcerative colitis, demonstrating neutrophilic infiltration in the crypt and a crypt abscess. (Courtesy of 

Jonathan Glickman, MD, Department of Pathology, Children’s Hospital, Boston). 

occur around damaged crypts and spilled mucin. 

These ‘mucin granulomas’ must be distinguished 

from true granulomas, which, by definition, are 

not seen in ulcerative colitis. 73 Histological skip 

areas, rectal sparing, focal inflammation and transmural 

inflammation also suggest the diagnosis of 

Crohn’s disease. How-ever, in children, histological 

skip areas may occur both at initial presentation 

of ulcerative colitis and as a result of 

therapy. 69,85 In addition, patients with ulcerative 

colitis can have histological evidence of upper 

gastrointestinal inflammation similar to that in 

Crohn’s disease. 76,77,79 Given the overlap of 

histopathology findings in ulcerative colitis and 

Crohn’s disease, it may be difficult to distinguish 

between these two diagnoses if granulomas are not 

present. 

If a clinician cannot reliably distinguish between 

Crohn’s disease and ulcerative colitis based on the 

available clinical, radiographic and endoscopic 

data, an interim diagnosis of ‘indeterminate colitis’ 

may be given until the patient can be more clearly 

classified in the future. The prevalence of indeterminate 

colitis in adults and children with IBD is 

estimated to be 10–20%. 10,86 Approximately onethird 

of these patients will later be classified as 

ulcerative colitis or Crohn’s disease. 87

394 


Extraintestinal manifestations 

Approximately 25–35% of patients with IBD 

develop extraintestinal symptoms. 88,89 Extraintestinal 

manifestations of IBD may occur before, 

during, or after the development of gastrointestinal 

symptoms and may appear after surgical removal 

of diseased bowel. 88,90–93 The clinical activity of 

the extraintestinal manifestations may or may not 

correlate with the activity of intestinal inflammation. 

Joint manifestations (arthropathy) occur in 5–20% 

of children with ulcerative colitis. 4,90 These can be 

classified into two main clinical forms: a peripheral 

arthropathy and an axial arthropathy (e.g. 

ankylosing spondylitis). 88,90 Patients with IBD 

develop peripheral arthropathies in approximately 

5–20% of cases. 88–90,94 The peripheral arthropathy 

is generally asymmetrical, non-deforming and 

migratory, affecting mostly the large joints of the 

lower extremities including the knees, ankles and 

hips. Less commonly, the upper limb joints or 

hands are affected. 88,90,94 Small joints of the hands 

and feet are generally spared. 90 

Exacerbations of peripheral joint disease seem to 

parallel increased activity of bowel disease in 

ulcerative colitis or Crohn’s disease. 95 Orchard et 

al, in a study of 976 adults with ulcerative colitis, 

suggested that there may be two subtypes of 

peripheral arthropathy: a pauciarticular form with 

fewer than five swollen joints, and a polyarticular 

form with more than five joints. Of these two 

subtypes, the pauciarticular arthropathy is more 

likely to be correlated with exacerbations of bowel 

disease. 93 

Axial arthropathies associated with HLA B27 

occur in 1–4% of patients. 88–90,94 Ankylosing 

spondylitis associated with IBD runs a course 

independent of the activity of bowel disease, and 

may progress to permanent deformity. 88,90,94 In 

addition to the two main forms of joint manifestations, 

individuals with ulcerative colitis can 

develop isolated arthritis involving large joints, 

including the sacroiliac joints, hips and shoulders. 

94 

Pyoderma gangrenosum and erythema nodosum 

are the two main skin manifestations associated 

with ulcerative colitis and Crohn’s disease. 

Pyoderma gangrenosum occurs in

aminotransferase (ALT) occur in 12% of children 

with ulcerative colitis and appear to be related to 

medications or disease activity. 106 Persistent ALT 

elevations suggest the presence of primary sclerosing 

cholangitis (PSC) or autoimmune chronic 

hepatitis. 106 Among children with ulcerative 

colitis, 3.5% develop sclerosing cholangitis and 

396 


precipitating factors, including narcotic agents for 

pain or antidiarrheal effects, anticholinergic 

agents, drugs that decrease motility, or antidepressants 

with significant anticholinergic 

effects. 121,128,129 A barium enema or colonoscopy 

may cause distension that can further impair the 

colonic wall blood supply and may increase the 

mucosal uptake of bacterial products. 122 Barium 

enema examinations have been reported in proximity 

to the development of toxic megacolon. 83,129 

The early discontinuation or rapid tapering of 

steroids or 5-aminosalicylic acid (5-ASA) may 

contribute to the development of toxic megacolon. 

121,122 Electrolyte abnormalities, such as 

hypokalemia, have been observed in the setting of 

toxic megacolon, although it is not clear whether 

this finding is a causative factor or secondary to 

the illness itself. 121 Along with colonic dilatation, 

patients with toxic megacolon present with 

systemic findings, including fever, tachycardia, 

leukocytosis and anemia. 124 A decrease in the 

number of stools may herald the onset of toxic 

Figure 25.4 Toxic megacolon in a teenager with fulminant 

ulcerative colitis. There is a massively dilated loop of 

transverse colon in the upper quadrants, with a paucity of 

bowel gas in the remainder of the abdomen. This patient 

developed the megacolon despite corticosteroid therapy, 

and subsequently underwent emergent surgery for a 

colonic perforation. (Courtesy of Carlo Buonomo, MD, 

Department of Radiology, Children’s Hospital, Boston). 

megacolon. With progressive disease, these individuals 

can develop dehydration, mental status 

changes, electrolyte disturbances, hypotension 

and increasing abdominal distension and tenderness, 

with or without signs of peritonitis. 122,124 

Abdominal X-ray reveals colonic dilatation, most 

frequently involving the transverse colon, sometimes 

accompanied by inflammatory changes 

including an absent or markedly edematous haustral 

pattern 130 (Figure 25.4). In two series of adults 

with toxic megacolon, the diameter of the colon 

varied, with a range of 5.8–16cm. 125,129 Because 

the transverse colon is the most anterior portion of 

the colon, air will tend to accumulate in this 

segment of the colon when the patient is in the 

supine position; however, with repositioning of 

the patient, the colonic air will redistribute, filling 

other segments of the bowel. 131 

The management of toxic megacolon is detailed in 

multiple reviews elsewhere. 121,122 If toxic megacolon 

is present, surgical consultation is essential, 

and the patient will probably require a colectomy. 

Some authors have utilized medical management 

of this condition; however, this requires very close 

monitoring to avoid complications. 132 Early surgical 

intervention is indicated in the setting of failed 

medical therapy with progressive colonic dilatation, 

worsening systemic toxicity, perforation or 

uncontrolled hemorrhage. 122 

Both benign and malignant colonic strictures can 

develop in longstanding ulcerative colitis. 75,133,134 

Benign strictures present most commonly in the 

rectum and the sigmoid, are due to smooth-muscle 

hypertrophy and are thought to be potentially 

reversible. 133 Colonic strictures should be evaluated 

for possible malignancy, but the majority of 

strictures in ulcerative colitis are benign. 75,133,134 

There is an increased risk of dysplasia and colon 

cancer in patients with longstanding ulcerative 

colitis, which is addressed later in this chapter (see 

Prognosis and follow-up, p.407). 


The treatment goals for children with ulcerative 

colitis are the control of active disease and induction 

of remission, the long-term maintenance of 

remission, and provision of education and

psychosocial support for the patient and family. 

The initial treatment of ulcerative colitis is 

medical, with surgery reserved for patients with 

severe disease, patients with medically refractory 

disease, or patients who develop adverse effects of 

medical therapy. 

Knowledge of the extent and severity of disease 

involvement will enable the clinician to choose 

the appropriate therapy for each individual 

patient. Distal ulcerative colitis (left-sided ulcerative 

colitis or proctitis) is characterized by involvement 

limited to the area distal to the splenic 

flexure, and potentially may be treated with 

topical agents (e.g. aminosalicylate or hydrocortisone 

enemas or suppositories). Extensive ulcerative 

colitis is defined by involvement extending 

proximally to the splenic flexure and requires 

systemic therapies with or without additional 

topical agents. Severity of disease is usually simple 

to ascertain, and can be determined by assessing 

stool frequency and consistency, abdominal pain, 

nocturnal diarrhea, hematocrit, albumin level and 

feeding intolerance. Separate published disease 

severity criteria for adults and children have been 

developed by Truelove and Witts, 135 and Werlin 

and Grand, 60 respectively (Tables 25.5 and 25.6). 

Other clinical scoring systems have been utilized 

in clinical trials to quantify disease severity of 


ulcerative colitis, but are less useful for day-to-day 

clinical management. 136–139 Typically, severe 

colitis requires hospitalization and administration 

of either intravenous corticosteroids or other 

immunosuppressive agents (e.g. cyclosporin). 

Many patients with severe colitis will require 

colectomy. 

Induction therapy 

Table 25.5 Severity of ulcerative colitis in adults* (from reference 135) 

Characteristic Mild Severe 

Grossly bloody diarrhea ≤ 4 stools per day ≥ 6 stools per day 

(≤ small amounts of blood) 

Mild-to-moderate colitis 

In the child with mild-to-moderate ulcerative 

colitis, with no or only minimal systemic signs 

Fever none mean evening temperature >37.5ºC, or 

temperature ≥37.8ºC, at least 2 out of 4 days 

Tachycardia none >90beats/min 

Anemia not severe; hemoglobin present; hemoglobin ≤75% of normal value 

essentially normal 

Erythrocyte ≤30mm/h >30mm/h 

sedimentation rate 

* Moderate severe – intermediate between severe and mild 

Table 25.6 Characteristics of severe colitis 

in children* (from reference 60) 

Grossly bloody diarrhea, ≥ 5 stools per a day 

Oral temperature >37.8ºC during the first hospital day 

Tachycardia (pulse ≥ 90) 

Anemia (hematocrit ≤ 30%) 

Hypoalbuminemia (serum albumin ≤ 3.0g/100ml) 

Toxic megacolon 

* Patients need to fulfill four of the first five criteria 

or the 6th criterion alone

398 


Table 25.7 Aminosalicylate agents* (from references 325, 326) 

Oral preparations Dosage form Mechanism of release Site of delivery 

Azo-bond 

sulfasalazine 500-mg tablet bacterial cleavage of colon 

(Azulfidine) azo bond 

olsalazine 250-mg capsule bacterial cleavage of colon 

(Dipentum) azo bond 

balsalazide 750-mg capsule bacterial cleavage of colon 

(Colazal/Colazide) azo bond 

Delayed-release 

mesalamine 400mg/800mg pH-dependent breakdown distal ileum 

(Asacol) tablets (pH >7) to colon 

mesalamine (Salofalk/ 250mg/500mg pH-dependent breakdown ileum to colon 

Mesasal/Claversal) tablets (pH >6) 

Sustained-release 

mesalamine 250mg/500mg/ ethylcellulose-controlled small intestine 

(Pentasa) 1000mg tablets time-release to colon 

Rectal preparations 

mesalamine suppository 400mg/500mg/ rectum 

(Canasa – 500mg) 1000mg 

mesalamine enema 1g/4g; 60-ml/ rectum to splenic 

(Rowasa – 4g/60ml) 100-ml suspension flexure 

* Availability of different preparations and dosage forms varies between different markets/countries 

(such as elevated ESR or mild anemia), aminosalicylates 

(ASAs) (e.g. sulfasalazine, olsalazine, 

mesalamine, balsalazide) are usually the first line 

of therapy (Tables 25.7 and 25.8). ASAs have 

multiple immunological effects. Potential mechanisms 

of action include the inhibition of the 

synthesis of leukotriene B4, a potent chemotactic 

and chemokinetic agent, and the inhibition of the 

activation of nuclear transcription factor κB (NFκB), 

an important mediator of the immune 

response in inflammatory processes. 140–142 Controlled 

studies suggest that currently available 

ASAs are superior to placebo for induction of 

remission and prevention of relapse. 143–146 

However, there do not appear to be any differences 

in efficacy between the older agent, sulfasalazine, 

and newer ASA drugs. 146,147 There are very few 

trials of ASA therapy in children with ulcerative 

colitis. One pediatric multicenter, randomized, 

double-blind study compared the efficacy and 

safety of olsalazine (30mg/kg per day; maximum 

2g/day) to sulfasalazine (60mg/kg per day; 

maximum 6g/day) in the treatment of mild-tomoderate 

ulcerative colitis. The findings demonstrated 

clinical remission after 3 months in 79% of 

the sulfasalazine-treated children, in comparison 

to 39% of the olsalazine-treated children. 148 The 

authors suggested the low dosage of olsalazine as a 

possible explanation for the difference in efficacy 

between sulfasalazine and osalazine. 148 

Potential advantages of the non-sulfa ASA agents 

include better tolerance compared to sulfasalazine 

147,149 and the availability of a non-sulfa

Table 25.8 Medical therapies for ulcerative colitis 

Medication Dosage Major side-effects 

ASA agent for sulfa-sensitive individuals. In adultonset 

ulceratimve colitis, balsalazide at higher 

doses (6.75g/day) may provide a faster improvement 

in active, mild-to-moderate ulcerative colitis 

than lower doses of balsalazide (2.25g/day) or mesalamine 

(2.4g/day). 150,151 Although some studies 


Sulfasalazine 50–75mg/kg per day PO divided nausea, headaches, diarrhea, 

qid, bid or tid (maximum 6g/day) photosensitivity, hypersensitivity reaction, 

adult dose: 3–4g/day pancreatitis, azoospermia, hemolytic 

divided bid or tid anemia, neutropenia 

Mesalamine 

oral formulation 50–75mg/kg per day PO divided qid, nausea, headaches, diarrhea, pancreatitis, 

tid, or bid (may vary according to 

preparation) (maximum 6g/day); 

adult dose: 3–4g/day divided qid, 

tid, or bid 

nephritis, pericarditis, pleuritis 

enema formulation 2–4g PR q 12–24 h 

suppository formulation 500mg PR q 12–24 h 


intravenous or 1–2mg/kg per day of prednisone or numerous; including Cushing’s syndrome, 

oral formulation equivalent, IV or PO, divided q 12 to growth suppression, immunosuppression, 

24h (maximum 60 mg/day) hypertension, hyperglycemia, increased 

enema formulation 50–100mg of hydrocortisone PR qhs appetite, osteoporosis, aseptic 

suppository formulation 25mg of hydrocortisone acetate PR qhs necrosis (hip), cataracts 

Azathioprine* 1.5–2.5mg/kg per day PO qd nausea, emesis, immunosuppression, 

hepatotoxicity, pancreatitis, myelosuppression 

6-Mercaptopurine* 1.0–2.0mg/kg per day PO qd nausea, emesis, immunosuppression, 

hepatotoxicity, pancreatitis, myelosuppression 

Cyclosporin induction regimen for fulminant colitis: nephrotoxicity, hypertension, headache, 

initial dose, 4mg/kg per day IV hirsutism, nausea, emesis, diarrhea, 

continuous or bid; maintenance oral tremor, hypomagnesemia, hyperkalemia, 

dose varies according to oral preparation hepatotoxicity, seizures, gingival 

hyperplasia, possibly lymphoproliferative 

disorder 

PO, orally; bid, twice a day; tid, three times a day; qid, four times a day; PR, per rectum; q, every; qd, every day; IV, 

intravenously; qhs, at bedtime 

* Thiopurine methyltransferase (TPMT) genotype determines metabolism and blood levels of metabolites; may help to 

determine risk of myelosuppression and optimal dosage of azathioprine or 6-mercaptopurine 

suggest an advantage of azo-bond ASA agents (e.g. 

balsalazide) in comparison to delayed-release ASA 

agents (e.g. mesalamine), the overall data suggest 

equivalence between the different oral ASAs, 

when comparable amounts of the ASA are released 

at the site of disease activity. 152

400 


Common side-effects of sulfasalazine include 

headache, nausea and fatigue, which improve 

with reduction of the dose 152 (Table 25.8). The 

sulfa moiety can cause hypersensitivity reactions 

resulting in rash, fever, hepatitis, hemolytic 

anemia, bone marrow suppression and pneumonitis. 

152,153 Other side-effects include neutropenia, 

oligospermia, pancreatitis and the exacerbation of 

colitis. 60,154 Folic acid supplementation is recommended, 

given that sulfasalazine impairs the 

absorption of folic acid and may lead to 

anemia. 152 To decrease side-effects, sulfasalazine 

is started at a dose of 10–20mg/kg per day and 

gradually increased to the full dose (50–75mg/kg 

per day) over 5–7 days. Mesalamine and the other 

non-sulfa ASA agents have also been associated 

with adverse reactions, including pancreatitis, 

hepatitis, nephritis, exacerbation of colitis, and 

pneumonitis. 152,155,156 

In addition to medical therapy, a low-residue diet 

(no popcorn, nuts, seeds, raw fruits and vegetables) 

and avoidance of spicy foods during acute 

symptoms has been anecdotally reported to reduce 

symptoms during a flare-up of disease. 157 

Moderate-to-severe colitis 

Children with moderate disease are usually 

managed with oral corticosteroids (usually 

1mg/kg per day, up to 60mg/day of prednisone) as 

out-patients. In an uncontrolled study of 20 children 

with active ulcerative colitis (three with 

mild, 13 with moderate, four with severe activity), 

85% of the children achieved clinical remission 

with combination therapy of corticosteroids (oral 

prednisolone for pancolitis or topical prednisolone 

for distal colitis) and mesalamine 

(20–40mg/kg per day). 158 Reassessment with 

colonoscopy at 8 weeks demonstrated complete 

endoscopic remission in 40% and full histological 

remission in only 15%, suggesting that clinical 

remission may not correlate with endoscopic or 

histological remission. 158 Potential short-term 

complications of steroid therapy in patients with 

ulcerative colitis include increased appetite, 

weight gain, fluid retention, mood swings, hyperglycemia, 

hypertension, insomnia, acne and facial 

swelling. 

Complications of long-term steroid therapy 

(usually of more than 3 months) include growth 

restriction, osteopenia with compression fractures, 

aseptic necrosis of the hip, and cataracts. 152,159 

Given these reasons and the suppression of the 

hypothalamic–pituitary–adrenal axis, corticosteroids 

should be tapered shortly after remission is 

achieved. A standard taper utilized by the authors 

is reduction by 5mg/week of prednisone down to 

20mg/day, and then a more gradual taper on alternate 

days, aiming for 10mg every other day with 

further taper and cessation if remission is maintained. 

159 Budesonide, a steroid with a high firstpass 

metabolism and fewer systemic side-effects, 

is available in capsule form for treatment of ileocecal 

Crohn’s disease. 160 In Europe and Canada, 

there is an enema form of budesonide for treatment 

of distal colitis. 161 Unfortunately, there is no 

available oral budesonide preparation shown to 

treat patients with pancolitis effectively. 162 

Children with severe disease (e.g. more than five 

bowel movements/day, liquid bloody stools, or 

severe pain with defecation, anemia and hypoalbuminemia) 

require intravenous corticosteroids 

(methylprednisolone at 40–60mg/day, divided 

into two doses/day, approximately 1–2mg/kg per 

day) and hospitalization for further evaluation, 

observation and management. 157,163 Rectal corticosteroids 

or 5-ASA agents may be used as an 

adjunctive therapy with parenteral corticosteroids 

for patients with severe tenesmus. 152 Intravenous 

fluid for rehydration and correction of electrolyte 

imbalances should be provided. Blood transfusions 

and albumin infusions may be required. If 

bowel rest is indicated, the child may require 

central venous access for parenteral nutrition 

support. In addition to high-dose steroids, empiric 

antibiotics are sometimes used in severe colitis, 

although the efficacy of antibiotics has not been 

proven. 164–167 Assessment for response to intensive 

medical therapy includes resolution of fever, 

tachycardia, abdominal tenderness and macroscopic 

blood per rectum. Stools should be 

decreasing in frequency, but may still be 

unformed. Once the child shows significant 

improvement, diet is advanced to a low-residue 

diet, intravenous methylprednisolone is switched 

to oral prednisone, and similar parameters for 

steroid wean are followed as outlined above. The 

optimal duration of intravenous corticosteroid 

therapy is unclear, but most children will respond 

within 7–10 days.

If the child has not responded to steroid therapy 

after 7–10 days, the options of surgery or more 

intensive immunosuppression (intravenous cyclosporin 

or oral tacrolimus) should be considered 

and discussed with the family. Intensive immunosuppression 

should not be started if surgery is 

believed imminent, such as in a septic patient, a 

patient with toxic megacolon, or a patient with a 

suspected perforation. Intravenous or oral 

cyclosporin therapy has successfully induced 

remission in children with steroid-refractory 

ulcerative colitis. 168–170 The exact dosage of 

cyclosporin varies in different protocols, depending 

upon whether intravenous or oral medication 

is utilized. 136,169–171 In a study of 14 children 

treated with oral cyclosporin therapy for severe 

active colitis, unresponsive to high-dose intravenous 

steroids, 80% achieved clinical remission 

within 2–9 days; however, the majority of children 

who initially responded to cyclosporin eventually 

required colectomy within a year. 170 In these 

studies, most of the children who improved with 

cyclosporin induction relapsed or underwent 

colectomy within a year. 169,170 Cyclosporin may be 

most useful in delaying emergency colectomy at a 

time when the child’s health status is most 

compromised (high-dose steroids, anemia, hypoalbuminemia, 

poor nutrition) and may allow time 

to improve the child’s health and mental status in 

preparation for future ‘elective’ colectomy. 170 A 

recent review outlines specific recommendations 

on the initiation and monitoring of cyclosporin 

therapy in children with IBD. 171 

Oral tacrolimus can also induce remission of 

disease activity in children with severe active 

colitis. 172 If either cycloporin or tacrolimus is 

utilized as induction therapy, the aim should be 

the transition of patients off these potentially toxic 

agents and onto a maintenance medication (e.g. 6mercaptopurine, 

azathioprine) over a 3–6-month 

period. Azathioprine or 6-mercaptopurine may be 

effective in preventing relapse after cyclosporininduced 

remission in children with ulcerative 

colitis. 173 Children on cyclosporin or tacrolimus 

should receive prophylaxis for Candida and 

Pneumocystis carinii, and have careful monitoring 

of electrolytes, blood glucose, renal function, 

blood pressure and neurological status. 

The timing of colectomy in a child who is not 

responding to intravenous corticosteroids or other 


immunosuppression can be difficult. It should be 

emphasized that, even if a child responds to 

immunosuppression, such as cyclosporin, there is 

a high likelihood that he/she will require a colectomy 

within a year. 170,172 If immunosuppression 

with cyclosporin is used and the child does not 

respond to these medications within 10–14 days, 

surgery should be strongly recommended. 

Close monitoring of patients with severe colitis for 

the development of fulminant colitis and associated 

complications including hemorrhage, toxic 

megacolon and perforation is essential, using 

serial abdominal examinations, complemented by 

serial abdominal films or other imaging as necessary. 

Physical examination should look for 

evidence of worsening abdominal tenderness, 

distension and hypoactive bowel sounds; these 

may herald the development of toxic megacolon. 

The appearance of persistent abdominal pain and 

distension, diffuse abdominal tenderness and 

rebound, fever and tachycardia are worrisome 

signs of an acute abdomen and may signal the 

need for emergency surgical intervention. Opiates 

and loperamide should be avoided, given the 

increased risk of developing toxic megacolon. 128 

Steroid therapy may mask the typical symptoms 

and signs of perforation, but these may be detected 

by serial upright abdominal films (see Complications, 

p.395). 

Left-sided colitis/proctitis 

Topical ASA or topical corticosteroids are effective 

in the treatment of proctitis, proctosigmoiditis, or 

left-sided ulcerative colitis174–176 (see Tables 25.7 

and 25.8). To be effective, topical therapy must 

reach the most proximal extent of the disease 

activity. Mesalamine enemas or suppositories are 

effective as first-line therapy/maintenance therapy 

for mild or moderately active left-sided ulcerative 

colitis or proctitis, respectively. 152 Rectal mesalamine 

may be superior to oral mesalamine in 

the treatment of active ulcerative proctitis. 177 

Mesalamine enemas may be superior to rectal 

corticosteroids178 and are also effective in treating 

distal colitis that is unresponsive to oral ASAs or 

corticosteroids. 179,180 Combination therapy with 

oral and topical mesalamine is more effective than 

one agent alone in the treatment of mild-to-moderate 

distal colitis. 181 Mesalamine suppositories 

spread to the upper rectum, and enemas and foams

402 


can reach the splenic flexure or into the distal 

transverse colon. 179,180 

Corticosteroid suppositories or enemas also can be 

used as first-line induction therapy in patients 

with mild or moderately active ulcerative proctitis 

or left-sided ulcerative colitis. 152 Rectal administration 

of hydrocortisone or prednisolone permits 

more direct delivery of steriods to distal ulcerative 

colitis sites; however, as with oral steroid therapy, 

prolonged treatment with topical steroids may 

induce systemic steroid side-effects, including 

adrenal suppression. 176,180 Topical agents such as 

budesonide enemas, may induce remission in 

distal colitis with fewer systemic steroid sideeffects. 

161,182 In a randomized, double-blind, 

placebo-controlled trial, budesonide enema 

therapy (2.0mg or 8.0mg/enema, once per 

evening) effectively induced remission, with 

significant improvement in sigmoidoscopy and 

histopathology scores, compared to placebo in 

adults with active distal ulcerative colitis/proctitis. 

161 However, in another controlled trial, less 

frequent dosing of twice weekly budesonide 

enemas (2.0mg/enema) was not superior to 

placebo in the maintenance of remission. 183 Some 

evidence suggests that ASA enemas may be 

superior to hydrocortisone enemas. 175,178,180 

Cyclosporin-A enemas have been used in the treatment 

of severe refractory distal ulcerative 

colitis, 184 but were not found to be effective in a 

placebo-controlled trial for mildly to moderately 

active left-sided ulcerative colitis. 185 

Maintenance therapy 

5-Aminosalicylic acid agents 

Medication for the prevention of relapse after 

induction of remission is often started before the 

induction therapy is discontinued. The clinician 

usually aims towards a transition of the patient 

from corticosteroids onto sulfasalazine or another 

ASA agent. Multiple studies of adults with ulcerative 

colitis demonstrate the effectiveness of 

sulfasalazine and other ASA agents in preventing 

relapse. 147 Mesalamine is well tolerated in the 

long-term treatment of children with IBD, with the 

principal adverse event being exacerbation of diarrhea. 

186 Sulfasalazine and newer ASAs are all 

effective in maintaining remission in ulcerative 

colitis. 149 Balsalazide, at a higher dose (6g/day), 

may be more effective in preventing relapses of 

ulcerative colitis in adults, compared to lowerdose 

balsalazide (3g/day) and mesalamine 

(1.5g/day). 187 Topical mesalamine can effectively 

prevent relapse of active distal ulcerative colitis, 188 

but because of the rectal route of administration, 

patients may prefer oral mesalamine for maintenance 

therapy. The combination of oral and topical 

5-ASA therapy may be more effective in preventing 

relapse than oral 5-ASA therapy alone, especially 

for distal disease. 189 Some authors suggest 

that 5-ASA agents may reduce the risk of colorectal 

cancer. 190–192 Children with ulcerative colitis 

require years of maintenance therapy. The exact 

duration that an ulcerative colitis patient in remission 

should remain on maintenance therapy is 

unclear, and there are no formal guidelines on 

when or whether maintenance therapy should be 

discontinued. The risk of discontinuing maintenance 

medication is the possibility of relapse. In 

addition, maintenance with 5-ASA or other agents 

may reduce the risk of colorectal neoplasia. 193 

6-Mercaptopurine and azathioprine 

The immunomodulatory drugs azathioprine and 

its metabolite 6-mercaptopurine can reduce 

disease activity and allow the withdrawal of 

steroid therapy in children with steroid-dependent 

ulcerative colitis. 194,195 In a small, open-label trial 

of children with Crohn’s disease or ulcerative 

colitis, six of nine patients with ulcerative colitis 

reduced their steroid use by at least 75% with 

azathioprine therapy. 194 In another series of 16 

children with severe, steroid-dependent or steroidrefractory 

ulcerative colitis, 6-mercaptopurine or 

azathioprine therapy allowed the discontinuation 

of steroid use in 75%, and 67% remained without 

steroid therapy for 3–65 months. 195 Given their 

steroid-sparing effects194,195 and reasonable tolerance 

by children with IBD, 196 azathioprine and 6mercaptopurine 

offer an alternative maintenance 

treatment of IBD in children. In a study of 95 children 

with either Crohn’s disease or ulcerative 

colitis, only 18% required discontinuation of the 

medication; the majority of side-effects responded 

to dose reduction, or improved spontaneously. 196 

Side-effects reported include aminotransferase 

elevations or hepatitis, pancreatitis, bone marrow 

depression, hypersensitivity reactions and recurrent 

infections; 196,197 children should be moni-

tored for the development of these complications. 

Some clinicians have utilized 6-mercaptopurine 

metabolite levels to monitor responsiveness, 

compliance and potential toxicity. 198.199 Evaluation 

for thiopurine methyltransferase genetic 

polymorphism should be obtained prior to the 

institution of 6-mercaptopurine or azathioprine 

therapy as it can identify those children at higher 

risk for drug toxicity 200 and guide the clinician to 

prescribe lower doses of azathioprine and 6mercaptopurine, 

if appropriate. 

Given the high relapse rate with withdrawal of 6mercaptopurine 

in adults with ulcerative colitis, 201 

the majority of children requiring azathioprine or 

6-mercaptopurine to suppress disease activity will 

probably require long-term maintenance therapy 

with these agents. There are no good data in ulcerative 

colitis addressing the question of when (or 

whether) immunomodulators should be discontinued 

after a patient has entered remission. Most 

patients are continued on the medication for 

several years if they respond to 6-mercaptopurine 

or azathioprine. At the present time, evidence does 

not suggest any definitive increased risk of malignancy 

secondary to long-term use of azathioprine 

in adults. 202–204 However, one paper has identified 

a slightly increased risk of Epstein–Barr virusassociated 

lymphoma in a large cohort of patients 

treated with long-term 6-mercaptopurine or 

azathioprine. 205 

Methotrexate 

Methotrexate appears to be less effective for the 

treatment of ulcerative colitis than for Crohn’s 

disease. 206,207 Although open-label trials in adults 

with ulcerative colitis suggested a benefit of 

methotrexate in the induction of remission, 137,208 a 

double-blind, randomized trial failed to show any 

advantage of methotrexate in the induction or 

maintenance of remission in adults with chronic 

active ulcerative colitis in comparison to 

placebo. 209 Another study of two different dosages 

of parenteral methotrexate in adults with IBD 

showed a remission rate of approximately 20%. 210 

While methotrexate can be useful in treating children 

with Crohn’s disease intolerant to 6-mercaptopurine, 

there are currently no published studies 

describing its efficacy in children with ulcerative 

colitis. 211 

Other therapies 


Despite the potential role of infectious agents in 

the pathogenesis of ulcerative colitis, 17 the use of 

antibiotic therapy in the treatment of ulcerative 

colitis remains controversial. There is a lack of 

consistent evidence of the effectiveness of antibiotics 

in the induction and maintenance of remission 

in ulcerative colitis. 165,212–215 In one study, 

oral tobramycin therapy improved short-term clinical 

and histological outcomes, 212 but there was no 

advantage in the prevention of relapse compared 

to placebo. 213 In two studies of active ulcerative 

colitis, the addition of 10–14 days of oral or intravenous 

ciprofloxacin to corticosteroid therapy did 

not improve rates of remission. 167,216 In another 

placebo-controlled study, the administration of 6 

months of treatment with ciprofloxacin, in addition 

to standard therapy with prednisone and 

mesalamine, resulted in a greater clinical response 

compared to placebo; however, this advantage was 

not sustained after the cessation of 

ciprofloxacin. 217 Empiric broad-spectrum antibiotics 

are often administered in the setting of severe 

active ulcerative colitis, 60,164 especially if there is 

concern for potential fulminant colitis or toxic 

megacolon. 122 

In open, uncontrolled trials, infliximab (chimeric 

monoclonal antibody to TNF-α) therapy resulted 

in clinical improvement in adults and children 

with ulcerative colitis. 218–222 However, the clinical 

response of infliximab therapy may not be 

sustained. 223 In an open-label study of nine children 

and adolescents with moderate-to-severe 

ulcerative colitis, seven children (77%) showed a 

decrease in disease activity measured by the 

Physician Global Assessment, and corticosteroid 

therapy was discontinued in six children (66%). 222 

A small, double-blind, placebo-controlled clinical 

trial of infliximab in 11 adults with severe, active 

steroid-refractory ulcerative colitis suggested a 

clinical benefit for patients treated with one dose 

of infliximab (5mg, 10mg or 20mg/kg per dose), 

compared to those who received placebo. 224 In this 

study, four of eight ulcerative colitis patients 

receiving infliximab improved, compared to none 

of three receiving placebo. Because of poor recruitment, 

the trial was terminated prematurely and no 

statistical analysis was performed. In a larger, 

randomized, double-blind, placebo-controlled 

study of 43 adults with moderately active gluco-

404 


corticoid-resistant ulcerative colitis, there was no 

significant difference in remission rate or sigmoidoscopic 

score between the infliximab-treated 

group (5mg/kg per dose, at weeks 0 and 2) and the 

placebo group. 225 Thus, the therapeutic benefit of 

infliximab in ulcerative colitis remains unclear at 

this time, and the treatment does carry a risk of 

infusion reactions, antinuclear antibody formation 

and opportunistic infections. 226–230 

Studies evaluating the effectiveness of mycophenolate 

mofetil therapy for ulcerative colitis show 

mixed results and may suggest increased sideeffects 

compared to other immunomodulatory 

agents such as azathioprine. 231–233 

Probiotics have been studied in the maintenance 

of remission in adults with ulcerative colitis. 234–236 

In an open-label trial of the probiotic VSL no. 3, 

performed in adults with inactive ulcerative 

colitis, 75% of patients remained in remission 

during the 12-month study, 234 but no controlled 

trials with VSL no. 3 for maintenance therapy for 

ulcerative colitis have been performed. In two 

randomized controlled comparison trials, nonpathogenic 

E. coli strains and mesalamine maintained 

similar rates of remission in adults with 

quiescent ulcerative colitis. 235,236 There are no 

formal studies on the effectiveness of probiotics in 

children with ulcerative colitis. 

In adults with ulcerative colitis, transdermal nicotine 

therapy, combined with mesalamine or corticosteroids, 

may result in clinical improvement, 

but is associated with unwanted side-effects. 237,238 

Transdermal nicotine therapy does not appear to 

be effective in the maintenance of remission of 

ulcerative colitis. 239 An open-label trial of nicotine 

enema therapy in adults with ulcerative colitis 

showed improvement in symptoms of urgency and 

stool frequency, and sigmoidoscopic and histological 

scores, 240 but controlled studies are needed to 

determine true efficacy. 

Several placebo-controlled studies suggested a 

benefit of adjunctive therapy with fish oil supplementation 

containing eicosapentaenoic acid, a 

potent inhibitor of leukotriene B4 synthesis, in the 

treatment of active ulcerative colitis. 241–243 

However, fish oil supplementation did not appear 

to show any benefit in maintenance therapy. 243,244 

Unfortunately, given the large number of capsules 

required for daily therapy and the intolerance to 

unwanted fishy odor, patients’ compliance has 

been suboptimal. 

Randomized, controlled trials in adults with active 

distal ulcerative colitis suggest that therapy with 

topical short-chain fatty acid (SCFA) preparations 

result in clinical symptomatic improvement, but 

there is no statistically significant advantage in 

comparison to placebo. 245–247 In one double-blind, 

placebo-controlled, 6-week trial of rectal SCFA, 

103 patients with distal ulcerative colitis were 

entered and those on SCFA had larger, but statistically 

non-significant, reductions in every component 

of their clinical and histological activity 

scores. 246 

In several open-label trials, adults with steroidresistant 

ulcerative colitis showed a clinical 

response to heparin therapy; 248–250 however, a 

controlled trial did not show any advantage of 

heparin treatment for moderate-to-severe ulcerative 

colitis, compared to corticosteroid therapy. 251 

In an open-label pilot study, daclizumab (humanized 

anti-IL-2R antibody; CD25) resulted in clinical 

and endoscopic improvement in adults with 

refractory ulcerative colitis; 252 further study is 

needed to determine the effectiveness of this novel 

therapy. 

Nutritional therapy 

The importance of nutrition in the management of 

ulcerative colitis is extensively reviewed elsewhere. 

253,254 Children with ulcerative colitis can 

develop nutritional deficits with poor oral intake 

secondary to symptoms; and thus, promotion of 

continued good nutritional intake is essential for 

appropriate healing and nutritional repletion. 255 

Enteral nutrition is preferred to total parenteral 

nutrition when possible. In contrast to Crohn’s 

disease, enteral nutrition is not an effective 

primary therapy for active ulcerative colitis. 152,171 

Studies suggest no advantage of total nutritional 

support and bowel rest in addition to conventional 

medical therapy alone in the treatment of ulcerative 

colitis. 256,257 In a randomized, controlled trial 

of corticosteroid therapy combined with either 

polymeric enteral nutrition or total parenteral 

nutrition, adults with moderate or severe ulcerative 

colitis showed no differences in remission 

rate, need for colectomy, or changes in anthropo-

metric parameters. 258 Total parenteral nutrition is 

often utilized for nutritional repletion in severe 

ulcerative colitis, especially if the patient develops 

severe cramps and diarrhea when challenged with 

enteral nutrition. 

Surgical therapy 

In the majority of cases, medical therapy remains 

the first-line treatment for ulcerative colitis. 

However, colectomy may be required for patients 

with severe or medically refractory disease, or to 

prevent colon cancer. Since the inflammation in 

ulcerative colitis is limited to the colon, colonic 

resection will most often result in resolution of 

symptoms. However, colectomy is not without 

potential complications, such as the development 

of pouchitis in patients who undergo ileoanal 

anastomosis. 259,260 It is important to consider 

timely surgical intervention in the appropriate 

setting to avoid complications of ulcerative colitis. 

Indications for colectomy in a patient with ulcerative 

colitis include fulminant colitis or a complication 

of colitis, such as massive hemorrhage, perforation, 

or toxic megacolon; medical therapy 

failure; steroid dependency, which may lead to 

undesired side-effects; and the presence of colonic 

dysplasia. 261 Prepubertal children may experience 

catch-up growth after colectomy for ulcerative 

colitis. In one series, 11 of 18 children increased 

their median height velocity from 3.85cm/year 

preoperatively to 7.35cm/year postoperatively. 262 

As medical treatment for ulcerative colitis was 

developed, the frequency of colectomy decreased. 

At one center, a retrospective review of children 

and adolescents with ulcerative colitis revealed a 

decrease in the frequency of colectomy from 

48.9% (between 1955 and 1964) to 26.2% (between 

1965 and 1974). 263 

There are no early predictors to help determine 

who will proceed to colectomy. Hyams et al, in a 

retrospective review, reported that the 5-year 

colectomy rate in patients with mild disease at 

presentation was 8%, compared to 26% in patients 

with moderate-to-severe disease at presentation. 264 

In another retrospective review of 73 children with 

ulcerative colitis between the ages of 1 and 18 

years, the combination of steroid dependency and 

pancolitis was associated with an increased need 


for colectomy. 265 Seventy-three per cent of the 

children with steroid-dependent pancolitis 

required colectomy within 3 years of diagnosis. 265 

Except in the setting of emergency colectomy, a 

complete evaluation should be performed to 

ensure that there is no evidence of Crohn’s disease 

prior to colectomy. If there is evidence suggesting 

the possibility of Crohn’s disease, the patient and 

family need to be informed of the potential for 

postoperative recurrence, and the relative 

contraindications of ileoanal pull-through procedures 

in patients with known Crohn’s disease. The 

authors recommend an upper gastrointestinal 

series with small-bowel follow-through and upper 

gastrointestinal endoscopy, in addition to a full 

colonoscopy with ileoscopy, if there is no clinical 

contraindication. Prior endoscopies and pathology 

reports should be carefully reviewed to establish 

that there is no evidence of Crohn’s disease. 

The surgical options available for ulcerative colitis 

are reviewed in detail elsewhere. 261 The ileal 

pouch–anal canal anastomosis (IPAA) is the operation 

most commonly performed in the majority of 

patients with ulcerative colitis. The IPAA removes 

the entire colon and the rectal mucosa, avoids 

permanent ileostomy, and preserves anorectal 

function. Several types of ileal pouches can be 

constructed, including the J-shaped, S-shaped, Wshaped 

and the lateral–lateral pouch. 261 The Jpouch 

design is now most commonly used for the 

IPAA operation. 266,267 If the rectal mucosa is in 

good condition, many centers use the two-stage 

operative approach. During the first stage, a subtotal 

colectomy of the cecum to proximal rectum, 

the removal of the distal rectal and proximal anal 

mucosa, and the formation of the ileal pouch are 

performed. In this initial stage, a diverting loop 

ileostomy is performed in order to allow the pouch 

to heal. The second stage involves closure of the 

loop ileostomy with restoration of fecal flow to the 

pouch. Surgeons at some surgical centers also 

complete the IPAA in one stage, without the loop 

ileostomy; 268 however, this would not be the 

procedure of choice in patients receiving highdose 

corticosteroids. 267 Some authors 261 believe 

that the omission of the diverting ileostomy may 

increase the risk of anastomotic leaks and prolong 

recovery; 269 thus, candidate patients for the onestage 

IAPP should be selected carefully. 270

406 


If the patient presents for emergency surgical intervention, 

such as with fulminant colitis, a threestage 

operative approach is often utilized. At the 

time of acute presentation, a subtotal colectomy is 

performed with formation of a rectal stump (the 

so-called Hartman pouch) and Brooke ileostomy. 

After the first operation, the rectal mucosa is 

treated with topical therapies (e.g. hydrocortisone, 

aminosalicylates) to induce mucosal healing. At 

the second operation, the distal rectal and proximal 

anal mucosa is removed and the ileal pouch is 

created. The ileostomy is reversed at the third 

operation. 

The potential complications of IPAA include 

small-bowel obstruction, pelvic sepsis, anastomotic 

leak, fecal incontinence, pouchitis, strictures 

or fistulae. 261,270,271 The development of 

fistulae raises the suspicion of Crohn’s disease. 261 

In one series of children aged 9–16 who underwent 

proctocolectomy with IPAA, 12/29 (41%) of 

patients with ulcerative colitis developed early 

complications (wound infection, early bowel 

obstruction, prolonged fever). 272 Late complications 

(bowel obstruction, pouch fistula) occurred 

in 11/29 (38%) and pouchitis developed in 9/29 

(31%) of the children with ulcerative colitis. 

Median follow-up was 4 years (range 6 months to 

9 years). In this same study, daytime continence 

was noted in 100% and night-time continence in 

93%. The median frequency of bowel movements 

was four in 24h, and 7% of patients had night-time 

bowel movements. 

Pouchitis, or inflammation of the newly created 

reservoir, is the most significant chronic complication 

in ulcerative colitis patients undergoing IPAA; 

as many as 44–53% of children and young adults 

with ulcerative colitis and ileoanal anastomosis 

will develop pouchitis on long-term followup. 

259,260 The etiology of pouchitis is unknown, 

but theories involve the role of genetic susceptibility, 

fecal stasis, bacterial overgrowth, disruption of 

the balance of luminal bacteria, nutritional deficiencies, 

ischemia and IBD recurrence. 273 

Symptoms of pouchitis include diarrhea, rectal 

bleeding, abdominal cramping, urgency and 

incontinence of stool, malaise and fever. 261,273,274 

Patients with ulcerative colitis who undergo IPAA 

develop pouchitis more commonly than patients 

with familial polyposis who undergo the same 

procedure. 275 Pouchitis may occur more frequently 

Figure 25.5 Chronic active inflammation of an ileal 

J-pouch (pouchitis) in a patient with a history of ulcerative 

colitis. Note that both limbs of the ileal reservoir are 

erythematous with exudate. 

in children and adults with primary sclerosing 

cholangitis (PSC)-associated ulcerative colitis 

276,277 and in individuals with extraintestinal 

manifestations of ulcerative colitis. 273 Laboratory 

studies may demonstrate anemia and an elevated 

ESR. The definitive diagnosis is established by 

flexible endoscopy of the pouch with biopsies 

(Figure 25.5). In some patients, a contrast enema 

may be useful in identifying fistulae. 

Broad-spectrum antibiotics are usually the firstline 

treatment for pouchitis. 273,278 Metronidazole is 

the most commonly used antibiotic, but alternative 

therapies include ciprofloxacin, amoxicillin– 

clavulanic acid, erythromycin and tetracycline. 

274,279 If there is no improvement with antibiotics, 

other options include mesalamine enemas 

and steroid enemas or oral therapy with 

mesalamine, sulfasalazine or steroids. 274,280,281 

Other therapies examined include cyclosporin 

enemas, SCFA enemas, butyrate suppositories and 

glutamine suppositories. 184,274,282,283 

Probiotic therapy may prevent the onset of acute 

pouchitis after ileostomy closure 284 and effectively

maintain remission after chronic pouchitis. 285 A 

double-blind, placebo-controlled study evaluated 

the efficacy of a probiotic preparation VSL no. 3, 

(containing 5 x 10 11 per gram of viable lyophilized 

bacteria of four strains of lactobacilli, three strains 

of bifidobacteria, and one strain of Streptococcus 

salivarius subsp. thermophilus), compared with 

placebo in maintenance of remission of chronic 

pouchitis in 40 patients in clinical and endoscopic 

remission. Three patients (15%) in the VSL no. 3 

group had relapses within the 9-month follow-up 

period, compared with 20 (100%) in the placebo 

group. 285 In another double-blind, placebocontrolled 

study performed by the same authors in 

40 patients, VSL no. 3, administered immediately 

after ileostomy closure for 1 year, effectively 

reduced the onset of acute pouchitis in the VSL no. 

3 group (10%) in comparison to the placebo group 

(40%). 284 

Several studies have suggested that the risk of 

dysplasia in the ileal pouch appears to be 

low 286,287 and may be associated with chronic 

pouchitis. 288 The development of adenocarcinoma 

has been reported in the ileal pouch. 289 In a followup 

study (mean of 5 years) of 76 children and 

adolescents with ulcerative colitis who had an 

IPAA, no dysplasia was identified in screening 

pouch biopsy specimens. 286 The authors 

cautioned that the long-term risk of development 

of dysplasia is not yet known and recommended 

screening of the pouch for dysplasia. In the rare 

patient who has undergone an ileorectal anastomosis 

without rectal mucosectomy, surveillance of 

the rectum should be performed to screen for 

rectal cancer. 

Psychosocial support 

The social impact of ulcerative colitis on the lives 

of children with the disease needs to be considered. 

Ulcerative colitis often has its onset in 

adolescence, a time when body image issues are 

paramount. Children and teenagers with IBD may 

often experience anxiety over the diagnosis of a 

chronic disease, the need for invasive procedures 

and the uncertainty of the future. In addition, 

there may be struggles with parents about proper 

diet, and ‘medication fatigue’ from having to take 

more than ten pills per day. Social, school-related 

and extracurricular activities may be affected and 

Prognosis and follow-up 407 

may need appropriate modification. For example, a 

self-limited reduction of physical education activities 

and permission for special bathroom privileges 

may be needed. 

Previous studies report an increased risk of psychiatric 

and behavioral issues in children with IBD 

including depression, anxiety and low selfesteem. 

290–294 Burke and colleagues reported that 

children are at increased risk for depression as 

early as the time of diagnosis. 290 The physician 

caring for these patients needs to discuss the above 

issues openly with the patient and family, and be 

alert to the possibility that a patient may develop 

anxiety or depressive symptoms. More recently, 

two patient-generated, disease-specific, healthrelated 

quality of life (HRQoL) questionnaires for 

children with IBD have been validated: the 

IMPACT and Impact-II questionnaires. 295,296 

Impact-II is a modified version of the IMPACT 

questionnaire. The use of these instruments may 

provide important information to improve the care 

of children with IBD. Referral to an educational 

support group, such as those sponsored by the 

Crohn’s and Colitis Foundation of America 

(www.ccfa.org), may be helpful for patients and 

their famililies. 

Prognosis and follow-up 

Whether children with ulcerative colitis are 

treated medically or surgically, they have an excellent 

long-term prognosis and good quality of life. 

The majority of children with ulcerative colitis 

respond to medical therapy. In one American 

retrospective study of 171 children ranging in age 

from 1.5 to 17.7 years, diagnosed with ulcerative 

colitis between 1967 and 1994, 43% had mild 

disease at presentation and 57% had moderate or 

severe ulcerative colitis. With treatment, 70% of all 

the children were in remission within 3 months of 

diagnosis and, by 6 months, 90% of the children 

with mild disease and 81% of the children with 

moderate-to-severe ulcerative colitis experienced 

resolution of their symptoms. In each yearly 

follow-up period, approximately 55% of the children 

were symptom free, 38% experienced chronic 

intermittent symptoms and 7% had continuous 

symptoms. 264 In this same study, children with 

mild ulcerative colitis at presentation had a lower

408 


frequency of colectomy than children with moderate-to-severe 

ulcerative colitis (9% vs. 26% at 5 

years, respectively). Patients with left-sided 

disease had comparable rates of colectomy at 5 

years to patients with pancolitis. 264 However, the 

authors cautioned that the number of patients in 

each subgroup of disease extent was small, and a 

true difference in colectomy rates may have been 

missed secondary to insufficient power of the 

study. 264 Another study of 80 children diagnosed 

with ulcerative colitis before the age of 15 years 

reported a slightly higher rate of remission of 

60–70% in each of the first 10 years, after the year 

of diagnosis. 3 In the same study, the cumulative 

probability of colectomy was 6% after 1 year and 

29% after 20 years. 3 

Limited distal ulcerative colitis (proctitis or proctosigmoiditis) 

diagnosed in adults and children 

can extend further to involve more proximal colon 

with time. 297–300 In a retrospective study of 38 children 

(mean age 11.6 years; range 4.2–17.7 years) 

diagnosed with ulcerative colitis proctitis between 

1975 and 1994, 29% of the children developed 

extension of disease involvement beyond the 

rectosigmoid. 299 Another retrospective evaluation 

of 85 patients under 21 years of age, diagnosed 

with ulcerative colitis proctosigmoiditis between 

1958 and 1983, demonstrated the extension of 

disease to the descending colon in 20% and to the 

hepatic flexure or beyond in another 38% of the 

patients. 300 The extension of disease may warrant 

a change in medical therapy to control disease 

activity and may have implications for an 

increased risk of potential colorectal cancer in the 

future. 301 

Women with ulcerative colitis generally experience 

similar rates of fertility to those of the general 

population; however, an increased risk of preterm 

births has been reported in some studies. 302–304 In 

contrast, women with ulcerative colitis who 

undergo proctocolectomy with IPAA may experience 

reduced fertility. 305 

Individuals with longstanding ulcerative colitis 

are at increased risk of developing colorectal 

cancer. 301,306,307 Risk of colorectal cancer increases 

with more extensive colonic involvement and 

longer duration of disease since diagnosis. 

301,306–309 Therefore, children with ulcerative 

colitis will potentially be at risk for colorectal 

cancer over a longer period of time, compared to 

individuals with adult-onset ulcerative colitis. In a 

population-based cohort study in Sweden, Ekbom 

et al reported standardized incidence ratios for 

colorectal cancer of 1.7 for ulcerative colitis proctitis, 

2.8 for left-sided ulcerative colitis and 14.8 

for ulcerative colitis pancolitis. 307 The absolute 

risk (cumulative risk) of colorectal cancer 35 years 

after diagnosis was 30% for patients with pancolitis 

at diagnosis for the entire cohort (adults and 

children), but 40% for individuals diagnosed with 

pancolitis at less than 15 years of age. 307 

Individuals with PSC and ulcerative colitis have a 

higher risk of developing colorectal neoplasia 

compared to those with ulcerative colitis alone, 

and of developing cholangiocarcinoma. 310–314 

Ursodeoxycholic acid (UDCA) may decrease the 

risk for developing colorectal dysplasia or cancer 

in patients with ulcerative colitis and PSC. 315 

Other risk factors reported for colorectal cancer in 

patients with ulcerative colitis include a family 

history of colorectal cancer 316 and the occurrence 

of backwash ileitis. 317 In contrast, some retrospective 

studies suggest that 5-ASA agents may provide 

a protective effect in the development of colorectal 

cancer in patients with ulcerative colitis, but not 

all studies support these findings. 190,191,193,318 A 

retrospective, case–control study suggested a risk 

reduction of colorectal cancer in ulcerative colitis 

with folate supplementation, but the findings were 

not statistically significant. 319 The role of pharmacological 

therapy and vitamin supplements in the 

development of colorectal cancer in patients with 

ulcerative colitis remains controversial. 320 Further 

prospective studies are needed to evaluate the 

potential risk reduction (preventive) effects of 

folate and 5-ASA agents. 192,321,322 

There are no randomized controlled trials examining 

the effectiveness of surveillance colonoscopy 

for dysplasia and colorectal cancer in patients with 

ulcerative colitis. 323,324 The reported general 

current practice includes surveillance colonoscopy 

every 1–2 years beginning at 8 years after 

the diagnosis of disease for pancolitis and 15 years 

in those with left-sided colitis. 324 However, it may 

be prudent to perform the initial surveillance 

colonoscopy beginning at 8–10 years after diagnosis 

in all patients with ulcerative colitis, in order to 

reassess the true extent of disease. 324 The consensus 

recommendations suggest that biopsy specimens

should be taken every 10cm in all four quadrants 

and additional biopsies should be performed for 

strictures and mass lesions. 324 It is not clear 

whether surveillance practice should differ for 

patients with younger-onset ulcerative colitis. 

There are no published formal recommendations 

to guide surveillance colonoscopy in children. 323 

Conclusions 

Ulcerative colitis in children presents in a similar 

manner to that in adults, although children often 

have more extensive disease at diagnosis. Once the 

diagnosis is established by colonoscopy, the first 

line of induction treatment in mild disease is 

usually an aminosalicylate, with corticosteroids 

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26 

Introduction 

Vasculitides 


Vasculitides is a general term for a group of 

diseases characterized by inflammation within or 

around the wall of blood vessels, with alteration of 

the vascular blood flow and deranged integrity of 

the vessels, leading to ischemia and necrosis of the 

dependent organs. Blood vessels of all sizes may 

be affected, from the largest vessel in the body (the 

aorta) to the smallest vessels in the skin (capillaries). 

The size of the affected blood vessels varies 

according to the specific type of vasculitis. 1–3 The 

symptoms of vasculitides depend on the blood 

vessels involved in the inflammatory process. 

However, vasculitides are a systemic illness, and 

Table 26.1 Classification of the vasculitic syndromes 

Systemic necrotizing vasculitis 

polyarteritis nodosa (PAN) (classic PAN, microscopic polyangiitis) 

allergic angiitis and granulomatosis of Churg–Strauss 

polyangiitis overlap syndrome 

patients have fever, weight loss, fatigue, a rapid 

pulse, and diffuse aches and pains. In some cases, 

identifying the source and underlying cause of the 

pain is extremely challenging. In addition to these 

diffuse, poorly localized systemic symptoms, 

vasculitides may involve virtually every organ 

system in the body. 

It should be stressed that, although several specific 

entities are identified, different vasculitides may 

also have overlapping features. Table 26.1 reports 

a classification that takes into account the heterogeneity 

of vasculitides, and also the fact that some 

syndromes are mainly systemic, leading to 

progressive organ system dysfunction, whereas 

Wegener’s granulomatosis 

Temporal arteritis 

Takayasu’s arteritis 


Predominantly cutaneous vasculitis (hypersensitivity vasculitis) 

exogenous stimuli proven or suspected (drug-induced, serum sickness and serum sickness-like reactions, 

associated with infectious diseases) 

endogenous antigens likely to be involved (associated with neoplasms, with connective tissue diseases, with other 

underlying diseases, or with congenital deficiencies of the complement system) 

Other vasculitic syndromes 

Kawasaki disease 

isolated central nervous system vasculitis 

thromboangiitis obliterans (Buerger’s disease) 

Behçet’s syndrome 

miscellaneous vasculitis 

419

420 

Vasculitides 

others are predominantly localized to the skin and 

rarely cause dysfunction of vital organs. Organ 

systems that can be affected by the vasculitic 

process are: skin, joints, lungs, kidneys, gastrointestinal 

tract, blood, sinuses, nose and ears, eyes, 

brain and nerves. In general, however, any type of 

systemic vasculitis can affect the gastrointestinal 

tract. For practical clinical work, vasculitides can 

also be differentiated into ‘primary’ and ‘secondary’. 

Primary vasculitides are not associated with 

systemic entities and the type of the disease 

depends on the caliber of the involved vessels. 

Secondary vasculitides are associated with underlying 

diseases, mainly rheumatic or connective 

tissue diseases, malignancy, infections, drugs and 

toxic agents. Rheumatic and autoimmune 

diseases, a cause of intestinal vasculitides, are 

systemic lupus erythematosus (SLE), rheumatoid 

arthritis, systemic sclerosis, dermatomyositis, 

primary biliary cirrhosis and autoimmune hepatitis. 

However, the most common infectious diseases 

underlying vasculitides are bacterial (streptococci, 

borrelia, mycobacteria, mycoplasms), viral (hepatitis, 

cytomegalovirus, herpes, HIV) and fungal. 

Vasculitides involving the gastrointestinal tract are 

part of a systemic process, although signs and 

symptoms may initially be limited. The onset of 

clinical manifestations may be acute and severe 

(mesenteric infarction) or chronic, due to mesenteric 

ischemia. 4 Acute intestinal vasculitides 

present as a rapidly evolving disorder, with a clinical 

picture mimicking embolic or thrombotic 

ischemia: intensive abdominal pain, signs of peritonitis 

and ileus. Chronic intestinal vasculitides 

can mimic each type of gastrointestinal disorder 

and require a detailed diagnostic procedure. The 

main symptoms of chronic vasculitides involving 

the intestine include abdominal pain, weight loss, 

nausea, vomiting, diarrhea, hematochezia and 

tenesmus. Endoscopy of both the upper and lower 

gastrointestinal tract often shows signs of inflammation 

such as petechiae, erosions and small 

ulcerations. Affected patients may also present 

acute episodes of small-bowel obstruction 

secondary to strictures, resembling Crohn’s disease 

or intussusceptions, or with massive gastrointestinal 

bleeding, secondary to aneurysm formation. 

4 In addition to mesenteric ischemia, systemic 

vasculitides can also cause ischemic damage to the 

liver, pancreas, gallbladder and, less commonly, 

esophagus or stomach. 

Epidemiology 

Certain forms of vasculitis occur more commonly 

in specific age groups. Vasculitides in childhood 

are dominated by Kawasaki disease and 

Henoch–Schönlein purpura, whereas primary 

systemic vasculitides, as well as conditions that 

can be complicated by a vasculitic process (e.g. 

SLE and juvenile dermatomyositis) are rarely 

reported in children. Furthermore, certain ethnic 

groups are at higher risk than others. The incidence 

of Kawasaki disease in children younger 

than 5 years doubled from 4.0 per 100000 in 

1991–92 to 8.1 per 100000 in 1999–2000, whereas 

for Henoch–Schönlein purpura the annual incidence 

is about 20 per 100000. 5 Recent data from 

the West Midlands of the UK indicated an incidence 

of 0.24 per 100000 for primary systemic 

vasculitides including cases of polyarteritis 

nodosa (PAN), microscopic polyangiitis, Wegener’s 

granulomatosis and Behçet’s disease. 6 

Pathogenesis 

Most of the vasculitides are thought to be mediated 

by immunopathogenetic mechanisms, although 

the evidence for this is mainly indirect. Three 

potential mechanisms of vessel damage in vasculitides 

have been suggested. 7 

Pathogenetic immune-complex formation 

The mechanism of tissue damage in immune 

complex diseases is derived from the occurrence of 

antigen–antibody complexes formed in antigen 

excess and deposited in vessel walls, whose 

permeability is increased by several vasoactive 

amines. The deposition of complexes determines 

the activation of complement components, mainly 

C5a, that recruit neutrophils. Neutrophils infiltrate 

the vessel wall, phagocytose the immune 

complexes and release enzymes that damage the 

vessel wall. When the process becomes subacute 

or chronic, an infiltrate of mononuclear cells 

predominates. The causal role of deposition of 

immune complexes in the wall of vessels has not 

been clearly defined in most vasculitides. Indeed, 

many patients with vasculitides do not show 

circulating or deposited immune complexes.

Antineutrophil cytoplasmic antibodies 

These are antibodies directed against certain 

proteins of the neutrophil cytoplasm, and are 

detected in a high percentage of patients with 

systemic vasculitides (particularly Wegener’s granulomatosis), 

microscopic polyangiitis and in those 

with necrotizing and crescentic glomerulonephritis. 

Two main categories of antineutrophil cytoplasmic 

antibodies (ANCA) are recognized, based 

on different targets: cytoplasmic ANCA (c-ANCA) 

have a diffuse cytoplasmic staining pattern at 

immunofluorescence microscopy, when 

proteinase-3 (located in neutrophil azurophilic 

granules) is the c-ANCA antigen; and perinuclear 

ANCA (p-ANCA) which have a perinuclear or 

nuclear staining pattern when the targets are 

myeloperoxidase, elastase, cathepsin G, lactoferrin, 

lysozyme or bactericidal/permeability-increasing 

protein. It is not clear why patients with 

certain vasculitides develop ANCA, but, once 

ANCA are present, they can contribute to the 

pathogenesis of the vasculitides. It is conceivable 

that when neutrophils are primed by tumor necrosis 

factor (TNF)-α or interleukin (IL)-1, intracytoplasmatic 

proteinase-3 translocates to the cell 

membrane, where it interacts with extracellular 

ANCA. The neutrophils degranulate and reactive 

oxygen species are delivered, causing tissue 

damage. Tanslocation of proteinase-3 close to the 

cell membrane also occurs in the endothelial cells 

upon priming with TNF-α, IL-1, or interferon 

(IFN)γ, thus making them susceptible to interaction 

with ANCA and consequent tissue damage 

due to complement-mediated cytotoxicity or antibody-dependent 

cellular toxicity. Although these 

in vitro data are attractive as explanations, there 

are no conclusive data that ANCA play a direct 

role in the pathogenesis of vasculitides, as they 

may represent epiphenomena. 

Pathogenic T-lymphocyte responses and 

granuloma formation 

Vascular endothelial cells can express HLA class II 

molecules following activation by cytokines such 

as IFNγ. They can take part in immunological reactions, 

such as interaction with CD4+ lymphocytes, 

similarly to antigen-presenting macrophages. They 

can also secrete IL-1, which is a powerful inducer 

of adhesion molecules such as endothelial leuko- 

Clinical manifestations 421 

cyte adhesion molecule 1 (ELAM-1) and vascular 

cell adhesion molecule 1 (VCAM-1) with consequent 

adhesion of leukocytes to the endothelial 

cells in the blood vessel wall. There is no strong 

evidence that other mechanisms, such as direct 

cellular cytotoxicity or antibodies directed against 

vessel components or antibody-dependent cellular 

cytotoxicity, have a causal contribution to the 

pathogenesis of vasculitides. 

Many aspects of the pathogenesis of vasculitides 

remain unclear. Other variables certainly implicated 

in the development of vasculitides are: 

genetic predisposition; defects of the regulatory 

factors of the immune responses to certain antigens; 

the ability of the reticuloendothelial system 

in clearing circulating complexes; the size and 

physicochemical properties of immune complexes; 

the degree of turbulence of blood flow; and the 

intravascular hydrostatic pressure in different 

vessels. 

Clinical manifestations 

It is clinically useful to distinguish between acute 

and chronic intestinal vasculitides, although both 

may have a severe course with deleterious effects. 

Acute intestinal vasculitis is a rapidly evolving 

disease, which presents with intense abdominal 

pain, followed by signs of peritonitis and ileus, 

and progressive cardiovascular shock syndrome 

with high lethality. It is often difficult to distinguish 

mesenteric ischemia due to vasculitides 

clinically from embolic or thrombotic ischemia in 

patients complaining of severe abdominal pain. It 

is therefore necessary to collect the patient’s 

history carefully, as well as clinical and laboratory 

parameters, in order to reach the diagnosis and 

begin treatment. Standard emergency laboratory 

values, serum concentration of lactate and coagulation 

parameters as well as disease-specific values 

must be measured. Table 26.2 gives a number of 

tests that are useful in establishing a link between 

‘vasculitis’ and an underlying disease. Every 

patient suspected of having ischemia should 

receive an abdominal ultrasonography including 

Doppler examination of the mesenteric arteries 

and an X-ray of the abdomen for assessing ileus, 

intestinal edema and perforation. If findings of 

mesenteric ischemia are evident or suspected,

422 

Vasculitides 

Table 26.2 Clinical features that raise suspicion of vasculitides 

General clinical feature Signs or presenting disorders Type of vasculitis 

Constitutional symptoms fever, fatigue, malaise, 

anorexia, weight loss 

any type of vasculitis 

Polymyalgia rheumatica proximal muscle pain with giant cell arteritis; less commonly 

morning stiffness other vasculitides 

Non-destructive oligoarthritis joint swelling, warmth, painful polyarteritis, Wegener’s 

range of motion granulomatosis, 

Churg–Strauss vasculitis 

Skin lesions livedo reticularis, necrotic lesions, polyarteritis, Wegener’s 

ulcers, nodules, digital tip infarcts granulomatosis, Churg–Strauss 

vasculitis, hypersensitivity 

vasculitis 

palpable purpura any type of vasculitis except 

giant cell arteritis and 


Multiple mononeuropathy injury to two or more separate polyarteritis, Takayasu’s 

(mononeuritis multiplex) peripheral nerves (e.g. patient arteritis; less commonly, 

presents with both right foot Churg–Strauss vasculitis 

drop and left wrist drop) and Wegener’s granulomatosis 

angiography and subsequent surgery should be 

planned. 

The diagnosis of chronic vasculitis should be 

considered in young children and adolescents 

with systemic symptoms and evidence of single 

and/or multiorgan specific dysfunction. In these 

cases, common complaints are fatigue, weakness, 

fever, arthralgia and abdominal pain. Common 

signs include fever, hypertension, neurological 

dysfunction and renal abnormalities with an 

active urine sediment (containing red cells, other 

cellular and granular casts). The above findings 

are neither sensitive nor specific for vasculitides, 

and the diagnosis is often delayed because the 

clinical manifestations of the vasculitides mimic 

those of other more common disorders. In addition, 

although each type of vasculitis usually has a 

characteristic pattern of organ involvement, a 

single approach to the diagnosis is difficult, owing 

glomerulonephritis microscopic polyangiitis, 

Wegener’s granulomatosis, 

cryoglobulinemia, 

Churg–Strauss vasculitis, 


to the variability of the manifestations of the 

vasculitides. All children suspected of having 

vasculitides should undergo a complete history 

and physical examination and certain basic laboratory 

tests (Figure 26.1). Both upper and lower 

intestinal endoscopy frequently reveal signs of 

mucosal inflammation, such as multiple 

petechiae, friability, erosions and small ulcers. A 

number of serological markers, such as antinuclear 

antibodies (ANA) and ANCA are associated with 

specific types of vasculitis, but tissue biopsy is 

often required to establish the diagnosis. 

History 

Diagnostic work-up starts with a detailed patient 

history. Postprandial abdominal pain that usually 

begins 30–60min after meals is a predominant 

symptom. Other aspects of the history include

whether the patient has recently been ill or taken 

medications or drugs, has a history of hepatitis 

(virus C), or has been diagnosed with any disorder 

known to be associated with vasculitis. Knowing 

the propensity of certain disorders to occur in 

specific ages, gender, or ethnic groups can be 

useful in making the diagnosis. Table 26.2 outlines 

clinical features that raise the suspicion of 

vasculitis. 


I 

Patient with symptoms and 

signs suggesting vasculitis 

History and clinical features Laboratory tests 

II 

III 

Determine category of 

the vasculitis syndrome 

Treatment 

Establish diagnosis 

A careful physical examination helps in determining 

the extent of vascular lesions, the distribution 

of affected organs and the presence of additional 

Yes 

Biopsy 

Determine pattern and 

extent of the disease 

Search for antigens Search for underlying disease 

Antigen removal 

Treat vasculitis 

Treat underlying disease 

Treat vasculitis 

Figure 26.1 Suggested algorithm for the approach to patients with suspected vasculitis. 

No 


Angiogram if appropriate 

Re-evaluation 

disease processes. The type and extent of organ 

involvement in vasculitis can be helpful in determining 

the specific type of vasculitides and the 

degree of urgency in initiating treatment. The clinical 

features in a given patient can be used to 

discern the size of vessels affected by vasculitis 

(Table 26.3). Table 26.4 reports the frequency of 

intestinal involvement in different vasculitides. 

Incomplete stenosis of one of the major vessels 

(e.g. mesenteric artery) may cause changes in the 

Doppler ultrasound flow pattern, as well as typical 

bruits at abdominal auscultation. In three series 

with a total of 351 patients, approximately onethird 

had gastrointestinal manifestations. 8 In a 

large series of patients with PAN or Churg–Strauss 

syndrome, for example, the following frequency of

424 

Vasculitides 

Table 26.3 Clues for identifying the type of vessel involvement in vasculitides 

Most commonly associated 

Clinical feature Vessels most likely to be affected systemic vasculitis 

Cutaneous 

Palpable purpura post-capillary venules any type of vasculitis except giant cell 

arteritis and Takayasu’s arteritis 

Skin ulcers arterioles to small arteries polyarteritis, Churg–Strauss vasculitis 


hypersensitivity vasculitis 

Gangrene in an small to medium-sized arteries polyarteritis, Churg–Strauss vasculitis, 

extremity Wegener’s granulomatosis 

Gastrointestinal tract 

Abdominal pain or small to medium-sized arteries Henoch–Schönlein purpura, 

mesenteric ischemia polyarteritis, Churg–Strauss vasculitis 

Gastrointestinal bleeding capillaries to medium-sized Henoch–Schönlein purpura, 

arteries polyarteritis, Churg–Strauss vasculitis 

Renal 

Glomerulonephritis capillaries microscopic polyangiitis, Wegener’s 

granulomatosis, cryoglobulinemia, 

Churg–Strauss vasculitis, 


Ischemic renal failure small to medium-sized arteries polyarteritis, Takayasu’s arteritis; less 

commonly, Churg–Strauss vasculitis, 


Pulmonary 

Pulmonary hemorrhage capillaries; less commonly microscopic polyangiitis, Wegener’s 

small to medium-sized arteries granulomatosis 

Pulmonary infiltrate small to medium-sized arteries Churg–Strauss vasculitis, 

or cavities microscopic polyangiitis 

Neurological 

Peripheral neuropathy small arteries polyarteritis, Churg–Strauss vasculitis, 


cryoglobulinemia 

Stroke small, medium-sized or giant cell arteritis, SLE-associated 

large arteries vasculitis 

SLE, systemic lupus erythematosus 

gastrointestinal symptoms and findings was noted: 

abdominal pain (25%), gastrointestinal bleeding 

(7%), peritonitis (4%), intestinal infarction (2%), 

pancreatitis (2%), duodenal ulcer (2%) and cholecystitis 

(1%), while ischemic hepatitis, gastritis 

and esophagitis occurred more rarely (

urea nitrogen, creatinine, liver enzymes, erythrocyte 

sedimentation rate (ESR), hepatitis serological 

markers and chest radiograph. Additional tests 

that may be required are cerebrospinal fluid analysis, 

central nervous system imaging, pulmonary 

function testing, and blood and tissue culture. 

These tests assess the extent of organ involvement 

and may suggest, confirm, or exclude additional 

diagnostic considerations. More specific laboratory 

tests may be indicated, depending upon the 

diagnosis being considered (Table 26.5). 

Imaging studies 

Imaging studies, such as computed tomography 

(CT) scanning or barium studies, are frequently 

normal in patients with symptomatic intestinal 

vasculitides and, when abnormal, reveal nonspecific 

abnormalities such as a thickened edematous 

bowel wall, unless a mesenteric infarction has 

occurred. Angiography may be useful in diagnosing 

small and medium vessel vasculitides, such as 

PAN. Nuclear medicine scanning using white 

blood cell markers such as indium-111 may localize 

bowel inflammation in vasculitis, but its clinical 

utility is uncertain. 

Endoscopy 

Endoscopy should be performed with great 

caution in patients with vasculitides because of an 


Table 26.4 Frequency of intestinal involvement in different vasculitides (from references 24, 38–47) 

Type of vasculitis Frequency of intestinal involvement (%) 

Primary vasculitis 

Polyarteritis nodosa (PAN) (classic PAN, microscopic polyangiitis) 30–50 

Churg–Strauss syndrome 25–50 

Behçet’s disease up to 30 

Takayasu’s arteritis up to 15 

Wegener’s granulomatosis 5–10 

Giant cell arteritis 1 

Secondary vasculitis 

Henoch–Schönlein purpura 50–90 

Systemic lupus erythematosus 50 

Rheumatoid arthritis vasculitis 10 

elevated risk of perforation of an edematous and 

ischemic bowel. In these cases, magnetic resonance 

imaging (MRI) of the intestinal tract can be 

used. As demonstrated recently, the two techniques 

show a good correlation in detecting 

inflammation of the intestinal mucosa. 9 

Tissue biopsy 

Biopsy examination of the involved tissue is 

almost always necessary for diagnosis. Obviously, 

specimens are more likely to yield a diagnosis 

when they are of adequate size and obtained from 

an involved area of an organ. The histological findings 

evolve as lesions progress and may vary from 

acute inflammation to healing and repair. The 

biopsy findings in the various vasculitides are 

discussed below (see Specific disorders). The decision 

to obtain a tissue biopsy is based upon the 

overall clinical assessment of the patient and 

complications associated with the procedure. As 

an example, the skin, which characteristically is 

involved in children with leukocytoclastic vasculitis, 

is easily accessible for biopsy, and skin biopsy 

in this setting has low morbidity. However, in this 

scenario, the biopsy adds little, if any, new information. 

The biopsy findings of leukocytoclastic 

vasculitis (inflammation of the small blood vessels 

most prominent in the post-capillary venules) are 

relatively non-specific, unless accompanied by 

vascular IgA deposition, which establishes a diag-

426 

Vasculitides 

Table 26.5 Laboratory parameters useful in the diagnostic approach to vasculitis 

Laboratory parameters Purpose of interpretation 

Routine tests (including complete blood cell evaluate for hematologic, renal and other 

count, liver enzymes, creatinine, urinalysis) organ involvement 

Blood cultures rule out infection 

ESR, C-reactive protein high values suggest active inflammatory disease 

Eosinophilia Churg–Strauss syndrome 

Anti-nuclear antibodies screen for SLE and Sjögren’s syndrome 

Anti-double-stranded DNA antibodies suggest SLE 

Rheumatoid factor very high titers in rheumatoid arthritis, Sjögren’s 

syndrome and cryoglobulinemia-associated vasculitis 

Complement (C3, C4, CH50) low complement levels suggest consumption by 

immune complexes, which are commonly found in 

SLE and cryoglobulinemia 

Cytoplasmic anti-neutrophil cytoplasmic 

(anti-proteinase-3) antibodies 


Perinuclear anti-neutrophil cytoplasmic 

antibodies (anti-myeloperoxidase) 

panarteritis nodosa, microscopic polyangiitis 

Creatine phosphokinase elevation suggests myositis, which can occur 

in many vasculitis syndromes 

Anti-glomerular basement membrane rule out Goodpasture’s syndrome, which can 

mimic vasculitis and cause pulmonary 

hemorrhage and glomerulonephritis 

Circulating immune complexes immune complex vasculitides 

HLA B51 suggests Behçet’s syndrome 

HLA B8 suggests SLE 

ESR, erythrocyte sedimentation rate; SLE, systemic lupus erythematosus 

nostic of Henoch–Schönlein purpura. 10 However, 

the diagnosis of Henoch–Schönlein purpura in 

children is usually made on clinical grounds, and 

biopsy may not be necessary. 

Arteriography 

Arteriograms can identify and characterize 

vasculitides of large and medium-sized arteries 

and giant cell arteritis with an aortic arch 

syndrome, whereas they are not helpful in the 

evaluation of vasculitides involving small vessels, 

because these are not visible with routine 

angiograms. Angiographic abnormalities may not 

be pathognomonic, but usually support a diagno- 

sis when combined with other clinical data. The 

decision to perform angiography in a patient with 

suspected vasculitis depends on the overall clinical 

judgement and assessment of the risk for 

complications associated with the procedure. 

Arteriography alone is usually performed to 

confirm the diagnosis of Takayasu’s arteritis: the 

arteriography changes tend to be most pronounced 

in the region of the aortic arch and its primary 

branches, which are relatively inaccessible for 

biopsy. In the patient with suspected PAN without 

an obvious area for biopsy, a mesenteric angiogram 

should be planned, particularly in the presence of 

abdominal pain: angiograms of mesenteric or renal 

arteries may show aneurysms, occlusions and

vascular wall irregularities. Magnetic resonance 

arteriography of the aorta and great vessels including 

some major branches such as the coronaries 

and renal arteries may be an alternative to contrast 

arteriography in children. When the two techniques 

were compared in ten children with 

various vascular lesions (age range: 1 month to 16 

years), excellent correlation was found between 

them. 11 

Specific disorders 

Primary vasculitides 

Polyarteritis nodosa 

PAN affects medium and small-sized arteries and 

can cause a wide spectrum of gastrointestinal 

symptoms and signs, which are mainly due to 

visceral ischemia and are detected in about twothirds 

of patients. Common intestinal features are: 

epigastric pain, nausea, anorexia, mucosal ulcerations 

(Figure 26.2), bleeding and diarrhea. The 

most severe intestinal findings are infarction, 

perforation, pneumatosis intestinalis and 

pseudomembranous colitis. 4 Survival after bowel 

Figure 26.2 A large (thick arrow) and a small (thin 

arrow) ulceration in a 14-year-old boy with polyarteritis 

nodosa at the level of the descending colon. The large 

ulceration is surrounded by hyperemic and friable 

mucosa. 

Specific disorders 427 

infarction requiring surgery is poor. Typical 

aneurysmal dilatation of small and medium-sized 

arteries on arteriogram will provide a definite diagnosis. 

In a series of 16 patients with severe PAN, 

five developed an abdominal crisis related to the 

disease: at laparotomy, all had evidence of mesenteric 

arteritis with infarcted bowel and intestinal 

perforation. 12 In another series of 165 patients 

with PAN or Churg–Strauss syndrome, 31% of 

deaths occurring at the follow-up were attributable 

to gastrointestinal disease (bleeding, peritonitis 

and pancreatitis). 12 Vasculitis of the hepatic arteries 

may cause elevated levels of transaminases, 

bilirubin and alkaline phosphatase. 

Treatment with corticosteroids and cyclophosphamide 

has relieved symptoms and improved the 

overall survival of these patients. 13 Adequate 

therapy for patients with PAN related to hepatitis 

B virus infection or hairy cell leukemia may 

require treatment of these underlying disorders. 12 

The tendency of PAN to involve large vessels has 

an important long-term implication. Some patients 

with PAN have gastrointestinal symptoms and 

other manifestations at a time when the disease is 

clinically inactive, owing to effective immunosuppressive 

therapy. In this setting, healing of 

inflamed vessels has led to progressive narrowing 

of the vascular bed. 

Churg–Strauss syndrome 

The Churg–Strauss syndrome (also called ‘allergic 

angiitis and granulomatosis’) is a multisystemic 

disease characterized by hypereosinophilia, 

pulmonary infiltration, extravascular granulomas 

and necrotizing vasculitis affecting small and 

medium-sized arteries and veins. 12 Involvement of 

the intestinal vasculature ranges from 25 to 50% 

and any intestinal organ can be affected with 

features such as ulcerations, bleeding, ileus, perforation 

and cholecystitis. Interestingly, microscopic 

polyangiitis resembles Churg–Strauss syndrome 

for the spectrum of gastrointestinal features as well 

as for its similar response to corticosteroids and 

cyclophosphamide. 14 Intestinal histology can 

reveal both eosinophilic infiltrates around the 

vessels and eosinophilic gastroenteritis. The 

syndrome commonly occurs in middle-aged adults 

and is rare in children. A 15-year-old girl with 

multiple colonic ulcers has recently been 

described. This patient also had vasculitic involve-

428 

Vasculitides 

ment of the major organs including migratory 

pulmonary infiltrates, myocarditis and central 

nervous system disease with hemiparesis. 15 


Wegener’s granulomatosis is characterized by a 

granulomatous (peri)vascular inflammation of the 

upper and lower airways combined with glomerulonephritis. 

It appears to be a disorder restricted to 

Caucasians, since only 3% of patients with 

Wegener’s granulomatosis are of other ethnic 

groups. Interestingly, although c-ANCA is considered 

a specific marker, it is not yet an accepted 

criterion for the diagnosis of Wegener’s granulomatosis. 

Gastrointestinal involvement seems to be 

rare, mostly producing granulomatous colitis and 

gastritis. 4 An unusual presentation of Wegener’s 

granulomatosis has been reported in a 16-year-old 

girl with symptoms and signs suggesting an 

inflammatory bowel disease (diarrhea, fever, 

weight loss, abdominal pain, arthralgias and 

mouth ulcers). However, biopsy specimens of 

rectal mucosa, oro- and nasopharynx, and skin 

conclusively demonstrated the vasculitic lesion of 

Wegener’s granulomatosis. 16 

Behçet’s disease 

Behçet’s disease is a necrotizing vasculitis of 

unknown etiology primarily affecting young adult 

males. The predominant features are recurrent oral 

and genital ulcerations (more than three times per 

year) in combination with other signs, such as 

uveitis, iritis, retinal vasculitis, skin lesions 

(erythema nodosum, acneiform or papulopustulous 

lesions, pseudofolliculitis) and pathergy 

(papulopustulous lesions 24–48h after cutaneous 

injection of 0.9% sodium chloride). A strong 

genetic component is thought to be part of the 

disorder, owing to the association with HLA B51. 17 

The disease has the highest incidence in Turkey 

(up to 3000 per million), and in southern 

Mediterranean and Asiatic regions. Gastrointestinal 

involvement is found frequently and 

includes major intestinal arteries as well as upper 

and lower parts of the gut. Oral lesions resemble 

aphthous ulcers commonly observed in Crohn’s 

disease and may be single or multiple; esophageal 

ulcerations and erosions are found frequently at 

endoscopy (Figure 26.3), although they do not 

Figure 26.3 Mucosa of the distal esophagus in an 8year-old 

girl with Behçet’s disease. Diffuse hyperemia, 

erosions and ulcerations are evident, together with an 

open cardia. 

cause bleeding or perforation. Intestinal involvement 

at the level of both small and large bowel can 

resemble Crohn’s disease; bleeding, abdominal 

pain and perforation may result. 18,19 The optimal 

management of Behçet’s disease is uncertain, since 

the disease is rare and symptoms tend to wax and 

wane. The mucocutaneous lesions can be treated 

with topical or intralesional corticosteroids, or 

systemic colchicine, dapsone, thalidomide, or 

steroids. Systemic disease is typically treated with 

corticosteroids and immunosuppressive drugs 

such as azathioprine, cyclosporin, or cyclophosphamide. 

Interestingly, systemic Behçet’s disease 

has been successfully treated with anti-TNF-α 

agents such as thalidomide and monoclonal antibodies 

(infliximab). 20 


Takayasu’s arteritis is a rare chronic vasculitis of 

unknown etiology that predominantly affects the 

aorta and its primary branches. 21,22 It characteristically 

affects young women, with an age of onset 

usually between 10 and 40 years (this is one of the 

major criteria for diagnosis). The prevalence is 

greatest in Asians. Gastrointestinal features result

from involvement of the large branches of the 

abdominal aorta such as the celiac trunk and the 

upper mesenteric artery. Although not a major 

feature, mesenteric ischemia can occur, leading to 

abdominal pain, diarrhea and gastrointestinal 

hemorrhage. An association of Takayasu’s arteritis 

with ulcerative colitis has also been reported. 23 

Severe cerebral, intestinal and coronary circulatory 

disturbances as well as an insufficient blood 

supply in both arms have been described in a 9month-old 

infant with extensive inflammatory 

lesions in the large arterial trunks originating at 

the aorta. 24 

Giant cell arteritis and polymyalgia rheumatica 

These two closely related vasculitides mainly 

affect the vessels of the shoulder girdle and the 

intra- and extra-cranial arteries; however, involvement 

of mesenteric vessels can also occur. 25 

Disseminated fibrinoid necrosis of small vessels 

can result in visceral ischemia, abdominal pain, 

nausea, anorexia, weight loss, bleeding and perforation. 

Hepatic artery involvement can determine 

disturbances of liver function and hepatitis with 

fibrin-ring granulomas. 26 

Kawasaki’s disease 

Also called mucocutaneous lymph node 

syndrome, Kawasaki’s disease is a multisystem 

vasculitis affecting children under the age of 5 

years. The principal symptoms are high fever for 

more than 5 days and resistance to antibiotics; 

polymorphonuclear cell exanthema, skin lesions 

in peripheral extremities (reddening, indurative 

edema, membranous desquamation), oral lesions 

(pharyngitis, enanthema, ‘strawberry tongue’), 

bilateral conjunctive congestion and acute cervical 

lymphadenopathy. In addition to these symptoms, 

gastrointestinal complications can determine deterioration 

of the overall condition of the patient. 

Intestinal features during the acute phase are 

abdominal pain, vomiting and diarrhea; whereas 

small-bowel obstruction has been reported as a 

consequence of acquired ischemic stricture. 27,28 

The vasculitic process underlying intestinal 

involvement in Kawasaki’s disease includes four 

stages: intensive perivasculitis, focal panvasculitis, 

ongoing inflammation and granulation and 

stenosis with aneurysms. The spectrum of 


gastroenterological complications also includes 

hepatitis, cholangitis, gallbladder hydrops and 

pancreatic ductitis. 

Secondary vasculitides 

Henoch–Schönlein purpura and leukocytoclastic 

vasculitis 

Henoch–Schönlein purpura is a generalized 

vasculitis of small to medium-sized vessels which 

characteristically occurs in children of all ages. It 

is secondary to an immune process that generates 

circulating immune complexes containing large 

amounts of IgA. Patients classically present lower 

extremity purpura, arthritis and acute glomerulonephritis. 

The gastrointestinal tract is frequently 

involved and intramural hemorrhages, bloody 

diarrhea or colic may result; erythema, friability 

and ulcerations of the gastrointestinal mucosa can 

be observed at endoscopy (Figure 26.4). Intestinal 

obstruction and intussusception have also been 

described. Gastrointestinal signs may have a recurrent 

course and may precede the onset of the characteristic 

purpuric rash, 29,30 which rarely may 

even be lacking. The clinical spectrum of gastro- 

Figure 26.4 Diffuse hyperemia and congestion with 

small erosions in a 6-year-old girl with Henoch–Schönlein 

purpura at the level of the gastric antrum.

430 

Vasculitides 

intestinal involvement in Henoch–Schönlein 

purpura ranges from a dull periumbilical pain to 

severe courses with intestinal perforation and 

necrosis of the bile ducts. Ultrasonography and CT 

provide useful information to support the diagnosis, 

which is commonly strongly suspected on 

clinical grounds. Confirmation of the diagnosis 

requires evidence by immunofluorescence microscopy 

of tissue deposition in the skin or kidney of 

IgA. Biopsy of the skin lesions reveals inflammation 

of the small blood vessels, called leukocytoclastic 

vasculitis (see below) that is most prominent 

in the post-capillary venules. The prognosis 

of this disease is good, except for cases with severe 

renal involvement. The efficacy of corticosteroids 

and immunosuppressants (azathioprine, 

cyclophosphamide) in the treatment of 

Henoch–Schönlein purpura is debated, especially 

when the kidneys are involved. 31 Some cases of 

Henoch–Schönlein purpura have been successfully 

treated by plasmapheresis. 32 Little experience 

concerning treatment of Henoch–Schönlein 

purpura during pregnancy exists, although corticosteroids 

and plasmapheresis have been used in 

these cases. 31 

Leukocytoclastic vasculitis 

Leukocytoclastic vasculitis is a disorder that 

mainly affects middle-aged patients (especially 

women), and has characteristic skin histopathological 

features revealing the presence of vascular 

and perivascular infiltration of polymorphonuclear 

leukocytes with formation of nuclear dust 

(leukocytoclasis), extravasation of erythrocytes 

and fibrinoid necrosis of the vessel walls. 7 This 

process is dynamic; and a biopsy of a lesion taken 

too early or too late in its evolution may not reveal 

these findings. The picture of leukocytoclastic 

vasculitis can occur in any vasculitic syndrome 

but may also occur in non-vasculitic diseases such 

as neutrophilic dermatoses, at the base of leg 

ulceration, or in some insect bite reactions. Careful 

clinical–pathological correlation is necessary. 7 

Immuno-fluorescent staining may reveal 

immunoglobulins (IgG, IgM) and complement 

components (C3, C4) deposited on the skin basement 

membrane, which are suggestive of immune 

complex deposition. 12 

Vasculitides in connective tissue diseases 

The term connective tissue disease includes 

numerous entities such as SLE, systemic sclerosis, 

polymyositis, dermatomyositis or Sjögren’s 

syndrome. Most clinical signs of these disorders 

are attributed to a small-vessel vasculitis, and 

gastrointestinal clinical problems most frequently 

occur in SLE. 


The vasculitis associated with SLE involves small 

and medium-sized vessels, and affects the 

gastrointestinal tract in up to 50% of patients. 

Lower abdominal pain secondary to mesenteric 

vasculitis is generally an insidious symptom that 

may be intermittent for months prior to the development 

of an acute abdomen with nausea, vomiting, 

diarrhea, bleeding and fever. Risk factors for 

the development of mesenteric vasculitis are 

peripheral vasculitis and central nervous system 

involvement. Patients with an acute presentation 

may also have mesenteric thrombosis and infarction, 

often in association with antiphospholipid 

antibodies. Mesenteric vasculitis is a potentially 

life-threatening disorder. In addition to the possible 

development of necrotic segments of bowel, 

patients may have septic complications and bowel 

perforation. In a series published in 1982, 15 of 

140 patients with SLE who required hospitalization 

developed a disease-related abdominal event 

and 11 underwent laparotomy. 33 The majority of 

the patients in this study had prodromic signs, 

such as insidious onset of intermittent, lower 

quadrant cramping and abdominal pain, which 

were present for an average of 34 days prior to the 

hospitalization. The presence of these symptoms 

in patients with SLE should raise suspicion of 

possible mesenteric vasculitis, thereby permitting 

early diagnosis and treatment. Interestingly, 

abdominal features such as pain, rectal bleeding 

by mucosal ulcers and protein-losing enteropathy 

due to increased mucosal permeability have been 

described as sole and initial manifestations in 

patients with SLE. 34,35 Chronic intestinal pseudoobstruction 

of the myogenic type has also been 

described to complicate the course of SLE. 36 

Simple laboratory tests may be helpful in making 

the diagnosis or in evaluating a flare-up. However, 

the diagnosis is mostly dependent on the historical

and physical findings. Antinuclear antibody, an 

antibody to nucleosomal DNA–histone complexes, 

is highly sensitive but not specific; anti-doublestranded 

DNA is more specific for SLE. This test 

may correlate with the degree of disease activity. 

Antiphospholipid antibodies are present in 30% of 

SLE patients. 

Antiphospholipid antibody syndrome 

The antiphospholipid antibody syndrome (APS), 

also known as Hughes syndrome, is a disorder 

characterized by multiple different antibodies that 

are associated with both arterial and venous 

thrombosis. There are three primary classes of 

antibodies associated with the APS: anticardiolipin 

antibodies; the lupus anticoagulant; and 

antibodies directed against specific molecules 

including a molecule known as β2-glycoprotein-1. 

The APS can occur in patients with SLE or as an 

isolated disorder. There are two main classifications 

of the APS: if there is an underlying autoimmune 

disorder, such as SLE, the patient is said to 

have secondary APS; if the patient has no known 

underlying autoimmune disorder, it is termed 

primary APS. Of the APS patients, over half of 

them have the primary form. In persons with SLE, 

around 30% will develop the APS. In general, anticardiolipin 

antibodies occur approximately five 

times more often than the lupus anticoagulant in 

patients with the APS. Approximately 10% of 

patients with an initial presentation of primary 

APS will eventually be diagnosed with an autoimmune 

disorder such as SLE or a mixed connective 

tissue disorder. The APS represents a hypercoagulable 

state, which can be associated with a variety 

of clinical features including arterial and venous 

thrombosis, livedo reticularis and spontaneous 

abortions. The exact mechanism by which the 

antiphospholipid antibodies and anticardiolipin 

antibodies induce the thrombophilic state is not 

known. Gastrointestinal manifestations of APS are 

due to ischemia involving any part of the intestinal 

tube, and resulting in bleeding, abdominal pain, 

acute abdomen, esophageal necrosis with perforation, 

or giant gastric ulceration. 37,38 

Juvenile dermatomyositis and juvenile polymyositis 

These are uncommon disorders. Juvenile dermatomyositis 

has an incidence of 2–3 per 100000 per 


year. The clinical manifestations resemble those of 

adult dermatomyositis and polymyositis and 

include symmetric proximal muscle weakness, 

myalgias, muscle tenderness, fever and rash (the 

latter commonly detected in juvenile dermatomyositis). 

In addition, calcinosis is seen in onethird 

of patients. Functional outcomes have 

become good with modern treatments, but the 

diseases remain chronic in a large number of children 

and sequelae are often seen. Affected children 

typically present prodromic non-specific 

signs such as malaise, muscle aching, fever and 

irritability that are often interpreted as a viral 

illness. A change in gait may be a clue to muscle 

disease at this stage. 39 Gastrointestinal tract 

involvement can also occur, and includes mucosal 

ulcerations due to vascular occlusion. Affected 

patients may present with abdominal pain, 

gastrointestinal bleeding, or perforation. 39 In a 

recently revised series of 25 patients aged between 

1.5 and 15 years, dysphagia and abdominal pain 

were present in 32% and 40% of cases, respectively. 

40 A case of atonic esophagus and gastroparesis 

has been described in a child with juvenile 

dermatomyositis. 41 Juvenile dermatomyositis can 

usually be diagnosed on a clinical basis in the 

child with a characteristic rash and proximal 

muscle weakness. The diagnosis of juvenile 

dermatomyositis can be more difficult with the 

lack of cutaneous manifestations. Certain laboratory 

features such as elevated muscle enzyme 

levels, increase in von Willebrand’s factor 8 

antigen (vWF) and autoantibodies are frequently 

present in both disorders: they provide confirmatory 

evidence of the disease and a means of following 

patients. Electromyography can assist in 

making the diagnosis in equivocal cases (e.g. those 

without a typical rash or with normal muscle 

enzyme levels). Muscle biopsy may also be necessary 

in these instances, and is often the definitive 

test. The mainstays of therapy are corticosteroids; 

some children require additional immunosuppressive 

agents because of corticosteroid resistance or 

intolerance. 

Rheumatoid vasculitis 

A small-vessel vasculitis can complicate the 

course of rheumatoid arthritis. Small arteries in 

the peripheral organs are usually affected, resulting 

in gastrointestinal vasculitis in up to 10% of

432 

Vasculitides 

the patients with rheumatoid arthritis. 42 In 

contrast to PAN, vasculitis in rheumatoid arthritis 

shows few signs of inflammation, but intensive 

intimal proliferation and vascular occlusion. 43 The 

gastrointestinal symptoms of rheumatoid vasculitis 

range from slight recurrent abdominal pain to 

severe bleeding, intestinal ischemia and necrosis. 4 

It should be observed that, in rheumatoid arthritis, 

abdominal pain is not necessarily due to vasculitis, 

but can arise from mucosal lesions such as 

ulcers or bleeding, as a consequence of the administration 

of anti-inflammatory drugs. 

Thromboangiitis obliterans (Winiwarter–Buerger’s 

disease) 

A non-atherosclerotic, segmental, inflammatory 

disorder, Winiwarter–Buerger’s disease most 

commonly affects the small and medium-sized 

arteries, veins and nerves of the extremities. 4 This 

condition is distinguished from other forms of 

vasculitis by the highly cellular and inflammatory 

thrombus with relative sparing of the blood vessel 

wall. ESR and serum C-reactive protein are usually 

normal; commonly measured autoantibodies (e.g. 

antinuclear antibody and rheumatoid factor) are 

normal, as are other serological tests such as circulating 

immune complexes, complement levels and 

cryoglobulins, despite an immune reaction in the 

arterial intima. Winiwarter–Buerger’s disease 

usually begins with ischemia of the distal small 

arteries and veins, followed by more proximal arterial 

involvement as the disease advances. Patients 

usually note ischemia of the digits, which may 

manifest as claudication of the feet, legs, hands or 

arms. 44 The disease can progress to include 

ischemic ulcerations of the fingers or toes, with 

accompanying ischemic pain at rest. Buerger’s 

disease should be suspected in passive or active 

smokers who present with distal ischemia of the 

hands and/or feet. Obliteration of the intestinal 

vasculature can occur with abdominal angina, 

resulting in bowel infarction that requires immediate 

surgery. 45,46 A definitive diagnosis is made 

when the histopathology identifies the acute phase 

lesion in a patient with a clinical history of 

smoking. Typical arteriographic findings help to 

exclude proximal atherosclerotic disease and to 

meet the criteria for thromboangiitis obliterans. 

Treatment and follow-up 

Childhood vasculitides, particularly Kawasaki 

disease and PAN, require prompt recognition, 

because they can be life-threatening in the absence 

of appropriate therapy. The diagnosis can be laborious 

and cumbersome, since the clinical features 

of the various disorders overlap. Furthermore, 

although the disorders usually have a characteristic 

pattern of organ involvement, each organ 

system can be affected. Available treatments are 

helpful, particularly in the acute phase. When 

chronic therapy is required, the adverse effects of 

drugs and secondary infections are clinically relevant. 

Mortality data suggest that early deaths in 

vasculitides are due to active disease, whereas late 

deaths mainly result from the complications of 

therapy. The treatment of vasculitides depends 

upon the nature and severity of the disorder, and 

may include antihistamines, corticosteroids, nonsteroidal 

anti-inflammatory drugs, or cytotoxic 

agents. Patients with systemic vasculitis usually 

need at least corticosteroid therapy. As an 

example, glucocorticoid therapy is used for the 

treatment of vasculitis accompanying connective 

tissue disease. In most patients, the dose can be 

reduced and gradually discontinued, but some 

patients require chronic long-term administration 

of low-dose corticosteroids. Patients with rapidly 

progressive vasculitic diseases, such as PAN, are 

likely to require therapy consisting of a combination 

of a cytotoxic drug (usually cyclophosphamide) 

and corticosteroids. Both oral and pulse 

cyclophosphamide are used, depending upon the 

physician’s experience and the disease severity. 

After 1–2 months of combined therapy, the corticosteroid 

dose may be reduced if symptoms 

improve; therapy is usually continued for 6–12 

months to decrease the risk of relapse. 

Azathioprine and methotrexate have been used in 

less severe forms of vasculitides and as maintenance 

therapy, after remission has been induced 

by cyclophosphamide. Corticosteroid therapy, 

even in low doses, can produce substantial toxicity. 

The risk is greater as the dose increases, with 

complications ranging from minor skin bruising to 

life-threatening infections and fractures. Some of 

these complications can be prevented with appropriate 

patient monitoring. Some manifestations of

vasculitis such as neuropathy can take months to 

recede, even if the underlying vasculitis has 

abated, whereas others may be permanent. 

Patients in whom a chronic course is expected may 

become discouraged about their lack of rapid 

improvement and possible poor outcome. These 

patients may benefit from extra support and 

encouragement. Once the treatment has been initiated, 

patient monitoring is based on most of the 

procedures used during the diagnostic approach. 

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31. Dillon MJ. Henoch–Schönlein purpura (treatment and 

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434 

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43. Achkar AA, Stanson AW, Johnson CM et al. Rheumatoid 

vasculitis manifesting as intra-abdominal hemorrhage. 

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N Engl J Med 2000; 343: 864–869. 

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or thromboangiitis obliterans revealed by an enteric 

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Best Pract Res Clin Rheumatol 2002; 16: 833–845.

27 

Introduction 



Important advances have occurred in the past few 

years in our understanding of celiac disease, its 

pathogenesis, its manifestations, its complications 

and its treatment. This fascinating condition is 

now regarded as a true autoimmune disorder, triggered 

by a well-known autoantigen, and affecting 

primarily the small intestine, where it progressively 

leads to severe villous blunting. However, it 

has clinical implications that reach far beyond the 

gut. 

Celiac disease occurs only in genetically susceptible 

individuals, and is triggered by the ingestion of 

gliadins contained in wheat, rye and barley. Wheat 

gluten and similar alcohol-soluble proteins in 

other grains (called prolamines) cause – when 

ingested – the intestinal damage in individuals 

who are genetically predisposed. Indeed, almost 

100% of celiacs are positive for either HLA DR3 (or 

DR5/DR7), or HLA DR4. 1 Although gluten is 

clearly the major environmental factor inducing 

celiac disease, other less known agents may be at 

play in modulating its onset, including the amount 

and type of gluten, and the utilization and duration 

of breast feeding. 2,3 An intriguing relationship 

between birth time and prevalence of celiac 

disease also suggests the influence of other environmental 

factors, such as infections. 4 

Epidemiology 

The estimated prevalence of celiac disease varies 

according to the method of defining the condition. 

Earlier investigations that included only florid 

cases of celiac disease with overt gastrointestinal 

manifestations found an overall low but highly 

variable incidence throughout several European 

countries. With the availability of tests for malab- 

sorption and of the pediatric peroral biopsy techniques, 

an increased incidence of celiac disease, to 

about 1:500, was reported in studies in Europe. 

Subsequently, sensitive serological tests have 

made it possible also to detect minimally symptomatic 

or even asymptomatic cases with the typical 

mucosal changes (thus fulfilling the definition of 

celiac disease). When these types of tool, and in 

particular the anti-endomysium antibodies, are 

utilized for screening studies, the prevalence of 

celiac disease soars to the current estimates of 

approximately 1:130 to 1:300 of the general 

European population. 5–8 

Until recently it was believed that celiac disease 

was a rare disorder in the USA, and rates of prevalence 

of lower than 1:10000 were often quoted. 

However, a recent multicenter investigation 

throughout the USA that screened more than 

13000 individuals with anti-endomysium antibodies 

and/or human tissue transglutaminase antibodies, 

found a prevalence of 1:133, 9 i.e. identical 

to that found in Europe. It is clear, however, that 

the current rates of diagnosis of celiac disease in 

the USA are well below those in Europe, perhaps 

owing to an overall later onset of the disease and 

more frequent extraintestinal manifestations. This, 

in turn, may be linked to various factors, with the 

more prolonged and more widespread use of breast 

feeding being a likely cause of postponing the 

onset of celiac disease. 2 The prevalence of celiac 

disease in other areas of the world has been less 

studied. Data are, however, available from Latin 

America, North Africa, the Near and Middle East 

and Northwest India: in all these areas celiac 

disease has been reported, and where prevalence 

data were sought, they do not differ significantly 

from those indicated above. In some ethnicities, 

such as in the Saharawi population, celiac disease 

has been found in as many as 5% of the general 

population. 10 Thus, it is fair to assume that celiac 

435

436 


disease constitutes one of the most common genetically 

induced chronic diseases. However, celiac 

disease is considered extremely rare or non-existing 

in people with African, Chinese or Japanese 

descent. 


Celiac disease is an autoimmune disorder. The 

initial event in the pathogenesis of the celiac 

lesion is thought to be abnormal permeability, 

allowing the entry of gliadin peptides not entirely 

degraded by the intraluminal and brush-border 

bound-peptidases. Interestingly, the initial ‘theory’ 

on celiac disease pathogenesis was the enzymatic 

one: for many years, research focused on ‘the 

missing enzyme’, unable properly to digest gluten 

and thus creating an indigestible, toxic fragment. 

However, there is no missing peptidase in celiac 

disease; simply, the most toxic amongst the fractions 

of gliadin that have been shown to be 

harmful to the celiac mucosa are remarkably resistant 

to digestion by gastric, pancreatic and 

mucosa-associated enzymes. 11 Under normal 

circumstances, the intestinal epithelium would act 

as a barrier to the passage of such macromolecules, 

but in celiac disease, a well-documented loosening 

of the intestinal tight junctions, 12 possibly even 

triggered by gliadin itself, 13 leads to increased 

permeability to macromolecules. The role of 

altered expression of zonulin, a novel human 

protein that induces tight junction disassembly 

and a subsequent increase in intestinal permeability, 

has been suggested. Zonulin expression was 

found to be elevated in intestinal tissues from 

patients with florid celiac disease. 14 

There are two pathways involved in the pathogenesis 

of celiac disease: an early one, involving 

mainly the innate immune system; and a subsequent 

one, involving T cells. Soon after reaching 

the serosal side of the intestinal epithelium, the 

toxic gliadin peptides elicit an early response that 

causes crucial modifications of the mucosal 

microenvironment that precede and prime the 

subsequent involvement of the pathogenic T cells. 

A recent elegant study by Maiuri et al 15 brings 

important new information on this early response, 

by showing that a non-immunodominant gliadin 

fragment can activate the innate immune system, 

affecting the in situ T-cell recognition of dominant 

gliadin epitopes. Although more than 50 epitopes 

have been identified, the dominant α-gliadin T-cell 

epitope appears to be a single tissue transglutaminase-modified 

peptide. 16 

During the first phase, there is a marked increase 

of HLA-DR expression on both the epithelium and 

the adjacent lamina propria macrophages; this is 

followed by overexpression of intercellular adhesion 

molecule 1 (ICAM-1). Finally, CD8 + T cells 

invaded epithelial cells (intraepithelial lymphocytes). 

About 95% of all celiac patients belong to the DR3 

(or DR5/DR7 heterozygous) genotype and express 

the DQ2 α,β-heterodimer, encoded by DQA1*0501/ 

DQB1*0201, while almost all of the remaining 5% 

are DR4 and show the DQ8 α,β-heterodimer, encoded 

by DQA1*0301/DQB1*0302. This strong 

association implies that the adaptive branch of the 

immune system, and in particular CD4 + T 

lymphocytes, must play a crucial role in the pathogenesis. 

In fact, DQ2 and DQ8 molecules are 

located on the surface of antigen-presenting cells 

and bind peptides to be presented to CD4 + T 

lymphocytes. The DQ2 or DQ8 molecules 

expressed by the antigen-presenting cells (mostly 

macrophages) possess unique peptide-binding 

properties. They typically bind peptides of 12–20 

amino acid residues, with a core region of nine 

amino acids being bound to the peptide-binding 

groove on the HLA class-II molecule via interactions 

between side chains of amino acids and 

pockets of the binding groove. The autoantigen in 

celiac disease, a major target of all autoantibodies 

such as anti-endomysium and anti-reticulin, has 

been found to be the ubiquitous enzyme tissue 

transglutaminase. This enzyme, among other functions, 

selectively converts glutamine residues 

within gluten to glutamic acid. Such deamidation 

increases the negative charges on the gliadin 

peptides, 17 thus resulting in a strong enhancement 

of DQ binding and T-cell recognition. 

From a morphological point of view, small-bowel 

mucosal damage occurs as a result of gradual 

changes from normal mucosa to overt mucosal 

atrophy with crypt hyperplasia. It is crucial to 

understand that these changes occur in a progressive 

manner, so that the ‘flat’ mucosa, for a long 

time thought to be the necessary key finding in 

celiac disease, is only the last stage in a continuum 

of morphological changes. At lest three degrees of

change are recognized, as classically described by 

Marsh. 18 The infiltrative (type 1) lesion, seen in 

the latent phase, is characterized by morphologically 

normal mucosa and is not usually associated 

with gastrointestinal symptoms. Initial changes 

seen include an increase in the number of intraepithelial 

lymphocytes, followed by infiltration of 

the lamina propria with plasma cells and lymphocytes. 

The hyperplastic (type 2) lesion is similar to 

type 1, but with elongation of crypts, owing to a 

marked increase in undifferentiated crypt cells. 

The destructive (type 3) lesion is synonymous 

with villous atrophy, the original lesion described 

in celiac disease. 

The mechanisms leading to such changes have 

been the matter of extensive research in past years, 

and are currently still largely obscure. Several 

hypotheses coexist, each supported by experimental 

evidence. The ultimate agent responsible for 


villous flattening appears to be the enterocyte 

expression of FAS (the prototype of the ‘death 

receptor’) and apoptosis. Indeed, the element that 

differentiates patchy lesions from areas with 

normal histology is the specific lack of expression 

of FAS in morphologically normal mucosa. 19 It is 

also thought 20 that interleukin (IL)-15 may be 

involved in both the proliferating and the atrophic 

epithelial phases of celiac disease. In an organ 

culture model, IL-15 was in fact able to induce 

proliferation in crypts and FAS expression in enterocytes. 

In the active phase of celiac disease, a 

specific increase of intraepithelial lymphocytes 

expressing CD94 has been demonstrated, 21 possibly 

induced by IL-15. In essence, it would appear 

that intraepithelial lymphocytes migrate into the 

epithelium to induce apoptosis of the enterocytes. 

A scheme of the main events currently thought to 

occur in the mucosa of celiac patients is shown in 

Figure 27.1. 

Figure 27.1 Scheme of the epithelial damage in celiac disease. After gluten is digested into gliadin peptides, they enter 

through an abnormally increased intestinal permeability and reach the serosal side, where they interact with tissue transglutaminase 

(tTG). Among several effects of this interaction is the deamidation of such peptides, a process that strongly 

enhances their affinity for the HLA-DQ2 or DQ8 heterodimer expressed at the surface of the antigen-presenting cell (APC). 

The peptide is thus presented to the T lymphocyte. This initiates a chain of events, including release of toxic lymphokines 

such as interleukin (IL)-2 and IL-15 that have a direct damaging effect on the epithelium. Interaction with B lymphocytes 

also leads (by unclear mechanisms) to the production of antibodies against the enzyme tTG (utilized in the diagnostic 

process). The reduced activation of the epithelium-protective peptide transforming growth factor (TGF)-β further contributes 

to the damage of the epithelium.

438 


Clinical presentations 

One of the most important advances in the past 

decade has been the understanding that, although 

characterized by intestinal damage, celiac disease 

may present with signs and symptoms not necessarily 

related to the gastrointestinal tract. 

Moreover, it may well remain asymptomatic, or 

oligosymptomatic, for many years or indeed for 

life. 

Thus, we have come to distinguish four forms of 

celiac disease: 

(1) Typical; 

(2) Atypical (or more exactly ‘extraintestinal’); 

(3) Silent; 

(4) Latent. 

Table 27.1 reports the corresponding definitions, 

and Figure 27.2 illustrates the so-called ‘celiac 

iceberg’ that depicts the relation between HLA 

status, duodenal morphology and clinical expression 

in these different forms. Interestingly, there is 

evidence from many epidemiological investigations 

that the less clinically evident conditions 

(silent, latent and oligosymptomatic forms) are 

much more common that the clinically overt ones. 

Genetic 

susceptibility 

DR3-DQ2 

DR5/7-DQ2 

DR4-DQ8 

Clinically overt celiac disease 

Silent celiac disease 

Potential celiac disease 

Healthy individuals 

Figure 27.2 The ‘celiac iceberg’. See text for details. 

Table 27.1 Definitions of the various forms 

of celiac disease 

Typical 

Gastrointestinal signs/symptoms predominate: 

diarrhea 

vomiting 

failure to thrive 

anorexia 

constipation 

recurrent abdominal pain 

Atypical or extraintestinal 

Gastrointestinal signs/symptoms are minimal or 

absent. Most common signs/symptoms are: 

fatigue 

malaise 

anemia 

Silent 

No signs/symptoms. Gluten-dependent duodenal 

mucosal changes consistent with celiac disease 

Latent 

No signs/symptoms. Duodenal mucosa normal. 

Gluten-dependent changes with or without 

symptoms to appear later in time 

Manifest 

mucosal 

lesion 

Normal 

mucosa

It should be noted that the factors ultimately 

responsible in any single individual for the expressivity 

of the disease (i.e. developing typical vs. 

extraintestinal vs. silent, etc.) are not known. It is, 

however, known that age influences the prevalence 

of the various forms, as schematically indicated 

in Figure 27.3. 

The typical form of celiac disease presents with 

gastrointestinal symptoms typically between 6 and 

24 months of age. Symptoms begin at various time 

intervals after the introduction of gluten in the 

diet, also depending on its amount and on other 

environmental factors such as the concomitant 

presence of breast feeding, occurrence of viral 

enteritis, etc. Affected infants have poor appetite, 

chronic diarrhea, abdominal distension, muscle 

wasting and failure to thrive. Vomiting is also 

common. As spontaneous avoidance of glutencontaining 

foods does not occur, symptoms may 

progress to serious malnutrition, even cachexia, if 

diagnosis is delayed. Behavioral changes are also 

often found: celiac infants and young children 

become less talkative, more irritable, avoid 

company and are sad. In the most severely affected 

infants, the clinical picture of the so-called ‘celiac 

crisis’ may develop. This acute syndrome, now 

rarely seen, is characterized by explosive watery 

100 

90 

80 

70 

60 

50 

40 

30 

20 

10 

0 

Atypical or extraintestinal celiac disease 439 

diarrhea often followed by no passage of stools, 

impressive abdominal distension, dehydration, 

hypotension and lethargy. This severe picture is 

accompanied by profound electrolyte abnormalities 

including dangerously low potassium levels. 

Atypical or extraintestinal celiac 

disease 

In recent years an increasing number of patients 

have been diagnosed without typical gastrointestinal 

manifestations at an older age. 22,23 It is 

currently believed that almost 50% of patients 

with newly diagnosed celiac disease, and up to 

two-thirds of the adults, do not present with 

gastrointestinal symptoms and have either atypical 

or silent celiac disease. Table 27.2 reports the main 

presentations of ‘atypical’ or ‘extraintestinal’ celiac 

disease. 

Dermatitis herpetiformis 

1–2 2–5 5–12 12–18 >18 

Age (years) 

This variant of celiac disease presents with a 

blistering skin rash involving elbows, knees and 

buttocks associated with dermal granular 

Diarrhea 

Vomiting 

Failure to 

thrive; 

constipation 

Irritability 

Short stature 

Anemia 

Fatigue 

Minor GI symptoms 

Others 

Figure 27.3 Celiac disease presentations vary with age. Most gastrointestinal (GI) signs and symptoms are more common 

in early years, while anemia, fatigue and minor GI symptoms predominate later in life.

440 


Table 27.2 Main presentations of so-called 

‘atypical’ (or ‘extraintestinal’) celiac disease 

Dermatitis herpetiformis 

Permanent enamel hypoplasia 

Iron-deficient anemia resistant to oral iron intake 

Short stature, delayed puberty 

Chronic hepatitis with hypertransaminasemia 

Primary biliary cirrhosis 

Arthritis 

Osteopenia/osteoporosis 

Epilepsy with occipital calcifications 

Primary ataxia, white-matter focal lesions 

Psychiatric disorders 

Infertility of women 

immunoglobulin (Ig) A deposits. Rash as well as 

mucosal morphology improve on a gluten-free 

diet. 24 Previously considered a skin disease occurring 

often concomitantly with celiac disease, but 

overall a rare occurrence, it is now thought to be a 

common although often unrecognized problem in 

celiac patients. 25 

Dental enamel hypoplasia 

Dental enamel defects may be the only presenting 

manifestation of celiac disease. 26 These patients 

may have no or minimal gastrointestinal symptoms. 

Iron-deficiency anemia 

Iron-deficiency anemia, resistant to oral iron 

supplementation, has been found to be the most 

common extraintestinal manifestation of celiac 

disease in some studies, and often its primary clinical 

manifestation. 23,27 In one study 5% of all 

patients with anemia had celiac disease, and the 

prevalence rose to 8.5% when only patients with 

microcytic anemia resistant to iron therapy were 

considered. 28 Recently, screening with serology for 

celiac disease a large number of adult patients who 

were found to have either folate or iron deficiency 

(in the absence of gastrointestinal manifestations) 

detected 11% positive. 29 In spite of these well- 

known data, general screening of this type of 

patient is still rarely conducted. 

Short stature and delayed puberty 

Short stature may be the only manifestation of 

celiac disease. 30 As many as 8–10% of children 

with ‘idiopathic’ short stature may have celiac 

disease that can be detected on serologic testing. 31 

Adolescents with untreated celiac disease may 

have delayed onset of menarche. 32 

Chronic hepatitis and hypertransaminasemia 

Elevated transaminase levels are a frequent finding 

in untreated patients with celiac disease. In the 

majority of cases liver enzymes normalize on a 

gluten-free diet. 33 As many as 9% of patients with 

elevated transaminase levels of unclear etiology 

may have silent celiac disease. 34 Liver biopsies in 

these patients showed non-specific reactive 

hepatitis. Transaminases returned to normal on a 

gluten-free diet. Very recently, celiac disease has 

been described as causing severe liver disease, 

indeed hepatic failure, that was further shown to 

be responsive to a gluten-free diet. 35 

Arthritis and arthralgia 

Arthritis can be a common extraintestinal manifestation 

in adults with celiac disease including 

those on a gluten-free diet. 36 Of children with juvenile 

chronic arthritis, 2–3% may have celiac 

disease. 37 

Osteopenia/osteoporosis 

Patients with celiac disease are at high risk for 

developing low bone mineral density and osteoporosis. 

38,39 This has been found even for asymptomatic 

celiac disease patients detected at screening, 

40 whose reduced bone mineral density 

improved on a gluten-free diet. As a result of this 

condition, celiac disease patients are known to 

have an increased incidence of fractures. 41 The 

British Society of Gastroenterology recommended 

measuring bone mineral density in all patients 

with celiac disease. 42 Recently however, a survey 

conducted in the UK in 244 adult patients and 169

controls showed no statistically increased prevalence 

of fractures, and concluded that screening 

for bone mineral density in all celiac patients may 

not be warranted. 43 Thus, this issue is still open. 

Bone mineral density improves in the majority of 

patients on a gluten-free diet. 44–46 The pathogenesis 

of osteoporosis is complex, and only partially 

understood. It seems clear that poor absorption of 

calcium and/or vitamin D is not the most important 

factor. Recently, some evidence has been 

provided that an autoimmune aggression of the 

bone matrix may take place in celiac disease. 47 

Neurological problems 

Celiac disease can be the underlying cause of idiopathic 

cerebellar ataxia. 48 Celiac disease may also 

be associated with occipital calcifications and 

intractable epilepsy. These patients can be resistant 

to anti-seizure medicines but can benefit from 

a gluten-free diet if started soon after the onset of 

seizures. 49 Interestingly, a new neurological 

presentation of celiac disease has recently been 

described: focal brain white-matter lesions leading 

to multiple neurological manifestations such as 

seizures, muscle hypotonia and mild ataxia. 50 

Psychiatric disorders 

Although in recent years a large number of behavioral 

problems and disorders, such as autism, 

attention deficit hyperactivity disorder, etc., have 

been thought to be caused by celiac disease, there 

is no evidence to date that this is the case. 51 Celiac 

disease nevertheless can certainly present with 

Associated diseases 441 

some psychiatric disorders, such as depression 52 

and anxiety. 53,54 These conditions can be severe, 

but will usually respond to a gluten-free diet. 

Infertility 

Celiac disease may be responsible for unexplained 

infertility in women. 55 Ciacci et al 56 reported that 

the relative risk of abortion in women affected by 

celiac disease was 8.9 times higher than in healthy 

subjects, and that a gluten-free diet reduced the 

relative risk of abortion. Of interest, a recent study 

showed that not only fetuses from celiac mothers, 

but also those from celiac fathers suffered adverse 

effects in pregnancy, resulting in lower birth 

weight and perhaps shorter duration of pregnancy. 

57 

Associated diseases 

In addition to being responsible for various 

presentations, as described above, celiac disease is 

also known to be more commonly associated with 

a number of other diseases. Although the mechanisms 

of such links are still largely obscure, it is 

important to be aware of such associations in order 

to detect celiac disease as early as possible. 

Table 27.3 lists the main medical disorders that are 

associated with celiac disease. It is evident that 

many disorders are also of the autoimmune type. 

The association of celiac disease with autoimmune 

conditions is well established. 58 Recently, even 

autoimmune myocarditis was added to the list of 

such disorders. 59 An important multicenter study 

Table 27.3 Conditions associated with an increased prevalence of celiac disease 

Condition Approximate prevalence of celiac disease (%) 

Insulin-dependent diabetes mellitus 6% 

Thyroiditis 4% 

Sjögren’s syndrome and other connective tissue diseases 5% 

Primary biliary cirrhosis 3% 

Down’s syndrome 12% 

Williams’ syndrome 6% 

Turner’s syndrome 6% 

First-degree relatives of celiac patients 8–10%

442 


established a strong positive correlation between 

age at diagnosis of celiac disease and prevalence of 

autoimmune disorders such as type 1 diabetes, 

thyroiditis and alopecia, 60 thus suggesting that it is 

indeed the presence of celiac disease that acts as a 

trigger for the development of other autoimmune 

conditions. 61 

Type 1 (insulin-dependent) diabetes 

Up to 8% of patients with type-1 or insulin-dependent 

diabetes mellitus have been found to have 

typical features of celiac disease on duodenal 

biopsy. However, it is thought that the ‘real’ percentage 

is higher, as studies of such patients in serial 

screening over a period of years have documented 

that many individuals who initially had negative 

serological tests eventually developed positive tests 

and characteristic intestinal changes. 62 Typically 

(90% of cases), diagnosis of diabetes precedes by 

years that of celiac disease, most commonly 

presenting with mild to only moderate gastrointestinal 

symptoms. 63 As some of these symptoms are 

also seen in patients with diabetes (e.g. bloating or 

diarrhea), the diagnosis of celiac disease may be 

missed, unless screening is performed. Laboratory 

abnormalities such as anemia, and iron and folate 

deficiency are also common. 

It is still debated whether or not diabetic individuals 

found to be celiacs at screening (i.e. essentially 

asymptomatic) need to be put on a gluten-free diet. 

So far there is no convincing evidence that the diet 

has any obvious effect on diabetes. Indeed, the same 

considerations apply to all of the other associated 

autoimmune conditions. However, the following 

two considerations seem to suggest that adherence 

to a gluten-free diet should be recommended. First, 

a gluten-free diet has been shown in some cases to 

help improve glycemic control and improve 

gastrointestinal symptoms in patients with both 

conditions. Second, it can be argued that complications 

of untreated celiac disease known to be 

prevented by adherence to gluten-free diet (including 

osteopenia, infertility and malignancy – all 

documented occurrences in diabetic individuals) 

may be prevented by the diet in asymptomatic 

celiacs. As a consequence, the case for screening a 

type 1 diabetic for celiac disease seems well 

founded. 

Down’s syndrome 

Perhaps the best documented and most widely 

reported association of celiac disease with a nonautoimmune 

disorder is that with Down’s 

syndrome. The prevalence of Down’s syndrome in 

celiac disease, as assessed by screening methods, 

has been found to be between 5 and 12% in studies 

from both Europe 64–66 and more recently also 

North America. 9,67,68 Unlike patients with type-1 

diabetes, the majority with Down’s syndrome and 

celiac disease have other gastrointestinal symptoms, 

such as abdominal bloating, intermittent 

diarrhea, anorexia and failure to thrive. However, 

in a large multicenter study, it was found that 

about one-third of all Down’s syndrome patients 

with celiac disease had no gastrointestinal symptoms; 

66 the patients with celiac disease as a group, 

more commonly than their counterparts, had 

anemia, low serum iron and calcium, and a 

tendency to be mildly stunted in height and 

weight. 66 It seems highly desirable that patients 

with Down’s syndrome be screened for celiac 

disease and, whenever found positive, they should 

begin the gluten-free diet. As celiac disease may 

start at any age, patients with Down’s syndrome 

who test negative for serological markers (see 

below) would have to be re-tested again and again. 

To avoid this, since celiac disease occurs only in 

specific HLA haplotypes (see Epidemiology, 

p.435), an algorithm based on first determining the 

HLA haplotypes (thus leaving out of the re-screening 

process all those with the HLA haplotypes 

inconsistent with celiac disease) has been 

proposed. 69 An analogous strategy might be 

applied to screen for celiac disease patients with 

the rarer Williams’ syndrome, where an increased 

incidence of celiac disease has been reported. 70 

Complications 

Untreated, celiac disease can lead to a number of 

complications. Some, such as chronic liver 

disease, osteopenia/osteoporosis, infertility or 

psychiatric disorders, have been discussed under 

clinical presentations. Other important complications 

include hyposplenism, non-responsive celiac 

disease (including refractory sprue) and malignancy.

Hyposplenism 

Often seen in older patients, less commonly in 

children, this condition is detected by the presence 

of Howell–Jolly bodies and thrombocytosis 71 

and confirmed by imaging techniques. 

Non-responsive celiac disease 

Uncommonly, patients who have been diagnosed 

with celiac disease either fail to respond to the 

diet, continuing to present the same symptoms 

and signs, or they soon relapse, after a brief apparent 

improvement. This condition can be defined as 

‘non-responsive celiac disease’ with initial or 

subsequent failure of what appears to be a strict 

gluten-free diet to improve symptoms and/or to 

restore normal intestinal architecture and function 

in patients who have celiac-like enteropathy. This 

syndrome, which includes true refractory sprue, 

can be due to a number of causes, which are 

reported in Table 27.4. 

It should be stressed that, in any population of 

celiacs reported to fail to respond to a gluten-free 

diet, whether pediatric or adult, by far the most 

common cause remains the continued ingestion of 

gluten, often inadvertent. Thus, a meticulous 

search for hidden sources of gluten is the recommended 

first-line investigative approach. 

Table 27.4 Main causes of apparently nonresponsive 

celiac disease (‘refractory sprue’) 

Continued ingestion of gluten 

Incorrect diagnosis, e.g. 


autoimmune enteropathy 

eosinophilic gastroenteritis 

giardiasis 

cow’s milk protein allergic enteropathy 

Presence of a concomitant food allergy 

Lactose intolerance 

secondary to reduced absorptive surface 

(transient) 

adult-type lactase deficiency (permanent) 


Pancreatic insufficiency 


Second, an erroneous diagnosis of celiac disease is 

to be suspected. Particular care should be used in 

all cases to rule out other conditions that also 

present with morphological changes in the duodenal 

mucosa (see Table 27.4 for some examples). 

Among them, Crohn’s disease is a growing 

concern. 

Third, particularly in pediatric cases of celiac 

disease apparently unresponsive to a gluten-free 

diet, a concomitant food allergy, such as to milk or 

egg protein, must be sought. Indeed, the high 

prevalence of cow’s milk protein allergy makes the 

coincidental overlapping of the two conditions a 

not uncommon occurrence. 

Also, in cases with overt gastrointestinal symptoms, 

lactase deficiency is commonly present at 

diagnosis, as a result of the reduction of the 

absorptive area and hence of enough available 

enzymatic activity. Under these circumstances, it 

is not surprising that for some time a secondary 

lactose intolerance causes symptoms such as 

abdominal bloating, gassiness and diarrhea. 

Unless lactase deficiency is the result of the 

permanent loss of this enzymatic activity (‘adulttype’ 

or ‘late-onset’ lactase deficiency), the 

problem is self-limited and within a few weeks in 

the majority of patients lactose can be reintroduced 

in the diet. 

Irritable bowel syndrome, whose recently 

proposed association with celiac disease in a 

proportion of cases 72 has spurred much debate, is 

not uncommonly found in celiac disease patients, 

mostly teenagers or young adults. Clearly, this 

remains a diagnosis of exclusion, and needs to be 

supported by evidence of lack of any problem with 

adequate weight gain or maintenance. Once irritable 

bowel syndrome is diagnosed in a celiac 

patient, obviously the gluten-free diet must be 

maintained, and any of the currently available 

modalities of management can be utilized. 

Pancreatic insufficiency, found also in patients 

who do not have an underlying important condition 

of malabsorption and malnutrition, 73 has been 

shown in newly diagnosed celiac patients to cause 

failure of an adequate response to the diet, particularly 

in terms of growth, 74 and can of course be 

treated with adequate pancreatic enzyme supplementation. 

75

444 


Refractory sprue 

A condition of persistence of severe symptoms 

(typically malabsorption), high serum autoantibodies 

and enteropathy in spite of a strict glutenfree 

diet and in the documented absence of any of 

the disorders mentioned above, is rare, and has 

never been described in pediatric age. It is termed 

refractory sprue. In a multicenter study conducted 

in France, it has been shown in the majority of 

cases to be characterized by abnormal monoclonal 

intraepithelial T lymphocytes expressing a cytoplasmic 

CD3 chain (CD3c), lacking CD3 and CD8 

surface expression, and showing T cell receptor-γ 

gene rearrangements. 76 These authors suggested 

that refractory sprue associated with an aberrant 

clonal population of intraepithelial lymphocytes 

may be classified as cryptic enteropathy-associated 

T-cell lymphoma. The same group subsequently 

developed an immunohistochemical technique 

that would allow rapid identification of this 

condition. 77 Refractory sprue is a difficult condition 

to treat, and multiple aggressive immunosuppressive 

regimens have been suggested, 

ranging from cyclosporine to infliximab. 78–83 

Malignancy 

The development of malignancy, particularly 

lymphoma of the small bowel, but also carcinoma 

of any segment of the esophagus and stomach, is 

the most serious complication to affect patients 

with celiac disease. 84 The association has been 

known for about 40 years, yet many questions are 

still unanswered. In particular, it is unclear why 

only some celiac patients develop malignancy. 

Development of malignancy is the main explanation 

for the well-documented shorter life 

expectancy of celiac patients who are either 

untreated, or diagnosed very late in the course of 

their disease, especially when presenting severe 

malabsorption. 85 

Diagnosis 

The European Society of Paediatric 


(ESPGHAN) established the criteria for diagnosis 

of celiac disease more than 30 years ago. 86 These 

original criteria, which have been widely followed 

by both adult and pediatric gastroenterologists for 

more than two decades, stated that diagnosis of 

celiac disease would require: 

(1) The presence of compatible symptoms and 

demonstration of a structurally abnormal 

small-intestinal mucosa when taking a diet 

containing gluten; 

(2) A clear clinical response to a gluten-free diet; 

(3) Documentation of unequivocal improvement 

of the villous structure after having taken a 

gluten-free diet for 1 year; 

(4) Deterioration of the mucosa and reappearance 

of symptoms during challenge with 

gluten. 

With increasing availability of serological tests for 

diagnosis, and following a report of an Italian 

multicenter investigation in more than 3000 celiac 

children, 87 ESPGHAN in 1990 proposed new diagnostic 

criteria. According to them, the diagnosis of 

celiac disease can be established on a definitive 

basis when the characteristic changes of the 

duodenal mucosa are found in a child with signs 

and/or symptoms consistent with celiac disease, 

provided that a full and unequivocal clinical 

remission after withdrawal of gluten is seen, associated 

with the disappearance of circulating antibodies. 

These criteria are currently universally 

utilized, and it can be seen that, although the 

emerging role of serology testing was recognized 

and taken into crucial consideration, diagnosis 

still clearly relies on intestinal biopsy findings. 88 

The role of the serological markers of celiac 

disease will be discussed later, but it should be 

clear that they must be considered an important 

means of screening and of monitoring compliance, 

offering only supportive evidence for the diagnosis. 

89 

Duodenal biopsy 

Currently, most of the bioptic samples are obtained 

from the duodenal mucosa during endoscopy. 

Endoscopic changes described in untreated celiac 

patients include scalloping, a mosaic pattern and 

flattening or paucity of the folds. 90 However, these 

findings are not specific 91 and occur only infrequently 

in the pediatric age. Adequate biopsy 

specimens can be obtained at endoscopy or with a

suction biopsy tube. Specimens should be 

obtained from the distal duodenum. Obtaining 

multiple biopsies is crucial for a correct diagnosis. 

In fact, the old teaching that celiac disease results 

in a continuum of lesions has recently been proved 

incorrect. The typical flattening of villi can be 

patchy, with blunted villi juxtaposed to normal 

mucosa. 92 The diagnosis therefore can be easily 

missed if at least four or five bioptic samples are 

not obtained. Histological examination of involved 

areas confirms the loss of normal villous structure 

with severe shortening up to complete absence 

(flat mucosa) of the villi. The intestinal crypts are 

markedly elongated and hyperplastic. Unlike the 

well-differentiated, mature absorptive cells, the 

undifferentiated crypt cells are markedly increased 

in number in untreated celiac disease, and this 

accounts for the obvious lengthening of crypts. 

The cellularity of the lamina propria is increased 

and the thickness of the mucosa is overall also 

increased. The cellular infiltrate consists largely of 

plasma cells and lymphocytes. Another typical 

(but not pathognomonic) change that occurs in the 

small intestinal mucosa of untreated celiac 

patients is the increase in the number of intraepithelial 

lymphocytes, particularly T cells expressing 

the γδ receptors. 93 This change (Figure 27.4) is 

considered an early and subtle sign of celiac 

disease and, if supported by concordant serology 

and clinical findings, can be considered sufficient 

to finalize the diagnosis. Indeed, it was shown that 

these patients would benefit from a gluten-free 

diet. 94 Some patients may also have only minor 

morphometric changes on jejunal biopsies with 

changes in mean surface/volume ratio without 

gross histological abnormalities. 95,96 As it can be 

seen therefore, it is imperative that an experienced 

pathologist carefully review intestinal biopsies for 

intraepithelial lymphocytes and morphometric 

changes in a patient with positive celiac antibodies 

before labeling serology results as false positive. 

Furthermore, to complicate matters, some studies 

have demonstrated that patients with totally 

normal histology but positive celiac serology who 

are labeled as false positive may develop typical 

celiac morphological changes on follow-up. 97,98 

Thus, development of serum antibodies seems to 

precede, at least in some well-documented cases, 

that of the morphological lesions. For this reason, 

it appears wise to continue to follow up patients 

who have high levels of anti-endomysium or tissue 

Diagnosis 445 

transglutaminase antibodies, even with a normal 

mucosa, and to repeat the endoscopy if clinical 

signs or symptoms consistent with celiac disease 

appear. 

Serology 

Serologic testing for celiac disease has included 

testing for food protein-directed antibodies 

(antigliadin (AGA)) and for an autoantibody (antiendomysium). 

99 It should be recognized that, in 

spite of high potential in clinical settings, particularly 

for screening purposes, the sensitivity and 

specificity of serology have varied widely, in part 

because of the lack of standardized protocols and 

of reference sera. Inter-laboratory variations have 

been wide, particularly for AGA, as pointed out by 

Figure 27.4 Morphologically normal villus with 

increased intraepithelial lymphocytes. In the early stage of 

the changes induced by celiac disease, an otherwise 

normal villus can be seen to have an increased intraepithelial 

infiltration of lymphocytes.

446 


multicenter studies performed both in Europe 100 

and in the USA. 101 AGA have been widely utilized 

since the early 1980s, having soon become widely 

available and inexpensive. Two classes are 

currently measured: IgG and IgA. The former, even 

though considered of high sensitivity (85–98% in 

most large series from Europe), has been repeatedly 

shown to be extremely non-specific. Indeed, 

AGA-IgG can be found in about 30% of a control 

population, and thus their positive value is of little 

use. AGA-IgA, on the other hand, are known to be 

generally much more specific (95–100%), but are 

unfortunately also less sensitive (sensitivities 

reported range between 70 and 92%). The value of 

measuring AGA for screening purposes is therefore 

at best doubtful. However, this class of antibodies 

maintains its usefulness in monitoring the compliance 

to the gluten-free diet in an already established 

celiac patient, as it is known that AGA are 

more prone to reappear in the presence of even 

minimal dietary transgressions, where antiendomysium 

antibodies are less sensitive. 102 In 

practice, when screening a patient for celiac 

disease, one should always obtain total IgA, along 

with anti-endomysium antibodies or tissue transglutaminase 

antibodies (see below for anti-tissue 

transglutaminase antibodies). If a condition of 

total IgA deficiency is found (a condition affecting 

approximately 3% of celiac patients 103 ), then antiendomysium 

antibodies or tissue transglutaminase 

antibodies should be sought, as, in IgA-deficient 

subjects, IgG- and specifically IgG1-anti-endomysium 

or IgG-tissue transglutaminase antibodies 

become reliable indicators of celiac disease. 104 

The anti-endomysium antibodies are detected by 

assessing the immunofluorescence of sections of 

monkey esophageal or human umbilical cord 

smooth muscle on exposure to sera from patients 

being tested. Although the test relies on subjective 

operator assessment of fluorescence, its specificity 

in detecting untreated celiac disease is extremely 

high. A recent study conducted with strict criteria 

by the European working group on Serological 

Screening for Celiac Disease showed that antiendomysium 

antibodies had, among seven laboratories, 

a remarkable mean specificity of 99% 

(93.9–99.9%), while the mean sensitivity proved to 

be 90% (82.7–92.5%). 105 Also, the inter-laboratory 

reliability proved to be quite good for this test, 

unlike the poor reproducibility of AGA. This assay 

is relatively costly, and its utilization of monkey 

esophagus further limits its use for the screening of 

large populations. 

Tissue transglutaminase antibodies 

In 1997 Dieterich et al identified tissue transglutaminase 

as the autoantigen of celiac disease. 106 In a 

subsequent study by the same group, an enzymelinked 

immunosorbent assay (ELISA) for guineapig 

IgA tissue transglutaminase antibodies was 

found to be 98.1% sensitive and 94.7% specific in 

patients with biopsy-proved celiac disease. 107 

Since then, many studies have confirmed the high 

sensitivity and specificity of these antibodies in 

the diagnosis of celiac disease. Sensitivity and 

specificity have been subsequently further 

improved by utilizing the human antigen instead 

of the guinea pig antigen. 108–110 A simple noninvasive 

immunological dot blot assay based on 

recognition of recombinant human transglutaminase 

has also recently been proposed as a practical, 

reliable alternative to both the immunofluorescence-based 

anti-endomysium test and tissue 

transglutaminase ELISA for the diagnosis of celiac 

disease. 111 

In summary, even though currently anti-endomysium 

antibody tests can still be considered more 

specific, it is likely that serological (or whole 

blood) tests based on human tissue transglutaminase 

antibodies will become the gold standard for 

celiac disease screening in the very near future, 

eventually replacing the semiquantitative, 

observer-dependent, costly and time-consuming 

anti-endomysium antibody test. 

Currently, however, it seems that anti-tissue transglutaminase 

antibodies are less specific than antiendomysium 

antibodies for celiac disease. 112 

Treatment 

Total lifelong avoidance of gluten ingestion is the 

cornerstone treatment for celiac disease. Wheat, 

rye and barley are the grains containing toxic 

peptides. For a long time, oats were also considered 

toxic, and their elimination from the diet was 

recommended. However, during the past few years 

a growing body of scientific evidence obtained 

from in vitro studies as well as from clinical inves-

tigations, particularly in adults 113–115 but also 

recently in children, 116 allows us to conclude that 

oats are indeed totally safe. This makes sense 

based on the genetics of the grains, showing that 

oats are genetically entirely unrelated to the group 

of wheat, rye and barley. 117 Indeed, a recent in 

vitro study looking at the specificity of tissue transglutaminase 

further supported the lack of toxicity 

of oats. 118 However, because of uncontrolled 

harvesting and milling procedures, cross-contamination 

of oats with gluten is still a concern, which 

will have to be addressed in the context of a more 

general policy concerning labeling of food certified 

to be gluten-free. 

Often in the initial phases of dietary treatment, 

lactose is also eliminated. This has its basis in the 

lactase deficiency that is thought to accompany 

the flat mucosa. 119 However, it should be pointed 

out that, as we have seen, today most new celiacs 

are diagnosed in the absence of overt malabsorptive 

symptoms, and in these circumstances clinically 

significant lactose malabsorption or intolerance 

is rarely seen. Furthermore, even in cases 

with obvious malabsorption, the recovery of 

lactase activity is typically fast, so that the use of a 

lactose-free diet even in these cases must be on a 

short-term basis only. The possibility of an association 

between celiac disease and milk protein 

allergy has been repeatedly raised in the past, but 

it is now clear that the two conditions may simply 

coexist as a result of a statistical association, so 

that again there is no need to recommend avoidance 

of ‘dairy products’. 

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28 

Introduction 

Protein-losing enteropathy 

Jorge Amil Dias and Eunice Trindade 

A number of pathological conditions cause excessive 

leakage of protein into the gastrointestinal 

tract. This common mechanism has been called 

protein-losing enteropathy (PLE) although the site 

of protein leakage may also be located in the 

stomach. 

The major clinical features of these diseases are 

edema and hypoalbuminemia, as the intestinal 

loss outweighs protein synthesis, therefore causing 

reduced oncotic pressure in the vascular space. 

This mechanism is different from maldigestion or 

malabsorption where nutrients escape intestinal 

absorption, owing to enzyme deficiencies, or 

mucosal lesions. 

Historically, the pioneer work of Albright et al 1 in 

1949 showed that hypoalbuminemia in PLE was 

caused by excess catabolism of intravenous 

albumin rather than abnormal synthesis. Later, 

Citrin et al 2 demonstrated that the gastrointestinal 

tract was the site of the protein loss. Usually, the 

digestive tract (stomach or intestine) is the sole 

source of protein loss in PLE, although nephrotic 

syndrome may coexist in some cases. 3 

Albumin is a water-soluble molecule with molecular 

weight of 60000Da. This protein acts as the 

major component of plasma oncotic pressure and 

is also a transporter for various substances, such as 

bilirubin, ions, metals or hormones. 

Synthesis of albumin occurs in the liver at a rate of 

approximately 150mg/kg per day (higher in the 

first year of life: 180–300mg/kg per day). In the 

absence of liver disease, synthesis depends mostly 

on protein intake, although hormones such as 

cortisol, thyroid hormone and insulin, also affect 

the rate of synthesis. Approximately one-third of 

the body albumin pool circulates in the intravas- 

cular space. In health, less than 10% of daily 

albumin degradation occurs through the gastrointestinal 

tract. However, in conditions causing PLE 

there is a marked leakage of protein into the bowel 

lumen, without an equivalent increase in hepatic 

synthesis. Reasons for increased loss of protein 

include lymphatic obstruction, mucosal inflammation 

and ulceration. When the loss of protein 

exceeds the limited hepatic adaptation there is a 

decrease in the vascular pool that leads to hypoalbuminemia 

and edema. 

The loss of protein in the gastrointestinal tract is 

independent of molecular weight and includes 

albumin, immunoglobulins and ceruloplasmin; 

this is different from abnormal losses from the 

kidneys, where molecular weight determines 

which proteins are lost. In fact, in PLE there are 

also losses of minerals, such as iron, copper and 

calcium, of lipids and even of cells, such as 

lymphocytes. However, most of these proteins are 

readily digested in the gut and the resulting amino 

acids are reabsorbed by the intact segments of 

bowel and reused for protein synthesis. The 

plasma levels of different proteins in PLE depend 

on the adaptative capacity to increase synthesis. 

As mentioned before, there is little response from 

the liver in albumin production and the same 

occurs with IgG, IgM or IgA. On the other hand, 

the plasma levels of proteins with increased 

turnover, such as IgE or insulin, may be sustained 

despite intestinal loss. 

In conditions affecting the lymphatic system, such 

as intestinal lymphangiectasia, there may also be 

lymphocyte losses leading to lymphopenia. 4–6 

Signs and symptoms of conditions associated with 

PLE may reflect the cause for hypoproteinemia. 

However, the common link among these diseases 

is the loss of proteins causing hypoalbuminemia 

and edema. As mentioned before, albumin is the 

451

452 


major element for oncotic pressure but there may 

be loss of other proteins. Although decrease in 

immunoglobulins, transferrin or ceruloplasmin 

may be documented by biochemical assay, rarely 

are there clinical manifestations from these abnormalities. 

If lymphatic obstruction is the major 

cause of PLE then malabsorption of fat may occur. 


Assessing protein loss from the gastrointestinal 

tract is not easy, because proteins secreted into the 

gut are readily degraded and reabsorbed. 

Therefore, alternative methods have been 

designed. One approach makes use of proteins 

tagged with radioactive labels injected intravenously. 

Several markers were used in the past 

(iodine, 7,8 chromium, 9,10 iron 11 and niobium 12 ) 

bound to several proteins, usually albumin, but 

also dextran or ceruloplasmin. Assessment of 

protein loss can be made by plasma clearance or 

stool content of the marker. However, these studies 

apart from demanding several days’ collections of 

stool or blood, had other drawbacks. It was 

required that the marker should not alter the metabolic 

pathway of the protein, that it should not be 

reabsorbed from the intestine and that it should 

not be excreted by the glands into the digestive 

fluids. The radiolabels used fulfill most of these 

aims, but calculations of catabolic rate are 

complex and stools free of urine must be collected 

for several days. These requirements, and the 

questionable use of radioactive elements, made 

these methods unpopular in pediatrics. 

The other approach to diagnosis made use of a 

protein resistant to digestive proteolysis. Crossley 

and Elliott 13 suggested α1-antitrypsin for this 

purpose. This protein has a molecular weight of 

50000Da, similar to albumin, and is resistant to 

proteolysis, therefore fulfilling the required needs. 

Several studies compared this method with the 

radiolabel tests and confirmed that it gave reliable 

results. 14–16 However, α1-antitrypsin may be 

degraded in the stomach by acid, and therefore has 

limited value in the assessment of gastric losses. 

The method has been widely accepted for clinical 

purposes. The contamination of collected stools 

with urine is not a problem, as the protein is not 

eliminated in urine. For exact assessment of α1- 

antitrypsin enteric loss, 24–72h of stool collection 

may be required. Clearance is calculated by the 

formula: 

(fecal α1-antitryspin concentration)x(24-h stool volume) 

Clearance= 

(serum α1-antitryspin concentration) 

However, it has been proposed that random 

sample determination also gives reliable results for 

clinical use. 17,18 Magazzu et al also showed that 

stools may be heat-dried rather than lyophilized, 

with comparable results, thus adding further 

simplicity to the method. The normal value of α1antitrypsin 

is below 3–4mg/g dry stools. 14,17 In 

some conditions there may be overestimation of 

protein loss from the assessment of α1-antitrypsin: 

in normal newborns, α1-antitrypsin may be increased 

in stools probably owing to meconium 

clearance of the gut 19 ; gross bleeding into the 

gastrointestinal tract may lead to a measurable 

amount of the protein in the stools. 16 

If the protein exudation comes from abnormal 

lymphatics, as in intestinal lymphangiectasia, 

imaging techniques may help locate the lesion. 

Several methods, such as lymphangiography, 

contrast radiology and computed tomography (CT) 

have been used. This will be discussed below 

under specific conditions. 

Diseases causing protein-losing 

enteropathy 

The main causes are shown in Table 28.1. 

Diseases related to lymphatics 

Intestinal lymphangiectasia 

This disease affects males and females equally and 

may present from birth, although the mean age is 

11 years. Even prenatal diagnosis has been 

reported. 20 Most cases are sporadic. 

Several rare diseases and syndromes have associated 

dyplasia of lymphatics leading to PLE. These 

include nephrotic syndrome 3 and other rare conditions 

(Table 28.2). 21–23 Familial clustering suggests 

genetic etiology at least in some cases with early 

onset of manifestations. 8 

Patients have abnormally dilated lymphatics in the 

mucosa, submucosa or subserosa that cause

Table 28.1 Main causes of protein-losing 

enteropathy 

Related to lymphatics 

Primary 

intestinal lymphangiectasia 

Secondary 

cardiac disease 

constrictive pericarditis 

congestive heart failure 

cardiomyopathy 

post-Fontan procedure 

obstruction of lymphatics 

vena cava obstruction 

tuberculosis 

sarcoidosis 

radiation therapy 

retroperitoneal fibrosis or tumor 

Related to mucosa 

Gastroenteritis 



Parasitosis (e.g. Giardia) 




Langerhan’s histiocytosis 

Vasculitides 


Connective diseases 


Vena cava obstruction 

Related to defective cellular synthesis 

Deficiency of enterocyte heparan sulfate 

Congenital disorders of glycosylation 

leakage of lymphatic fluid and cells into the gut, 

thus causing PLE with hypoproteinemia, 

hypogammaglobulinemia and lymphopenia, especially 

depletion of CD4 T cells. 5 This may lead to 

abnormal delayed hypersensitivity skin tests or 

reduced allograft rejection tests, 4,24 but these 

patients do not appear to be more sensitive to 

infections. Hyposplenism, thymic hypoplasia 

and neutrophil dysfunction have also been 

reported. 25–27 

Signs and symptoms include edema that may be 

asymmetric, variable diarrhea and steatorrhea 

Diseases causing protein-losing enteropathy 453 

Table 28.2 Uncommon causes of proteinlosing 

enteropathy 

Noonan’s syndrome 21 

Congenital glaucoma 

Peliosis hepatis 

Charcot–Marie–Tooth syndrome 

Klippel–Trénaunay–Weber syndrome 

Hennekam syndrome 22 

Hypobetalipoproteinemia 23 

related to impaired fat absorption by abnormal 

lymphatics. Leakage of fluid into other body cavities 

may also cause chylous effusions such as 

ascites that may lead to intestinal adhesions and 

obstruction. Reversible blindness has been 

reported, due to macular edema. Tetany secondary 

to hypocalcemia can occur and is usually associated 

with severe steatorrhea. Growth restriction 

reflects the increased loss of protein and other 

elements. The presence of a lymphatic–venous 

anastomosis may also cause gastrointestinal bleeding. 

28 

Examination of patients may be unremarkable 

except for edema and malnutrition. The coexistence 

of hypoalbuminemia, edema, lymphopenia 

and steatorrhea may suggest the diagnosis. Tetany 

may also be present, related to hypocalcemia. Fatsoluble 

vitamins may be deficient. 

Demonstration of intestinal protein loss can be 

made from increased α1-antitrypsin in stools. A 

number of imaging techniques have been used to 

demonstrate the effects of abnormal intestinal 

lymphatics or to show localization of segmental 

disease. Lymphangiography may show abnormal 

lymphatics, absence of the thoracic duct or 

drainage of contrast into the bowel, but this procedure 

is difficult to perform in children. Contrast 

radiology with barium may reveal thickening of 

intestinal folds, or flocculation of barium due to 

intestinal hypersecretion. The use of radiolabeled 

Tc-99m incorporated in to a microcolloid may 

show localized accumulation of the marker on 

scintigraphy. CT may also show signs suggestive of 

intestinal lesions causing PLE. 29–31 The use of CT 

may even allow identification of segmental 

lymphangiectasia, as recently reported. 32

454 


When the proximal intestine is involved, 

endoscopy may show an abnormal mucosal 

pattern with scattered white plaques (Figure 

28.1a). Diagnosis may then be confirmed from 

biopsy specimens showing subepithelial dilated 

lacteals (Figure 28.1b). Although a small intestinal 

biopsy would reveal these typical features, there 

are some limitations: the use of a biopsy capsule 

may miss the lesion, owing to its focal distribution, 

making endoscopic guidance preferable when the 

diagnosis is suspected; and normal histology does 

not preclude the diagnosis in patients on a low-fat 

diet or with deeper lesions not available to superficial 

mucosal biopsy. 

Treatment When disease is confined to a 

segment of intestine, surgery may be curative by 

resecting the affected part or allowing anastomosis 

of abnormal lymphatics to the circulatory system. 

Unfortunately, surgical treatment is not available 

(a) (b) 

for the majority of patients and reducing the 

lymphatic flow may decrease the leak into the gut. 

This may be achieved by reducing the intake of 

long-chain fatty acids. Medium-chain triglycerides 

(6–10 atoms of carbon) are absorbed and passed 

directly into the portal vein and bypass the 

lymphatic system. Therefore, part of the dietary 

lipid may be given using medium-chain triglycerides 

as oil or in formulas. It must be kept in 

mind that medium-chain triglycerides do not 

contain essential fatty acids and some long-chain 

fatty acids must be ingested regularly. The diet 

should contain high protein to circumvent ongoing 

minor losses. 

Dietary treatment must be permanent and guided 

by clinical symptoms. As mentioned above, other 

losses must be born in mind, and supplementation 

with calcium and vitamins, both water-soluble and 

fat-soluble must be provided. Octreotide has 

Figure 28.1 Intestinal lymphangiectasia. (a) Endoscopic view of duodenum showing numerous dilated lymphatics within 

the mucosa. (b) Histology of the small intestine of the same patient with a dilated lymphatic along the villus axis and 

normal surface epithelium. (Courtesy of F. Pereira).

shown effects in reducing the thoracic duct lymph 

flow and fluid loss in the enteric vasculature. 33 

This effect has been used to treat patients with 

considerable success. 34 

In the rare occurrence of gastrointestinal bleeding, 

the beneficial effect of the low-fat diet may be 

enough to reduce the vascular pressure causing 

hemorrhage. 28 In adults antiplasmin therapy was 

reported in patients with persisting bleeding 35 but 

this has not been used in children. 

Protein-losing enteropathy secondary to 

increased lymphatic pressure 

PLE may arise from increased lymphatic pressure 

that causes leakage of fluid and protein into the 

bowel. This has been widely known after the 

Fontan operation for complex congenital cardiac 

disease. In this procedure the systemic venous 

circulation is directly connected to the pulmonary 

veins, bypassing the abnormal heart; the left 

ventricle is the only pumping mechanism for 

circulation. Therefore, there is an overall increase 

in venous pressure and lymphatic pressure 

causing congestion and leakage of fluid. PLE has 

been reported in 2.5–10% of patients. 36 The pathophysiology 

of PLE in this situation is not fully 

known, although mechanisms have been proposed, 

such as raised central venous pressure and 

increase in mesenteric vascular resistance. 37 A 

longer cardiopulmonary bypass time and single 

right ventricle anatomy may be risk factors. 38 

The first symptoms may occur weeks to years after 

the operation and severity is variable determining 

morbidity and mortality. 39 Common signs and 

symptoms are similar to other forms of PLE. 

Edema is the most frequent; half of affected 

patients have diarrhea and one-third also have 

steatorrhea. Investigations reveal hypoproteinemia, 

hypoalbuminemia, hypogammaglobulinemia, 

increased α1-antitrypsin and fat in stools. There 

may also be dilatation of intestinal lymphatics 

similar to intestinal lymphangiectasia. 8 Immunological 

alterations have also been described, 

although these may be quantitative rather than 

qualitative. 40 

The therapeutic strategy in affected patients 

depends on the severity of each case. Diuretics, 

albumin infusions and nutritional supplementa- 


tion with protein and medium-chain triglycerides 

may provide symptomatic relief. Conversion 

enzyme inhibitors, e.g. captopril, reduce afterload 

pressure and facilitate hemodynamic improvement. 

Stabilization of intestinal membranes with 

high doses of steroids 41,42 or high molecular 

heparin 43–45 showed improvement in protein loss. 

Various vascular surgical options including 

cardiac transplantation have also been used. 46,47 

Other cardiac and vascular diseases causing elevation 

of systemic pressure may lead to PLE: 

constrictive pericarditis, restrictive cardiomyopathy, 

congenital pulmonary stenosis, ventricular 

septal defect, tricuspid regurgitation in rheumatic 

disease 48 and vena cava obstruction. 49 

Protein-losing enteropathy related to the 

mucosa 

Diseases causing extensive lesions of the gastric or 

intestinal mucosa may damage the mucosal barrier 

and allow leakage of protein. Common intestinal 

infections such as rotavirus gastroenteritis, giardiasis 

or shigellosis usually cause mild protein 

loss that can be documented 50–52 but the magnitude 

of the loss is proportional to the severity of 

the mucosal lesion. Crohn’s disease also causes 

PLE although the level of stool α1-antitrypsin does 

not correlate with disease activity. 53,54 

Patients with untreated celiac disease also may 

have PLE. 55 Langerhans histiocytosis usually does 

not involve the intestine but in rare instances may 

cause severe lesions in the mucosa with considerable 

loss of albumin (Figure 28.2). 56,57 

In food allergy there may be involvement of the 

stomach, causing PLE. 58 In these patients there are 

the common features of increased protein loss – 

edema, microcytic anemia due to iron loss, hypoalbuminemia, 

hypogammaglobulinemia – plus 

eosinophilia. Digestive symptoms may be mild and 

particularly related to the ingestion of the offending 

foods. Other signs and symptoms of allergy, 

such as eczema, asthma and rhinitis, as well as a 

positive family history may help in directing the 

diagnosis. Gastric and intestinal biopsy may show 

an eosinophilic infiltrate of the lamina propria. 

Patients usually recover on a restricted diet, 

usually cow’s milk-free.

456 


Figure 28.2 Langerhan’s histiocytosis. Endoscopy of the 

duodenum revealing multiple mucosal erosions. 


Ménétrier’s disease is a particular form of gastropathy 

causing PLE. It is usually caused by 

cytomegalovirus infection, although there may be 

an underlying abnormality of regulation of gastric 

epithelial growth, as suggested by animal models 

and clinical evidence. 59,60 Most cases occur before 

10 years of age. Clinical manifestations include 

digestive symptoms – vomiting, abdominal pain 

and edema. Laboratory investigations show mild 

anemia and hypoalbuminemia without protein- 

(a) (b) 

uria. As mentioned above, the use of stool 

α1-antitrypsin to demonstrate digestive protein 

loss may not be used in this case because of the 

rapid inactivation in the acidic gastric environment. 

In this case it may be necessary to use radiolabeled 

proteins. Ultrasonographic and radiological 

patterns have been described to reveal the 

thickened gastric folds but endoscopy is the 

method of choice as it reveals abnormal inflamed 

folds covered with thick mucus and allows diagnostic 

biopsy (Figure 28.3). 

Vasculitides 

Among uncommon causes of PLE, syndromes due 

to vasculitic processes (vasculitides; see also 

Chapter 26) have been described. Systemic lupus 

erythematosus (SLE) involves various organs, but 

the digestive system is seldom involved. However, 

various cases have been reported starting in 

childhood. PLE may occur before the diagnosis of 

SLE or present years later. 61,62 The likely pathophysiology 

of PLE is probably immunological 

involving cytokines rather than mechanical 

disruption of lymphatics. 63,64 Clinical manifestations 

are similar to other forms of PLE, namely 

abdominal pain, diarrhea, edema and hypoalbuminemia. 

Diagnosis rests on demonstration of 

increased protein loss. Intestinal biopsy may show 

lymphangiectasia. Interestingly, these patients 

Figure 28.3 Ménétrier’s disease. (a) Endoscopic view of the stomach showing inflamed mucosa of thickened folds 

covered by a thick layer of viscous mucus. (b) Histology of the stomach of the same patient. There is marked elongation 

and tortuosity of the gastric pits with cystic dilatation of some glands. (Courtesy of F. Carneiro).

may respond to steroids without relapse after stopping 

treatment. In severe cases pulses of cyclophosphamide, 

65 plasmapheresis 66 and octreotide 67 

have been used. 

PLE has also been associated with 

Henoch–Schönlein purpura in as many as 1.3% of 

cases. 68,69 It may be underdiagnosed, especially in 

severe multivisceral cases. 

Protein-losing enteropathy related to defective 

cellular synthesis 

Recent advances in molecular biology have uncovered 

the etiology of many previously unclarified 

conditions and allowed reclassification of 

some diseases. 70 

The epithelial expression of sulfated glycosaminoglycans 

(GAGs) seems to be essential in the 

maintenance of albumin homeostasis. This expression 

may be compromised in inflammatory 

states. Congenital defects may cause absence of 

synthesis, 71 and congenital glycosylation defects 

may lead to mislocation of sulfated GAGs. 72 This 

group of diseases must also be considered in otherwise 

unexplained PLE, as the histology may be 

unspecific. 

Deficiency of enterocyte heparan sulfate 

Deficiency of enterocyte heparan sulfate is a rare 

cause of congenital severe PLE described by 

Murch et al71 in three patients with malabsorption, 

secretory diarrhea and normal intestinal histology. 

There was almost complete absence of sulfated 

GAGs in the basolateral membrane of enterocytes 

despite normal distribution in vascular cells and 

in the lamina propria. The pathophysiology is 

probably similar to that of congenital nephrotic 

syndrome, where protein loss is due to decreased 

negative charges of heparan sulfate. 73 The reduced 

expression of sulfated GAGs allows abundant loss 

of albumin and water due to the reduced electrostatic 

interaction between anion sites of GAG and 

arginine residues within the albumin molecules. 

74,75 

Congenital disorders of glycosylation 

Congenital disorders of glycosylation are multisystemic 

diseases with variable clinical expression 


and several subtypes. The common feature is the 

alteration of N-glycosylation which may be defective 

in several points. This is a fundamental 

mechanism that regulates protein folding and 

allows intracellular quality control. 76,77 Most 

secretory and membrane proteins require glycosylation 

for proper folding and subsequent transport 

via the secretory pathway. In congenital disorders 

of glycosylation there is underglycosylation of 

several proteins including antithrombin III, factor 

IX or protein C, leading to cytoplasmic retention of 

the abnormal protein. The common screening test 

is identification of carbohydrate transferrin deficiency 

by isoelectric focusing analysis of serum 

transferrin. It is likely that the high turnover rate of 

epithelial cells may render them particularly 

vulnerable to this type of disease. 72 PLE is 

common in congenital disorders of glycosylation 

type 1b (mutation of phosphomannose isomerase) 

and type 1c (mutation of α-1,3-glucosyltransferase). 

72,78 Patients with type 1b have severe 

diarrhea, vomiting and PLE. Intestinal biopsy 

shows partial villous atrophy, and the enterocyte 

endoplasmic reticulum is distended and engorged 

with precipitated abnormal protein. Mannose is 

effective in the treatment of these patients, 

correcting both symptoms and biochemical abnormalities. 

79,80 

Patients with congenital disorders of glycosylation 

type 1c have variable clinical expression and may 

present features of types 1a and 1b. Westphal et al 

described one patient with recurrent PLE after 

acute gastroenteritis starting at the age of 3 

months. Intestinal biopsies showed marked reduction 

of epithelial heparan sulfate in the basolateral 

membrane during exacerbations and normalization 

in remission. 72 It is probable that increased 

cellular turnover during exacerbations cause 

intracellular retention rather than defective 

synthesis. The authors speculated that the already 

inefficient glycosylation was overwhelmed by the 

increased epithelial turnover in gastroenteritis, 

effectively leading to complete loss of heparan 

sulfate in the small-intestinal epithelium. Heparin 

may have a role in the stabilization of the cellular 

membrane.

458 


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29 

Introduction 

Short-bowel syndrome 


Short-bowel syndrome is characterized by a state 

of malabsorption following extensive resection of 

the small bowel. It is a functional rather than an 

anatomical definition. The resection results in a 

state of insufficient nutritive supply requiring artificial 

nutrition. Until 20 years ago, the prognosis 

after extensive bowel resection was poor, especially 

in the neonatal period. The onset of 

parenteral nutrition (PN) and enteral feeding in the 

daily practice has transformed the outcome during 

the past two decades. 1–4 These methods allow 

infants and children with short-bowel syndrome to 

grow normally during the long period required for 

adaptation of the remaining small intestine. In 

addition to the requirement for PN, the child with 

intestinal failure from short-bowel syndrome may 

benefit from other established medical and surgical 

interventions, intended to improve the function 

of the remaining gut. 5 This chapter reviews 

the pathophysiology of short-bowel syndrome and 

describes the principles of its medical and surgical 

management. 

Consequences of intestinal resection 

The functional consequences of short-bowel 

syndrome depend on the length, surface and site of 

the resected small intestine (Table 29.1). The cause 

of resection and the age of the patient at the time 

at which surgery was carried out also influence the 

capacity of the remaining gut function and potential 

for adaptation. At birth, the small-bowel length 

is 250±40cm, and the increase in length is 

maximal during the first year of life. 6 The smallbowel 

length doubles during the last trimester of 

gestation, suggesting that a short-bowel remnant 

does not have the same prognosis in a preterm 

infant as in a full-term baby. 7,8 The same difference 

exists between neonates and older children. 

Despite this potential for growth and other factors 

determining the outcome, it is classical to consider 

three levels after small-bowel resection. According 

to the length of the small intestine measured along 

the anti-mesenteric border at surgery, short resection 

leaves more than 100–150cm of small intestine, 

large resection leaves between 40 and 100cm 

and massive resection less than 40cm. In all cases, 

one should consider the age of the patient at the 

time or resection, the portion of small bowel 

resected and the functional integrity of the remaining 

small intestine. 

Resection of the jejunum 

Both the transit time and the direct contact of 

intraluminal nutrients with the jejunal epithelium 

determine the malabsorption syndrome following 

Table 29.1 Consequences of intestinal 

resection 

Malabsorption (nutrients, vitamins, minerals) 1–3 

Gastric acid hypersecretion 4 

Pancreatic insufficiency 4 

Water and electrolyte losses 1–4 

Hyperoxaluria 1–3 

Biliary lithiasis 1, 3, 5 

Liver disease 1, 3, 5 

Bone disease 5 

The numbers refer to the following: 1, disruption of 

the enterohepatic cycle; 2, reduction of the absorptive 

surface; 3, bacterial overgrowth; 4, gastric acid 

hypersecretion; 5, long-term parenteral nutrition 

461

462 


extensive jejunal resection. The resulting malabsorption 

concerns all nutrients as well as minerals, 

electrolytes, trace elements and most of the vitamins. 

Severe diarrhea following extensive jejunal 

resection is associated with steatorrhea and creatorrhea. 

The degree of malabsorption is proportional 

to the length of jejunum resected and will be 

compensated, to some extent, by the ileum and/or 

by the process of adaptation in response to loss of 

intestinal surface. 

Resection of the ileum 

Despite the fact that, normally, most nutrients are 

absorbed in the proximal jejunum, the residual 

ileum is able to adapt and to assume the role of 

macronutrient absorption. However, the specialized 

cells of the terminal ileum, where vitamin B12/ 

intrinsic factor receptors are located and where 

bile salts are reabsorbed, cannot be replaced by 

jejunal hypertrophy. Thus, the ileum has specific 

functions which the jejunum cannot substitute. In 

addition, resection of the distal ileum usually 

includes the ileocecal valve (ICV). Finally, ileal 

resection impairs vitamin B12 absorption which 

can cause macrocytic anemia and neuropathy. 

Malabsorption of bile salts is responsible for 

specific complications: 

(1) Secretory diarrhea may be severe and is 

related to the presence in excess of bile salts 

within the colon, causing injury to the 

colonic mucosa. The consequences are 

proportional to the concentration and dehydroxylation 

of bile salts into the lumen 

(deoxycholic and chenodeoxycholic acids). 9 

(2) The decrease of bile salt reabsorption by the 

ileum reduces their circulating pool and leads 

to lipid malabsorption and steatorrhea. 10 

Unabsorbed fatty acids are then hydroxylated 

by colonic bacteria increasing mucosal injury 

and secretory diarrhea. Because of the 

decreased pool of bile salts, fat-soluble 

vitamins (A, D, E and K) are also prone to be 

malabsorbed. 

(3) Cholelithiasis seems to be the direct consequence 

of the reduced concentration of bile 

salts in bile. 11,12 Resection of the terminal 

ileum, by disrupting the enterohepatic circu- 

lation of biliary acids, increases the lithogenicity 

of bile. Premature infants are especially 

exposed to cholelithiasis because of 

their low production of conjugated bile 

acids. 13 

(4) Hyperoxaluria with formation of renal stones 

results from loss of the ileum and subsequent 

lipid malabsorption. 14 This complication 

became rare with the increased use of diets 

rich in medium-chain triglycerides (MCTs) 

(see below). 

Finally, extensive loss of the ileum reduces transit 

time by suppressing the so-called ‘ileal brake’. It 

has been shown that the ileum has a greater potential 

for adaptation than the jejunum. 15 In 

addition, the ileum is the site of release of enteric 

hormones such as enteroglucagon, which are 

essential in the process of adaptation after extensive 

resection (see below). 

Ileocecal valve resection 

The resection of the ICV decreases transit time 

(ileocecal brake) and allows colonic bacteria to 

enter and populate the small intestine. Bacterial 

overgrowth may negatively impact on digestion 

and nutrient absorption, as bacteria compete for 

nutrients with enterocytes. Thus, ICV resection 

represents an additional major cause of malabsorption 

of nutrients, water and electrolytes, dehydroxylation 

of bile salts, mucosal injury and 

motility disorders. 16,17 The lack of the ICV appears 

greatly to influence the period required to achieve 

intestinal autonomy following efficient smallbowel 

adaptation. 18–20 In addition, ICV resection 

increases the risk for sepsis of intestinal origin. 

This occurred three times more frequently in 

infants without the ICV than in those with an 

intact cecum. 1 

Associated disorders 

Beside the anatomical impairment and its consequences, 

massive small-bowel resection may be 

aggravated by several associated disorders. 

(1) Gastric acid hypersecretion occurs in 50% or 

pediatric patients with short-bowel syndrome

while hypergastrinemia is inconstant. 21 Acid 

hypersecretion occurs early after resection and 

depends on the extent of the resection. 

Hypersecretion is transitory, but it increases 

with enteral feeding, leading to a larger 

amount or intestinal fluid loss. Gastric acid 

hypersecretion, by reducing the duodenal pH, 

decreases the activity of pancreatic enzymes 

such as amylase and lipase, which, in turn, 

increases fat malabsorption. 

(2) Gastric emptying of liquids is more rapid 

following jejunal resection, although intestinal 

transit may still remain normal, because of 

the braking effect of the ileum. 22 The loss of 

inhibition on gastric emptying and intestinal 

transit in children without colon is related to 

a significant decrease in peptide YY, glucagonlike 

peptide I (GLP-I) and neurotensin. 23 

Peptide YY is normally released from L cells 

in the ileum and colon when stimulated by fat 

or bile salts. These cells are missing in 

patients who have undergone distal ileal and 

colonic resection. Rapid gastric emptying may 

contribute to fluid losses in children with 

short-bowel syndrome. 

(3) Alteration in gut motor activity may be 

observed, especially in case of prenatal smallbowel 

malformations (atresia) or severe postnatal 

pathology such as extensive necrotizing enterocolitis. 

They contribute together with repeated 

surgical procedures, by increasing plastic peritonitis, 

to impair motor activity leading to bacterial 

overgrowth and the above-mentioned complications. 

These particular patients are at highest 

risk of developing rapid and severe liver disease 

that impairs the intestinal adaptation process 

and may require combined liver–intestine transplantation 

(see below). 

(4) Colonic and/or gastric resection is sometimes 

associated with small-bowel resection. The 

former aggravates water and electrolyte losses 

while the latter, by altering duodenal contents, 

further decreases intestinal absorption. 

Finally, the main factors determining the outcome 

of short-bowel syndrome are the length of the 

intestinal remnant, whether this includes the 

ileum or not, the conservation of the ICV and the 

degree of injury or the functional integrity of the 

remaining small intestine. 

Small-bowel adaptation after extensive intestinal resection 463 

Small-bowel adaptation after 

extensive intestinal resection 

The goal of intestinal adaptation after massive 

small-bowel resection is to develop the ability to 

withdraw artificial nutrition thanks to a compensatory 

increase in the mucosal surface area and 

absorption capacity. Adaptation is a slow process 

accompanied by a gradual increase in the 

absorption capacity of nutrients, electrolytes and 

minerals. 24,25 Soon after resection, the physiological 

process of adaptation of the remaining 

small-bowel develops. 26 This comprises muscular 

hypertrophy (increased bowel diameter and wall 

thickness) and hyperplasia of the intestinal 

mucosa. This mucosal hyperplasia is characterized 

by an increased number of enterocytes per unit of 

small-bowel length, an increased rate of enterocyte 

proliferation and an increased villous height and 

crypt depth. 27 In animals, it was demonstrated that 

epithelial hyperplasia following gut resection 

resulted in increased mucosal mass, including 

higher mucosal wet weight, higher protein content 

as well as higher DNA and RNA content per unit 

of bowel length. 28 The complex regulation of gut 

mucosal growth involves a multitude of factors 

including hormonal mediators such as 

enteroglucagon, glucagon-like peptides, neurotensin, 

peptide YY, growth hormone and insulinlike 

growth factor (IGF). 28–32 Additionally, oral or 

enteral feeding stimulates the release of 

enterotrophic hormones such as gastrin, cholecystokinin 

(CCK) and neurotensin, which may 

further improve the process of gut adaptation. 29–32 

Intraluminal substrates and nutrients, provided by 

oral or enteral feeding, are essential for achieving 

intestinal adaptation after extensive resection. 

Intraluminal nutrients stimulate the adaptation 

of the intestinal mucosa through several 

mechanisms: 

(1) Direct contact of intraluminal nutrients with 

intestinal cells; 33,34 

(2) Trophic effects of gastrointestinal secretions 

enhanced by food; 35,36 

(3) Release of several trophic hormones secreted 

by the gastrointestinal tract, mainly enteroglucagon. 

37 

The postulated influence of CCK and secretin 

might be an indirect action via the stimulation of

464 


pancreatic secretions that could lead to the release 

of enteroglucagon. 38 In turn, enteroglucagon stimulates 

the cell turnover, motility and absorptive 

capacity of the small intestine. 39 

Glutamine (Gln) is the most important circulating 

amino acid. Many findings have emphasized the 

role of Gln for the metabolism of enterocytes 

suggesting the importance of Gln as a substrate 

during PN in patients with short-bowel 

syndrome. 40–43 

Ornithine-α-ketoglutarate has been shown to 

improve mucosal trophicity and to enhance 

intestinal adaptation in a rat model of extensive 

intestinal resection. 44 Ornithine-α-ketoglutarate is 

a precursor of glutamine and could also act by an 

increased production of polyamines by the enterocytes. 

Short-chain fatty acids (SCFA) are produced from 

the fermentation of fibers by the colonic 

microflora. SCFA could be energetic substrates for 

the topical nutrition of intestinal cells. 45,46 In rats 

with short-bowel syndrome, pectin, a watersoluble, 

non-cellulose dietary fiber, was shown to 

enhance jejunal and colonic mucosal adaptation 

when added to the enteral diet 47 or PN mixture. 48 

The question as to whether patients with shortbowel 

syndrome would benefit from diets 

enriched in pectin remains unanswered. 

Besides nutrients, other factors seem to play an 

important role in the mucosal adaptation process: 

(1) Growth-stimulating peptide has been shown 

to be synthesized in the rat proximal intestine 

after small-bowel resection; 49 

(2) Epidermal growth factor (EGF), produced in 

the salivary glands and duodenal cells, is a 

trophic substance for the gastrointestinal 

tract. 50–52 EGF is a polypeptide able to stimulate 

[ 3 H] thymidine incorporation into 

intestinal DNA when given at pharmacological 

doses to mice. 53 ln addition, EGF 

infusion in rats is associated with a rise in 

galactose as well as in glycine absorption; 54 

(3) Polyamines (spermine, spermidine), whose 

synthesis is dependent on ornithine decarboxylase 

activity, greatly enhance intestinal 

cell turnover and protein synthesis; 55,56 

(4) Exogenous prostaglandin (16,16-dimethyl 

prostaglandin E1) has been shown to stimulate 

mucosal hyperplasia in the gastric 

antrum and in the jejunum. 57,58 

Thus, adaptation of the remaining small bowel is 

dependent on exogenous and endogenous factors, 

emphasizing the usefulness of early enteral 

feeding after resection. It is hoped that in the 

future the utilization of exogenous trophic 

peptides will further enhance and optimize 

adaptation of the remaining intestine. 

Clinical management of short-bowel 

syndrome 

Initial surgery 

Every time intestinal resection is performed for an 

acute event such as midgut volvulus, the initial 

surgery should aim at saving as much intestinal 

tissue as possible. In some situations, a so-called 

‘second-look procedure’ can be performed 2–3 

days later if the patient’s condition permits it. The 

intestinal segments which have not recovered 

from the initial procedure can then be resected. In 

the case of intestinal atresia with a very dilated 

proximal loop, performing an enterostomy is 

indicated in order to avoid intestinal stasis and 

subsequent bacterial overgrowth. If an end-to-end 

anastomosis is performed, the proximal intestinal 

loop should undergo tapering anti-mesenteric 

enteroplasty. 

When small-bowel resection includes the terminal 

ileum it is recommended that a gallbladder resection 

be performed. 12 We perform this whenever 

an extensive ileum resection is made in order to 

prevent the occurrence of cholelithiasis. 

The question as to whether a gastrostomy should 

be performed at the initial phase depends on the 

experience of the team. Nevertheless, if long-term 

enteral nutrition is planned, a gastrostomy is better 

for the patient’s comfort. Extensive small-bowel 

resection will require fluid replacement after 

surgery (see below) and, in a number of patients, 

long-term PN. Therefore, a permanent indwelling 

central venous catheter must be placed, such as a 

Broviac or Hickman catheter.


Whatever the etiology of the short-bowel 

syndrome (Table 29.2), it is customary and informative 

to consider three phases in the clinical 

course after extensive resection. 

The first phase follows small-bowel resection and 

is associated with massive losses of water and 

electrolytes. Severe diarrhea is increased by 

gastric hypersecretion. During this period, total 

PN is required in association with small amounts 

of substrates provided by the enteral route, orally 

or by continuous gastric infusion, as soon as 

intestinal transit has recovered. During the 

second phase, when intestinal transit is permanently 

re-established, intestinal function improves 

as a result of progressive adaptation of the 

remaining small bowel. PN allows the short 

bowel to develop and to become functional 

without exceeding its capacities. This period can 

take several months or years before the stage of 

maximal adaptation is reached. The third phase 

starts when intestinal function is sufficient to 

absorb nutrients, enabling PN to be withdrawn. 

All calories are provided by the oral route. Oral 

intake can then be further liberalized, both in 

volume and in variety, according to the tolerance 

of the patient. This long period requires special 

management and follow-up. 

Phase 1 

The major goals of medical therapy are to compensate 

for the intestinal losses while attempting to 

reduce them and to achieve nutritional repletion. 

Replacement solutions not uncommonly require a 

Table 29.2 Etiology of short-bowel syndrome 

Prenatal Neonatal Postnatal 

Clinical management of short-bowel syndrome 465 

very high sodium concentration replacement, 

often as high as 80–100mmol/l, in order to maintain 

fluid and electrolyte homeostasis. The 

requirements of massive intravenous fluids and 

the necessity to avoid multiple peripheral 

perfusions necessitate the early insertion of a 

central venous catheter. Such vascular access 

allows the safe replacement of volumes of fluid 

according to the evaluation of intestinal losses. 

Water, sodium and potassium requirements are 

also increased. When losses stabilize and the clinician 

becomes familiar with the management of 

the infant, fluid and electrolyte losses can be 

added to the PN solution and administered 

through a single infusion device. Patients with 

proximal enterostomy require special trace 

element supplementation. Zinc deficiency can 

lead to a decreased activity of zinc-dependent 

intestinal metalloenzymes such as alkaline phosphatase, 

leucine aminopeptidase and other intestinal 

disaccharidases. 59 On the other hand, PN 

provides adequate nutritional supply to the child, 

allowing optimal growth. Such nutritional support 

includes the use of 1.5–2.5g/kg per day of amino 

acids through a pediatric solution, a caloric intake 

consisting of 70–80% of non-protein energy 

substrates such as dextrose and 20–30% energy 

provided by a 20% intravenous fat emulsion. 

Maintenance amounts of vitamins and trace 

elements are added to the PN solution by using 

commercially available preparations. Calcium, 

phosphate and magnesium are also added to the 

solution according to the patient’s needs and the 

stability of the solution. 

During the early phases of therapy, serum electrolytes, 

glucose, urea and calcium should be 

Atresia (unique or multiple) Midgut volvulus Midgut volvulus (malrotation, 

Apple peel syndrome (midgut or segmental) bands or tumor) 

Midgut volvulus (malrotation) Necrotizing enterocolitis Complicated intussusception 

Segmental volvulus (with Arterial thrombosis Arterial thrombosis 

omphalomesenteric duct or Venous thrombosis Inflammatory bowel disease 

intra-abdominal bands) Post-trauma resection 

Abdominal wall defects Extensive angioma 

Gastroschisis > omphalocele 

Extensive Hirschsprung’s disease

466 


measured daily. When the patient’s condition and 

the intestinal losses become stable, blood monitoring 

can be less frequent. During the first stage after 

resection, H2-receptor blocking agents (ranitidine) 

should be given intravenously to inhibit gastric 

hypersecretion: 15–20mg/kg per day of ranitidine 

added to the PN solution, the drug being delivered 

as a continuous infusion. H2-receptor-blocking 

agents, by increasing duodenal pH, also improve 

the digestion and absorption of nutrients. 

The end of the phase of management is considered 

to be accomplished when the patient has recovered 

from the surgical procedure and is stable 

on PN with controlled intestinal losses and 

motility. 

Phase 2 

This phase of management is marked by the 

initiation of enteral and/or oral feeding and the 

gradual cycling of PN. As supported by the 

mechanisms of adaptation, there is a clear advantage 

in providing early gradual amounts of 

nutrients into the residual intestine. Indeed, intraluminal 

nutrition is mandatory for stimulating 

mucosal hyperplasia. The absence of luminal 

nutrients slows the intestinal hyperplasia process 

even when the appropriate amount of calories is 

given by PN. 60 

Phase 3 

The transition between total PN and full 

enteral/oral feeding is achieved during phase 2 

either in hospital or, better, on home PN when 

necessary. Phase 3 begins with the discontinuation 

of artificial nutrition. When the patient receives no 

more than two or three perfusions per week, PN 

discontinuation is attempted. If both protein– 

energy intake and intestinal function are adequate, 

normal weight gain and growth velocity must be 

achieved. If the weight gain remains correct after 3 

months without PN, the central venous catheter is 

removed. If not, PN should be restarted for a few 

weeks or months. In about 80–90% of cases, the 

first attempt to stop PN completely is successful. 

When all the necessary calories are provided by 

oral feeding, oral intake can be further liberalized 

in both volume and variety. In a very small 

number of neonatal cases of short-bowel syndrome 

(less than 5% in our experience) eating disorders 

may be a serious problem. After eliminating all 

organic causes, reinforcement of psychological 

support is mandatory. 

Mode of feeding 

The mode of administration of feeding varies 

among different groups. Oral feeding seems to 

have several advantages, especially in neonates. 

Oral feeding is more physiological, by stimulating 

salivary secretion containing EGF, gallbladder 

motility and gastrointestinal secretions. In addition, 

oral feeding reduces PN-related liver disease. 

Early initiation of oral feeding, by allowing the 

infant to learn how to suck and swallow, is in addition 

the best way to prevent anorexia secondary to 

the absence of suckling and long-term hospitalization. 

The use of breast milk has the advantage of 

containing additional non-nutritive factors such as 

prostaglandins or EGF and it seems logical, despite 

the fact that it contains lactose. Oral feeding 

increases stool volume output and frequency even 

when a semi-elemental diet is used. Intestinal 

tolerance can be determined by the volume of the 

stools, their consistency, the number of bowel 

movements, the presence or absence of reducing 

substances and pH (

tain no fiber, have an osmolality below 

310mOsm/kg, and contain substrates that are 

rapidly transferred across the intestine without 

leaving intraluminal residues. A dilute concentration 

is gradually increased from 0.6 to 1kcal/ml 

according to digestive tolerance (stool losses, 

reducing substances). It is also important to avoid 

excessive fluid administration concurrently with 

PN which may overload the patient with fluid. 

CEF enhances absorption by permitting total saturation 

of the transporters in the gut 24h a day. 

Bolus feeding through the nasogastric or gastrostomy 

tube is not tolerated and should be avoided. 

Adapted CEF subsequently decreases the PN 

requirements and reduces liver injury. The recent 

development of new portable infusion devices and 

backpacks permits older children, who are able to 

walk independently, to have reasonable mobility 

as they grow and develop physically. If the child is 

managed by using CEF, oral feeding should be 

maintained. Introduction of solid feedings by 6 

months of age is also important to help the child 

learn to eat and swallow at an appropriate age, 

again to avoid feeding-aversion behavior. 

Type of diet 

The choice of an appropriate diet for CEF remains 

controversial. During the past decades, special 

diets were first used; each of the constituents 

could be modified independently. An important 

improvement has been the introduction of semielemental 

diets containing protein hydrolysates, 

oligosaccharides and a mixture of MCTs and longchain 

triglycerides (LCTs). 

Protein in the diet 

It was demonstrated that the absorption of amino 

acids is more rapid and more efficient when given 

in the form of short peptides than in the form of 

free amino acids. 61–63 In addition to the quality of 

the protein, digestion and intestinal absorption of 

protein hydrolysates depends on the type of 

hydrolysate used: α-lactalbumin is better than 

casein. 64,65 Amino acid-based formulas have been 

used in pediatric patients with short-bowel 

syndrome and are well accepted by the infants. 65,66 

Their beneficial effects have to be demonstrated by 

further studies. 


Energetic substrates: carbohydrates and lipids 

Because of the increased turnover of enterocytes in 

the small bowel, lactase activity appears to be 

depressed in patients with short-bowel syndrome. 

Oligosaccharides provide low osmolality and 

allow the amount of carbohydrates to be increased. 

The behavior of MCTs, their split products in the 

intestinal lumen and their absorption characteristics 

are mainly due to their greater water solubility. 

67 MCTs are hydrolyzed more rapidly than 

LCTs in the small intestine by pancreatic lipase; 

they are converted almost exclusively into free 

fatty acids and glycerol and reach the liver directly 

via the portal circulation. Thus, even in the case of 

pancreatic insufficiency, MCTs may be absorbed 

intact. Moreover, MCTs have been shown to be 

absorbed, to some extent, within the stomach and 

duodenum. The unabsorbed fraction is then 

absorbed within the proximal part of the jejunum. 

The excessive content in the diet of MCTs can lead 

to osmotic diarrhea as a result of rapid hydrolysis 

of the MCTs’ bulk. 68 Studies in animals with 

enterectomy have shown that MCTs are not as 

effective as LCTs in stimulating mucosal hyperplasia. 

69 LCTs appear to be potentially more 

trophic than other nutrients for the mucosal mass. 

LCTs stimulate biliary and pancreatic secretions, 

which are themselves trophic factors. In addition, 

LCTs are a substantial source of linolenic and 

linoleic acids, which are essential substrates for 

endogenous prostaglandin synthesis. 70,71 Most of 

the formulas containing MCTs also include up to 

50% of lipid in the form of LCTs. LCTs stimulate 

biliary and pancreatic secretions, which promote 

increased intestinal motility; when LCTs are in 

excess in the intestinal lumen, they may be 

hydroxylated by bacteria and reverse the rate of 

water and electrolyte absorption, resulting in 

aggravation of malabsorption. Under these conditions, 

oral therapy with cholestyramine (0.5–2g/kg 

per day) may be helpful, and supplementation 

with essential fatty acids is crucial. Thus, an 

intake of 2–4g/kg per day of lipids is recommended, 

depending on the absorption capacity 

and digestive tolerance. 

Dietary fibers 

It is possible for an intact colon to absorb daily 

energy from dietary fiber. 45,46 The role of SCFAs 

has been demonstrated in animals. 47,48 In patients

468 


with a preserved colon, a reasonable amount of 

dietary fiber may be progressively included in oral 

feeding. Because SCFAs are supposed to stimulate 

sodium and water absorption, infants and children 

might be expected to have a decreased stool output 

and sodium losses. However, this is not always 

observed in clinical practice. Therefore, soluble 

non-starch polysaccharides and some starches 

should be given, according to digestive tolerance 

and especially stool output as well as abdominal 

distension due to intracolonic fermentation of 

fiber by an abundant and modified intestinal 

bacterial microflora. In patients without a colon or 

with reduced colon length without an ICV, dietary 

fiber should be reduced or even avoided. 

Bacterial overgrowth 

Bacterial overgrowth is a frequent complication, 

causing mucosal injury, malabsorption and bacterial 

translocation. In addition, bacterial overgrowth 

exacerbates hepatotoxicity related to PN. 72–80 

Indeed, deconjugation of bile acids by bacteria 

facilitates their reabsorption, leading to hepatotoxicity. 

Bacterial overgrowth is likely to occur in the 

case of ICV resection, poor motility of a dilated 

small-bowel segment, or when a tight anastomosis 

is present. After bacterial overgrowth has been 

confirmed by intestinal flora analysis (fecal and 

duodenal) and the hydrogen breath test, it is 

mandatory to stop it. Antimicrobial therapy as the 

combination of metronidazole and colimycin three 

times a day may be helpful. The efficiency of the 

antimicrobial therapy can be assessed by the clinical 

improvement or by the intestinal tolerance to 

food and mainly by performing stool balance 

studies. The use of broad-spectrum antimicrobial 

therapy is, in our opinion, contraindicated, 

because of the high risk of emergence of multiresistant 

bacteria and the anti-physiological effect 

on colonic flora. In the case of bacterial 

overgrowth, the administration of Saccharomyces 

boulardii may be effective. Whenever possible, 

performing an intestinal tapering procedure or 

resecting a tight anastomosis may be required to 

obtain the disappearance of bacterial overgrowth 

(see below). The use of prokinetic drugs for 

enhancing gut motor activity is strictly contraindicated 

in these conditions. 

Parenteral nutrition cycling 

Besides enteral feeding, phase 2 is characterized 

by the cycling of PN. As soon as the metabolic and 

nutritional status or the patient permits it, cyclic 

PN should be started. Cyclic infusion of nutrients 

allows the periods of feeding and fasting to be 

alternated, which induces a more physiological 

regulation of metabolism by insulin and glucagon; 

it prevents hyperinsulinism which is responsible 

for fat accumulation within the liver and adipose 

tissue. 81,82 Furthermore, cyclic PN favors a more 

normal physical activity whose importance in 

terms of nutrition and psychology has been 

demonstrated. The tolerance of this mode of 

nutrient delivery has been well documented in 

children. In addition, cyclic PN is the most appropriate 

condition for home PN whose development, 

since 1980, has dramatically improved the wellbeing 

and quality of life of patients requiring longterm 

PN. 83,84 Cyclic PN can be progressively 

achieved by slowly decreasing the infusion rate, 

followed by complete discontinuation of nutrient 

infusion for several hours per day. Long-term PN 

has to be adapted in order to avoid complications 

related to excessive or insufficient intakes. 85–88 

Adaptation to fluid losses 

Extensive small-bowel resection is associated with 

gastric hypersecretion. The H2 antagonists and 

proton pump inhibitors are useful in reducing 

gastric fluid secretion, and therefore will also 

reduce fluid losses. However, absorption of orally 

dosed medications may be impaired, and either 

large doses, oral medication, or intravenous delivery 

may be required. Although fluid losses are 

decreased, macronutrient and electrolyte absorption 

are not affected by H2 antagonists and proton 

pump inhibitors. 

Reduction of fluid loss 

Fluid losses may require chronic control with 

hypomotility agents. Synthetic opiate derivatives 

such as loperamide may be beneficial in delaying 

gastric emptying and decreasing gastrointestinal 

motor activity. They allow the transit time to

decrease and enhance intestinal transport. 

Nevertheless, loperamide must be used very carefully 

and should be avoided whenever a motility 

disorder leads to intestinal distension with subsequent 

bacterial overgrowth. In patients with ileal 

resection and watery stools, cholestyramine may 

bind bile acids and reduce biliary colitis and diarrhea. 

However, cholestyramine causes fat malabsorption 

and increases the risk of fat-soluble 

vitamin deficiency. Somatostatin analogs may be 

helpful for short-term use. 89 The mechanism of 

action is unclear, but octreotide may be useful in 

slowing intestinal transit time and increasing 

water and sodium absorption. However, octreotide 

reduces splanchnic protein synthesis, thereby 

reducing mucosal protein incorporation and 

villous growth rate, and may impair postresectional 

intestinal adaptation. There is also an 

increased risk for cholelithiasis in the patient 

group already predisposed to this problem. Use in 

children has not been well studied and there are 

some concerns regarding the suppression of 

growth hormone in this population already at risk 

of poor growth. 

Prevention of dehydration 

In a child on cyclic PN, because of reduced water 

intake and persistence of intestinal losses, one 

should be careful when restarting PN. It is 

important to increase the infusion rate progressively 

during the first hour of PN, because the 

child may be mildly dehydrated. Especially infants 

with an extremely short-bowel or with a smallbowel 

stoma have obligatory losses of water and 

electrolytes even when fasting. The volume of 

effluent rises in proportion to the amount of distal 

intestine removed. Since the sodium concentration 

of the effluent is almost constant at about 

90mEq/l or greater, the sodium losses correlate 

directly with the volume of effluent and are 

increased by oral feeding. Despite large amounts of 

sodium given parenterally, fasting periods of cyclic 

PN should be carefully adapted. Patients with less 

than 60cm of jejunum remaining between the 

duodenojejunal flexure and the stoma lose more 

fluid and sodium from the stoma than they can 

take in orally and may be at risk for developing 

negative water and sodium balance. Those 

patients with severe diarrhea are also subject to 

magnesium deficiency. Oral rehydration solutions 


with adequate sodium concentration can be given 

to maximize water and salt absorption. Such 

patients should be discouraged from drinking large 

quantities of water or diluted sodium solutions. 

Complications of short-bowel syndrome and 

parenteral nutrition 

Long-term PN exposes the patient to several 

complications, including catheter-related sepsis 

and thrombosis, bone disease and liver impairment. 

72–80 Daily catheter care and prevention of 

septic complications are essential (see Chapter 33). 

Liver function tests should be performed on a 

regular basis because of the risk of cholestasis and 

liver injury. If initial surgery did not include a gallbladder 

resection, ultrasonography aiming to look 

for sludge or cholelithiasis should be repeated 

every 3 months. In addition, the phosphorus and 

calcium status should be assessed and, if necessary, 

supplies should be given to prevent PNrelated 

bone disease. 

Liver disease is certainly the most frequent and the 

most severe complication in patients with shortbowel 

syndrome. Premature babies and/or smallfor-gestational-age 

babies with severe necrotizing 

enterocolitis are at specially high risk of developing 

liver disease and, rapidly, end-stage liver 

failure, because of the combination of prematurity, 

sub-occlusion, Gram-negative sepsis and repeated 

catheter-related sepsis. In general, liver disease is 

mostly related to the impaired small intestine and 

is further aggravated by inadequate PN. 

The main factors related to liver disease 

These are thought to be: 

(1) Disruption of the enterohepatic cycle (ileal 

disease or resection); 

(2) Intestinal stasis with consecutive intraluminal 

bacterial overgrowth and/or translocation 

(endotoxinemia); 74–76 

(3) Recurrent catheter-related sepsis; 90 

(4) Prematurity itself, which might be an associated 

factor; 78 

(5) Inadequate PN intakes such as continuous PN 

infusion with excessive glucose intake (hyper-

470 


insulinism) and subsequent steatosis or inadequate 

amino acid supply. 81 

Management for prevention or resolution of liver 

injury 

This should include: 

(1) Stimulation of the enterobiliary axis by ingestion 

of LCTs or breast milk, or by injection 

of CCK analogs; 38 

(2) Suppression of intraluminal bacterial overgrowth 

caused by intestinal stasis, by giving 

metronidazole and/or performing tapering 

enteroplasty; 91 

(3) The use of ursodesoxycholic acid (10–20mg/kg 

per day) which might contribute to the decrease 

of liver injury; 92 

(4) PN intake, which should be adapted in terms of: 

(a) limiting glucose intakes to reduce hepatic 

fat accumulation; 93 

(b) decreasing aluminium content of parenteral 

nutrition solution; 94 

(c) using appropriate type and amount of intravenous 

fat emulsion which provides essential 

fatty acids and reduces glucose load; 95 

(d) using the new pediatric adapted amino 

acid solutions which provide appropriate 

amino acids as well as taurine; 96 

(e) performing cyclic parenteral nutrition that 

contributes towards reducing hyperinsulinism 

and reducing liver steatosis. 81 

Transition to parenteral nutrition weaning 

When oral feeding and home PN are commenced 

in combination, the amounts and/or rate of PN 

infusion are progressively decreased. In our experience, 

the combination of oral feeding and cyclic 

PN allows home PN to be achieved in the best 

conditions. The combination of CEF and cyclic PN 

seems to us less logical, since nutritional support 

would take place only during the nocturnal period. 

If not, the patient would be dependent on artificial 

nutritional support for 24h a day. In the past 20 

years we have treated, in hospital and/or by home 

PN, over 200 patients, mainly infants, with shortbowel 

syndrome. The duration of stage 2 depends 

on several factors, which include: the length of the 

remaining total intestine, conservation of the ICV 

and the functional capacity of the remaining small 

intestine. The slow transition from total PN to full 

oral feeding requires time, during which the nutritional 

status has to be maintained at the optimal 

level. In this regard, home PN is the best tool both 

to maintain nutritional status and to achieve bowel 

adaptation. This is a physiological anabolic process 

which requires optimal nutritional status and liver 

function. The delay in achieving intestinal autonomy 

(PN weaning) depends on residual smallbowel 

length and ICV preservation (see below). 1–3 

By using stool balance analysis we have shown that 

most patients who have been weaned from PN 

remain with a certain degree of malabsorption that 

is compensated by relative hyperphagia. 97 

Conversely, trying to wean an infant with shortbowel 

syndrome from PN too rapidly leads to the 

risk of metabolic complications and failure to 

thrive. 97,98 

Long-term complications 

The loss of ileum can lead to hyperoxaluria and 

subsequent renal stone formation. Oxaluria evaluation, 

as well as ultrasonography of the kidney, must 

be repeated every 6 months. Prevention of oxalic 

lithiasis includes a restricted diet containing LCTS, 

the addition of calcium to the diet and elimination 

from the diet of foods containing large amounts of 

oxalic acid. 99,100 

In the case of resection of the terminal ileum, 

vitamin B12 supplementation is required. An intramuscular 

dose of 1mg every 6 months is recommended. 

Because of poor absorption of fat-soluble 

vitamins (A, D, E and K) follow-up and supplementation 

are necessary. Nutritional evaluation 

must also include research of zinc and biotin deficiency. 

After an extensive small-bowel resection 

and even after adaptation, one must take into 

account the possibility that the medications administered 

orally will not be absorbed at optimal levels. 

This becomes particularly important in the case of 

pediatric infections requiring antibiotics. On the 

other hand, unjustified use of antibiotics may lead 

to severe and protracted intestinal microflora 

impairment. Thus, antibiotic therapy should whenever 

possible be avoided, and if necessary be 

performed by a pediatric gastroenterologist.

D-Lactic acidosis 

D-Lactic acidosis is a classical disorder following 

extensive small-bowel resection with preservation 

of the colon. Lactobacilli and other bacteria, 

including Clostridium perfringens and Streptococcus 

bovis, when present, ferment non-absorbed 

carbohydrate to D-lactic acid, which cannot be 

metabolized by D-lactate dehydrogenase. These 

organisms may proliferate in an acidic environment 

that may be promoted by the metabolism of 

unabsorbed carbohydrate to SCFAs. A metabolic 

acidosis may develop in the absence of hepatic 

dysfunction if significant absorption of D-lactic 

acid occurs. 101 Clinical symptoms include, in the 

rare and severe form, encephalopathy, headache, 

ataxia and dysarthria. D-Lactate concentrations 

will be increased in blood and urine (L-lactate 

concentration, is usually measured when serum 

lactate concentration is normal). The mechanism 

for the neurological symptoms is unknown. 

Thiamine deficiency should be excluded. 102,103 

Spontaneous resolution is possible while treatments 

include oral metronidazole, neomycin, 

vancomycin (for 10–14 days) and avoidance of 

‘refined’ carbohydrates. 104,105 Saccharomyces 

boulardii may be used in these circumstances. 106 

Finally, chronic metabolic acidosis may cause 

impaired growth in some children with shortbowel 

syndrome. 

Long-term follow-up and growth monitoring 

During the long-term follow-up, weight gain and 

growth velocity must be regularly monitored. 

Dietary intake should be adapted to digestive tolerance, 

the child’s preference and growth. Whenever 

failure to thrive occurs, it is important to perform 

a dietetic evaluation of the nutrient intake, stool 

balance studies and investigations for bacterial 

overgrowth. 80 Bone mineral mass has to be 

assessed by dual X-ray absorptiometry. 107 At this 

point one should discuss the opportunity for 

restarting artificial nutrition by enteral feeding or 

in some cases PN. We performed a retrospective 

study to analyze the outcome, the prognosis 

factors and the long-term growth of children after 

extensive small-bowel resection in the neonatal 

period. 108 The study included 87 children who 

had undergone extensive neonatal small-bowel 

resection, followed up over a mean 15-year period. 

The overall survival was 89.7%, depending on the 


date of birth. The duration of PN dependency 

varies according to the intestinal length and the 

presence of the ICV (Figure 29.1). All patients who 

remained PN dependent had less than 40cm of 

small bowel and/or the absence of the ICV. A group 

of patients with a mean smal-bowel length of 

35±19cm, resection of the ICV in 50% of cases 

and a PN duration of 47.4±23.8 months had 

significant decrease in height and weight gain 

within the 4 years after cessation of PN, requiring 

a new period of enteral or parenteral feeding. 

Finally, the largest group included patients with a 

mean small-bowel length of 57±19cm, the presence 

of the ICV in 81% of cases and a PN duration 

of 16.1±11.4 months. After PN weaning, they 

grew normally with normal puberty and final 

height as expected from genetic target height. PN 

duration is clearly influenced by the length of 

residual small bowel and the absence of the ICV. 

With good anatomic prognosis factors and short 

duration of initial PN, normal long-term growth 

may be predicted. Conversely, poor anatomical 

factors and protracted initial PN require careful 

monitoring of growth and may sometimes require 

nutritional support to be restarted. Patients permanently 

dependent on PN might be candidates for 

intestinal transplantation. 

% Children PN-dependent 

100 

80 

60 

40 

20 

0 

0 12 24 36 48 96 

PN duration (months) 

< 40 cm, ICV – 

≥ 40 cm, ICV – 

< 40 cm, ICV + 

≥ 40 cm, ICV + 

Figure 29.1 Parenteral nutrition (PN) duration according 

to anatomical factors. Note that 100% of children with 

small-bowel length 40–80cm and the presence of 

ileocecal valve (ICV) are weaned from PN within 1 year. 

Conversely, a large percentage of children with

472 


Long-term outcome and management 

of ‘unadapted’ short small bowel 

Since the review published in 1972 by Wilmore, 

the prognosis of neonatal short-bowel syndrome 

has dramatically changed. 108–113 More than 90% of 

infants and children now survive after extensive 

small-bowel resection. 1–3 After neonatal extensive 

resection, the residual small intestine can adapt, 

even when its remaining length below the ligament 

or Treitz is shorter than 15cm, the ICV being 

left intact. In older children having undergone 

extensive resection, the criterion for length is 

different. Adequate adaptation to ensure normal 

growth without artificial nutrition requires at least 

40cm below the Treitz angle measured at the time 

of resection. 114,115 In neonatal short-bowel 

syndrome, by separating our series of patients into 

two groups according to PN duration (48 months), assessments of factors such as 

functional capacity of the remaining short bowel 

or bacterial overgrowth emerge as being essential 

(Table 29.3). 116 Thus, a small number of patients, 

because of motility disorders or an especially short 

small bowel, will adapt only very slowly, if at all. 

In such patients, different medical and/or surgical 

approaches have been proposed. 

Pharmacological enhancement of intestinal 

adaptation 

Growth hormone and insulin-like growth factor-I 

A number of studies have indicated that pituitary 

hormones modulate small-bowel growth in 

rodents. 117–119 In hypophysectomized rat pups, the 

rate of growth of the small intestine was 

decreased. 117 Administration of growth hormone 

(GH) to hypophysectomized rats restored the 

growth deficit of the small bowel. GH also stimulated 

small-bowel growth in intact animals. 120–122 

Although GH receptors have been detected in rat 

intestinal mucosal cells, 123 the effects of GH on the 

gut may be mediated through IGF-I, since both type 

I and type II receptors for IGF have been demonstrated 

in rat 124 and rabbit gastrointestinal epithelium. 

125 IGF-I is synthesized in the rat small intestine 

in a GH-dependent manner. 126 IGF-I treatment 

increased small-bowel mass in rats after 80% smallbowel 

resection or in rats with mucosal atrophy 

due to glucocorticoid treatment. 127 

In humans, it was shown that GH enhanced amino 

acid uptake by the small intestine ex vivo 128 and 

promoted crypt cell proliferation in cultured 

explants of duodenal mucosa. 129 Both open and 

randomized clinical trials have now been 

conducted in humans. 130–134 Their results are 

controversial and do not allow conclusions to be 

drawn on a long-term benefit in patients with 

short-bowel syndrome. GH administration 

(0.5IU/kg per day or 0.024mg/kg per day) alone for 

8 weeks had no effect on the absorptive capacity of 

energy, protein, or fluid in ten patients (four with 

colon in continuity). 134 

In infants with short-bowel syndrome, recombinant 

human GH (rhGH) has been used for a 10-day 

period at a dose of 0.3IU/kg per day. Reported data 

include only significant weight gain during rhGH 

treatment and a tendency to increase polyamine 

Table 29.3 Factors predicting parental nutrition duration to be >48 months in infants with neonatal 

short-bowel syndrome, by univariate analysis 

>48months

concentration in the small-bowel mucosa. 135 

Recently, we performed a small, pilot, open-labeled 

trial in eight children with short-bowel syndrome 

with more than 3 years of PN dependency, still 

receiving >50% of their protein– 

energy requirements from PN. After 3 months of 

rhGH treatment (0.6IU/kg per day) all the patients 

were weaned from PN. One-year follow-up indicated 

that 25% had been definitively PN weaned, 

50% had decreased PN requirements and 25% did 

not change their PN dependency. 136 More 

prolonged and perhaps earlier use of rhGH in 

infants or children with short-bowel syndrome 

might be helpful for future management. 

Glucagon-like-peptide-2 

Glucagon-like peptide-2 (GLP-2) has been proposed 

for enhancing intestinal adaptation in patients with 

short-bowel syndrome. 137,138 GLP-2 is secreted from 

L cells of the ileum as well as from pancreatic A 

cells. It was shown that postprandial serum GLP-2 

concentration was not unexpectedly depressed in 

patients who have had extensive small-bowel 

resection, especially including the ileum. 139 The 

relative lack of jejunal hypertrophy following ileal 

resection might be partly related to the resection of 

GLP-2-producing L cells. GLP-2 was used in a clinical 

setting (400µg subcutaneously, twice a day for 

35 days) was administered in a small, pilot, openlabeled 

trial to four patients with short-bowel 

syndrome without residual colon who required 

total PN and in four patients with sufficient residual 

jejunum where total PN was not required. 140 

Jejunal villous height and crypt depth tended to 

increase, energy absorption tended to increase and 

fecal wet weight decreased, indicating increased 

fluid absorption. Regarding its origin (ileum) and 

its physiological effect, GLP-2 might be the most 

logical medical approach for early management of 

the patient with short-bowel syndrome with ileal 

resection. GLP-2 is not commercially available, but 

might be helpful in the near future if a genetically 

engineered analog of GLP-2 is developed. 

Surgical treatment of the short-bowel 

syndrome 

Under some circumstances, surgical procedures 

can slow down intestinal transit or increase the 

Conclusion 473 

area of absorption. Several surgical procedures 

have been proposed for decreasing intestinal transit 

time. The construction of a valve or a sphincter 

with sutures and synthetic material, the denervation 

segments of the intestine, and the intussusception 

of intestinal loops have all been experimentally 

assessed. 141–145 The clinical experience is, 

however, more limited. Reversing segments of 

intestine aims at creating an antiperistaltic segment 

acting as a ‘physiological valve’ by causing retrograde 

peristalsis. Experimental results are conflicting, 

because the ideal length of the antiperistaltic 

segment has not been clearly established. 146,147 

Pediatric patients having undergone such a procedure 

have been reported. 148 Most of the time, 

transit time is slowed down and absorption 

increased. A serious limitation of this procedure is 

that patients with very short remaining small 

bowel may not be able to afford the sacrifice of a 

10-cm segment for reversal. Therefore, this procedure 

has never been used by our team. 

Interposition of a colonic segment has also been 

proposed both in isoperistaltic and in antiperistaltic 

fashions. Clinical results are poor, and show 

little benefit. 149–151 Intestinal tapering and lengthening 

have been performed in selected patients 

with dilated bowel segments. 152–157 Marked 

dilatation of the proximal intestine may occur 

secondary to chronic obstruction or adaptation. 

This situation leads to stasis and bacterial overgrowth 

which further aggravates malabsorption. 

Intestinal tapering and lengthening has the theoretical 

interest of not only tapering the dilated 

segment but also of using the divided intestine to 

increase in length. The procedure should be 

applied with caution, since there is a risk or ‘jeopardizing’ 

the divided segments. Long-term patency 

and function have been shown to occur in some 

patients. 158–160 Finally, in cases or non-adapted 

small bowel despite long-term trials, the only alternative 

is a small-bowel transplantation. 

Conclusion 

Infants with short-bowel syndrome from birth or 

early life should adapt, thanks to the physiological 

process of adaptation. Everything has to be done to 

promote intestinal adaptation and digestive 

autonomy, especially by using the digestive tract 

and the oral route as soon and as much as possible.

474 


Unfortunately, too many infants have complications 

related to unadapted PN and become 

cholestatic with a course of end-stage liver disease 

requiring liver transplant. Some pediatric patients 

were reported to have received an isolated liver 

transplantation for end-stage liver disease compli- 

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30 

Introduction 

Lymphonodular hyperplasia 


Small lymphoid nodules inside the mucosa lining 

the gastrointestinal tract are normal endoscopic 

findings among children. 1 However, greatly 

enlarged lymphoid nodules or a mass covering 

most of the view area and described as lymphoid 

nodular hyperplasia (LNH) may be considered 

abnormal. The most typical sites for LNH are the 

bulb of the duodenum, the colon and the terminal 

ileum, where small nodules are visible in nearly 

all subjects. 2,3 Assessment by videoendoscope has 

made LNH now perhaps the most common finding 

seen in pediatric examinations. During the era of 

X-ray examinations and fiberoscopes only heavy 

accumulations of lymphoid tissue were diagnosed, 

most cases with minor lesions remaining undiagnosed. 

4 As we may examine only patients with 

long-term symptoms, for understandable reasons, 

we will never know the true prevalence of LNH in 

healthy subjects. 

The clinical significance of LNH has long 

remained obscure. It was previously considered as 

normal or age-related in pediatric patients diagnosed 

as infants or small children. 2,4 Even now it 

may be considered as a finding peculiar to children, 

being only rarely diagnosed in adults. 5 In 

earlier literature, intestinal LNH was a rare 

finding, but was clearly associated with congenital 

or acquired immunodeficiency states, including 

IgA deficiency. 6–8 It has also been seen in HIV 

subjects even before the development of AIDS. 9 

LNH may now be considered as a state indicating 

an ongoing or earlier up-regulated immune activity 

of the underlying mucosa. 10 

In a microscopic examination, a biopsy sample 

from the LNH site reveals follicles with or without 

germinal centers but usually no dense mononuclear 

or eosinophilic inflammation. LNH repre- 

sents a multiplication of Peyer’s patches, an accumulation 

of lymphoid cells specialized in handling 

antigens cross the mucosal barrier and regulation 

of the innate immune response. Recent evidence 

suggests that in subjects with LNH the local 

cytokine populations are skewed, showing similarities 

both with celiac disease and atopic allergy. 

Assessment 

To date there has been no objective method of 

measuring or evaluating the amount of intramural 

accumulations of lymphoid tissue downstream of 

the intestinal mucosa. Clusters of lymphoid nodules 

seen during an endoscopic examination may 

be considered significant. LNH may be considered 

as a hypernormal phenomenon, an enlargement 

and multiplication of normal lymphoid tissue 

(Figures 30.1a and b, 30.2a and b, 30.3a and b). 

Wakefield et al used a four-step classification to 

describe the prominence of LNH at the terminal 

ileum. 11 We have also used this practical grading, 

using the following description: grade 0, no 

lymphoid follicles; grade 1, mild – lymphoid follicles 

dispersed on the walls; grade 2, moderate, 

lymphoid follicles filling the walls; and grade 3, 

severe – terminal ileum massed with lymphoid 

tissue, the valve protruding. However, in some 

patients there are segments where the one wall 

may be massed with lymphoid tissue while the 

other wall has no visible lymphoid accumulation. 

The same classification may also be applied to the 

bulb of the duodenum and colon, where mostly 

only grades 0–2 are usually seen. 

A patchy and segmental appearance is a typical 

feature of LNH. In the foregut the nodules are most 

often seen in the bulb. Only in a quarter of cases 

479

480 


(a) (b) 

(c) 

does the lesion continue to the descending duodenum. 

In the terminal ileum, LNH is usually 

restricted to an area of about 10–15 cm proximal to 

the valve. If massed just above the valve it usually 

becomes nodular and disappears entirely as it 

proceeds proximally in the ileum. 

LNH must be actively sought during the examination. 

The underlying mucosa is healthy in that 

there is usually no inflammation. The visible LNH 

bubbles may be hidden between the folds. During 

the videoendoscopic examination the lesion is 

Figure 30.1 Normally in a close endoscopic view of the 

bulb of the duodenum, the villous architecture is visible 

on a plain mucosa (a). In lymphoid nodular hyperplasia 

(LNH) small bubbles are dispersed along the walls covering 

otherwise normal mucosa (b). A biopsy sample from 

the site of the LNH reveals a lymphoid nodule with a 

germinal center but surrounded by normal villi (c). 

sought and assessed after the segments of the areas 

inspected are filled with air to the maximum possible 

and the nodularity is evaluated by sight. In the 

terminal ileum a protruding valve may reveal LNH 

inside the small intestine. 

Histology and immunohistochemistry 

A typical feature in the microscopic examination 

of a biopsy sample from a patient with LNH is an 

increased occurrence and enlargement of 

lymphoid follicles with or without germinal 

centers (Figures 30.1c, 30.2c, 30.3c). The centers 

are usually grossly enlarged and reactive as indicated 

by numerous tingle body macrophages. In 

advanced cases the outer margins of the T-cell 

zone may not be as well defined as in normal or 

mild cases, with the lymphoid compartment 

extending into the adjacent villi. There may also

(a) (b) 

(c) 

be disruption but not destruction of adjacent 

crypts, the number of which may be decreased. 

Typical cases have no villous atrophy, no slight 

villous abnormalities or mononuclear or even 

eosinophilic infiltration, as seen in celiac 

disease. 12 The histology of the colonic samples is 

quite similar, subepithelial apoptosis/debris being 

increased as well. 

LNH may also be associated with other disorders 

such as celiac disease or colitis, which have their 

Histology and immunohistochemistry 481 

Figure 30.2 On the healthy mucosa of the colon the 

vascular pattern is clear (a). Lymphoid nodular hyperplasia 

may cover the mucosa as a dense madras (b) or be 

sparsely dispersed. A biopsy sample in a histological 

examination reveals accumulation of lymphoid tissue (c). 

own characteristics. LNH seems to have a weak 

predilection for IgE-mediated diseases or IgEprone 

subjects; these may have excessive 

eosinophilic cells in the histology of their 

samples. 13 These patients may also show markers 

of atopic food allergy, namely positive skin prick 

tests or food-specific IgE class antibodies. 

However, these patients are a minority. 

An increased density of intraepithelial lymphocytes 

has been measured in the biopsy sample 

sites of LNH, especially γδ + T-cell receptor (TCR)bearing 

T cells. 14,15 Accordingly, the proportion of 

γδ + T cells of the total amount of CD3 + T cells, i.e. 

the γδ + /CD3 + ratio, is greater than in the controls. 

Another type of intraepithelial cell that is 

increased in LNH subjects is the cytotoxic TIA-1expressing 

cell. 16 

The rise in both types of intraepithelial cell seems 

to be more associated with the underlying disorder 

than with the LNH itself. Indeed, in recent reports 

the numbers of intraepithelial γδ + cells as well as

482 


(a) (b) 

(c) 

TIA-1 presenting T cells have been observed to be 

high in patients with food allergy. 13,15 However, we 

found the increased densities in untreated cases, 

but low densities in the subjects on an elimination 

diet. These findings indicate that in the delayed 

and local types of food allergy, as in celiac disease, 

the increment of γ/δ + T cells is associated with the 

activity of the disease. 17,18 However, even after an 

Figure 30.3 On the mucosa of the terminal ileum there 

are nearly always tiny lymphoid nodules (a), but in states 

of lymphoid nodular hyperplasia they are highly enlarged 

(b) and may mass on the walls. The biopsy may be filled 

with lymphoid tissue as large nodules (c) but interspersed 

normal villi may be found. 

elimination diet, LNH seems to linger. Whether it 

is permanent or abates with time remains 

unknown. 

To date, the exact pathogenetic significance of γ/δ + 

and TIA-1 T cells still remains obscure. Being typically 

increased in untreated celiac disease and 

food allergy, they may have profound significance 

in the pathogenesis of these disorders. 


The segmental or patchy appearance of LNH probably 

underlines the fact that the lesion develops as 

an in situ activation of the innate immune 

response leading to multiplication of the lymphoid 

tissue. As hyper-reactivity to food-borne antigens 

is the most common state underlying LNH, this 

suggests that the lesion develops at the contact 

between luminal allergens and the immunologically 

activated cells inside the mucosa. Because of 

the passage of food juice and the timing of its 

contact with the mucosa, the most vulnerable 

places may be the bulb of the duodenum and the

terminal ileum and colon, giving a reasonable 

explanation for the spread of the lesion in the 

gastrointestinal tract. 

In a recent study we found evidence to suggest 

that, in food allergy as in celiac disease, cellmediated 

immunity may be active and may cause 

the symptoms. However, we also found evidence 

showing that in LNH patients humoral immunity 

is also activated. The IgG and IgA class antibodies 

against milk proteins were increased in 

patients with LNH of the bulb of the duodenum. 19 

These antibodies may have no pathogenetic 

significance in the process, their role being 

simply secondary, owing to the increment of B 

cells in and around the lymphoid follicles and 

through the interaction between B and T 

cells. 20,21 However, the humoral response relating 

to LNH may be dichotomous. We also found 

lower-than-normal levels of IgA and IgG class 

antibodies against milk allergens in subjects 

reacting rapidly in a blind challenge test. 

Lacking villous atrophy and/or mononuclear 

inflammation, the symptoms in typical LNH 

cases may be due to an imbalance in cytokine 

cascades. LNH patients have more intraepithelial 

γδ-TCR + cells, which can produce a multiplicity 

of cytokines, including interleukin (IL)-2, interferon 

(IFN)-γ, tumor necrosis factor (TNF)-α, IL-4, 

IL-10 and transforming growth factor (TGF)-β, 

although to date there has been no detailed study 

of the subject. In infants with food allergy, Hauer 

et al showed an up-regulation of IFN-γ and, to a 

lesser extent, IL-4. 22 We found evidence in two 

experiments to show that, in patients with LNH 

and food allergy, the free secretion of IL-6 as 

measured in a biopsy sample was increased, as in 

celiac patients, but we failed to demonstrate any 

difference in the secretion of regulatory cytokines 

such as IL-10 and TGF-β. Examining the biopsy 

samples by a counter-polymerase chain reaction 

(PCR) method we found an up-regulation of 

chemokine receptor 4 (CCR-4) and IL-6 and 

down-regulation of IL-2 and IL-18 in LNH/food 

allergy cases (Paajanen et al, personal communication). 

Even in this study we saw no change in 

the regulatory cytokines as compared to the 

controls. At present, it seems possible that in 

LNH patients there is an imbalance in pre-allergic 

and pre-inflammatory cytokine function on the 

mucosa. 


Unlike patients with celiac disease, subjects with 

LNH and food allergy display no increased prevalence 

of the HLA DQ-2 antigen (A0501/B0201). 14 

HLA-DR seems to be only slightly up-regulated in 

the duodenal mucosa in these patients. There 

currently seems to be no evidence for genetic 

selection of LNH subjects. It seems clear that the 

process leading to an accumulation of lymphoid 

cells and tissue may take place in any subject with 

a temporary or permanent disorder in the protective 

mechanisms of the mucosal layer, leading to 

invasion of luminal antigens and up-regulation of 

the immune response in situ in any part of the 

gastrointestinal tract. 


In our series of 724 consecutive patients over 4 

years, LNH was diagnosed in 135 (19%) in all 

(Table 30.1). The incidence was highest among the 

patients with food allergy, being found in more 

than 50% of the definitely diagnosed cases. It was 

found equally among the treated and untreated 

cases. As in the other centers regularly using endoscopic 

examinations to diagnose celiac disease, 

LNH was found in 10% of cases. The proportion 

was the same in both main types of inflammatory 

bowel disease (IBD) as well as in patients in whom 

we could make no definite diagnosis, even after 

rigorous examination. 

LNH may be spread throughout the colon or as 

patches at any of the main segments. Among 301 

consecutive subjects undergoing colonoscopy, we 

found 36 children with diffuse disease and 101 

with segmental lesions. The transverse colon was 

the most common site for patchy lesions, followed 

by the cecum. Even in the colon the incidence of 

LNH was greatest among the patients with food 

allergy as diagnosed by history and a positive elimination–challenge 

test, rising to 77% of all cases. 

The patients also showed a 50% coincidence with 

diagnosed LNH in the foregut. 

Within the spectrum of IBD, a quarter of patients 

with colitis showed LNH, but only a few presented 

with Crohn’s disease. Colon et al found a similar 

association between LNH of the colon and IBD in 

13 subjects in a 10-year retrospective study in 

which patients were examined mostly by radiographic 

methods, while 84 had no underlying 

disorder. 4

484 


Table 30.1 The presence of lymphoid nodular hyperplasia (LNH) on an 

endoscopic view in children examined for the first time with gastroduodenoscopy 

A new diagnostic entity showing LNH of the colon 

in half the patients is chronic constipation. 

Among these patients undergoing a challenge 

with cow’s milk, a quarter showed a positive 

response during the succeeding 4 weeks. The 

other definite disorders occasionally showing 

LNH on the mucosa of the colon are diabetes, 

rheumatoid arthritis, vasculitis and chronic 

aggressive hepatitis. Finally, it could be demonstrated 

in about 10% of cases without any final 

diagnostic conclusions (Table 30.2). 

Number of subjects LNH present 

n % 

Esophagogastroduodenoscopy 724 135 19 

untreated food allergy 96 47 49 

celiac disease 138 9 7 

IBD 76 10 13 

Colonoscopy 301 137 46 


IBD 83 28 34 

Ileoscopy 204 105 51 


IBD 64 20 31 

IBD, inflammatory bowel disease 

In the colonoscopic examinations lymphoid mass 

or LNH of the terminal ileum was diagnosed in 

two-thirds of subjects in whom this end-point was 

reached. The valve of Bauchini was markedly 

protruded inside the colon in a quarter, all with an 

abundance of lymphoid tissue inside the ileum. 

LNH of the terminal ileum was demonstrated in 

two-thirds of the subjects with defined food 

allergy, most having a mass of lymphoid tissue on 

the wall. It was seen in one in five with colitis, 

Table 30.2 Clinical association of endoscopically visible lymphoid nodular hyperplasia (LNH) of the 


Level of gastrointestinal tract LNH present 

Foregut 

Stomach, normally no nodules Helicobacter pylori infection 

Upper small intestine, normally no nodules food allergy and celiac disease 

autoimmune disorders: diabetes, chronic aggressive 

hepatitis, rheumatoid arthritis, vasculitis. IgA deficiency, 

unknown 

Lower gastrointestinal tract 

Terminal ileum, normally small nodules dispersed food allergy 

evenly on the mucosa inflammatory bowel disease: right-sided or pancolitis 

Colon, normally small nodules seen in infants and autoimmune disorders: chronic aggressive hepatitis, 

small children rehumatoid arthritis, unknown

while in subjects with Crohn’s disease it was a 

surprisingly rare finding. In our series half the 

subjects with chronic constipation showed the 

lesion in the ileum. Wakefield et al reported an 

endoscopic LNH of the terminal ileum with histologically 

reactive follicular hyperplasia in 93% of 

children with developmental disorders, most 

having diarrhea and abdominal pains as well. 23 

The same group also provoked a discussion about 

the coincidence of the measles virus and especially 

the measles vaccine and reactive follicular 

hyperplasia and/or ileocolitis. 24,25 In their original 

work they found virus antigens in 95% of the children 

with developmental disorders and LNH 

using the cell reverse transcriptase (RT) PCR 

method compared with 11% of the controls. 

However, the significance of finding virus particles 

with an extremely sensitive methods from the 

lymphoid tissue of the gastrintestinal tract 

remains open. 26 

As stated above, LNH can be seen in association 

with congenital or aquired immunodeficiency 

states including IgA deficiency and HIV infections. 

7–10 It has also been seen in subjects even 

before the development of AIDS. Recently, the 

lesion has also been described also in patients 

with intestinal lymphomas. 27,28 

Food allergy 

Food allergy may indeed be considered the most 

common disease underlying LNH. 29–33 However, 

in most cases the question is not about IgE-mediated 

disease but a local, T-cell mediated immune 

response, an immunological state close to celiac 

disease and a delayed immune response against 

food-borne allergens. In small children we may 

see infiltrations of eosinophils in biopsy samples, 

but most of the children of school age have no 

increment of eosinophils and mononuclear cells. 

Two-thirds of subjects examined by both gastroduodenoscopy 

and colonoscopy, and shown by an 

elimination and challenge test to have food 

allergy, had LNH on the mucosa of the duodenum, 

ileum or colon. Only a few cases have had 

nodules spread all through the gastrointestinal 

tract. This finding confirms the view that food 

allergy in children may produce patchy or diffuse 

LNH in any part of the gastrointestinal tract. 34 

Symptoms 

Food allergy 485 

LNH in itself may not cause any symptoms, the 

underlying and altered immune response and 

skewing of the cytokine populations probably 

explaining the symptoms. As listed in Table 30.3, 

the most common symptoms in upper endoscopies 

have been abdominal pain, with or without ‘from 

table to toilet’ diarrhea. In the lower endoscopies 

the symptoms vary even more, from diarrhea/loose 

stools to constipation or blood in stools. A cascade 

of symptoms resembling irritable colon has 

perhaps been the most prominent seen in our 

patients. Indeed, at least in young adults with irritable 

colon, Simren et al found symptoms of food 

hypersensitivity but no general malabsorption in 

their patients, suggesting that some patients with 

this symptom cascade might have the same disease 

as we demonstrated in our subjects with LNH. 35 

Examining a group of school children who had 

milk allergy in their infancy and half of the study 

group with abdominal symptoms, we also found 

no signs of general malabsorption, but the subjects 

had lactose intolerance three times more often and 

the height of the symptom group was lower than in 

the controls. 36 Our interpretation is that the 

ongoing immune activity might disturb the epithelial 

cell layer with the net result described above. 

Table 30.3 Clinical symptoms of patients 

examined with gastroduodenoscopy and/or 

colonoscopy and having lymphoid nodular 

hyperplasia as an endoscopic finding 

Upper instestinal symptoms 

Recurrent abdominal pains 

Nausea/vomiting 

Eating disorders 

Growth restricted 

Anemia 

Heartburn/regurgitation 

Lower abdominal symptoms 

Loose stools, intermittent diarrhea 

From table-to-toilet diarrhea 

Constipation 

Blood in stool 

Toiletting difficulties 

Lactose intolerance

486 


However, much investigation is still necessary to 

clarify the clinical significance of LNH. 

Treatment and prognosis 

As stated above LNH may be considered as an 

expression of an underlying immune response. 

There is no specific treatment. If the lesion is 

associated with another diagnosed disorder such 

as food allergy or IBD, these patients should be 

treated. In our clinical practice we have used 

budenoside in cases with LNH and a clinical 

picture of irritable colon but without definite 

association with food allergy. Most patients have 

shown a favorable response, but the approach still 

awaits controlled trials. Immunosupressive drugs 

in combination with other chemotherapy in 

patients with malignant lymphoma have been 

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Durie PR, Hamilton JR, Walker-Smith J, Watkins JB, eds. 

Pediatric Gastroenterology. Philadelphia: Decker, 1991: 

256–269. 

2. Rossi T. Endoscopic examination of the colon in infancy 

and childhood. Pediatr Clin North Am 1988; 35: 

331–356. 

3. Kaplan B, Benson J, Rothstein F et al. Lymphonodular 

hyperplasia of the colon as a pathologic finding in children 

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hyperplasia of childhood: patterns of 

presentation. J Clin Gastroenterol 1991; 13: 163–166. 

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7. Jacobson KW, de Shazo RD. Selective immunoglobulin 

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Gastrointest Dis 1997; 8: 22–32. 

9. Levendoglu H, Rosen Y. Nodular lymphoid hyperplasia 

of gut in HIV infection. Am J Gastroenterol 1992; 87: 

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reported to diminish the nodules on the gut 

mucosa. 28 

LNH seems to be anatomic tissue in the sense that 

at least in subjects with food allergy, the nodules 

remain, even after avoiding the triggering foodstuff. 

This conclusion may be judged from the fact 

that the nodules are seen nearly as often in children 

with treated food allergy as in untreated 

cases. Moreover, we have re-examined a group of 

children with an abundance of LNH on the 

mucosa of the bulb or colon, and saw an equal 

amount of lymphoid tissue to that seen before the 

treatment. However, the immune activity as 

measured by γ/δ + intraepithelial lymphocytes 

seemed to diminish during the treatment. 

In summary, LNH is a recently described 

condition. To date, there is only limited understanding 

of the phenomenon and its behavior. 

10. Kokkonen J, Karttunen T. Lymphonodular hyperplasia 

on the mucosa of the lower gastrointestinal tract in 

children: an indication of enhanced immune response? 


11. Wakefield AJ, Anthony A, Murch SH et al. Enterocolitis 

in children with developmental disorders. Am J 


12. Kokkonen J, Haapalahti M, Laurila K et al. Cow’s milk 

protein sensitive enteropathy at school age. J Pediatr 

2001; 139: 797–803. 

13. Kokkonen J, Ruuska T, Karttunen T et al. Mucosal 

pathology of the foregut associating with food allergy 

and recurrent abdominal pains in children. Acta Pediatr 

2001; 90: 16–21. 

14. Kokkonen J, Holm K, Karttunen T et al. Children with 

untreated food allergy express a relative increment in 

the density of duodenal g/d + T-cells. Scand J 


15. Furlano RI, Anthony A, Day R et al. Colonic CD8 and 

gamma delta T-cell infiltration with epithelial damage 

in children with autism. J Pediatr 2001; 138: 366–372. 

16. Augustin M, Kokkonen J, Karttunen T. Increased 

densities of TIA-1 antigen bearing T-cells in duodenal 

samples of children with gastrointestinal food allergy. J 


17. Mäki M, Holm K, Collin P et al. Increase in 

gamma/delta T cell receptor bearing lymphocytes in 

normal small bowel mucosa in latent coeliac disease. 

Gut 1991; 32: 1412–1414. 

18. MacDonald T, Spencer J. Evidence for cell-mediated 

hypersensitivity as an important pathogenetic 

mechanism in food intolerance. Clin Exp Allergy 1995; 

25 (Suppl 1): 10–13.

19. Kokkonen J, Tikkanen S, Karttunen TJ et al. Similar high 

level of immunoglobulin A and immunoglobulin G class 

milk antibodies and increment of local lymphoid tissue 

on the duodenal mucosa in subjects with cow’s milk 

allergy and recurrent abdominal pains. Pediatr Allergy 

Immunol 2002; 13: 129–136. 

20. McGhee JR, Lamm ME, Strober W. Mucosal immune 

responses. An overview. In Ogra PL, Mestechy J, Lamm 

ME, Strober W, Bienenstock J, McGhee JR, eds. Mucosal 

Immunology. San Diego: Academic Press, 1999: 

485–506. 

21. Soothil JF, Stokes CR, Turner MW et al. Predisposing 

factors and development of reaginic allergy in infancy. 

Clin Allergy 1976; 6: 305–319. 

22. Hauer AC, Breese EJ, Walker-Smith JA et al. The 

frequency of cells secreting interferon-gamma and interleukin-4, 

-5, and -10 in the blood and duodenal mucosa 

of children with cow’s milk hypersensitivity. Pediatr Res 

1997; 42: 629–638. 

23. Wakefield AJ, Murch SH, Anthony A et al. 

Ileal–lymphoid–nodular hyperplasia, non-specific 

colitis, and pervasive developmental disorder in children. 

Lancet 1998; 351: 637–641. 

24. Ekbom A, Wakefield AJ, Zack M et al. Perinatal measles 

infection and subsequent Crohn’s disease. Lancet 1994; 

344: 508–510. 

25. Taylor B, Miller E, Farrington CP et al. Autism and 

measles, mumps, and rubella vaccine: no epidemiological 

evidence for a causal association. Lancet 1999; 

353: 2026–2029. 

26. Madsen KM, Hviid A, Vestergaard M et al. A 

population-based study of measles, mumps, and rubella 

vaccination and autism. N Engl J Med 2002; 347: 

1477–1482. 


27. Matuchansky C, Touchard G, Lemaire M et al. 

Malignant lymphoma of the small bowel associated 

with diffuse nodular lymphoid hyperplasia. N Engl J 

Med 1985; 313: 166–171. 

28. Jonsson OT, Birgisson S, Reykdal S. Resolution of 

nodular lymphoid hyperplasia of the gastrointestinal 

tract following chemotherapy for extraintestinal 

lymphoma. Dig Dis Sci 2002; 47: 2463–2465. 

29. Gottrand F, Erkan T, Fabriaux J-P et al. Food-induced 

bleeding from lymphonodular hyperplasia of the colon. 

Am J Dis Child 1993; 147: 821–823. 

30. Beaoui M, Guezmir M, Hamdi M et al. Lymphoid 

hyperplasia of the intestine in children. 15 cases. Ann 

Pediatr (Paris) 1992; 39: 359–364. 

31. Kokkonen J, Karttunen T, Niinimäki A. Lymphonodular 

hyperplasia as a sign of food allergy in children. J 


32. Kokkonen J, Tikkanen S, Savilahti E. Residual intestinal 

disease after milk allergy in infancy. J Pediatr 


33. Kokkonen J. Lymphonodular hyperplasia of the 

duodenal bulb indicates food allergy in children. 

Endoscopy 1999; 31: 464–468. 

34. Crowe S, Perdue M. Gastrointestinal food hypersensitivity: 

basic mechanisms of pathophysiology. 


35. Simren M, Mansson A, Langkilde AM et al. Food-related 

gastrointestinal symptoms in the irritable bowel 

syndrome. Digestion 2001; 63: 108–115. 

36. Tikkanen S, Kokkonen J, Juntti H et al. Status of 

children with cow’s milk allergy in infancy by 10 years 

of age. Acta Paediatr 2000; 89: 1–7.

31 

Introduction 

Malnutrition 


Nutrition is the process by which dietary 

constituents are converted into, maintain and 

sustain the body in health. Nutrition and genetic 

coding are the determinants of the body’s development 

and composition; they modulate and control 

its function and enable it to resist disease. 

Nutrition is the major variable that determines the 

quality of the body – the ‘soil’ in which the ‘seeds’ 

of disease germinate. The battle between the nutritional 

‘soil’ and the etiological ‘seed’ determines 

the course of most diseases. Both nutritional state 

and genetic endowment should be viewed separately 

from the agents of disease. They determine 

the internal environment in which the seeds of 

disease flourish or fail. Why should measles be a 

relatively minor exanthem in Europe and North 

America and a deadly killer in Africa, even in 

those with normal weight for age? Good nutrition 

gives ‘positive health’. There is a whole spectrum 

of deteriorating nutrition that gradually compromises 

physiological reserve and function. In severe 

malnutrition there has been dietary inadequacy 

severe enough to compromise every function of 

the body including its ability to resist disease 

agents. Just as good nutrition leads to positive 

health and resistance to disease, poor nutrition 

leads to ill health and susceptibility to many 

diseases. If a patient has HIV and dies from pneumonia 

we conceive of this as a death from HIV. If a 

malnourished child dies from pneumonia we 

conceive of this death as being due to the pneumonia 

itself. This is wrong. The commonest cause 

of immunodeficiency is nutritional deprivation – 

the underlying cause of death is really malnutrition. 

The stark differences between the perception 

of HIV and malnutrition as causes of death illustrate 

the neglect of nutrition; academic kudos, 

research effort and funding interest hardly exist. 

The nutritional state, by itself, alters the expression, 

course and response to treatment of all 

‘primary’ diagnoses. Notwithstanding the diagnostic 

label attached to a patient, the accompanying 

malnutrition is often the main reason for morbidity 

and mortality; and yet, it is frequently the most 

amenable to treatment. A clinical history of severe 

weight loss or anorexia is not just a diagnostic 

pointer making a debilitating disease more probable; 

it is a signal calling for active treatment of the 

malnutrition and modification of treatment regimens 

for the primary diagnosis. The soil needs 

care and consideration equal to that given to the 

seed. Up to half of all patients admitted to hospital 

suffer from anthropometric malnutrition; many 

more suffer from micronutrient malnutrition. 

If a malnourished patient with carcinoma is given 

radiotherapy, low antioxidant nutrient status often 

results in intolerable side-effects so that the treatment 

cannot continue and the patient dies – from 

carcinoma? Treatment has not just failed, it has 

been inadequate, if not wrong, because the nutrition 

of the patient has been neglected. Ensuring 

adequate nutrition of every patient is every pediatrician’s 

duty. 

Primary malnutrition is a condition of the dependent 

and vulnerable who rely on others for nourishment. 

It is seen most frequently in the young 

child, the elderly and groups such as prisoners and 

the mentally ill or disabled. Secondary malnutrition 

accompanies any disease that disturbs appetite, 

digestion, absorption or utilization of nutrients. 

In poor, technologically backward countries, 

malnutrition-associated disease is the major cause 

of death. More than half of all deaths have anthropometric 

malnutrition as the underlying cause; 1 

many more are compromised by micronutrient 

malnutrition, not associated with weight loss. 

Malnutrition stunts the physical and mental 

489

490 

Malnutrition 

development of the majority of the surviving population. 

Winston Churchill once said that he could 

think of ‘no better investment than to put good 

food in the mouths of babies’; that statement is 

true today. 

The term protein–energy malnutrition has been 

used to cover a number of clinical conditions in 

both adults and children, including: failure to 

thrive, marasmus, cachexia, phthisis, nutritional 

dwarfism, kwashiorkor and nutritional or famine 

edema. The large number of terms reflect the 

emphasis on particular clinical features. However, 

regardless of the clinical differences, most of the 

physiological, biochemical and body compositional 

features are common to all varieties of 

severe malnutrition. The principles of classification, 

investigation and management are the same 

for adults and children. The term protein–energy 

malnutrition is best avoided; it carries the false 

implication that protein and/or energy deficiencies 

are the direct cause of all these conditions. 

Nature of nutritional deficiency 

If a growing animal is given a diet devoid in folate 

there is a consumption of stores; the animal develops 

clinical signs characteristic of folate deficiency 

(and may die); and the concentration of folate in 

the tissues is markedly reduced. However, there is 

no effect upon growth or body weight until the 

illness is terminal. 

If a growing animal is given a diet devoid of 

protein there is an immediate cessation of growth 

and then loss of weight. When such an animal dies 

from protein deficiency, the concentration of 

protein in its major tissues is absolutely normal; 

the animal will have died from a nutrient deficiency 

without any direct evidence of depletion of 

the nutrient except for failure to grow or loss of 

weight. 

The absolute amount of the nutrient within the 

body in both folate and protein deficiency is less 

than normal, but with folate the reduced amount is 

contained within a normally sized body, whereas 

with protein the body size has contracted and the 

concentration maintained. 

There is clearly a fundamental and distinct difference 

between these two responses to deprivation 

of a single nutrient. Most nutrients can be classified 

into those that give a folate-like (type I) or a 

protein-like (type II) response (Table 31.1). The 

characteristics of the two types of deficiency are 

summarized in Table 31.2. 

Type I deficiency 

When one thinks of deficiency of an essential 

nutrient, one automatically considers a type I deficiency. 

The diet is deficient. The low intake leads 

to a reduction in the tissue concentration. The 

metabolic pathways that depend upon this nutrient 

are compromised. Characteristic clinical signs 

and symptoms develop. The diagnosis is conceptually 

straightforward – measure the nutrient 

concentration in a tissue, test the metabolic 

pathway where the defect lies, demonstrate an 

Table 31.1 Classification of nutrients 

according to whether the response to a 

deficiency is a reduced concentration in the 

tissues or a reduced growth rate. Energy 

does not fit into the classification. The type I 

can be looked upon as ‘functional’ nutrients, 

type II as the building blocks of tissue, and 

energy as the fuel that runs the system. The 

position of some essential nutrients, such as 

the essential fatty acids, is not clear 

Type I Type II 

Iron Nitrogen 

Iodine Sulfur 

Selenium Essential amino acids 

Copper Potassium 

Calcium Sodium 

Manganese Magnesium 

Thiamine Zinc 

Riboflavine Phosphorus 

Pyridoxine Chlorine 

Niacin Water 

Ascorbic acid 

Retinol 

Tocopherol 

Calciferol 

Folic acid 

Cobalamine 

Vitamin K

Table 31.2 Characteristics of the different types of nutritional deficiencies 

Type 1 Type II 

effect of replacing the nutrient in vitro or in vivo, or 

recognize the specific clinical signs. 

A critical feature of a type I deficiency is that there 

is no weight loss or growth failure. One cannot 

assume that all is well nutritionally from a growth 

chart. There may be one, several or multiple type I 

nutritional deficiencies and normal growth. Hence 

the devastation of measles in African children 

with a normal growth trajectory. Children in the 

West who exist on soft drinks, candy (sweets), 

crisps and other forms of ‘empty calories’ to 

become obese can have multiple micronutrient 

deficiencies. Obesity denotes only a chronic positive 

energy balance; it is a ‘fat storage disease’, not 

‘over-nutrition’ – it is just as likely to be due to 

‘under-nutrition’ from an unbalanced diet. Indeed, 

it is possible that nutritional deficiency is a cause 

of this fat storage disease. Recently in a besieged 

city in Angola there was a pellagra epidemic. Only 

the fat people developed pellagra (M.H. Golden, 

unpublished). To understand how this can occur is 

to understand the nature of nutritional deficiency. 

Type II deficiency 

The position with respect to the type II nutrients is 

different. Indeed, none of the strategies that can be 

used to diagnose a type I deficiency can be used to 

diagnose a deficiency of a type II nutrient. This 

gives rise to major difficulties, both conceptual 

and practical, when we try to understand, define, 

diagnose and treat these deficiencies. Much of the 

Nature of nutritional deficiency 491 

Tissue level variable Tissue level fixed 

Used in specific pathways Ubiquitously used 

Characteristic physical signs No characteristic signs 

Late or no growth response Immediate growth response 

Stored in the body No body store 

Buffered response Responds to daily input 

Not interdependent Control each other’s balance 

Little excretory control Sensitive physiological control 

Variable in breast milk with maternal status Fixed concentration in breast milk 

controversy that surrounds the definition of a deficiency, 

the signs and symptoms of deficiency, the 

requirements and the diagnosis of deficiency, of 

type II nutrients, stems from attempts to conceive 

of them as analogous to the type I nutrients. 

The type II nutrients are the fundamental building 

blocks of the tissue itself. The tissue cannot be 

sustained without the normal complement of these 

nutrients, so, with deficiency, the whole tissue is 

catabolized and all the components of the tissue 

are excreted. When the tissue is to be resynthesized 

all the components have to be supplied 

in a balanced way. These nutrients can be 

thought about as being interdependent, just as the 

essential amino acids are usually considered 

together under the rubric protein. They have characteristic 

ratios that vary over quite a narrow 

range. They are required to be absorbed in approximately 

the same ratios as occur in the body. Some, 

such as phosphorus, zinc and magnesium, have a 

low availability from the diet, so they should be 

present in higher concentration and available in 

chemical form in any diet designed to promote 

convalescence. 

As an understanding of these particular nutrients 

is integral to the problem of malnutrition, they will 

be considered in more detail. 

Common response 

The response to a deficiency – growth failure with 

a mild deficiency and weight loss with more

492 

Malnutrition 

profound deficiency – is the same for each type II 

nutrient. When nutritional growth failure or 

weight loss is seen, the particular nutrient that is 

lacking cannot be identified. 

Every animal experiment in feeding a diet lacking 

a type II nutrient results in progressive diminution 

or cessation of growth, then weight loss. This 

response has been observed consistently and 

universally in all species studied, in both acute 

and chronic experiments, with each of the type II 

nutrients. The response to a habitual mild deficiency 

is progressive stunting (with the body in 

proportion). The extent of the stunting is a function 

of the degree of shortfall of the nutrient and 

time. With an acute deficiency, in either the child 

or the adult, there is a loss of tissue leading to 

wasting. The balance between the severity of the 

deficiency and its duration will determine the relative 

amounts of stunting and wasting produced. 

Mild, chronic deficiencies are more common than 

severe, acute deficiencies and stunting is consequently 

more common than wasting. 

Type II nutrients are not stored in the body 

There is a common repertoire of metabolic 

changes and ‘reductive adaptations’ that occur in 

response to each type II deficiency. However, 

because whole tissue is being broken down, or at 

least there is no net synthesis, all the nutrients 

released from the catabolized tissue and are in the 

diet in excess relative to the deficient nutrient 

have to be excreted. These nutrients are not stored 

in the body. The balance between the various type 

II nutrients in the diet is thus very important. In 

the face of a deficiency of any one of them there is 

a negative balance for them all. For example, if 

potassium is omitted from a parenteral feeding 

regimen, the patient will loose nitrogen, zinc, 

phosphorus and magnesium from the body. He 

will not necessarily be in negative balance for the 

type 1 nutrients such as calcium, iron or folate 

whist he is losing weight. 

Dietary deficiency 

When a deficient diet is given, the body has mechanisms 

to avidly conserve and recycle the deficient 

nutrient to maintain itself. For this reason, it is 

extremely difficult to produce clinical signs of a 

deficiency of these nutrients in the non-growing 

animal by dietary means alone. There usually has 

to be a pathological loss of the nutrient from the 

body. This is commonly by diarrhea. The loss can 

be sufficiently severe to compromise intestinal 

function so that the deficiency and diarrhea 

become persistent. The treatment has to be a 

change of diet to replace all type II nutrients that 

have been lost. Zinc, phosphorus and magnesium 

are frequently not replaced adequately. 

Determinant of requirements 

The rate of weight gain is the main determinant of 

the dietary requirement for a type II nutrient. For 

example, children given a diet that supplied just 

enough energy for them to maintain their body 

weight, without growing, are able to remain in zinc 

balance, and maintain their plasma zinc concentration, 

with an intake of only 0.08mg Zn/kg per 

day. When the same children were gaining weight 

rapidly, their plasma zinc fell precipitously despite 

a ten-fold increase in the amount of zinc 

consumed (1mg Zn/kg per day); this limited lean 

tissue synthesis so that the children became obese 

without regaining muscle. They required an 

amount that far exceeded the recommended 

dietary allowance to maintain synthesis of new 

lean tissue. During convalescence from illness the 

recommended daily allowance (RDA) for type II 

nutrients is not sufficient. RDAs are set for normal 

individuals. Of course an increased nutrient 

density must be supplied for all type II nutrients in 

the right balance to make the new tissue. 

Children do not need a richer diet than adults 

This contradicts what most pediatricians, nutritionists 

and lay people believe. A diet that has a 

sufficiently low concentration of a type II nutrient 

to give clinical signs, other than growth failure, 

will affect the elderly first, then adults and lastly 

children. This is a consequence of the higher relative 

energy requirement of the child. Thus, the 

protein requirement of the child, for maintenance 

of body weight, is about the same as for an adult 

(0.6g/kg per day). However, the energy requirement 

for maintenance of the child is about 400kJ/kg per 

day whilst that for the adult is about 160kJ/kg per 

day. Hence, an adult must have a diet that supplies 

6% of the energy as protein, whereas a child

equires only about 2.4% of the energy as protein. 

Of course, for the child to grow normally, very 

much more protein is required. Interestingly, the 

increased requirement for normal growth brings 

the protein density up to that of the adult. We have 

evolved so that all the family can take the same 

diet. If the family has an adequate diet, it can be fed 

to the infant and child. It is not necessary to have 

special weaning foods. Nutritional requirements, 

when expressed as nutrient densities (per unit 

energy) are the same for infants, children, adolescents, 

adults, and the pregnant and lactating. 

In a community, we do not expect to find anything 

other than growth failure in children, unless they 

have diseases which cause a pathological loss of 

the nutrient. If the local diet is sufficiently deficient 

to give rise to other clinical signs, these 

should be seen first in the elderly and last in children. 

However, there is such a wide gap between 

the concentration that gives growth failure and 

that which gives any other feature of deficiency, 

that even where growth failure is common other 

clinical signs are rare. 

Anorexia 

Anorexia is common to a deficiency of each type II 

nutrient; this is corrected if the nutrient is 

supplied. Thus, on supplementation of the single 

missing component a patient will regain his 

appetite and then have an increased intake of the 

newly balanced diet. Dietary intake data are often 

wrongly interpreted as indicating ‘energy deficiency’. 

This is rarely the cause of a low dietary 

intake. Even in famine situations, the diet is 

normally so restricted that type II (and type I) deficiencies 

are usually present long before the total 

amount of food energy becomes limiting. 

Of course, there are other causes of anorexia, in 

particular liver disease, infection and psychiatric 

abnormality, but type II nutrient deficiency is very 

common. This is one reason why most people with 

malabsorption do not increase their intake to 

compensate for the amounts being lost in the 

stools. Refusal to eat a diet that leads to disordered 

metabolism is defensive. There is a metabolic preference 

for ‘consumption’ of one’s own tissues (a 

very good ‘diet’, to satisfy nutritional demands). 

This may have benefit in restoring metabolic 

balance, but in the long term it leads to severe 

malnutrition. 

Classification of severe malnutrition 493 

The anorexia is related to a balance of the type II 

nutrients. It is the relative surfeit of other nutrients, 

particularly amino acids, which need to be 

metabolized and excreted to prevent the toxicity 

that causes the anorexia. If the nutrient density of 

all the type II nutrients is low, but they are in 

balance, for example by adding lipid to the diet, 

the individual may not develop anorexia, but may 

become obese from the excess energy in the diet. 

They are still under-nourished. 

When a supplementary diet is given to children 

which does not contain all the nutrients required 

for new tissue synthesis, it is possible to unbalance 

the diet and make the malnutrition worse, by 

diluting the marginal nutrients in the basic diet to 

a deficient level. 

The type II nutrients have always given problems 

to clinicians and nutritionists because of the 

difficulty with diagnosis. Unfortunately, the nonspecificity 

of weight loss and lack of confirmatory 

tests of an inadequate intake have led these nutrients 

to be largely ignored by clinicians, and their 

nutritional importance to be grossly underestimated. 

The phosphorus requirement is set as a 

function of calcium not as a critical nutrient in its 

own right. Textbooks of nutrition hardly mention 

potassium, magnesium, sodium, sulfur or chlorine 

deficiency. Yet, as a group, type II nutrient deficiency 

is responsible for malnutrition in half the 

World’s children and for unrecognized problems of 

ill health in many others. 

Classification of severe malnutrition 

Any system of classification should have practical 

use, either to identify those individuals who 

require intervention or to examine the prevalence 

within a community so that preventive measures 

can be taken. 

The rest of this chapter is devoted to severe 

wasting and edematous malnutrition. 

Children 

Weight-for-height and height-for-age 

During childhood the most sensitive indicator of 

malnutrition (type II deficiency) is failure to

494 

Malnutrition 

achieve normal growth. The systems of classification 

compare the size of the child to a ‘normal’ 

reference; the reference recommended by the 

World Health Organization (WHO) is the American 

NCHS standard. Other standards have been used; 

however, standards derived from elite healthy 

populations from around the world are all very 

close to NCHS values. The NCHS standards are 

derived almost exclusively from artificially fed 

infants. They have a higher early weight gain than 

exclusively breast-fed children, much of the additional 

tissue being adipose. Thus, healthy normal 

breast-fed infants ‘fall off’ the present NCHS standards 

so that infants may appear to be more 

malnourished than they are. New standards are 

being prepared by WHO for infants and young 

children. 

Normal growth is a continuous, balanced accretion 

of tissue in a predictable way that results in a 

steady, co-ordinated increase in height, weight and 

organ size. A mild insult which continues for a 

period of time results in slowing or cessation of 

growth. The child is normally proportioned but as 

time passes he falls further and further behind the 

actively growing child. Because of the shape of the 

normal growth curve the younger the child the 

more rapidly he will fall behind. If a normal child 

suddenly slows to half the normal growth rate, he 

will be twice his present age before he falls below 

70% of normal height for his age and can be diagnosed 

as severely stunted. 

A child who is exposed to a more severe insult will 

not only stop growing in height but will also lose 

weight. He becomes underweight for age much 

Table 31.3 The classification of severe malnutriton 

more quickly and is thin. The weight is low in relation 

to his height. Thus, within the group of children 

underweight for their age there are two 

conceptually different conditions: first, the 

stunted but normally proportioned (nutritional 

dwarfism); and second, the child of normal height 

who is thin and wasted (the original concept of 

marasmus). The two conditions can be differentiated 

by measuring the height as well as weight and 

age. Stunting is measured by the height of the 

child in relation to the height of a normal child of 

the same age (height-for-age) and wasting as the 

weight of the child in relation to a normal child of 

his same height, even though the normal child is 

usually chronologically younger (weight-forheight). 

The grades of stunting and wasting are 

shown in Table 31.3. 

Two methods of expressing the data are in 

common use. The simplest is to express the 

weight/height of the child as a percentage of the 

normal. The second is to express the deficit in 

terms of multiples of the standard deviation of the 

normal (NCHS) population. The result is called a 

Z-score. The Z-score is much more difficult to 

calculate, but it is relatively age independent and 

expresses stunting and wasting in the same relative 

units. Clearly, any child who has a Z-score 

within ± 2 is, by definition, normal. Children who 

are more than three standard deviations from the 

normal have severe stunting or wasting. In children 

over 6 months of age, a deficit of 5% in 

height-for-age or 10% in weight-for-height is 

approximately equal to one Z-score. In terms of 

admission to feeding programs the weight-forheight 

percentage is preferred. This is because it 

Normal Mild* Moderate* Severe* 

Weight-for-height 90–120% † 80–89% 70–79%

more closely relates to prognosis, is easier to 

understand and can be extended to the adolescent 

(Figure 31.1). 2 

The wasted child presents an immediate clinical 

problem where rehabilitation can lead to restoration 

of lost tissue and function. Correction of 

stunting, on the other hand, is more likely to 

depend upon public health measures designed to 

improve the circumstances of the family. This 

system, together with the presence or absence of 

edema, anorexia and complicating illness is the 

most useful and appropriate for deciding which 

individuals require intensive treatment. Because 

stunting is much more common than wasting, 

systems based upon weight-for-age are no longer 

used (for example, these include the Gomez and 

Wellcome classifications). 

Mid-upper-arm circumference 

Between the ages of 1 and 5 years there is very 

little change in a normal child’s arm circumference. 

This measurement thus gives a simple 

anthropometric measure of wasting which is 

almost age independent. Because stunting is 

common in most countries with a high prevalence 

Weight (kg) 

10 

9 

8 

7 

6 

5 

4 

3 

2 

Risk of death 1% 

2% 

5% 

10% 

Classification of severe malnutrition 495 

of severe malnutrition a chronological age of more 

than 1 year is unreliable, so the cut-off point is 

usually 75cm in height. 

Adult 

Height (cm) 

Body mass index 

The assessment of malnutrition in adults is 

conceptually similar to weight-for-height in children. 

Stunting in adults usually represents chronic 

undernutrition in childhood. It is irreversible. This 

may have implications for the pathogenesis of 

adult disease. However, as there is no therapeutic 

action that can be taken, adult stunting is mainly 

of theoretical interest. 

The object with adults is to classify their degree of 

‘thinness’. The most useful measure is the body 

mass index (BMI), defined as weight (kg) divided 

by the square of height (m): wt/(ht) 2 . Exactly the 

same index is used to define grades of obesity. 

Many sick adults cannot stand to have their height 

measured, and in those with kyphosis or scoliosis 

the measurement is not useful. In these patients 

there are several proxy measures for height that 

50 55 60 65 70 75 80 85 

Figure 31.1 Weight-for-height curves for 70% of the NCHS (blue) standard and minus 3 Z-score units (red). The other 

lines are calculated as ‘risk of death’ cut-off points from the data of Prudhon et al. 2 Note that the 70% line is smooth and 

more closely parallel to the risk of death lines. The children admitted by Z-score but excluded by per cent of the median 

have a very low mortality (2%), whereas those admitted by per cent of the median and excluded by Z-score are young and 

have a high mortality (18%).

496 

Malnutrition 

can be used. Although arm span is said to be equal 

to height, this is only so in those about 1.6m tall. 

Clinically, the most useful measurement is demispan. 

This is measured as the distance from the 

middle of the sternal notch to the tip of the middle 

finger in the coronal plane. Both sides should be 

measured; if there is a discrepancy the measurements 

should be repeated before taking the longest 

demi-span. Height (m) in both males and females 

can then be calculated from the formula: 

Height = 0.73 * (2 x demi-span) + 0.43 

Mid-upper-arm circumference 

As with children, the mid-upper-arm circumference 

can be used to grade the degree of body 

wasting in adults. It is particularly used for pregnant 

women where the weight is higher than in the 

non-pregnant state. 


Severe malnutrition can broadly be divided into 

three clinical syndromes: marasmus, kwashiorkor 

and nutritional dwarfism. In primary malnutrition 

each of these conditions is associated with poverty, 

deprivation and infection; therefore, they often coexist 

in the same individual, just as other conditions 

which share etiological features (such as the 

various sexually transmitted diseases or helminthiasis) 

are frequently found in the same individual. 

Therefore, the clinical features often present a 

mixed picture. 

Marasmus 

The patient with classical marasmus has obviously 

lost weight with prominent ribs, zygoma and limb 

joints, gross loss of muscle mass particularly of the 

limb girdles – shoulders and buttocks – and almost 

absent subcutaneous fat. The bottom looks like 

‘baggy pants’ because the skin, which is thin and 

atrophic, lies in redundant folds. 

The textbooks describe the face as having a 

pinched look like an ‘old man’. This does occur but 

is uncommon. It is much more common to have a 

relatively normal-looking face (Figure 31.2). This 

is important, because one cannot tell whether a 

person is severely wasted by just looking at the 

face. Many cases are missed in busy out-patient 

departments because the children are not stripped 

and examined properly, or screened with weightfor-height. 

Kwashiorkor 

The clinical syndrome of kwashiorkor was first 

described by Spanish doctors in the West Indies 

and then by the French in Vietnam; it did not enter 

the English literature until described by Williams 

in 1933. 3 

The sine qua non of kwashiorkor is bilateral pitting 

edema. Typically, a child of 1 to 2 years with fine 

friable discolored hair develops a typical skin rash, 

edema and hepatomegaly. Kwashiorkor is an acute 

illness which comes on abruptly. The history of 

swelling, loss of appetite and mood change is of a 

few days only (Figure 31.3). 

Nutritional dwarfism 

On casual observation the nutritional dwarf 

appears perfectly normal. It is only when the age of 

the patient is known that the short stature 

becomes apparent. However, dental development 

is less retarded than height, so that these children’s 

facial shape is inappropriate for their size (Figure 

31.4). 

Edema 

The edema is usually dependent and periorbital. 

Small accumulations of fluid may be found at post 

mortem in the pericardium, pleura and peritoneum, 

but large effusions are uncommon; if 

serous effusion is present, associated conditions 

such as tuberculosis should be sought. Adults with 

kwashiorkor are more likely to have serous effusions. 

In severe cases the entire body and internal 

organs are edematous. 

The extent of sodium and water retention in the 

extracellular fluid is variable. It is almost always 

overestimated by clinicians. In mild edema of the 

feet only, the weight loss with resolution of edema 

is about 3% of body weight, with moderate edema 

5% and with severe edema 10%. There are

(a) (b) 

children with up to 30% or more recorded, but 

such cases are extremely rare. 

Circulation 

The retained sodium and water are not evenly 

distributed throughout the extracellular compartments. 

Depletion of the intravascular volume 

usually accompanies the enormous expansion of 

the interstitial space. This maldistribution gives 

rise to the anomalous statement that an edematous 

patient can be ‘dehydrated’. This is semantically 

incorrect and we should use the adjective ‘hypovolemic’ 

to describe these patients. The use of the 

word ‘dehydration’ and the attendant concepts 

Clinical features 497 

Figure 31.2 (a) A severely wasted child from the Democratic Republic of Congo (DRC). This child did not have edema. 

His face appears fat, not unlike the facial shape of many children with kwashiorkor. (b) A severely wasted youth from DRC. 

Note that he does not have an ‘old man face’ – if he were clothed, you would not realize that he was wasted. Note also 

the displacement of his cartilaginous rib forwards. This is a sign of a longstanding low intake of vitamin C or copper. 

have led physicians to treat these patients, incorrectly, 

with rehydration solutions. In fact, the 

hypovolemia in edematous patients is a form of 

toxic shock and should not be treated with 

sodium-containing fluids. 

Hepatomegaly 

Hepatomegaly is frequently encountered in the 

West Indies. It is much less common in Africa or 

Asia, although it does occur. The liver may extend 

to the iliac brim. It is smooth, firm and not usually 

tender. The liver enlargement is due to fat accumulation, 

mainly as triglyceride. Up to half the wet 

weight of the liver can be fat, but it is usually

498 

Malnutrition 

Figure 31.3 A child with extensive skin lesions and 

edema from Uganda. Note that this child is receiving breast 

milk. The mother appears anthropometrically normal. 

much less than this. Signs of liver dysfunction such 

as petechiae or very slight hyperbilirubinemia are 

serious prognostic signs. 

Splenomegaly 

An enlarged spleen is very unusual in uncomplicated 

malnutrition. Where it occurs it is likely to 

be associated with particular infections such as 

malaria, kala azar or HIV, or a hemoglobinopathy. 

Anorexia 

Loss of appetite is a common feature of all forms of 

severe malnutrition. The most likely underlying 

causes are type II nutrient deficiency, infection 

and liver dysfunction. These patients nearly 

always have all three of these underlying causes 

compounding each other. 

Figure 31.4 These three Jamaican children are the same 

age. The one on the left is stunted. The one on the right is 

wasted and the one in the middle is normal. The wasted 

and stunted children have the same weight. The normal 

child is much heavier. 

Mood and behavior 

Classically the children are apathetic when left 

alone and complain when they are picked up. The 

passsivity can be profound, so that the children lie 

in one position for prolonged periods. These children 

can develop bed sores. Quite frequently catatonia 

can be demonstrated. If the limbs are raised 

then moved, the child will maintain each posture 

for prolonged periods. This passivity and the lack 

of crying is extremely serious. A good mother will 

find out why a child cries – hunger, thirst, cold, 

pain, unhappiness or being uncomfortable – and 

then put it right. If the child does not cry the 

mother thinks that none of these problems are 

affecting her child. The child is neglected. When a 

malnourished child is in the hospital the staff also 

neglect these children for the same reasons. This is 

why they should always be nursed together in a 

special unit. 

A series of stereotyped, self-stimulating repetitive 

movements may occur; this is typical of psychosocial 

deprivation. One of the most damaging forms 

of self-stimulation is rumination. When alone, the 

child regurgitates the last meal, to re-taste it, then 

re-swallows it. Inevitably some is lost. In less 

severely deprived children intentional regurgitation 

may be the only way in which the child can 

get attention from a busy mother; it then becomes 

a learned habit that leads to malnutrition. 

Rumination and attention-seeking regurgitation 

are frequently confused with vomiting from a

physical cause, so that many of these children 

undergo extensive gastrointestinal investigations. 

Skin 

In kwashiorkor there are skin changes that appear 

and progress like sunburn. The skin changes are 

acute, occurring over the course of a day or so. The 

skin first becomes darker in color, particularly over 

areas exposed to minor trauma or pressure. The 

superficial dermal layers then dry like thin parchment 

and split wherever they are stretched to 

reveal pale areas between the cracks (Figure 31.5). 

The dry cracked layer then peels off to leave 

hypopigmented extremely thin skin. If it is gently 

pinched between the fingers numerous small 

wrinkles appear, showing how thin and atrophic 

the epidermis is. The skin is very friable and ulcerates 

or macerates easily, particularly in the flexures, 

perineum and behind the ears. In severe 

cases it may appear as if the child has been burnt. 

Hair 

There is atrophy of the hair roots of the scalp. They 

cease to synthesize protein, the bulb shrinks and 

the hair may be plucked out easily and painlessly. 

The patients may go completely bald. The reduction 

in synthesis is also seen in chemotherapy. 

When this sign is present there are also low levels 

of hepatic export proteins, such as albumin and 

transferrin showing that the slowing of synthesis is 

general throughout the body. 

The hair itself becomes thin and straight and ‘lifeless’. 

In patients with naturally curly hair the curls 

may be lifted up by the new straight hair to give 

the appearance of trees with straight trunks and a 

canopy – the ‘forest sign’. 

The hair may change color to red, brown, gray or 

blond. The basis for this change in color is 

unknown. Hair color changes bear no relation to 

prognosis and should not be used to classify these 

children. 

Feminization 

Unlike the hair on the scalp, the eyelashes grow 

long and luxuriant. There may also be excessive 

Clinical features 499 

Figure 31.5 The stripping skin from this foot shows the 

different stages of the skin lesions of kwashiorkor. 

growth of lanugo hair. The face of little boys starts 

to look like girls. Breast enlargement is not uncommon; 

it occurs particularly in patients with gross 

hepatomegaly. The reason is not only the diminution 

of conjugation and excretion of steroid 

hormones by the liver. The small bowel bacterial 

overgrowth, that is almost universal in these children, 

deconjugate the conjugated steroids so that 

they are reabsorbed. These signs of feminization 

indicate longstanding chronic malnutrition with 

small-bowel overgrowth and fatty liver. 

Cheeks 

Fullness of the cheeks is commonly associated 

with edematous malnutrition (so-called jowls). 

The cause is unknown; it is not due to parotid 

enlargement. 

Although there is usually marked parotid atrophy, 

in some patients, particularly malnourished 

adults, there is painless parotid enlargement. This 

seems to be associated with particular geographical 

locations. For example, it is common in one of 

the Comoro islands off the African coast but not on 

a neighboring island. The reason is unknown. 

Bone 

There is nearly always an enlargement of the 

costochondral junctions giving a ‘rickety rosary’. 

The cause is not usually related to vitamin D

500 

Malnutrition 

deficiency. It is related to the very low available 

phosphorus and calcium in the diet. Harrison’s 

sulci and other chest deformities are not only due 

to the pliability of the bone, but also to repeated 

chest infections. Smoke pollution from cooking 

fires is very common in the developing world – 

the reason why chest infections are more frequent 

in the wet seasons is that the cooking is then done 

indoors. Chronic vitamin C (or copper) deficiency 

gives rise to dislocation of the costochondral junctions 

with the cartilaginous chest protruding 

forwards. This is the so-called ‘scorbutic rosary’. 

It is also common. Signs of acute scurvy are 

extremely uncommon. The sclera may be blue 

because the choroid pigment shows through, 

similar to that seen in congenital defects of collagen 

formation or structure. There is nearly always 

very marked osteopenia on X-ray. Despite the 

demineralization and collagen defects, and unlike 

osteitis fragilis, these children very rarely have 

fractures. The mothers must handle the children 

very gently indeed. 

Abdominal swelling 

The abdomen is usually protuberant. This is due 

to gas in the intestine rather than the enlarged 

liver. The gut gas is due to the very slow lowamplitude 

peristaltic waves. This is the main 

cause of the bacterial overgrowth. Frequently the 

abdominal wall is sufficiently thin for peristalsis 

to be easily visible. Bowel sounds are infrequent. 

In newly admitted patients there may be a succussion 

splash from the stomach or bowel. 

Inflammation 

The tympanic membranes are white and thickened 

(tympanosclerosis), usually without signs of 

inflammation. The tonsils are atrophic. It is 

unusual to find lymphadenopathy. When it occurs 

symmetrically it is usually associated with HIV 

disease. When asymmetrical it is usually tuberculosis. 

There is frequently oral, esophageal, gastric, 

colonic and perineal candidiasis. 

Pus does not form, even on open skin lesions. 

There is almost no inflammatory response. This is 

why fever is uncommon; when it occurs, it is 

usually due to a high environmental temperature. 

Similarly, lobar pneumonia does not usually 

occur in the absence of inhalation. 

Anemia 

Anemia is almost universal to some degree. It is 

due to multi-micronutrient deficiency and infection. 

Thus, there is frequent evidence of deficiencies 

of folic acid, copper, vitamin E, pyridoxine, 

riboflavin and vitamin C, all of which can cause 

anemia. Schistocytosis is not uncommon because 

of the fragility of the red cells. Malaria is also a 

common cause of anemia. In urban areas the 

blood content of lead is often high. The iron stores 

are normally replete and iron deficiency is not 

usually the cause of anemia in severe malnutrition. 

Other signs 

Angular stomatitis, lingual atrophy, follicular 

hyperkeratosis, vitamin A-deficient eye signs and 

other signs of specific type 1 nutrient deficiencies 

frequently occur. 


The sequence of events that occur in any 

malnourished individual is shown in Figure 31.6. 

Although the defects reinforce each other in a 

cyclical way, the best starting point is the reduction 

in dietary intake. This can be due to psychiatric 

illness, the anorexia associated with liver 

disease, infection, neoplasia, drug intoxication or 

a type II nutrient deficiency, to famine or starvation, 

upper intestinal disease, malabsorption or 

other losses of nutrients from the body. 

Reduced mass 

A reduction in body mass is the most obvious 

abnormality clinically, and forms the basis for the 

various anthropometric classifications of malnutrition. 

As weight is lost, the absolute nutritional 

requirements are reduced simply on the basis of 

the decreased mass. There is also a relative reduction 

in requirement so that each gram of 

body tissue requires less energy. This reduces

equirement by about one-third and is achieved 

over weeks or months by metabolic adaptation. 

Efficient use and reduced work 

Type II nutrient deficiency Psychological 

Anorexia 

Infection 

Neoplasm 

Starvation 

Pathological loss 

Reduced mass 

Body composition 

changed 

Organs, tissue and chemical 

Small-bowel overgrowth 

Infection 

Figure 31.6 Schematic representation of the sequence of events in marasmus. 

The reduction in requirement comes about in two 

ways. First, nutrients are used more efficiently. 

However, we normally use our food quite efficiently, 

so that there is a relatively small absolute 

saving possible from increased efficiency. By far 

the most important adaptation is in the actual 

work performed by the whole body, its organs, 

tissues, cells, organelles and enzymatic machinery. 

In the well-nourished individual the metabolic 

capacity far exceeds the demand. Energy is used to 

maintain this excess capacity for metabolic work. 

The excess allows us to cope with rapid increases 

in demand for activity or imposed stress. Thus, we 

Reduced intake 

Efficient use 

Loss of reserve 

Tissue and functional 

capacity 

Loss of homeostasis 

Death 

Malabsorption 

Neglect 

Reduced requirement 

Reduced work 

Physiological and 

metabolic responses 

changed 

Specific deficiency 

Pathological losses 

Skin, intestine, kidney 


can run at 30km/h achieving a cardiac output of 

20l/min, eat 70g protein and 10g sodium at one 

sitting, then fast for several days without untoward 

effects. In health, we maintain all the digestive, 

absorptive, hepatic and renal capacity to deal with 

feast or famine. This ‘physiological redundancy’ is 

why ‘unphysiological’ stress tests need to be used 

to diagnose disordered function at an early stage. 

These ‘reserves’ of tissue and functional capacity 

are nutritionally expensive to synthesize, replace 

and maintain; they are sacrificed in malnutrition 

(Table 31.4). 

Physiological and metabolic changes 

The reduction in work of the cells of the body 

leads to major changes in the physiological and 

metabolic responses of the body. Indeed, no physiological 

function has so far been studied in severe

502 

Malnutrition 

Table 31.4 Some changes in physiological function in malnourished children 

undernutrition and found to be ‘normal’. Some of 

the changes are listed in Table 31.5. 

At the level of the whole body, spontaneous activity 

is severely curtailed – apathy and passivity. 

Children no longer play or explore, and adults sit 

in a state of suspended animation, only moving 

when absolutely necessary. 

At the other end of the organizational spectrum is 

a fundamental adaptation: slowing of the sodium 

pump. Normally about one-third of basal energy 

requirements is consumed, pumping sodium out 

of cells and potassium back into the cells. This 

adaptation is at the cost of allowing the intracellular 

sodium concentration to rise and potassium to 

fall. The potassium lost from the cell cannot be 

accommodated in the extracellular fluid and is 

excreted. Slowing of the sodium pump also leads 

to a reduction in cellular electrical potential and 

delay in its restoration, hence there is a reduction 

in neuromuscular function and muscle rapidly 

fatigues. Other processes that depend upon a 

sodium gradient, such as amino acid and glucose 

transport, have a reduced capacity in malnutrition. 

Malnourished Recovered Difference (%recovered) 

Metabolic rate (kJ/kg 0.75 per day) 315 417 -24 

Sodium pump activity (/h) 3.62 4.94 -27 

Intracellular sodium (mM/kg DS) 169 109 +55 

Intracellular potassium (mM/kg DS) 341 387 -12 

Protein synthesis (g/kg per day) 4.0 6.3 -37 

Protein breakdown (g/kg per day) 3.7 6.4 -42 

Cardiac output (l/min per m 2 ) 4.77 6.90 -31 

Stroke volume (ml/beat per m 2 ) 44.1 53.0 -22 

Circulation time (s) 13.7 10.5 +30 

GFR (Cin – ml/min per m 2 ) 47.1 92.4 -41 

Renal blood flow (Cpah – ml/min per m 3 ) 249 321 -22 

H + excretion after NH4Cl (µEq/min) 10.4 28.4 -63 

Osmolal clearance rate (ml/min) 0.20 0.66 -70 

% Infused sodium excreted 22.3 48.7 -54 

Sodium excreted (% of sodium filtered) 

Normal ECF 0.50 1.23 -59 

Expanded ECF 0.82 11.07 -93 

Response to temperature change poikilotherm homeotherm — 

DS, dry stool; GFR, glomerular filtration rate; Cin, inulin clearance; Cpah, p-aminohippurate clearance; 

ECF, extracellular fluid 

A further one-third of basal energy requirement is 

used for the continual cycle of protein synthesis 

and breakdown in a process known as protein 

turnover. This is reduced by about 40%. 

There is a reduction in cardiac output due to both 

a lowered heart rate and a lowered stroke volume. 

The ventricular function curves (stroke work/pressure) 

are altered so that the point of maximum 

performance occurs at a lower mean pressure; 

these patients are very easily precipitated into 

heart failure. 

The maximum concentrating ability of the kidney 

is severely restricted. This means that one has to 

be very careful not to give a diet with a high renal 

solute load, and to ensure that sufficient water is 

taken. There is a very limited capacity to excrete 

free hydrogen ions, titratable acid and ammonia in 

response to an acid load. A common acid load 

comes from giving magnesium chloride as a 

dietary supplement. However, the most important 

renal abnormality is a particular and severe limitation 

of the ability to excrete sodium, particularly in 

response to an expanded extracellular fluid

volume. These abnormalities are shown in Figure 

31.7 and 31.8. With an expanded circulation it 

takes 10h for a malnourished child to excrete the 

sodium that a normal child can excrete in 20min. 

The motility of the whole intestine is reduced and 

small-intestinal transit time increased. This leads 

directly to small-bowel bacterial overgrowth and a 

distended abdomen. However, it also affects the 

pharyngeus and esophagus. These children very 

readily inhale food because of these neuromuscular 

abnormalities. They should never be force-fed 

or held recumbent whilst they are fed. Inhalation 

of the liquid diet, insufficient to obstruct the main 

bronchi, is probably the most common reason for 

pneumonia in the malnourished child. It is 

preventable. 

There is a reduction in gastric acid, bile and 

pancreatic enzyme production. The cellular 

enzymes and transport systems for nutrient 

absorption are compromised and the mucosa 

becomes flattened, but rarely to the degree found 

in primary intestinal disease such as gluten 

enteropathy; mitotic figures in the crypts become 

rare. That the defect is one of capacity and not a 

specific abnormality is demonstrated by absorption 

at low rates of presentation (perfusion) being 

Sodium excretion 

(% of sodium filtered) 

12 

10 

8 

6 

4 

2 

0 

Normal ECF 

Expanded ECF 

Figure 31.7 The fractional excretion rate of sodium 

(expressed as a per cent of filtered sodium) of 

malnourished (red) and normal patients (blue) who have a 

normal circulating volume and after expansion with a 

saline infusion. ECF, extracellular fluid. 


relatively normal, whereas at high rates the digestive 

and absorptive capacity is overwhelmed. 

The malnourished patient becomes poikilothermic. 

Even a modest reduction to 21°C or elevation 

to 33°C in environmental temperature may lead to 

hypothermia or pyrexia, respectively. It is not 

unusual for malnourished children in the tropics 

to develop hypothermia; in temperate climates 

hypothermia is common in the elderly. They are 

qualitatively different from normal. Normal individuals 

increase their oxygen consumption in 

response to a cool environment to maintain body 

heat; malnourished patients reduce their oxygen 

consumption in response to a cool environment 

(Figure 31.9). They never shiver. Once they 

become cold the slowing metabolism means that 

they will not recover without some form of external 

heat. 

There are marked changes in the hormonal 

balance in malnutrition. Growth hormone levels 

are elevated with a low insulin concentration and 

a reduced insulin response to a test meal. Insulinlike 

growth factor (IGF)-I and II, catecholamine, 

glucagons, thyroxine and tri-iodothyronine, both 

free and bound, are all low; cortisol tends to be 

high. The response to injected hormones is diminished, 

with down-regulation of most receptors. 

Although there is glucose intolerance, glucose 

levels are generally lower than normal. The intolerance 

is partly due to liver dysfunction (thought 

to be due to slow initial phosphorylation of the 

monosaccharide) as the degree of galactose intolerance 

is similar to the degree of glucose intolerance. 

There is a very marked reduction in gluconeogenesis. 

The febrile, acute phase and inflammatory 

responses, and the immune system also partake in 

the reductive adaptation; they are either absent or 

severely blunted in seriously malnourished patients. 

Infection is normally recognized by the 

body’s response in terms of a fever, leukocytosis, 

pus formation, tachypnea, etc. When these 

responses do not occur, life-threatening infection 

may go completely unrecognized. 


There are changes in body composition. Most 

tissues contribute to the loss of weight, but, they

504 

Malnutrition 

Table 31.5 The main physiological changes in severe malnutrition and their implications for management 

Physiological change 

Cardiovascular system 

The heart is smaller and thinner than normal. The 

cardiac output and stroke volume are reduced. Saline 

infusion leads to greatly increased venous pressure. 

Overload of the heart readily leads to heart failure. 

Blood pressure is low. Renal perfusion is reduced. The 

circulation time is reduced. Plasma volume is usually 

normal and red cell volume reduced. 

Genitourinary system 

Glomerular filtration is reduced. The excretion of acid or 

of an osmolar load is greatly reduced. Urinary phosphate 

output is low. Sodium excretion is lower than 

normal. The kidney is physiologically unresponsive. An 

expanded intravascular or extracellular volume does not 

lead to increased sodium excretion. Urinary tract infection 

is common. 

Gastrointestinal system 

The stomach produces much less acid than normal. The 

motility of the whole intestine is reduced. The pancreas 

is atrophied and produces a reduced amount of digestive 

enzymes. The small-intestinal mucosa is atrophic with 

reduced levels of digestive enzymes. Absorption is 

reduced when a lot of substrate is given either from a 

high concentration or from large amounts of more dilute 

solutions. 

Liver 

There is a reduction in the synthesis of all hepatic export 

proteins. Abnormal metabolites of amino acids are 

produced. The ability of the liver to take up, metabolize 

and excrete toxins is severely limited. The energy 

production from substrates (such as galactose, fructose) 

is much slower than normal. The capacity for gluconeogensis 

is limited, leading to hypoglycemia with stress 

of infection. Biliary secretion is reduced. Limited output 

of bile salts. Jaundice is uncommon. Liver function tests 

unreliable, because intracellular enzyme levels very 

low. Indocyanine green uptake very abnormal. 

Diagnostic and therapeutic implication 

The children are vulnerable to both an increase and 

decrease in blood volume. Any decrease will further 

compromise tissue perfusion; an increase can easily 

produce acute heart failure. If dehydrated give restricted 

amounts of ReSoMal: do not give intravenous fluid 

unless in severe shock. Restrict blood transfusion to 

10ml/kg per day and cover with diuretic. Restrict the 

sodium intake from the diet and drugs. Give additional 

potassium, magnesium and phosphorus. 

Treat with diets that have a low renal solute load. 

Ensure that there is sufficient water in the diet. Do not 

overconcentrate the diet. Prevent further tissue breakdown 

(treat infection and give adequate energy – 

80–100kcal/kg per day) and do not give excess protein 

over and above that needed to restore tissue, to limit 

urea production. Protein should have balanced amino 

acids (high quality). Avoid salts that can give an acid 

load (e.g. magnesium chloride, high protein). There has 

to be adequate phosphorus in the diet to excrete acid 

equivalents (this is supplied in adequate amounts by 

cow’s milk, but is inadequate with soy substitutes). 

Only use diets in phase 1 that are hypo- or isotonic. 

Feed small amounts of diet often, to remain within 

absorptive capacity. If food is malabsorbed the first step 

is to increase the frequency and reduce the size of each 

feed (do not dilute the diet and give the same volume). 

The food is necessary to stimulate the intestine to 

regrow. Use antibiotics active against small-bowel 

bacterial overgrowth. Occasionally addition of pancreatic 

enzymes is useful. Persistent diarrhea nearly always 

responds to the diet alone. 

The child should not be given a large meal to metabolize 

at one time. The amount of protein should be 

within the capacity of the liver to metabolize it, but 

sufficient to stimulate synthesis of export proteins. This 

is much lower than the RDA. Prevention of catabolism 

is important. Drugs which depend upon hepatic 

disposal or are hepatotoxic should be given in reduced 

doses or not at all. Adequate carbohydrate should be 

given to prevent the necessity for gluconeogensis. 

continued

Table 31.5 Continued 

Immune system 

All aspects of immunity are diminished. Lymph glands, 

tonsils and the thymus are atrophic. Cell-mediated (T 

cell) immunity is particularly depressed. There is very 

little IgA in secretions. Complement components are 

low. Phagocytes do not kill ingested bacteria efficiently. 

Inflammatory response 

Tissue damage is not associated with inflammation; 

white cells do not migrate into areas of damage. The 

acute phase response is diminished. 

Endocrine system 

Insulin is reduced and there is glucose intolerance. IGF- 

I is very low, although growth hormone is high. Cortisol 

is usually high. 

Temperature regulation 

The children are poikilothermic. Both heat generation in 

the cold and sweating in the heat are impaired. The children 

become hypothermic in a cold environment and 

pyrexial in a hot environment. 

Cellular function 

The activity of the sodium pump is reduced (marasmus). 

The cell membranes are more leaky than normal (kwashiorkor). 

This leads to an increase in intracellular sodium 

and a decrease in intracellular potassium and magnesium. 

Protein synthesis is reduced. 

Metabolic rate 

The basal metabolic rate is reduced by about 30%. The energy 

expenditure due to activity of these children is very low. 


There is particular atrophy of skin, subcutaneous fat and 

muscle. Fat is lost from the orbit. There is atrophy of 

many glands including the sweat, lachrymal and salivary 

glands. 

ReSoMal; IGF, insulin-like growth receptor 


Assume all malnourished children have infections and 

overgrowth of mucosal surfaces. Blind antibiotic treatment 

should be given on admission to all children. 

Treatment will have to continue until the improved 

nutritional state leads to improvement of the immune 

system. Physically separate acute admissions from 

recovering children. Give measles vaccine and vitamin 

A. Treat with an antifungal agent. 

Signs of infection are often absent even after careful 

examination. Localized infection such as lobar pneumonia 

is uncommon, generalized infection (bronchopneumonia) 

is common and may be present with no 

radiographic or other signs. Assessments of raised white 

cell count and fever are not necessary. Otitis usually 

does not give an inflamed or bulging ear. Urinary tract 

infection is normally symptomless. Hypoglycemia and 

hypothermia are both signs of severe infection. 

The endocrine system may not be able to respond 

appropriately to large meals. Give small frequent meals. 

Do not give steroids; they are already high. 

Maintain environment between 25 and 30ºC. Put a 

max–min thermometer in the ward. Cover the children 

with clothes and blankets. Children to sleep with their 

mothers. Keep windows closed at night. Dry children 

quickly and well after washing and clothe them. Cool 

fevered children with tepid (not cold) water. 

All the children need large doses of potassium and 

magnesium. Sodium intake should be restricted. During 

recovery the sodium has to come out of the cells and 

potassium has to go in; this easily leads to cardiac overload 

and hypokalemia. Reversal of the electrolyte 

abnormality should be gradual and should occur after 

the kidney has recovered. If used at all digoxin doses 

should be halved. 

Internal heat production is limited. Most metabolic 

processes are sluggish. 

Most signs of dehydration are unreliable: eyes may be 

sunken with loss of orbital fat. Atrophy leads to folds of 

skin. Skin, mouth and eyes are dry owing to gland 

atrophy. The children have limited reserves of energy. 

The respiratory muscles are easily exhausted.

506 

Malnutrition 

(a) 

Intracellular sodium (mmol/l) 

140 

120 

100 

80 

60 

40 

20 

0 

Malnourished 

Recovered 

Figure 31.8 The intracellular sodium (a) and potassium (b) before and after recovery from marasmus. 

(a) 

Core temperature (°C) 

37.5 

37.0 

36.5 

36.0 

35.5 

35.0 

-30 0 30 60 90 120 150 

Time (min) 

(b) 

Intracellular potassium (mmol/l) 

180 

160 

140 

120 

100 

Malnourished 

Recovered 

Figure 31.9 The body temperature response of exposure of malnourished (red) and recovered children (blue) to a low 

environmental temperature (a). The oxygen consumption (b) corresponding to (a). Note that, as the body temperature falls 

in the normal child, there is an increase in oxygen consumption, whereas in the malnourished child the oxygen consumption 

falls. 

(b) 

Metabolic rate (kcal/kg per 30 min) 

1.8 

1.5 

1.2 

0.9 

-30 0 30 60 90 120 

Time (min)

do not contribute equally. Subcutaneous fat may 

virtually disappear and muscle mass is often 

reduced by more than half. Skin and intestine are 

also disproportionately affected, whereas the 

viscera and the central nervous system are relatively 

well preserved. 

The chemical composition of the whole body is 

altered because of the changes in the relative size 

of the organs. Those that are most atrophic are 

those that are used least. Thus, although the 

gluteus muscle may shrivel, the external ocular 

muscles are almost normal. The viscera are 

preserved at the expense of muscle, fat and skin. 

However, where loss would be critical to survival, 

it is much less marked. For example, malnourished 

children in Tchad, in the Sahara desert, have good 

skin. In this environment if the skin lost its function 

the children would rapidly desiccate. 

However, there are also changes as a consequence 

of the reductive adaptations themselves. Critically, 

the reduction in activity of the sodium pump 

invariably leads to an increased total body sodium 

and reduced total body potassium, irrespective of 

the patient’s state of hydration or the serum electrolyte 

concentrations. When there is also edema, 

the malnourished patient also has an increased 

extracellular as well as intracellular sodium 

concentration. The reduction in the enzyme, 

soluble protein and RNA complement, with relative 

increase in structural protein, is accompanied 

by reduction in those trace elements and vitamins 

used as enzymatic co-factors. They are not 

retained in the tissues without the parent proteins. 

The proportionate reduction in each of these 

components of soft tissue is about the same. Of 

course, during reversal of the adaptation the 

deficits of all these components has to be made 

good before any weight gain could occur. Iron is an 

exception. There is an increased concentration of 

tissue iron in most forms of severe malnutrition 

(but not in patients with chronic blood loss from, 

say, intestinal helminthiasis). 

Loss of reserve 

The cost of both the reductive adaptations and the 

reduction in functional tissue mass is to dispense, 

to a greater or lesser extent, with the reserve capacity. 

The malnourished individual has a reduced 


capacity to respond appropriately to the metabolic, 

environmental or infective stresses that do little 

harm to a well-nourished individual. 

Vicious cycles 

Superimposed upon the reduced ability to respond 

to metabolic and environmental changes are the 

pathological effects of the stresses themselves. The 

curtailment of the inflammatory and immune 

responses make infections ubiquitous. The atonic 

gut, achlorhydria, and poor secretion of IgA and 

bile salts combine to allow normal intestinal flora. 

Both bacteria and fungi overgrow the small intestine 

and stomach. These organisms directly 

damage the intestine, deconjugate bile salts and 

exacerbate any malabsorption. Unless they are 

suppressed, diarrhea may worsen when additional 

food is given. The gas produced and the intestinal 

stasis is the reason for abdominal swelling in 

malnutrition; such swelling is characteristic of 

small-bowel overgrowth. 

The diarrhea and repeated infections give rise, in 

turn, to specific nutrient deficiencies, particularly 

of mineral elements. When the integrity of the skin 

is breached from the burn-like lesions of severe 

childhood malnutrition, bed sores, fistulae and 

traumatic or surgical lesions which become indolent, 

blood, serum and heat can be lost in considerable 

amounts. 

The effect of the infections, small-bowel overgrowth, 

malabsorption, nutrient losses and 

thermal stress in the patient already adapted to 

malnutrition, is to exacerbate the anorexia and 

further reduce the intake. The cycle is now 

complete. The adaptations are reinforced and 

physiological function increasingly compromised. 

The debilitated patient reaches a self-perpetuating 

stage where increasing anorexia and organ 

dysfunction lead to rapid deterioration and death. 

Loss of homeostasis 

As the physiological and tissue reserve is whittled 

away and the effects of chronic infection and diarrhea 

deplete the patient, he becomes more and 

more ‘brittle’, like a diabetic patient losing homeostatic 

control of his blood sugar. However, unlike

508 

Malnutrition 

the diabetic, in the severely malnourished patient 

it is not just one organ or system that is functionally 

deranged but all of them. Finally, the patient 

simply cannot control his ‘milieu interieur’, everything 

slows down and stops. 

When treatment regimens are planned they must 

always work within the patient’s limited metabolic 

capacity whilst the reductive adaptations are 

reversed dietetically. Disequilibrium syndromes 

can occur during this reversal and lead to sudden 

unexpected death during early refeeding, even in 

previously obese patients who have been undergoing 

a prolonged period of energy restriction. 

Although the classification of marasmus is based 

entirely upon anthropometric criteria, sickness 

and death are related to the disordered physiology 

rather than the precise degree of wasting. There is 

not a close correspondence between the two. 

There are usually accompanying type I nutrient 

deficiencies and pathological losses. The difficulty 

of relying solely on anthropometry is illustrated by 

the patient with anorexia nervosa. She normally 

has had a very restricted amount of a high-quality 

diet and is abnormally active. Even though the 

anthropometry is similar, many of the physiological 

changes are different, and these patients can 

tolerate a much lower body mass before they 

become dysfunctional. Bulemic patients are more 

like those with severe malnutrition. 

Edematous malnutrition 

In community surveys about 80% of patients with 

edematous malnutrition are not wasted, and most 

are not stunted. Ecologically the condition is ‘overdispersed’ 

following a negative binomial distribution, 

whereas marasmus follows a normal Poisson 

distribution. That means that kwashiorkor occurs 

in geographical pockets; one village may have no 

cases whereas another in the same region has more 

cases than would be expected. Marasmus and 

kwashiorkor do not share a distribution, even 

when they are prevalent in the same area. Some 

villages have predominantly marasmus and others 

kwashiorkor. 

Contrary to what is generally believed, about 25% 

of children with kwashiorkor are being breast fed, 

some exclusively. The type II nutrient concentra- 

tion in breast milk is defended by the mother. In 

contrast, the concentration of type I nutrients in 

breast milk varies with the mother’s intake and 

status. Samples of the breast milk, from mothers 

feeding children with kwashiorkor, are very low in 

antioxidants. These are all type I nutrients. 

Edematous malnutrition, unlike other forms of 

malnutrition, is an acute illness. A patient who 

appears quite well may, over the course of a few 

days, become extremely irritable, progress through 

the various stages of the skin lesions and suddenly 

‘blow up’ with edema. When they present they 

have almost complete retention of ingested 

sodium. Although they have a low blood pressure 

and signs of hypovolemia the sodium retention 

appears to be renal in origin, as it often does not 

recover with restoration of blood pressure and 

even over-expansion of the vascular volume. 

Although the level of aldosterone is high, it is 

unlikely to be the cause of the sodium retention, as 

it paradoxically increases when these patients 

commence diuresis to lose edema. Natriuretic 

peptides and their receptors have not been 

measured in kwashiorkor. 

Kwashiorkor belongs to the family of diseases that 

includes toxic shock syndrome, adult respiratory 

distress syndrome, multiple organ failure and sickcell 

syndrome. It also has similarities to patients 

with radiation injury, cytotoxic drug overdose and 

HIV infection in that they all lead to profound 

immuno-incompetence and abnormal glutathione 

metabolism. 

In edematous malnutrition, in contrast to marasmus, 

there is an increased excretion of urinary 

nitrate. Nitrate is the end product of nitric oxide 

metabolism and a measure of the whole body 

nitric oxide production rate. The circulating levels 

and urinary excretion of the leukotrienes are also 

specifically increased. There is always a reduction 

in cellular glutathione concentration, a key intermediate 

in protection of the body from free radicals. 

Measurement of the ratio of NADPH/NADP in 

cells from these children shows that they have a 

marked deficit in reducing equivalents. 

Furthermore, examination of the sulfhydryl groups 

on proteins shows that an unusually large proportion 

of them are oxidized. Incubation of normal 

red cells in vitro with peroxides reproduces the 

profile of membrane lipids found in kwashiorkor.

Although they also have a high intracellular 

sodium and a low potassium concentration, as in 

marasmus, this comes about by quite a different 

mechanism. Their cell membranes become leaky 

to sodium and potassium; it is this membrane leakiness 

that leads to the loss of intracellular potassium 

and an increase in intracellular sodium. In 

fact, the sodium pump is quite the opposite to that 

in marasmus; in kwashiorkor it is more active than 

normal and their cells have an increased complement 

of Na + K + ATPase. When cellular glutathione 

is reduced in normal cells experimentally, to the 

levels seen in edematous malnutrition, the leakiness 

of the membrane is reproduced and the same 

electrolyte abnormalities that are seen in kwashiorkor 

arise. In kwashiorkor, the cell membranes 

have been damaged by oxidation. 

In kwashiorkor there is also effacement of the 

podocytes of the glomerulus to resemble minimalchange 

nephrotic syndrome. However, there is no 

proteinuria. This is a morphological expression of 

a change in the surface anionic charge on the cell 

membranes. The defect can be corrected, in vitro, 

by perfusion with strongly anionic substances 

such as heparin. The loss of surface charge is due 

to the disruption of the glycosaminoglycans 

(GAGs) on the cell surface. Interestingly, these 

children do not get infections such as cholera 

which depend upon the organism attaching to 

surface complex carbohydrate receptors. Such 

receptor dysfunction may account for the abnormal 

renal sodium homeostasis, but at present there 

is no direct evidence for this speculation. The 

blood–brain barrier is dependent upon the 

integrity of surface GAGs. This may account for 

the fact that meningitis is uncommon in kwashiorkor 

(but not in marasmus). It also means that 

drugs that are neurotoxic if they enter the cerebrospinal 

fluid, but are normally excluded, should 

be used with extreme caution in edematous 

malnutrition. Ivermectin would be in this category. 

Protein synthesis is disrupted. Electron microscopy 

of various tissues shows a marked reduction 

of the protein synthetic machinery. Hepatic export 

proteins are not made at a sufficient rate to maintain 

their circulating concentrations. Reduction in 

lipoprotein synthesis may be sufficient to account 

for the vast accumulation of triglyceride in the 

liver although it is likely that other mechanisms 

are involved. For example, there are very few 

Edematous malnutrition 509 

peroxisomes seen in the cells and the abnormalities 

of NADPH biochemistry are likely to affect 

lipid metabolism profoundly. 

Most textbooks ascribe kwashiorkor to protein 

deficiency. However, this theory is now untenable. 

Protein deficiency would not account for the physiological 

and biochemical abnormalities. Further, 

experimental protein deficiency does not reproduce 

the clinical features of kwashiorkor in any 

species of animal. Being a type II nutrient, protein 

deficiency does give stunting and wasting. The 

edema can resolve completely on a very low 

protein diet with no change in plasma albumin 

level. In the community, no differences have been 

found in the protein contents of the diets of those 

who develop kwashiorkor and those who develop 

marasmus. 

How might poverty lead to kwashiorkor? First, 

poor people live crowded together, in a highly 

contaminated environment. They get many severe 

infections and small-bowel overgrowth. Indeed, 

epidemics of kwashiorkor follow epidemics of 

measles in the tropics, but not in the rich countries. 

Second, their diets are lacking in many of the 

type I nutrients that are crucial to protection from 

free radical damage, particularly: selenium, 

vitamin E, carotene, vitamin C, riboflavin, thiamine 

and nicotinic acid. From this list special 

mention should be made of selenium. Red cells 

become more dense as they age. Thus, by separating 

cells by their density, it is possible to look back 

in time to observe the selenium status during the 

evolution of the illness. Examination of the selenoenzyme, 

glutathione peroxidase, in age-fractionated 

cells shows that the children with kwashiorkor 

have become selenium deficient in the 

recent past. The areas of the world where kwashiorkor 

is common have mostly selenium-deficient 

soils. 

When an infection, toxin or drug gives rise to 

tissue damage, cytokine release, leukotriene 

synthesis and free radical production, these 

patients lack the ability to protect and repair their 

liver, skin and vessels from acute damage. These 

defenses depend upon an orchestra of type I nutrients 

collectively referred to as antioxidants. It is 

this acute oxidative damage that both causes the 

syndrome of kwashiorkor and accounts for its 

similarity to several other serious conditions 

usually found in intensive care units.

510 

Malnutrition 

Changes that occur during treatment 

During successful treatment the physiological and 

body compositional changes reverse. Unfortunately, 

the order in which normal function 

returns can endanger the patient. With increased 

intake of antioxidants the leak in the cell 

membrane of kwashiorkor is repaired. With the 

increase in dietary intake the slow pump of marasmus 

regains its function. The sodium inside the 

cell is exported. In malnutrition the intracellular 

sodium is about 70mmol/l cell water; the normal is 

about 30mmol/l cell water. If 40mmol/l were to be 

suddenly exported from the cell to be retained in 

the extracellular fluid at a concentration of 

135mmol/l, then there would be an increase of 

about 30% in the extracellular fluid volume. If this 

fluid were retained in the circulation it would 

precipitate volume overload and acute heart 

failure. In kwashiorkor, if the defect in the interstitial 

space is corrected, then edema fluid moves 

from the interstitial space to the vascular compartment; 

again, this leads to an additional expansion 

of the circulating volume in kwashiorkor. 

Although the children often present with hypovolemia, 

during early treatment the situation is 

completely reversed to a situation of hypervolemia. 

This is always associated with a fall in 

hemoglobin concentration. Indeed, the red cells 

function as a ‘marker’ of blood volume. The expansion 

of the total blood volume can be assessed by 

the magnitude of the fall in hemoglobin concentration. 

The liver enlarges with the expansion of 

the blood volume and there may be an increase in 

respiratory rate, distension of the neck veins, 

increased vascular shadows on chest X-ray and 

signs of pulmonary edema. 

The movement of sodium and water, to accumulate 

potentially in the vascular compartment, 

needs to take place after the kidney recovers its 

ability to excrete sodium. Where this does not 

happen the child is in great danger. 

The determining factors are thus: 

(1) The initial amount of edema fluid and increase 

in intracellular sodium; 

(2) The rate and degree of recovery of the tissue 

and cellular lesions; 

(3) The rate and degree of recovery of the renal 

lesions; 

(4) Sodium intake from the diet, oral rehydration 

fluid and intravenous fluid; 

(5) The additional expansion of the blood volume 

from a transfusion. 

Children with edema are more susceptible than 

those without edema, children with severe edema 

are much more susceptible than those with 

minimal edema, and children with marasmus from 

areas where kwashiorkor is also common are much 

more susceptible than marasmic children from 

areas where the dietary deficiencies that give rise 

to kwashiorkor are uncommon. This electrolytic 

dysequilibrium, leading to heart failure, accounts 

for the majority of deaths after admission and for 

the differences in mortality rates between different 

regions of the developing world. 

How can this be avoided? Even though antioxidant 

deficiency may be the immediate etiology of 

kwashiorkor, we should not treat the children with 

large amounts of antioxidants acutely. Modern 

diets (F75 and F100) contain significant amounts 

of the antioxidants, and the pathological changes 

reverse quite quickly in comparison to the diets 

that used to be used. If the staff do not understand 

the dangers of rapid reversal of the condition, fail 

to follow the protocol for the management of 

complications faithfully and do not guard against 

giving additional sodium or blood at this time, 

they should not use these treatments. 

As we do not understand the renal lesions, it is 

unclear how to ensure that they are corrected at an 

early stage. During the early phase of treatment, 

when the sodium pump is recovering and the 

excess intracellular sodium is being exported to 

the extracellular compartment, acute circulatory 

overload and sudden death can easily occur when 

the kidney recovers more slowly than the sodium 

pump. 

A low-sodium diet should always be used in the 

early stages. On admission the edge of the liver 

should be marked upon the skin with an indelible 

marker. Expansion and contraction of the liver is 

the easiest clinical way of assessing changes in 

blood volume (or changes in hematocrit, provided 

no one on the team will misinterpret this as 

anemia that requires transfusion). 

After admission diarrhea should be ignored unless 

it is associated with significant weight loss that is

not accounted for by resolution of edema, and 

contraction of the liver if it was initially enlarged. 

With treatment, great care should be taken that 

the weight, the respiratory rate or liver size does 

not increase excessively. If a blood transfusion is 

to be given, it must be given in the first 24h after 

admission and the diets should not be given 

simultaneously. After this window is passed a 

blood transfusion should not be given (unless the 

staff have the capacity to do a small exchange 

transfusion) for at least 2 weeks. A hemoglobin 

level that falls after admission should not be 

treated. Intravenous lines should not be established 

to give drugs. Quinine infusions should be 

avoided. Indwelling canulae are also dangerous 

because of the need to administer anticoagulants. 

Large doses of the sodium salts of drugs (antibiotics, 

antacids, etc.) should not be used. 

Heart failure is not easy to diagnose in this situation 

and many children are incorrectly diagnosed 

as having pneumonia. Persistent diarrhea, with 

which the child has already survived for several 

weeks, should not be treated acutely with rehydration 

fluids. 


A careful history and examination usually provide 

all the information required to treat these patients. 

The laboratory has a relatively minor role to play 

and is used for the identification and characterization 

of infection. 

Tuberculosis is common; its diagnosis presents 

special difficulties as the mantoux test is usually 

negative irrespective of the presence or absence of 

active disease. Acid-fast bacilli can sometimes be 

recovered from laryngeal aspirate obtained with a 

mucus extractor. A chest X-ray should be scrutinized 

carefully for small tuberculous lesions. 

Children with tuberculosis should not be transferred 

to a tuberculosis ward where the staff have 

not been trained and organized to manage malnutrition. 

The management of the malnutrition takes 

precedence (over the course of a few weeks, 

malnutrition has a much worse prognosis and 

higher mortality rate than tuberculosis); tuberculosis 

treatment can be given in the malnutrition unit. 

Investigations 511 

On the chest X-ray, infection causes much less 

shadowing than in well-nourished children and 

may even be absent in the presence of bronchopneumonia. 

The blood should be examined for 

malarial parasites if routine treatment is not being 

given to all severely malnourished patients. 

Testing for sickle cell disease is important in many 

communities. Hematocrit or hemoglobin may be 

helpful immediately on admission, although 

anemia is usually clinically obvious. Measurement 

of plasma constituents is unhelpful in 

management. Plasma concentrations bear no 

necessary relationship to whole body content. 

This is particularly true for potassium and 

sodium. Hyponatremia is frequently found and is 

a poor prognostic sign. 

Therapy should be based upon clinical criteria; it 

should be guided by frequent reappraisal of the 

direction of clinical progress and does not require 

laboratory data. Investigations are used for help 

with diagnosis, not to control treatment. 

Management 

The aims of treatment are to identify and treat all 

the life-threatening problems whilst reversing the 

pathological and physiological abnormalities and 

deficiencies safely, then to feed the patient so that 

weight is gained at an accelerated rate to ‘catch 

up’ towards normal. In children the aim is to start 

to stimulate mental development, to protect the 

patient from relapse and to secure continued 

normal development after discharge. 

There are two main criteria for admission to residential 

care: first, the presence of anorexia of 

more than a few days’ duration; and second, any 

child who does not respond immediately to a trial 

of out-patient management, and who has either 

edema, regardless of weight, or

512 

Malnutrition 

The acute phase 

The mothers have often visited traditional healers, 

waited until it is clear that help is needed and the 

expense justified, and then traveled long distances. 

The ill children have to be triaged and ‘fast 

tracked’ through registration and out-patient 

clinics. They should all be given 10% sugar water 

as soon as they arrive. They should then have their 

weight and height measured, have a brief history 

and examination taken and be admitted. They 

should not be washed or manipulated excessively. 

The caretaker (mother) should be admitted with 

the child. There should be low adult beds for the 

child and the mother to sleep together. 

We need to treat infections and start to reverse the 

physiological changes without the treatment overloading 

the limited capacity of the heart, kidney, 

intestine or liver. The therapeutic implications of 

the reductive physiological adaptations are given 


Dehydration 

Marasmus itself emulates all the signs of dehydration. 

It is almost impossible to make the diagnosis 

by examination. For this reason diagnoses of dehydration 

in the malnourished are always provisional. 

Only significant acute diarrhea needs treatment; 

children with persistent diarrhea should not 

be ‘rehydrated’. A history of recent sinking of the 

eyes with significant watery diarrhea should be 

present. If the patient has true dehydration then 

this has to be treated with rehydration fluid. The 

patients are very vulnerable to over-hydration and 

fatal heart failure is common during the early 

stages of treatment. Additionally, there is nearly 

always some element of ‘toxic shock’ arising from 

their infections and small-bowel overgrowth. 

These patients are quite different from ‘normal’ 

persons with diarrhea or other types of dehydration. 

The management of diarrhea in the normal 

child intentionally and correctly gives excess fluid 

to ensure that all children receive adequate 

amounts. The kidney will readily excrete any 

excess that is given. This situation does not apply 

to the malnourished child. They are sensitive to 

sodium. For these reasons, oral rehydration fluids 

are given for a only short time in limited amounts. 

The normal solution used, ReSoMal, has a 

lower sodium (45mmol/l) and higher potassium 

(40mmol/l) content than that used for normally 

nourished patients (Table 31.6). The patients 

are also depleted in magnesium, zinc and phosphorus 

– solutions that contain these ions as well 

as the major electrolytes are particularly useful. 

Because of their difficulty with homeostasis, intravenous 

treatment is particularly dangerous and 

should be used only for unconscious patients with 

severe shock from dehydration. 

Rehydration is managed by taking serial weights. 

This gives an accurate, quick and reliable way of 

assessing rehydration. On admission, with even 

small amounts of weight gain, there should be 

definite and obvious clinical improvement if the 

diagnosis was correct. If there is weight gain 

without clinical improvement then the diagnosis 

was incorrect. Daily weights are taken from all 

patients under care; the dehydrating effect of diarrhea 

occurring after admission can then be 

assessed accurately from the weight change. 

Rehydration should never be given that increases 

the weight more than the pre-diarrheal weight. 

Dehydration denotes a lower than normal electrolyte 

and water content of the body. Edema 

denotes a higher than normal electrolyte and water 

content of the body. To say that an edematous 

patient is dehydrated is like diagnosing fever in a 

hypothermic patient – they are mutually exclusive 

diagnoses. That is not to say that a patient with 

kwashiorkor cannot be hypovolemic, indeed many 

are; but they are not dehydrated. The signs of 

‘dehydration’ are nearly always related to toxic (or 

cardiogenic) shock in the edematous patient. 

Shock 

There are three common types of shock in the 

severely malnourished: dehydration, toxic shock 

due to sepsis and cardiogenic shock. There are 

frequently elements of all three in the moribund 

malnourished child. They are very difficult to 

differentiate. Toxic shock is difficult to treat 

successfully. In toxic shock, the stress of endotoxemia 

is superimposed upon the other problems of 

severe malnutrition. The veins and capillaries 

dilate, the cardiac muscle is weakened and the 

blood pressure falls. The combined effects of the 

toxin, the metabolic changes produced by 

cytokines and low perfusion of the organs leads to 

increasing shock. Renal perfusion is reduced to a

Table 31.6 Composition of an oral 

rehydration solution suitable from 

malnourished children 

Component Concentration per liter 

Sodium 45mmol (45mEq) 

Potassium 40mmol (40mEq) 

Magnesium 3mmol (6mEq) 

Glucose 10g 

Sucrose 25g 

Osmolality 291mOsm 

Zinc 300µmol (19.5mg) 

Copper 45µmol (2.9mg) 

Selenium 0.6µmol (47µg) 

level where the kidney cannot excrete the endproducts 

of metabolism; the intestine fails to 

absorb and then secretes fluid, bowel movement 

diminishes and petechial bleeding occurs 

throughout the intestine; liver perfusion is 

reduced, gluconeogenesis becomes ineffective 

and the blood sugar falls; even the metabolic 

stress of processing dietary protein can give liver 

failure, and high-protein diets are dangerous; 

there is a progressive decrease of awareness 

because of poor cerebral perfusion, anoxia, electrolyte 

disturbance and hypoglycemia. The low 

perfusion of the tissues reduces the metabolic rate 

to a stage where there is insufficient heat to maintain 

body temperature. Incipient toxic shock 

needs to be recognized in its early stages and this 

progression prevented. Management depends 

upon the maintenance of cardiac output, the 

removal of the source of the toxin by treating 

infection, the prevention of hypoglycemia and 

hypothermia, the strict avoidance of any stress 

such as giving excess fluid or protein, the provision 

of nutrition and the correction of deficiencies. 

If the circulation is compromised, treatment 

is by plasma expansion. 

Diet 

The principle of dietary management in the acute 

stage is to give enough to prevent hypoglycemia 

and hypothermia, to prevent any further tissue 

catabolism and to allow the patient to begin to 

Management 513 

reassemble his cellular enzymes; this must be 

done within the capacity of the intestine, liver and 

other organs. However, at this stage, not only may 

the functional capacity be easily exceeded, but 

deficiencies and nutrient imbalances may be 

aggravated if the patient is given too much food. It 

is as important for the patient not to gain new 

tissue when he is in this state as it is to prevent 

the further loss of existing tissue. This is done by 

carefully controlling the amount of food that is 

given. Children are given not less than 80kcal/kg 

per day and not more than 100kcal/kg per day; 

infants can be given somewhat higher levels; in 

adults the intake should be 30–40kcal/kg per day. 

If less than 80kcal/kg per day is given to a child, 

he will continue to use his own tissues for food 

and will deteriorate; if more than 100kcal/kg per 

day is given, the child may develop a metabolic 

imbalance. 

Because the amount of food that the intestine, 

liver and kidney can handle is limited, to keep 

within the capacity of the organs the diet is 

divided into small portions given at frequent 

intervals (normally eight feeds per day). The more 

‘brittle’ the patient, the more restricted is his 

capacity and, thus, the smaller each feed has to be 

and the more frequently they are given. In the 

extremely ill patient, the diet is put into a nasogastric 

drip and given continuously; intravenous 

feeding can be used in specialized centers in rich 

countries, but the principles of management are 

exactly the same with these patients as with orally 

fed children in the tropics. 

In the less severely ill patient, the diet is given 

less frequently. Recently the success of day-care 

treatment has shown that uncomplicated cases 

can be fed during the day and allowed home at 

night. 

The diet should contain every essential nutrient 

(all the minerals, particularly potassium and 

magnesium, vitamins, protein and energy) the 

child needs to repair his tissues. If any one of the 

nutrients is not given in adequate amounts the 

child will not recover. He will suffer an acute 

deficiency of this nutrient as the energy intake 

increases. On the other hand, the diet should not 

contain a great excess of any nutrient as the 

excess will again cause a metabolic stress. The 

amounts of each of the nutrients that should be

514 

Malnutrition 

Table 31.7 The desirable nutrient intake (per kg body weight) from the diet during the 

catch-up phase of treatment. The diet is most easily formulated as a single diet of 1kcal/ml 

for transition phase and phase 2 

Per kg body weight/ 

Nutrient Per kg body weight 100kcal 

Water 120–140ml 120–140ml 

Energy 420kJ 100kcal 

Protein 1–2g 1–2g 

Electrolytes 

Sodium 160mg 

Magnesium >0.6mmol >10mg 

Phosphorus 2.0mmol 60mg 

Calcium 2.0mmol 80mg 

Trace minerals 

Zinc 30µmol 2.0mg 

Copper 4.5µmol 0.3mg 

Selenium 60nmol 4.7µg 

Iodine 100nmol 12µg 

Water-soluble vitamins 

Thiamine 70µg 70µg 

Riboflavin 200µg 200µg 

Niacin 1000µg 1000µg 

Pyridoxine 70µg 70µg 

Cobalamin 100ng 100ng 

Folic acid 100µg 100µg 

Ascorbic acid 10mg 10mg 

Pantothenic acid 300µg 300µg 

Biotin 10µg 10µg 

Fat-soluble vitamins 

Retinol 150µg 150µg 

Calciferol 3µg 3µg 

Tocopherol 2.2mg 2.2mg 

Vitamin K 4µg 4µg 

Lipids 

Total lipid 25–55% energy 

N-6 fatty acids 4.5% energy 

N-3 fatty acids 0.5% energy 

used for treating malnourished patients are given 


Infections 

Because of the poor inflammatory response, the 

usual physical signs of infection in the malnourished 

are unobtrusive or absent; infection expresses itself 

as apathy, drowsiness, hypothermia, hypoglycemia 

and death. Nearly all malnourished children have 

infections; many have multiple infections. They 

have overgrowth of their small intestines with organisms 

normally present in the colon, and normally 

commensal organisms, such as Staphylococcus

epidermidis, become invasive. Infections are 

frequently the immediate cause of death. 

Early, effective treatment with antibiotics is critical 

in suppressing small-bowel overgrowth, pre-venting 

toxic shock, improving the nutritional response to 

feeding and preventing mortality. For these reasons 

blind unselective wide-spectrum antibiotic treatment 

is recommended for all patients with severe 

malnutrition. Oral amoxicillin is a good choice. It 

effectively suppresses the bowel overgrowth (this 

disturbance of the flora is why it sometimes 

provokes diarrhea in normal children) and is also 

active against most of the common organisms. Some 

clinicians believe that antibiotics should be 

prescribed only for clearly defined infection. This is 

to confuse prophylaxis with blind treatment. Often 

microbiologists advocate specific treatment of the 

organisms they manage to isolate and recognize as 

pathogenic; this can be dangerous in malnourished 

patients because of the multiple organisms, the 

need to suppress commensals and failure to sample 

most of the potential sites of infection. 

Measles 

This involves herpes and other systemic viral infections. 

The mortality rate of severely malnourished 

patients with measles is very high. To reduce the risk 

of cross-infection from a newly admitted patient 

who is incubating measles, it is recommended that 

measles vaccine be given to all malnourished children 

on admission. Children with severe malnutrition 

often have vitamin A deficiency. This is particularly 

associated with death from measles. 

Vitamin deficiency 

In regions where measles or vitamin A deficiency is 

known to occur, even if clinical vitamin A deficiency 

is uncommon, vitamin A should be 

routinely given to all malnourished children on 

admission. They should receive three doses: one 

each on the 1st, 2nd and 14th day. The patients are 

normally also folic acid deficient. All patients 

should receive a single dose of 5mg folic acid 

orally, on admission. It should not be repeated, as 

large doses of folic acid interfere with malaria treatment. 

Many patients are also deficient in 

riboflavin, ascorbic acid, pyridoxine, thiamine and 

the fat-soluble vitamins D, E and K. Where specific 


deficiencies are known to be common, the amounts 

can be increased in the therapeutic diet. However, 

for patients with clinical signs, therapeutic doses of 

the nutrients should be given. The commercial 

preparations of F75 and F100 have ample micronutrients 

and none need be given individually. 

Hypoglycemia 

All malnourished patients can develop hypoglycemia 

when they are fasted. However, this 

complication has been overemphasized in the past. 

In one series, one case of asymptomatic low blood 

sugar was found in 200 patients. The success of 

home, out-patient and day-care programs has 

confirmed that this is an uncommon complication. 

If there is concern about hypoglycemia then it can 

be prevented by giving frequent feeds throughout 

the day and night. 

Eyelid retraction is a sign of sympathetic overactivity 

that is frequently present in children who 

are actively attempting to maintain their blood 

sugar (or circulating volume in dehydration). If a 

child sleeps with its eyes open, that child should be 

awoken and given sugar water (10%). A low body 

temperature, lethargy, limpness and clouding of 

consciousness are other features of hypoglycemia; 

unlike normal persons, sweating and pallor do not 

usually occur. If hypoglycemia is suspected, treatment 

should be given immediately. 

If the patient is conscious or can be roused and will 

drink, give sugar in water or a formula feed by 

mouth, whichever is most quickly available, and 

stay beside the patient until he is alert. 

If the patient is losing consciousness, is unrousable 

or has convulsions, a bolus injection of 1ml/kg 

body weight of sterile 10% glucose should be given 

intravenously followed by nasogastric 10% sucrose 

to prevent recurrence. 

When the patient regains consciousness, an oral 

feed of a milk preparation or of sugar water is given 

immediately. This patient should then be given 

frequent oral feeds to prevent recurrence. 

Hypothermia 

The neutral temperature for malnourished patients is 

25–30°C. Staff, who are active and fully clothed,

516 

Malnutrition 

often find this temperature uncomfortably warm. 

They do not realize that a room temperature that is 

comfortable for themselves (20–24°C) is too cold 

for malnourished patients, particularly small, 

immobile, malnourished children. Young infants, 

those with marasmus, those with large areas of 

weeping skin and infected patients are particularly 

susceptible to hypothermia. Newly admitted patients 

should not be nursed near windows or other 

drafts. At night the mother should sleep in the 

same bed as the child. Little cages (cots or cribs) 

are used in many pediatric wards – they promote 

hypothermia, inhibit breast feeding and cause 

psychological stress for the child. The mother does 

not get adequate rest and this compromises her 

care of her child. Cots are for the benefit of the 

staff. The patients should be properly covered with 

hats, clothes and blankets. Washing should be kept 

to a minimum and done during the day; when 

patients are washed they must be immediately and 

carefully dried and not left wet. Hypothermia is a 

consequence of a low metabolic rate. 

When rectal temperature is below 35.5°C (94.9°F) 

or underarm temperature below 35°C (95°F) the 

patient should be warmed. This is best done by 

using the ‘kangaroo’ technique. The carer is the 

‘incubator’. The child is put on the mother’s bare 

chest and both are covered with a blanket; the 

mother is then given a hot drink to increase her 

skin blood flow. All hypothermic patients must 

also be treated for hypoglycemia. 

Severe anemia 

Deficiencies of the hematinics, folate, copper, 

vitamin E, ascorbic acid, pyridoxine and riboflavin 

are common. In urban areas blood levels of lead 

can be high. Malaria, hemoglobinopathies, favism 

and hookworm are regionally common. However, 

iron deficiency is not common, except in patients 

with chronic blood loss from intestinal helminths. 

The hemoglobin level usually increases rapidly 

during catch-up growth. Iron is added to the treatment 

only after transferrin has been resynthesized 

and bacteria are adequately treated. Moderately 

severe anemia is not otherwise treated. 

If the hemoglobin concentration is less than 40g/l 

on admission, then the patient can have a slow 

blood transfusion: 10ml/kg body weight of whole 

blood or packed cells over at least 3h. Anemia that 

is recognized after admission should not be 

treated. If the patient has heart failure secondary to 

anemia then the blood should be given as an 

exchange transfusion (an equal volume of blood is 

taken to that transfused; this is done by taking 

2.5ml/kg before transfusion and then at hourly 

intervals during the transfusion). It should be 

noted that anemia and heart failure often coexist. 

Heart failure that is due to the anemia is a highoutput 

failure, similar to beriberi, with warm 

peripheries and a wide pulse pressure. It is dangerous 

to transfuse a patient with anemia in heart 

failure, if the heart failure is due to other causes. 

Congestive heart failure and acute left heart failure 

These are common complications and causes of 

death. They occur as a complication of overhydration 

(especially when intravenous fluids are 

given), blood transfusion, plasma transfusion, or 

with formulae or drugs that have a high sodium 

content. It can also occur during early recovery 

when sodium effluxes from the cells and edema 

fluid is resorbed into the circulation at a faster rate 

than can be excreted by the kidney. Heart failure 

may be more common in areas where the diet is 

low in selenium. 

The important signs to look for are clinical deterioration 

with a gain in weight, an increasing respiratory 

rate or a rapid enlargement of the liver 

(Figure 31.10). Treatment should be started at this 

stage. However, heart failure has to be differentiated 

from inhalation, respiratory infection and 

toxic shock. The simplest way to make this differentiation 

is to examine the weight change. 

Respiratory distress with weight loss should be 

treated as pneumonia; with weight gain it should 

be treated as heart failure. The patient must be reexamined 

at very frequent intervals after any treatment 

is started so that, if there is not a rapid 

improvement, the diagnosis can be revised. The 

most useful signs are liver size and respiratory 

rate. Later signs are respiratory distress, rapid 

pulse, venous engorgement, cold hands and feet 

and a purple discoloration under the fingernails 

and tongue. Left heart failure often presents as 

sudden unexpected death. 

When heart failure is diagnosed, all oral intake and 

intravenous fluids should be stopped (the treatment 

of heart failure takes precedence over

feeding); the patient is fasted. This will ensure a 

negative fluid balance. If there is a danger of hypoglycemia 

then small amounts of 10% sugar water 

should be given orally. The fasting may also have 

the effect of allowing some sodium to return to the 

intracellular or interstitial compartments. It 

should be continued until the weight gained (a 

measure of the amount of fluid retention) since the 

start of symptoms has been re-lost, the respiratory 

rate has settled and the liver has returned to its 

admission size. A diuretic is given intravenously; 

the most appropriate diuretic is 1mg/kg of frusemide. 

Most malnourished patients do not respond 

to this diuretic; it is given because some 

patients do respond and this cannot be predicted. 

As these patients have a low total body potassium 

level, frequently hypokalemia, full doses of digitalis 

are never given; however, digitalis inhibits the 

sodium pump and allows sodium to re-enter the 

cell. A single dose of 5µg/kg digoxin should be 

given. 

If the patient continues to deteriorate, the physician 

is certain of the diagnosis of heart failure and 

heroic measures are definitely called for. The 

patient can then be given a 5ml/kg venesection. 

The blood should be kept sterile in the syringe, 

and the patient’s condition carefully watched. If he 

deteriorates, then the blood should be slowly 

returned; if there is marked improvement over the 

next 10min then the diagnosis was correct. No 

more than 10ml/kg should ever be taken. Although, 

in the right circumstances this is a highly 

effective treatment, it should be used only by those 

with considerable experience. In practice, unless 

the parent fully understands and trusts the staff, 

such treatment opens the staff to being accused of 

causing the death by bleeding the child. 

Experience with using agents that are used in 

other forms of heart failure have not been reported 

in heart failure associated with malnutrition. 

When heart failure is due to severe anemia then 

the treatment is by exchange transfusion, which is 

effectively transfusion and venesection combined. 

The amount of anemic blood withdrawn should 

exceed the amount of normal blood given. 

Transition phase 

By the end of the acute phase the patients should 

have all their complications treated, edema should 


Figure 31.10 An autopsy of a child with marasmickwashiorkor. 

Note the fatty liver, the presence of some 

subcutaneous fat, the greatly distended loops of bowel 

and the thinned transparent nature of the bowel wall. 

be resolving and treatment for infections started. A 

return of appetite is the sign that the patient is 

ready to progress to the transition phase. The 

appetite is used as a barometer of progress. Loss of 

appetite occurs when the patient’s metabolic 

processes cannot cope with the dietary intake. 

Great care must be taken not to overload the 

patient whilst he has a poor appetite – this is a 

warning that something is wrong metabolically. 

The diet is changed to a high-energy diet called 

F100, but it is given in restricted amounts (Table 

31.8). The volume given is the same as the diet 

given during the acute phase (F75), but as it is 

more concentrated the intake is increased by 25%. 

One would anticipate a weight gain on this diet of 

about 6g/kg per day. No other changes are made to 

the regimen.

518 

Malnutrition 

Because these patients may not be able to express 

thirst, their requirement for water may not be met 

from the formula alone. There is a considerable 

renal solute load from F100. High respiratory rates 

and fever, and infants and those treated in dry 

environments require extra water. This should be 

added to the formula, and the amount dispensed 

commensurately increased, if there is any doubt 

that all the children who require additional water 

will receive it. 

If any complications arise during the transition 

phase the children should be returned immediately 

to phase 1. No child should be force-fed or 

have a nasogastric tube in the transition phase. 

Milk intolerance 

Lactose or milk intolerance is seldom seen, even 

among severely malnourished patients. All patients 

should be started on the milk-based formulas. 

Intolerance is diagnosed only if copious watery 

diarrhea occurs with the introduction of milk feeds, 

it clearly improves when milk intake is reduced and 

it recurs again when the patient is challenged with 

milk a second time. In such cases, milk formulas 

can be partially or totally substituted by other liquid 

foods. Milk feeds should be reintroduced and their 

effects noted before a patient is discharged with a 

‘diagnosis’ of milk intolerance. 

Very occasionally other strategies are needed. The 

simplest is to ferment the milk to yoghurt. This is 

highly effective. Lactose- and milk-free formulas 

can be used but they are rarely available where 

severe malnutrition is common. Sometimes the 

addition of pancreatic enzymes (such as Pancrex 

V ® ) to the diet is beneficial, particularly in cases of 

severe kwashiorkor. 

Rehabilitation phase 

Together the acute and transition phases of treatment 

usually take about 7 days, but this is quite 

variable. The features that determine whether the 

patient has entered the rehabilitation phase are the 

complete loss of edema and a good appetite. In older 

patients with primary intestinal disease who 

require intravenous or nasogastric drip feeding, 

feelings of hunger and ‘well-being’ denote this 

phase of management. 

Table 31.8 A formula for use in 

malnourished children (F100) 

Ingredients Amount 

Dried skim milk 80g 

Sugar 50g 

Oil 60g 

Mineral mix to give the concentrations in 

Table 31.7 

Vitamin mix to give the concentrations in 

Table 31.7 

Water to 1000ml 

There is a great deal of flexibility in the way in 

which the rehabilitation phase of treatment is 

managed. There are now safe ready-to-use therapeutic 

formulas that can be used to continue the 

treatment at home. When well organized, with a 

home visitor and a good home environment, this 

approach is preferable. 

The return of appetite means that infections are 

under control and there is no major electrolyte 

imbalance or deficiency, even though the patient’s 

physiological responses are still abnormal and his 

capacity may be limited. At this stage the patient 

has resynthesized the cellular components needed 

to absorb and metabolize more food than is necessary 

for mere maintenance; he is ready to make new 

tissue. The single most important thing that determines 

the rate of recovery is the amount of the diet 

taken by the patient. The overriding principle of 

this phase is to feed the patient to appetite and to 

actively encourage him to eat. 

Moving from the transition and the rehabilitation 

phases is achieved simply by increasing the amount 

of the same diet that is given until the patient starts 

to refuse to finish the feed. Sufficient time must be 

spent with the patient to enable him to try to finish 

each feed; the attitude of the caretaker is crucial to 

success. The patient should never be left alone to 

‘take what he wants’ by himself – this is not what is 

meant by feeding to appetite. 

As the patient gains weight, his appetite and 

requirement steadily increase. Each day the weight,

the record of intake and the amount refused are 

plotted on a specially designed treatment chart. 

During rehabilitation most children and even adults 

take between 150 and 200kcal/kg per day. 

The formula should not be discontinued if visible 

fat appears in the stools, as a high proportion of 

fat is still absorbed. Fat malabsorption is, 

however, a frequent cause of the patient’s failing 

to gain weight at the expected rate. Fat content 

should be decreased only if it clearly produces 

watery diarrhea. 

It is appropriate to maintain the patients on the 

formula until they have achieved about 85% 

weight-for-height (children) or a BMI of 18kg/m 2 

(adults). At this time they usually signal their individual 

needs by reducing their appetites somewhat. 

They are then ready for discharge. 

With adults the general principles of giving sufficiently 

high intakes of energy, protein and all minerals 

and vitamins to enable them to gain weight 

rapidly must still be followed, despite the fact that a 

mixed diet is given. Many normal diets have a low 

energy density (in the tropics), and have insufficient 

protein, minerals and vitamins to sustain the rapid 

rates of growth. Further, the mixed diets often 

contain phytic acid and other anti-nutrients that 

markedly reduce the absorption of phosphorus, 

zinc, iron and calcium. To counter these effects, 

F100 should be given between meals of the mixed 

diet. For example, if a mixed diet is given three 

times daily the formula feed should also be given 

three times daily to make six ‘meals’ each day. 

Severely malnourished patients have a reduced 

iron-binding capacity; they are neither able to withhold 

iron from invading organisms nor to prevent 

the toxic effects of free iron itself. During the acute 

and intermediate phases of treatment iron should 

not be given, even in the presence of severe anemia. 

In the rehabilitation phase an iron supplement 

should be given. 

Assessing progress 

The patients should be weighed daily and their 

weight plotted on the special chart. It is useful to 

mark the target weight (BMI for adults) on the 

graph. They should gain weight at 5–20g/kg per day, 

usually about 10–15g/kg per day. 


Emotional and psychological stimulation 

At home patients, particularly children, are 

surrounded by familiar places and people. It is a 

major psychological trauma for a child to be separated 

from its mother, family and surroundings and 

to be closed into a cot with bars. The child needs to 

be with its mother and there should be adult beds 

for even very young patients so that the mother can 

sleep with the child. When the child is acutely ill 

the mother will sit by the bed. As he recovers he 

should be actively encouraged to interact with the 

other children. This is often discouraged by hospital 

staff on the grounds that it increases crossinfection 

and makes their job more difficult. This 

attitude, usually from senior staff, retards recovery 

and is much more damaging than the risk of crossinfection. 

The malnourished child needs affection and tender 

care from the very start of treatment, and interaction 

with other children when he becomes active. This 

requires patience and understanding by the hospital 

staff and the caretaker. When the children are over 

the acute and intermediate phases, they can be up 

and about for prolonged periods on large play mats. 

The risk of cross-infection is not increased substantially 

and the benefit for the children is much more 

important than the convenience of the staff. 

In hospital, it is not infrequent for ten different 

adults to interact with a patient over the course of a 

day, each one manipulating but rarely talking to or 

‘cuddling’ the patient. This is not good. It is particularly 

bad if the mother is not with the child. Each 

adult should talk, smile and laugh with the patient 

affectionately. 

Provision of child-oriented care, with affection and 

tenderness, is, of itself, insufficient. Severely 

malnourished children have delayed mental and 

behavioral development that requires treatment 

just as much as their delayed physical development. 

If such delays persist untreated they become 

the most serious long-term result of malnutrition. 

Psychological stimulation through play programs 

that start in hospital and continue after discharge 

can substantially reduce the mental retardation. 

The austerity of the traditional hospital should not 

be used for children in phase 2. Traditional buildings 

such as the child lives in at home are much 

more appropriate. They can often be erected in the 

grounds of a hospital or health center.

520 

Malnutrition 

There should be a large, safe, fenced area, with mats 

on the floor, where the children can play. Either 

mosquito nets or brightly colored mobiles should be 

over every bed. Hospital rooms should be brightly 

colored, with cheerful decorations that the children 

can relate to. Where possible the staff should not 

wear uniforms, or at least, have uniforms similar in 

design to standard maternal dress. Care is to be 

taken to avoid sensory deprivation; the child’s face 

should not be covered, they must be able to see and 

hear what is going on around them; they should not 

be wrapped or tied to prevent them moving around 

in the bed or on the floor. 

Toys must always be available. The mothers should 

be taught the importance of play and shown how to 

make the play materials. The toys should be safe, 

washable and appropriate for the child’s level of 

development. 

In hospital, one person should be in charge of organizing 

and running a play program. The play therapist 

should introduce new activities and play materials 

regularly; the activities should develop motor 

and language skills. It is useful to have a curriculum 

of activities and to play with each child in a structured 

way for 15–30min each day. This is in addition 

to the informal mixing of the children. The 

mothers should be taught the elements of the 

curriculum, at the appropriate level. It must be 

emphasized that the family should continue to 

make toys and play with their children after 

discharge, and indeed, throughout the whole period 

of development of their child. For this reason, teaching 

the mother is even more important than teaching 

the child. The mother should be intimately 

involved in the play therapy. 

Not only does increased physical activity encourage 

the development of the motor skills needed to 

explore the environment and play effectively but it 

may also enhance growth during nutritional rehabilitation. 

In immobile children, passive limb movements 

and allowing them to splash in a warm bath 

are helpful. 

Preparation for discharge 

There is not a sharp dividing line between the end 

of the rehabilitation phase and the preparation for 

discharge. The latter should be started during 

rehabilitation and completed after discharge. 

By the time of actual discharge the child needs to 

be ready for full integration into the family and 

community. As this is the environment that led to 

malnutrition in the first place, the family has to be 

equipped to cope with the patient to prevent recurrence. 

A child is usually considered ready for discharge 

when he reaches 85% of weight-for-height. 

Although these children are often referred to as 

‘recovered’, this is not usually true. Many have the 

underlying effects of chronic malnutrition with 

stunting in height and delayed mental development; 

these defects also require attention. 

However, management of these conditions 

depends upon long-term changes aimed at improving 

the resources, diet, hygiene, knowledge and 

skills of the family as a whole, and not upon care 

directed at the child alone. 

Attaining normal weight-for-height, of itself, is 

insufficient to discharge a child from the program. 

One of the problems with traditional hospital 

management is that anthropometric criteria alone 

are used for discharge, and follow-up is inadequate. 

Whenever possible, a home visit should be made. 

The child should be enrolled in a supplementary 

feeding program and followed there with regular 

weighing for 4–6 months after ‘recovery’. If there is 

no supplementary feeding program then community 

health workers or the local health clinic should 

follow these patients particularly. Where the patient 

is abandoned or the social and economic conditions 

at the home are hopeless, often because of absence 

of a caretaker, appeals should be made for foster 

homes or other forms of community support. 

The patient and caretaker have much to achieve and 

learn while they are in contact with the health staff. 

Education cannot be left to the last few days before 

the patient is discharged. Parents or caretakers 

should be taught about the causes of the patient’s 

malnutrition and how to prevent it in the future, 

whether the malnourished person is a child or 

infirm and elderly. For children, the parents need to 

know the consequences of malnutrition on future 

development and the steps that need to be taken, 

over a considerable time, to reverse any mental 

impairment and stunting in height. Practical 

instructions should be given on how to feed the 

child and continue nutritional rehabilitation at

home. As these families are the most vulnerable 

within a community, the opportunity can usefully 

be taken to give instruction on child feeding and 

rearing practices, family planning, personal 

hygiene, methods of income generation, sexually 

transmitted diseases and many other topics. 

Before discharge, children must be vaccinated in 

accordance with the local health regimen and provision 

made for booster doses to be given at the appropriate 

time. 

General considerations 

A child with severe malnutrition may indicate a 

serious problem in his household; the other children 

are also at risk. Therefore, nutritional and 

health education is not restricted to avoiding a 

recurrence of the index case, but should include the 

prevention or correction of nutritional problems of 

all the family members, especially young children, 

pregnant and lactating women and the elderly. 

The presence of children with severe malnutrition 

also suggests a high prevalence of malnutrition in 

that community. Perhaps a survey should be 

conducted. Most relief agencies determine where 

the malnourished live in order to plan their surveys 

and programs. Health promotion can include 

education and promotional programs for community 

leaders, local action groups and the community 

as a whole. Such programs focus on the psychological 

needs of vulnerable groups, promotion of breast 

feeding, appropriate use of weaning foods, nutritional 

alternatives using traditional foods, the 

absolute importance of dietary variety in order to 

get all the essential nutrients, personal and environmental 

hygiene, water management, adequate 

feeding practices during illness and convalescence, 

immunizations, early treatment of diarrhea, pneumonia 

and other diseases, income-generating strategies 

and adult literacy classes. 

Additional problems with management of 

malnourished patients 

Staff attitudes 

Sometimes a patient fails to respond because staff 

have a ‘feeling’ that their efforts for a particular 

patient are unlikely to succeed. This is particu- 

General considerations 521 

larly acute if they think that the child has HIV. In 

some places all failures are put down to HIV 

without any justification. Where such attitudes 

exist, the progress for the patient is poor; this in 

turn falsely confirms the ‘correctness’ of the original 

attitude and efforts are not made for future 

similar patients. This cause of failure-to-respond 

is among the most difficult to address, because it 

is usually based on the ‘experience’ of a longserving 

senior staff. The dependence of each 

patient’s well-being and survival on the attitudes 

of staff should be earnestly reviewed with them. 

Infections 

Atypical clinical manifestations of common 

infections occur in malnourished children. 

Infections with organisms that are not pathogenic 

in the well nourished are also common. The 

infections that are most commonly overlooked 

and interfere with a good nutritional response 

include: urinary tract infection, otitis media, 

tuberculosis, congenital syphilis, cytomegalovirus 

infection, hepatitis, AIDS, dengue, giardiasis, 

cryptosporidiosis and small-bowel bacterial 

overgrowth with secondary malabsorption. 

HIV is often thought to be a major factor in 

centers that have poor results. This is a false 

assumption. In one center in Burundi, patients 

with HIV had a 6% mortality whilst those 

without had a 5% mortality (difference not significant; 

Y. Grellety, personal communication). The 

length of phase 1 and total stay was only 1 day 

longer in the HIV-positive patients. A high prevalence 

of HIV is not a reason for failure; these children 

and adults should not be abandoned. 

Treating the malnutrition is one very positive 

thing that can be done for these patients. In retrospect, 

this result should not surprise, because the 

state of the immune system and infection is very 

similar in HIV disease and severe malnutrition. 

Specific nutrient deficiencies 

Many specific nutrient deficiencies impair the 

immune response. They can be the underlying 

cause of an infection that does not respond as 

expected to antibiotics. Occasionally patients may 

have a profound deficiency of one or more specific 

nutrients that are not adequately replaced by the

522 

Malnutrition 

therapeutic diet or nutrient supplements. Many 

commercial multivitamin-and-mineral preparations 

lack particular nutrients or do not contain 

sufficient amounts to treat a deficiency. They are 

generally designed for use as supplements by 

healthy individuals. Use of such preparations 

leads to overlooking a deficiency assumed to be 

‘covered’ by the treatment. The most frequently 

overlooked specific deficiencies include those of 

zinc, magnesium, copper, selenium, folic acid and 

vitamin E, although other micronutrients may be 

involved. Insufficient amounts of potassium, 

magnesium and phosphorus in the diet are common 

errors. 

Associated pathological conditions 

Malnutrition accompanies many congenital abnormalities, 

inborn errors of metabolism, tumors, 

immunological diseases and diseases of the major 

organs. All these conditions occur in areas where 

primary malnutrition is frequent, just as in rich 

countries, although they are less frequently recognized. 

Where primary malnutrition is prevalent 

children with secondary malnutrition are usually 

misdiagnosed as having primary malnutrition. As 

the prevalence of primary malnutrition falls the 

proportion of malnourished children who have an 

associated pathology rises. Failure to respond to 

treatment should lead to investigation of the major 

organ systems for primary pathology. 

Specific dermatosis of kwashiorkor 

Spontaneous resolution can be expected with 

improved nutrition. Atrophy of the skin in the 

perineum leads to severe napkin dermatitis, especially 

in children or the elderly with diarrhea or 

incontinence. The perineum should be left 

exposed to dry without napkins. A barrier such as 

zinc and castor oil ointment, petroleum jelly or 

paraffin gauze dressing (tulle gras) to raw areas 

helps to relieve pain and prevent infection. The 

management should be the same as that used for 

burns. The zinc supplement contained in the diet 

may be insufficient in these patients, as zinc deficiency 

almost always accompanies severe skin 

lesions. These patients should always be given 

systemic antibiotics. 

Candidiasis 

Most malnourished children have candidiasis. In 

the mouth it can be seen as whitish plaques. 

However, even when the mouth is free of lesions, 

it may occur in the esophagus, stomach and 

rectum as well as on any damp moist skin. In 

severe malnutrition systemic candidiasis with 

growth in the respiratory tract and blood also 

occurs. Oral nystatin suspension should be given 

to all patients with candidiasis. In addition, 

nystatin cream should be applied to any cutaneous 

lesions. Systemic candidiasis should be treated 

with drugs such as ketoconazole. 

Drug metabolism in malnourished patients 

Clearly the physiological and body compositional 

changes in the malnourished patient will alter the 

pharmocokinetics of many drugs. There has been 

very little research on this aspect of either primary 

malnutrition or even the malnutrition associated 

with neoplasia or intestinal disease. A patient with 

7% of body weight as fat will have a very different 

response to a fat-soluble drug from one with 40% 

of body weight as fat, and yet this is rarely taken 

into consideration in prescribing. Poor absorption 

from the intestine, disordered hepatic conversion 

of drugs, reduced renal clearance, increased bacterial 

deconjugation of drugs excreted in the bile, 

and alterations in receptors and enzyme targets for 

drugs each affect their efficacy and potential toxicity. 

The changes are sufficiently complex for the 

result of giving a new drug to be unpredictable. 

Nevertheless, these factors should be considered 

in the treatment of all malnourished patients and, 

where available, therapeutic drug monitoring 

should be used. Clearly the variables are potentially 

extremely important. For example, if a 

patient with malnutrition, secondary to neoplasm, 

has features of kwashiorkor, is depleted in antioxidant 

nutrients and has a low cellular glutathione 

level, then giving cytotoxic drugs or radiotherapy 

may damage the patient irretrievably. 

Unnecessary drugs should never be given during 

the acute stage. Unwanted toxic effects are more 

likely for most drugs. The list of drugs that do not 

need to be used is long. In particular, fever should 

be treated with tepid sponging, not with paraceta-

mol. Vomiting should not be treated with the usual 

antiemetics (promethazine, etc.) and diarrhea 

should never be treated with an antispasmodic. 

Many of the drugs used to treat tuberculosis are 

hepatotoxic. It is wise to use these drugs carefully 

during the first few days after admission. 

Conclusions 

The problems raised by malnutrition affect not 

only the individual but society as a whole, at 

medical, social, ethical, moral and political levels. 

REFERENCES 

1. Pelletier DL. The relationship between child anthropometry 

and mortality in developing countries: implications 

for policy, programs and future research. J Nutr 

1994; 124 (10 Suppl): 2047S–2081S. 

2. Prudhon C, Briend A, Laurier D et al. Comparison of 

weight- and height-based indices for assessing risk of 


Malnutrition in its numerous guises, especially 

amongst children and the elderly, is the most 

common serious illness in the world today. 

Lessons learnt from the study and management of 

these children have relevance for malnourished 

individuals of all ages and with a wide variety of 

disorders. A clear understanding of the etiology 

and pathogenesis is a prerequisite for designing 

effective intervention and prevention programs. 

The legacy of childhood malnutrition is to be seen 

in adults who are stunted physically and 

mentally; it may lay the seeds for many of the 

chronic diseases of unknown etiology in adult 

life. 

death in severely malnourished children. Am J 

Epidemiol 1996; 144: 116–123. 

3. Williams CD. A nutritional disease of childhood associated 

with a maize diet. Arch Dis Child 1933; 8: 423–428.

32 

Biotherapeutic and 

nutraceutical agents 

Kirsi Laiho and Erika Isolauri 

The science of nutrition: from basic 

needs to specific health effects 

The role of the diet in health has changed as scientific 

knowledge has increased (Figure 32.1). The 

basic foundation lies in a healthy, balanced diet 

that follows the dietary recommendations and 

guidelines appropriate for age and life-stage with 

the aim of meeting the metabolic requirements and 

the needs for growth and development in children. 

The first goal of nutritional management is 

directed towards the prevention of direct dietrelated 

deficiencies, such as scurvy caused by low 

Basic 

diet 

Balanced 

diet 

Specific 

diet 

Figure 32.1 The steps of nutrition management. 

Nutraceuticals 

Dietary recommendations and guides for a balanced diet 

to meet metabolic requirements and growth and development 

vitamin C intake. The second target is the prevention 

of nutrition-related chronic diseases. For 

example, an unbalanced diet containing excessive 

amounts of saturated fatty acids has been shown to 

be associated with an increased risk of coronary 

heart disease. Furthermore, specific requirements 

for nutritional management are set by a variety of 

diseases necessitating carefully planned diets or 

usage of clinical dietary products. The current 

research interest is directed towards the invention 

of novel dietary compounds with specific effects 

in health promotion and management of diseases 

beyond the nutritional impact of food. 

Dietary management and risk reduction 

of specific diseases by means of diet with 

added or modified nutrients or compounds 

nutraceuticals 

Dietary management of specific diseases by 

means of clinical dietary products 

e.g. hydrolyzed infant formula for cow's milk allergy 

or gluten-free cereals for celiac disease 

Dietary management of specific diseases (e.g. diabetes mellitus) 

by means of ordinary food 

Balanced diet with additional benefit to reduce 

the risk of nutrition-related chronic diseases 

Increasing scientific knowledge 

525

526 

Biotherapeutic and nutraceutical agents 

Dietary recommendations and guidelines 

appropriate for age and life-stage 

Dietary recommendations and guidelines are set to 

direct dietary food and nutrient intake for maintenance 

of health. Specifically, dietary recommendations 

aim at prevention of nutrient deficiencies but 

also at reducing the risk of developing nutritionrelated 

chronic diseases. 

The dietary recommendations vary amongst 

regions so that many countries have formed their 

own recommendations. However, major international 

health-related organizations such as the 

Food and Agriculture Organization (FAO) and 

World Health Organization (WHO) have searched 

for more uniform recommendations. 1–3 The reader 

is advised to refer to these or national original 

reports for detailed description of the recommendations. 

Dietary guidelines for populations have 

been given both as recommended daily intakes 

(recommended daily allowances, recommended 

nutrient intakes, dietary reference values/intakes) 

of certain nutrients and as food guides (e.g. food 

pyramid) that direct the consumption of foods and 

food groups. Food guides may also include recommendations 

on eating behavior and food habits. 

The recommended nutrient intake is generally 

understood as the level of nutrients sufficient to 

meet the daily nutrient requirements of most individuals 

of a specific age and gender, based on an 

estimated average nutrient requirement plus two 

standard deviations above the mean. Specific 

recommendations are given for children and 

adults as well as for pregnant and lactating 

women. The recommendations can be deployed to 

provide guidance on appropriate dietary composition, 

for the assessment of dietary surveys, for 

outlining food policies or for food labeling 

purposes. The food guides, such as the 

well-known food pyramid, are more comprehensible 

and particularly helpful in nutrition counseling. 

The guides direct the use of foods or food 

products and aim to meet the nutrient intakes set 

by the recommended daily intake. 

Early nutrition and later consequences 

It is understood that dietary intake that satisfies 

nutritional demands and maintains a good nutritional 

status is important for the growth and devel- 

opment of children. However, the nutrition of the 

infant begins before birth, in utero, when the nutrition 

of the mother and also placental function 

regulate the growth and development of the fetus. 

The nutrition of the mother even before pregnancy 

may be important for the well-being of the fetus 

and child, as the nutrient stores that are being 

utilized during pregnancy and breast feeding are 

accumulated at an early stage. 4 As a good example, 

a sufficient availability of folic acid and the 

prophylactic supplementation of folic acid to the 

mother reduce the incidence of birth complications 

and neural tube defects. 5 Indication of an 

unbalanced nutrient intake (maternal hypercholesterolemia 

during pregnancy) induces changes 

in the fetus that determine the susceptibility of 

children to fatty-streak formation and subsequent 

atherosclerosis. 6 

Both epidemiological 7–9 and experimental 10,11 

studies suggest that several chronic diseases of 

later life, including coronary heart disease, hypertension 

and type 2 diabetes, are programmed 

during the fetal period. This theory on the fetal 

origins of adult disease suggests that alterations in 

fetal nutrition and endocrine status result in developmental 

adaptations that predispose individuals 

to cardiovascular, metabolic and endocrine 

disease in adult life. One of the first reports 

showed that those individuals who had had low 

birth weights had relatively high death rates from 

coronary heart disease in adult life. 9 The results 

have since been replicated in other populations 

and with other chronic lifestyle-related diseases. 

Also, the mechanisms have been searched for in 

experimental studies and the specific causal relations 

are actively being explored. The research is 

also directed towards identifying critical phases in 

which the impact of nutrition is most important 

for the risk of chronic diseases. 

Specific dietary requirements of disease 

A disease state may set specific requirements for 

energy and nutrients, the deficiency of which may 

contribute to the deterioration of nutritional status 

and growth failure in children (Figure 32.2). The 

reduced energy availability may originate from 

three main sources: reduced food intake due to 

poor appetite or symptoms of disease such as 

gastrointestinal complaints or poor utilization of

nutrients; increased losses, e.g. due to steatorrhea; 

or increased requirements, e.g. due to infections. 

On the other hand, physical activity may be 

reduced, owing to ill health, and compensates for 

increased energy requirements. Although 

cause–consequence relationships are difficult to 

prove, such events may result in exacerbation of 

the disease or in reduced survival. A careful monitoring 

of diet and nutritional status and intervention 

at an early stage are vital for the prevention, or 

halting the development, of this vicious cycle with 

possibly deleterious effects. 

Nutritional intervention includes provision of 

sufficient amounts of energy and nutrients, by 

increasing the amount of food eaten or the nutrient 

density of the diet, or by using clinical nutritional 

products to enhance the nutrient density, or by 

providing an additional source of energy, for 

example as snacks. In a range of diseases with 

known nutritional management, the specific products, 

such as hydrolyzed infant formulas for cow’s 

milk allergy, 12 low-protein and special amino acid 

products for phenylketonuria 13 or gluten-free 

products for celiac disease 14 are critical in the 

management of these patients. The next step might 

be the dietary management and risk reduction of 

specific diseases by means of diet with added or 

Intake, 

utilization 

Losses 

Energy deficit 

Weight loss, growth 

failure 

Deterioration of end-organ function 

e.g. gastrointestinal tract, 

immune defense 

Needs 

Figure 32.2 Possible causes for deterioration of 

nutritional status and growth failure in children. 

The science of nutrition: from basic needs to specific health effects 527 

modified nutrients or compounds, i.e. nutraceuticals. 

Food consumption and risk of chronic diseases 

The diet in Western societies has faced changes 

that reflect industrialization, urbanization, 

economic development and market globalization 

15 . The availability of a more diverse selection 

of foods has improved the nutritional status of 

populations. However, not all the changes in food 

consumption have led to beneficial effects with 

regard to health status. The impacts of changes in 

the diet are further enforced by alterations in 

lifestyle such as decreased physical activity and 

increased tobacco use. In a recent report by expert 

panels in WHO and FAO, the global and regional 

food consumption patterns and estimated trends 

from 1960 to 2030 and their impact upon the 

prevalence of chronic, non-communicable, 

diseases were discussed. 15 According to the report, 

it may be possible to reduce the risk of cardiovascular 

diseases, cancer, diabetes and obesity by 

changing dietary habits. Particularly important 

targets contributing to deaths from chronic 

diseases are obesity, high blood pressure, high 

cholesterol concentrations and low levels of physical 

activity. According to the WHO/FAO expert 

panel, the key changes in food consumption in 

recent decades and also in the next 15–30 years, 

are increased energy intake and increased 

consumption of fat and added sugar, greater saturated 

fat intake and reduced intakes of complex 

carbohydrates and fiber. 15 Intakes of fruits and 

vegetables have increased in some areas, whilst 

the recommended high average intakes have been 

reached only in a minority of the world’s population. 

15 

In light of the link between early nutrition with 

later consequences, the importance of pediatric 

nutrition is further emphasized. Furthermore, 

dietary habits are established at an early age, by 

the number and type of experiences with various 

foods and also by model learning from parents, 

friends, day-care centers and schools. 16 

A population study comparing data on serum 

cholesterol, anthropometric indices and dietary 

intakes in children aged 1–18 years of age from 

Japan, Spain and the USA showed the effects of

528 


Westernization on blood cholesterol concentration. 

17 Both in Japan and in Spain the intake of 

total and saturated fat had increased substantially. 

In studies from Northern Europe, changes in food 

consumption and consequently in nutrient intakes 

towards the recommended intakes seemed to 

explain the serum cholesterol concentration which 

was reflected in a decline in coronary heart disease 

mortality. 18 It has also been shown that the unfavorable 

dietary habits, reflected in high intake of 

fat and saturated fatty acids contributing to the 

risk of coronary heart disease, may be adopted 

already in childhood. 19 

Cardiovascular diseases are a good example of 

diseases in which associations between food 

consumption, nutrient intake, biological markers 

of disease (serum cholesterol concentration) and 

risk of disease have been documented. It has also 

been shown that dietary interventions modifying 

food intake in adults 18 or in children 20 to resemble 

that recommended for healthy eating, result in 

beneficial changes in anthropometry and serum 

cholesterol concentration that are reflected in 

reduced risk of chronic Western diseases. 

Although fat intake in accordance with the recommended 

intake has been shown to be safe in terms 

of growth and neurological development, 21,22 

concerns have been raised over low fat intake 

(

long-chain polyunsaturated fatty acids, oligosaccharides 

and nucleotides have since been used in 

immunonutrition beyond formula-age. Even the 

pre-milk provided by the cow after delivery – 

bovine colostrum – has been suggested to be used 

in humans for modulation of the immune system, 

as reviewed by Solomons. 33 

At weaning, the infant gradually transfers to adulttype 

feeding. The transition period may be significant 

in terms of adopting dietary habits. Intakes of 

some nutrients, particularly vitamin E and zinc, 

may be low during dietary transition in early 

childhood and may actually decrease, despite 

increases in energy intake. 34 

The integrity of the gut barrier function – 

the target of protective nutrients 

The primary role of the gastrointestinal tract is 

digestion and absorption of nutrients to meet the 

metabolic requirements and the demands of 

normal growth and development. In addition to 

this, the intestinal mucosa provides a protective 

host defense against the constant presence in the 

gut lumen of antigens from food and microorganisms. 

An abrupt change in gut barrier function 

occurs at birth, when it is switched from 

processing amniotic fluid to digesting milk and 

when the intestinal colonization commences. 

Gut barrier 

Protection against potentially harmful agents is 

ensured by a number of factors, including saliva, 

gastric acid, peristalsis, mucus, intestinal proteolysis, 

intestinal microbiota and epithelial cell 

membranes with intercellular junctional 

complexes. 35 The surface of mucosal membranes 

is protected by a local adaptive immune system. 

The gut-associated lymphoid tissue represents the 

largest mass of lymphoid tissue in the human 

body. Consequently, it comprises an important 

element of the total immunological capacity of the 

host. The regulatory events of the intestinal 

immune response take place in different compartments: 

aggregated in follicles and Peyer’s patches, 

distributed within the mucosa and in the intestinal 

epithelium, as well as in secretory sites (reviewed 

The integrity of the gut barrier function 529 

in reference 24). IgA antibody production is abundant 

at mucosal surfaces. In contrast to IgA in 

serum, secretory IgA is present in dimeric or polymeric 

form. Secretory IgA is resistant to intraluminal 

proteolysis and does not activate inflammatory 

responses, which makes secretory IgA ideal for 

protecting mucosal surfaces. These elements in the 

gut are part of the common mucosal immune 

system, including the respiratory tract and 

lacrimal, salivary and mammary glands, and 

thereby an immune response initiated in the gutassociated 

lymphoid tissue can affect immune 

responses at other mucosal surfaces. 

There are specialized antigen transport mechanisms 

in the villous epithelium and particularly in 

Peyer’s patches, which are crucial in determining 

the subsequent immune responses to the antigen. 

35 In addition to the first line of gut defense – 

immune exclusion – there are specialized antigen 

transport mechanisms in the villous epithelium. 

Antigens are absorbed across the epithelial layer 

by transcytosis, and here the main degradative 

pathway entails lysosomal processing of the 

antigen. 36,37 A minor pathway allows the transport 

of unprocessed antigens. Peyer’s patches are 

covered by a unique epithelium. Antigen transport 

across this epithelium is characterized by rapid 

uptake and reduced degradation. In health, paracellular 

transfer of macromolecules is controlled 

by intact intercellular tight junctions, which 

prevent aberrant antigen absorption. The second 

line of host defense – immune elimination – is 

directed towards antigenic compounds penetrating 

the mucosa. Antigens are presented to subjacent 

T cells; these differentiate into various effector 

cells that mediate active immune regulation 

and promote the differentiation of IgAsecreting 

B cells. 38 

Initial signals for the maturation of the gut barrier 

functions are considered to stem from components 

of the innate immunity, which generates the necessary 

initial step for the targeted and specific function 

of the adaptive immune system. 

Gut microbiota 

The human gastrointestinal tract harbors a 

complex collection of micro-organisms, a specific 

microbiota for each person. 39 The generation of the

530 


immunophysical regulation in the gut depends on 

the establishment of the indigenous microbiota. 

At birth the gastrointestinal tract of the newborn is 

sterile. The maternal intestinal microbiota is the 

first source of colonizing bacteria. Subsequently, 

the feeding practice and the home environment of 

the child influence the composition. Breast 

feeding encourages the growth of bifidobacteria, 

while formula-fed infants have a more complex 

microbiota with bifidobacteria, enterobacteria, 

lactobacilli, bacteroides, clostridia and streptococci. 

40 New molecular methods indicate that bifidobacteria 

can reach up to 90% of the total fecal 

microbiota in breast-fed infants. After weaning, 

the composition of the microbiota resembles that 

of the adult. Although bacteria are distributed 

throughout the intestine, the major concentration 

of microbes and metabolic activity can be found in 

the large intestine. From culture-based data, it is 

thought that at least 500 different microbial 

species exist, although on a quantitative basis 

10–20 genera probably predominate: Bacteroides, 

Lactobacillus, Clostridium, Fusobacterium, Bifidobacterium, 

Eubacterium, Peptococcus, Peptostreptococcus, 

Escherichia and Veillonella. 39 

The composition of the microbiota is associated 

with several disease states within the intestine and 

also beyond the gastrointestinal tract. Inflammation 

is accompanied by imbalance in the 

intestinal microbiota in such a way that the 

host–microbe interaction is disturbed and an 

immune response may be induced by resident 

bacteria. 41,42 

Modification of intestinal microbiota to increase 

the predominance of specific non-pathogenic 

bacteria and thereby to alter the intestinal milieu 

has been taken as an alternative to attain prophylactic 

or therapeutic effects in intestinal infectious 

conditions in childhood. Recent clinical and nutritional 

studies and characterization of the 

immunomodulatory potential of specific strains of 

the gut microbiota, beyond the effect on the 

composition of the microbiota, may lead to future 

applications also for allergic and inflammatory 

diseases. Such probiotics, acting as nutraceutical 

agents, need their mechanisms to be thoroughly 

clarified, either to control specific physiological 

processes in the evolution of disease in populations 

at-risk or to manage of specific diseases. 

Protective nutrients for the gastrointestinal 

tract 

The integrity of the intestinal mucosa and the 

structure of the villi are crucial for assimilation of 

nutrients from the gastrointestinal tract and for 

intestinal defense against invading pathogens and 

antigens. This is obvious in diseases such as celiac 

disease, where the structure of the intestinal villi is 

disturbed by dietary gluten thereby affecting nutrient 

assimilation and the nutritional status of the 

patients if an appropriate diet is not followed. 

However, despite an apparently normal histological 

presentation of the mucosa, the functionality of 

the enterocytes may be altered. It has been shown 

in malnourished patients that, despite a normal 

villous structure of the small intestine, the intestinal 

permeability may be increased. 43 Reduced 

integrity of the mucosa could even result in an 

outward diffusion of nutrients towards the lumen 

which would further prevent the absorption of 

nutrients. 

Increased permeability of the intestinal mucosa 

may also result in increased susceptibility to infections. 

Infections may further cause deterioration of 

the intestinal integrity, owing to increased cell 

turnover, and therefore increase nutrient requirements. 

Turnover of cells in the gastrointestinal 

mucosa is rapid and its integrity mainly depends 

on the production of new cells at a rate equal to 

that at which cells are lost. 44 Therefore, even a 

short-term deficit in the nutrient supply to the 

mucosa may affect the mucosal integrity and result 

in villous atrophy. Nutrition through the gastrointestinal 

tract is important in maintaining the 

mucosal structure and function; lack of nutrients 

may result in decreased villous height, increased 

permeability and decreased immunity. 

Probably the single most important nutrient to the 

mucosa is glutamine (both from luminal and 

vascular sides), which is consumed by replicating 

cells and affects the structure and function of the 

cells. Glutamine may be required in increased 

amounts by patients suffering from a catabolic 

insult such as injury or severe infection. In 

parenteral nutrition, glutamine improves nitrogen 

balance, supports gut function and alleviates catabolic 

demands upon muscle mass. However, 

whether glutamine is necessary for the preservation 

of normal intestinal morphology and function

in humans during parenteral nutrition is not clear, 

as reviewed by Buchman. 45 In another systematic 

review, in enteral feeding of critically ill patients, 

the immune-enhancing nutrients including glutamine, 

arginine, neucleotides and n-3 fatty acids 

reduced the appearance of infectious complications, 

but not the overall mortality. 46 

Vitamin A is also important for the differentiation 

of cells and may have a central role in mucosal 

function. Deficiency impairs innate immunity by 

diminishing the function of neutrophils, 

macrophages and natural killer cells as well as 

antibody-mediated responses by T helper (Th) 

cells. 47 Vitamin A deficiency compromises 

mucosal epithelial barriers in the gastrointestinal 

tract, particularly when complicated by infection. 

Most data concerning the effects of nutrients on 

the structure and function of the epithelium are 

derived from experimental studies, but it has also 

been shown in children that recovering from diarrhea 

may be faster when vitamin A supplement is 

received compared to placebo. 48 

Probiotics and prebiotics 

Recent demonstration that the gut microbiota is an 

important constituent of the intestine’s mucosal 

barrier has introduced new therapeutic strategies 

for fighting enteric infections and possibly other 

intestinal inflammatory conditions (Figure 32.3). 

Three approaches for improving intestinal 

integrity include the use of probiotics, prebiotics 

and symbiotics. Probiotics are ‘a live microbial 

food ingredient that is beneficial to health’. The 

prerequisites for probiotic action include survival 

in and adhesion to specific areas of the gastrointestinal 

tract and competitive exclusion of 

pathogens or harmful antigens. The application of 

probiotics has since been supplemented with the 

concept of prebiotics. A prebiotic is a ‘nondigestible 

food ingredient that beneficially affects 

the host by selectively stimulating the growth 

and/or activity of one or a limited number of bacteria 

in the colon that have the potential to improve 

host health’. The most commonly used prebiotics 

are carbohydrate substrates with the ability to 

promote the components of the normal intestinal 

microbiota that may evince a health benefit to the 

host. However, prebiotics can also be nonabsorbable 

substrates which stimulate the growth 

Increased 

intestinal 

permeability 

The integrity of the gut barrier function 531 

Antigen 

degradation 

Antigen 

absorbtion 

route/rate 

Antigen 

Probiotic 

therapy 

Balance of pathogenic/ 

beneficial strains 

Microbiota 

Antigen 

presentation 

Balance of 

pro-/antiinflammatory 

cytokines 

Figure 32.3 Potential targets for probiotic therapy 

(adapted from reference 42). 

Inflammatory 

response 

of probiotics. When the two are applied together, 

the concept is defined as symbiotic. 

Recent research has expanded the definition of 

probiotics, by demonstrating that genetically engineered 

microbes and non-viable microbes may 

equally possess such potential. 42 However, 

normalization of the properties of unbalanced 

indigenous microbiota by specific strains forms 

the rationale of probiotic therapy. Oral introduction 

of probiotics has been shown to reinforce the 

various lines of gut defense: immune exclusion, 

immune elimination and immune regulation. 

Probiotics also stimulate non-specific host resistance 

to microbial pathogens and thereby aid in 

their eradication. 

So far, the best-documented clinical application is 

the treatment of acute diarrhea by specific probiotic 

bacteria. 49 The beneficial clinical effect in 

infantile diarrhea by probiotic therapy has been 

explained by stabilization of the indigenous microbiota, 

reduction in the duration of rotavirus shedding 

and reduction in increased gut permeability 

caused by rotavirus infection, together with a 

significant increase in cells secreting IgA against 

rotavirus. The probiotic performance of strains is 

such that different probiotic strains, even strains 

belonging to the same species, have different 

immunomodulatory effects. Hence, current probiotic 

research is directed towards identification of 

specific strains with potential to reduce the risk of 

diseases associated with gut barrier dysfunction.

532 


Modern nutrition for children – 

allergic disease 

Allergic diseases, manifesting as atopic eczema, 

allergic rhinitis and asthma, are on the increase in 

industrialized countries, currently constituting the 

most common chronic diseases of childhood. 

Despite the pronounced hereditary element in 

allergic disease, genetic factors are unlikely to 

explain the increased emergence of the atopic-type 

immune responsiveness to environmental antigens. 

In contrast, changes in nutrition along with 

general environmental changes appear to shape 

the immune responder type of the host during a 

critical period of life. Specifically, the changes 

associated with Western lifestyle tend to favor the 

atopic Th 2-biased immune responder type. 

The specific processes that initiate the vicious 

cycle of allergic inflammation, remain unresolved. 

Recent advances, however, call into question a 

causal cascade of exposure to antigenic proteins, 

sensitization and hypersensitivity; the exposure to 

allergens sensitizing the host immune system may 

not necessarily induce allergic disease. Indeed, 

sensitization to indoor allergens such as house 

dust mite, as assessed by specific IgE, but not the 

level of exposure to these allergens, has been associated 

with asthma, wheeze and increased 

bronchial responsiveness. 50 In like manner, exposure 

to cow’s milk antigen during 3 days after 

birth, in 1533 breast-fed neonates, did not carry a 

risk of atopic disease during the first 5 years of 

age. 51,52 These data would imply that eradication 

of potential allergenic proteins from the early environment, 

including the diet, may not apply in 

allergy-prevention strategies. 

In contrast, one justifiable strategy against allergic 

disease may be based on the administration of 

tolerogenic gut-processed peptide fragments of a 

specific protein, and the use of specific dietary 

compounds such as fatty acids and antioxidants, 

or on providing a microbial stimulus for the immature 

immune system by means of cultures of beneficial 

live micro-organisms characteristic of the 

healthy human gut microbiota. 53 However, before 

such strategies can be developed, a better understanding 

will be necessary of the processes initiating 

and regulating the allergic inflammatory 

response. Further, a better understanding of the 

interaction between nutrients is required. 

Consequently, the properties of specific dietary 

compounds and their combinations, in an optimal 

food matrix, might be exploited in the development 

of specific prophylactic and therapeutic 

interventions. 

Elimination diets 

Elimination of potentially allergenic foods, e.g. 

cow’s milk, egg, wheat and fish, from the pregnant 

or breast-feeding mother’s or the infant’s diet has 

been a common approach in attempts to prevent 

allergic disease in high-risk infants. The approach 

of eliminating foods from the diet is perplexing, for 

two reasons. First, the benefits of elimination diets 

in prevention of allergic disease have been inconclusive. 

54 Especially in long-term prevention of 

allergic disease, elimination diets have proved 

unsuccessful. Dietary antigens may actually be 

protective from allergic disease as they may induce 

tolerance to antigens rather than sensitization. 52,55 

Second, besides allergenic proteins in the diet, 

other dietary factors might be associated with the 

development of allergic disease. 

Recent studies on the immunomodulatory properties 

of fatty acids and the antioxidant properties of 

certain nutrients including ascorbic acid, αtocopherol, 

β-carotene, selenium and zinc, have 

shown that food is not only a source of dietary 

antigens causing sensitization, but may also 

contain protective factors. Thus, elimination diets, 

i.e. eliminating specific offending antigens, should 

be reserved only to the management of proven 

food allergy. A better approach in the prevention of 

allergic disease might be to search for protective 

nutrients in the diet that may reinforce the immature 

immune defense of the infant. 

Modification of allergenic proteins 

The nutritional theories attracting current research 

interest relate to identification of active 

compounds which reinforce an anti-inflammatory, 

potentially tolerogenic type of immune response to 

assimilate allergenic challenges. Factors that influence 

the allergenicity of a protein include molecular 

complexity, solubility and stability, and its 

concentration. Heat treatment of cow’s milk 

proteins can affect the conformational epitopes of

allergens and facilitate their hydrolysis. To 

produce the least allergenic formulas for patients 

with documented cow’s milk allergy, cow’s milk 

proteins are modified by multiple enzymatic 

hydrolyses with progressive destruction of sequential 

epitopes. Such products are classified as 

partially hydrolyzed or extensively hydrolyzed 

formulas. However, enzymatic hydrolysis does not 

render the formula non-allergenic, as the optimal 

extent of hydrolysis is not known and traces of the 

original protein are detected in the hydrolysate. 56 

The approach may also be used in an attempt to 

reduce the risk of allergic disease. 57 Degradation of 

antigens is a necessary initial step in controlling 

inflammatory responsiveness to dietary antigens. 

55,58,59 Such processing has been linked to the 

potential to generate peptides with suppressive 

effects on lymphocyte proliferation in healthy 

subjects; systemic immune responses to gutprocessed 

antigens are preferentially directed 

towards suppression. The mechanisms of the 

preventive potential of specifically modified 

dietary proteins remain still poorly understood. 

Dietary lipids 

Increasing evidence has been provided to suggest 

that dietary lipids, especially long-chain polyunsaturated 

fatty acids (PUFA), and mediators 

synthesized from PUFA, regulate immune function 

and therefore contribute to the development and 

severity of the symptoms of allergic disease. 

Polyunsaturated n-6-series fatty acids derived from 

dietary linoleic acid (18:2, n-6) result in the production 

of eicosanoids, which are considered to 

have proinflammatory properties, whilst n-3-series 

fatty acids derived from dietary α-linolenic acid 

(18:3, n-3) appear to have less potent biological 

functions, even anti-inflammatory properties. 60 

Owing to the typically higher dietary intake of 

linoleic acid than α-linolenic acid in developed 

countries, it is thought that the metabolism of 

linoleic acid predominates. 

The most notable of the PUFA-derived mediators is 

arachidonic acid (20:4, n-6)-derived eicosanoid 

prostaglandin (PG)E2. PGE2 results in elevated IgE 

synthesis, owing to the induction of B-cell differentiation 

in the presence of interleukin IL-4. 61 

Indeed, the most frequently reported abnormality 

Modern nutrition for children – allergic disease 533 

in cell fatty acid composition of atopic patients has 

been an imbalance between series n-6 and n-3 

fatty acids, 62–64 predisposing the patients to the 

adverse effects of PGE2. Nevertheless, whether the 

observed alterations in the fatty acid composition 

of cells in the patients with atopic disease result 

from a primary defect that contributes to the onset 

of atopic disease or are a consequence of the atopic 

disease itself is currently poorly understood. This 

is especially intriguing as, despite their apparent 

proinflammatory role, n-6 fatty acids may also 

contribute to an anti-inflammatory intestinal environment, 

as antigen stimulation up-regulates PGE2 

production from arachidonic acid with ensuing 

suppression of antigen-specific T-cell proliferation 

in gut-associated lymphoid tissue. 65 However, the 

effects on dietary n-6 fatty acids may be counteracted 

by n-3 series fatty acids derived from dietary 

α-linolenic acid (18:3, n-3) or directly from marine 

food sources (eicosapentaenoic acid; 20:5, n-3 and 

docosahexaenoic acid; 22:6, n-3). Eicosanoids 

derived from α-linolenic acid appear to have a less 

potent biological, even anti-inflammatory, function 

compared to n-6-series fatty acids. The antiinflammatory 

properties of n-3 fatty acids arise 

from their capacity to inhibit the release of arachidonic 

acid from membrane phospholipids, thereby 

reducing the production of arachidonic acidderived 

eicosanoids whilst the synthesis of n-3 

fatty acid-derived eicosanoids increases. 66 Owing 

to the likely interactions between the nutrients, 

the overall fatty acid composition and the quantity 

of fat within the diet with respect to other nutrients 

may be crucial in the search for the optimal 

diet for prevention and management of allergic 

disease. 

Dietary antioxidants 

In atopic disease, inflammatory processes result in 

endogenously generated oxidative stress which 

dietary antioxidants, such as ascorbic acid, βcarotene, 

α-tocopherol, selenium and zinc may 

counteract. 67 Both cellular enzyme-based antioxidants 

and diet-derived antioxidants counteract 

oxidative stress and dampen the inflammatory 

response. 67 Dietary antioxidants may thus be 

important in implementing the ability of the individual 

to restrain the inflammatory response and 

in avoiding injury to tissues. Low concentrations

534 


of β-carotene, ascorbate and α-tocopherol have 

been measured in plasma in wheezing illness, 

suggesting that antioxidant deficiencies may be 

associated with symptoms of allergic disease. 68 

However, at present the role of antioxidants in the 

onset of allergic disease remains obscure. 

Moreover, data accumulated to date on the specific 

antioxidant agents and their dose and mechanisms 

are insufficient to provide any recommendation on 

their use, either in the prevention or in the 

management of allergic disease. 

Probiotics in allergic diseases 

Probiotics represent one example of immunomodulatory 

compounds for the allergic host. The 

immunomodulatory potential of the healthy 

gastrointestinal microbiota, the source of specific 

probiotic strains, is possibly associated with two 

structural components of bacteria, the lipopolysaccharide 

portion of Gram-negative bacteria (endotoxin) 

and a specified CpG motif in bacterial 

DNA. 69,70 These structures activate immunomodulatory 

genes via Toll-like receptors present, for 

example on macrophages, and dendritic and 

intestinal epithelial cells. The net effect on intestinal 

epithelial cells is immunosuppressive by way 

of inhibition of the transcription factor NF-κB 

pathway. 71 In addition, specific strains of the gut 

microbiota have been shown to contribute to a Th 

cell population promoting oral tolerance induction, 

and to counter allergy by generation of antiinflammatory 

IL-10 and transforming growth 

factor (TGF)-β (reviewed in reference 41). The 

importance of the immunoregulatory potential of 

the gut microbiota is emphasized in the recent 

demonstration of cross-talk between the innate 

and the adaptive immune system; the nature of the 

initial immune response governs the homeostasis 

of the adaptive immune response. 

The compositional development of the gut microbiota 

differs between infants developing and those 

not developing atopic manifestations. Healthy 

infants harbor a natural predominance of bifidobacteria 

with specific strains present, while 

those later manifesting atopy present with a 

reduced ratio of bifidobacteria to clostridia 72 and 

with distinct bifidobacterial microbiota. 73 Further, 

intestinal Bifidobacterium species from allergic 

infants induce proinflammatory cytokine produc- 

tion, in contrast to those from healthy infants. 74 

Thus, the antiallergic potential of Bifidobacterium 

biota may be strain-specific. 

Probiotics may aid in degradation/structural modification 

of enteral antigens, normalization of the 

properties of aberrant indigenous microbiota and 

of gut barrier functions, regulation of the secretion 

of inflammatory mediators and direction of the 

development of the immune system during the 

critical period of life when the risk of allergic 

disease is heightened. 

Preliminary studies have revealed that cow’s milk 

casein, a common allergen in cow’s milk allergy, 

hydrolyzed with probiotic-derived enzymes 

suppresses lymphocyte proliferation and, more 

specifically, production of allergen-specific Th2 

cytokins. 58,75 In experiments conducted by von der 

Weid et al, 59 probiotics inhibited proliferation of T 

cells and reduced secretion of both Th1 and Th2 

cytokines whilst inducing the development of a 

population of T cells producing TGF-β and IL-10, 

reminiscent of tolerogenic Th3 cells. Furthermore, 

a specific probiotic strain has been demonstrated 

to suppress IgE responses and systemic anaphylaxis 

in a murine model of food allergy. 76 

Different probiotic strains appear to induce 

distinct and even opposing responses in murine 

dendritic cells and thus specific strains of the gut 

microbiota and probiotics may play a crucial role 

in determining the Th1/Th2/Th3-driving capacity 

of intestinal dendritic cells. 42 So far, clinical 

effects have been seen as a significant improvement 

in the clinical course of atopic eczema in 

infants given probiotic-supplemented elimination 

diets. The preventive potential of probiotics in 

atopic disease has been demonstrated in a doubleblind, 

placebo-controlled study. 77 Probiotics 

administered pre- and postnatally for 6 months to 

children at high risk of atopic diseases succeeded 

in reducing the prevalence of atopic eczema by 

half, as compared with that in infants receiving 

placebo, and the effect was recently shown to 

extend beyond infancy. 78 

The challenge in terms of prevention and management 

of allergic disease is to identify and clarify 

the mechanisms of action of the dietary factors 

that may be protective. Well-controlled intervention 

studies are required to address the potential 

effects of different dietary modifications and

supplementation to prevent and treat allergic 

disease or other chronic, mostly immunoinflammatory, 

diseases. In future, the most likely option 

may be the incorporation of probiotics and specific 

nutrients into the same products (nutraceuticals) 

to provide an optimal diet for individuals at risk. 

Unquestionably, the interactions between probiotics 

and nutrients need to be studied. However, 

nutraceuticals alone cannot resolve the challenge 

of atopic disease if the crucial role of the total 

composition of the overall diet is neglected. 

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33 

Introduction 

Enteral nutrition 


Enteral nutrition (EN) or enteral feeding is a technique 

for nutritional support which delivers a 

homogeneous, liquid nutritional admixture into 

the digestive tract by tube, into the stomach, or, 

more rarely in children, into the duodenum or the 

proximal jejunum. EN, has been used in pediatric 

patients for more than 30 years, in order to preserve 

nutritional status and normal growth, or to treat 

malnutrition when oral feedings cannot fill the 

protein–energy demand. EN is more physiological, 

usually safer, easier to administrate and less expensive 

than parenteral nutrition (PN). Therefore, EN 

should be preferred to PN in infants and children 

with malnutrition and/or nutritional risk, 1 when 

the intestinal tract is usable to provide nutrients. 

The physiological basis of continuous EN make it of 

great interest in pediatric patients with gastrointestinal 

(GI) disorders. 2,3 Nevertheless, this therapy 

is now widely used in a variety of extradigestive 

conditions. 

EN, like PN, is always initiated in the hospital, but 

may be performed at home in case of chronic 

disease, leading to long-term dependency. Home 

EN has enlarged the field of indications and 

improved the psychological tolerance to long-term 

nutritional therapy. 

Physiological basis of continuous 

enteral feeding 

Gastrointestinal motility 

In case of gastric administration of continuous 

enteral nutrition (CEN), a continuous gastric 

emptying related to infusion rate can be achieved, 

if the infusion rate, the caloric load and the osmolarity 

of the mixture are not excessive. When the 

infusion rate is below 3kcal/min, the gastric emptying 

rate increases with increasing caloric load, up 

to the same level as that of the infusion rate. 4 Thus, 

a steady state is achieved between the amount of 

nutrients delivered into the stomach, the gastric 

secretion volume and the gastric emptying rate. 

When the infusion rate is excessive and higher than 

the gastric emptying rate, the risk of vomiting 

increases. As the caloric load and/or osmolarity of 

the formula increase, the gastric emptying rate is 

reduced, to maintain a constant caloric load delivered 

to the duodenum; therefore, formulas with a 

concentration above 1kcal/ml should be used with 

caution. 5 The nature of the energy supply does not 

seem to play a role in gastric function, except for 

the type of triglyceride (long-chain triglycerides 

(LCTs) or medium-chain triglycerides (MCTs)). 6 

The effects of CEN on intestinal motility can be 

analyzed by manometry. Migrating complexes are 

observed in adult patients during CEN, as during 

the fasting state. 7 The type of formula influences 

jejunal motility according to the nature of triglycerides 

and/or the molecular weight of peptides and 

proteins. 8 Infusion of MCTs or short peptides 

within the duodenal lumen is associated with the 

persistence of migrating complexes, as during 

fasting. 9 Very few data are available about the 

changes of colonic motility induced by CEN; the 

continuous gastric infusion of the nutritive formula 

modifies the gastrocolic reflex. 

Gallbladder motility is maintained during EN, as 

assessed by ultrasonography. 10 The type of infused 

lipids (MCTs versus LCTs) influences gallbladder 

motility. 11 Biliary complications, such as sludge or 

cholelithiasis, are very rare during long-term CEN. 

539

540 


Digestive secretion and hormonal response 

Gastric secretion depends mostly on protein 

intake, and in case of elemental diet, on amino 

acid composition. 12 The secretory response is not 

influenced by carbohydrates, but is reduced by 

lipids. It has not been demonstrated whether or 

not the type of diet (i.e. elemental, semi-elemental 

or polymeric) modifies gastric acid secretion. 6 

Cholecystokinin secretion as well as pancreatic 

secretion are maintained during CEN. The amount 

of nitrogen infused within the jejunum correlates 

with the secretion of chymotrypsin and lipase. 13 

Secretory responses do not differ between an 

elemental or polymeric nitrogen supply. 14 

Gastrin secretion is also maintained during CEN, 

but its response to protein load is decreased. 

Gastric or duodenal CEN stimulate insulin secretion, 

depending on the type of infused nutrients. 

The lack of steatosis during CEN suggests that the 

insulin response is lower when carbohydrates are 

infused enterally as compared to parenterally. 15 

Effects of continuous enteral nutrition on 

mucosal trophism 

The effects of artificial nutrition on small-bowel 

mucosal trophism remain controversial. In experimental 

animal systems, CEN has been shown not 

to modify the absorption capacity of the proximal 

small bowel. In the distal small bowel and colon, 

however, enzymatic and functional capacity are 

decreased, despite a normal mucosal architecture; 

in addition, DNA as well as protein content are 

reduced. 16 These changes could be the consequence 

of the almost complete absorption of nutrients 

within the proximal part of the small bowel, 

leading to lack of stimulation of the distal segment. 

This suggests an ability of CEN to achieve bowel 

rest in the distal part of the bowel, providing efficient 

treatment for ileocolic inflammatory diseases. 

Effects of continuous enteral nutrition on 

energy expenditure 

The thermogenic effect of feeding is related to the 

increase of energy expenditure following ingestion 

of food. The increase in energy expenditure 

induced by CEN in normal subjects is lower than 

that for the same nutrient load as a bolus. 17,18 

Thus, the constant administration of energy 

substrates might reduce the energy storage and 

maintain homeostasis at a lower energy expenditure. 

19 

Finally, CEN by the slow and continuous administration 

of nutrients into the GI tract enables their 

optimal utilization to be achieved, despite intestinal 

illness. By changing the conditions of flow and 

of contact between the nutritive formula and the 

digestive tract, CEN may increase the capacity for 

intraluminal digestion and intestinal absorption. 

This feeding technique seems logical and efficient 

when the absorptive surface is reduced, e.g. in 

short-bowel syndrome, villous atrophy, enterocutaneous 

fistula or proximal enterostomy. 

Indications 

Indications for EN are different from indications 

for PN, since the use of EN as nutritional support 

is based on normal or at least partially preserved 

gut functions (Table 33.1). 

Digestive indications 

Since EN has a trophic effect on the intestinal 

mucosa, and helps maintain mucosal integrity, it 

plays an important role in the treatment of many 

digestive diseases, either replacing or completing 

oral feeding. Digestive diseases leading to an 

anatomical or functional reduction of the absorption 

capacity of the small bowel represent the first 

group; they include short-bowel syndrome, 

protracted diarrhea with villous atrophy and 

inflammatory bowel disease. 


Short-bowel syndrome (see Chapter 29) can be 

defined as malabsorption following small-intestinal 

resection. Prognosis after extensive intestinal 

resection has improved with the expanded use of 

PN over the past 20 years. 20–24 Following massive 

resection of the small intestine, the remaining 

small bowel undergoes an adaptative process characterized 

by epithelial hyperplasia (see Chapter

Table 33.1 Indications for enteral nutrition 



Protracted diarrhea of infancy 

Immunodeficiency 



Neonatal abdominal surgery 

gastroschisis 

omphalocele 

meconial ileus 

distal intestinal fistulae 

small-bowel resection 

necrotizing enterocolitis 

complicated Hirschsprung’s disease 

chronic intestinal pseudo-obstruction syndrome 

Other malabsorption syndromes 

cystic fibrosis 

cholestatic liver disease 

In children with normal intestinal function 


disorders of sucking and swallowing 

neurological impairment 

Esophageal diseases 

Hypermetabolic states 

head injury 

extensive burns 

cancer, AIDS, bone marrow transplantation 

renal failure 

congenital heart diseases 

chronic pulmonary diseases 

Inborn errors of metabolism 

glycogen storage diseases 

deficiencies of urea cycle 

Neonatology and prematurity 

Abnormal eating behavior 

anorexia nervosa 

failure to thrive 

29). 25 An early and optimal use of the enteral route 

is the condition of small-bowel adaptation. 

However, in children with short-bowel syndrome, 

oral feeding rarely permits a rapid reduction of the 

PN supply, because numerous patients have eating 

disorders instead of hyperphagia. In such conditions, 

CEN enables the delivery of nutrient to be 

increased to the digestive tract independently of 

the feeding behavior, with a known benefit on socalled 

intestinal adaptation, and added benefits on 

Indications 541 

the prevention of PN-associated liver disease. 25 

The delay for postoperative adaptation to occur 

depends on the length and quality of the residual 

bowel and on the presence of the ileocecal valve 

and colon. 21 

Severe protracted diarrhea of infancy 

A syndrome of intractable diarrhea of infancy was 

first described by Avery et al in 1968. Its definition, 

presentation and outcome have considerably 

changed during the past two decades. 26 This 

syndrome could now be defined as persistent diarrhea 

despite prolonged bowel rest requiring longterm 

total PN in children when no effective treatment 

is available. 27,28 According to that definition, 

EN in this circumstance is indicated and often 

effective. 29,30 In fact, the reduction of digestive 

secretions, villous atrophy and acquired brushborder 

disaccharidase deficiency lead to malabsorption 

and malnutrition. Most of the time, a 

short course of PN followed by protracted CEN 

provides control of the disease within 6–8 

weeks. 31,32 In a prospective study of CEN versus 

PN, Orenstein showed that the resolution of diarrhea 

was faster in the enterally fed group. 32 

The use of CEN in children and mainly infants 

with protracted diarrhea also presenting severe 

malnutrition may prove difficult. If the response to 

CEN is not good enough to provide rapidly 

adequate caloric supplies with resolution of diarrhea, 

PN should be started. Such decisions must 

be taken by experienced teams in specialized and 

well-staffed units. 

Severely malnourished infants with some types of 

particularly severe celiac disease, intolerance to 

cow’s milk proteins, protein hydrolysates, or 

specific malabsorption syndromes such as 

Anderson’s disease, may also benefit from CEN. 33 

Inflammatory bowel diseases 

Enteral feeding has been used for many years, 

particularly in Europe, not only to improve nutritional 

status and growth, but also to influence 

disease activity in patients with Crohn’s 

disease. 34–43 It has been shown that CEN using an 

elemental diet is as effective as a high dose of 

steroids in inducing remission in pediatric 

patients with Crohn’s disease involving the small

542 


intestine. The meta-analysis by Griffiths et al 

suggested that EN was inferior to steroid therapy. 44 

This was largely an analysis of adult studies and 

excluded several pediatric studies showing striking 

efficacy. More recent meta-analyses have shown an 

equivalent effect of EN and steroids in achieving 

remission. 45,46 In addition, it is clear that EN is 

advantageous in preserving growth while remission 

is achieved. There are no relevant data in children. 

However, in adults, studies on the comparative 

effect of elemental diets, protein hydrolysates 

and intact protein formulas have shown induced 

remission of polymeric diets in controlling Crohn’s 

disease involving the small bowel. How such treatment 

works in children with Crohn’s disease is not 

clear. Certainly, the increased energy intake 

provided by EN must be one factor. However, there 

is evidence that such treatment may have a specific 

anti-inflammatory effect. A reduction of cytokine 

production by isolated lamina propria lymphocytes 

following EN with a polymeric casein-based 

formula was shown to an extent equivalent to that 

produced by steroids or cyclosporin. 43 In addition, 

Fell et al have shown a massive reduction in mRNA 

transcripts for interleukin (IL)-1β using its derivative 

CT3211. 47 Removal of antigenic material, alteration 

in intestinal microflora, changes in gut 

hormone levels and the presence of bioactive transforming 

growth factor (TGF) β-1 in casein-based 

formulas may all play a role in the clinical success 

of EN. 48,49 A glutamine-enriched polymeric diet 

offered no advantage over a standard low-glutamine 

polymeric diet in the treatment of active 

Crohn’s disease. 50 EN may also be helpful in correction 

or maintenance of the nutritional state, especially 

during a relapse of Crohn’s disease. 45 EN is 

part of the preparation for a surgical procedure and 

may be useful during recovery, especially after 

intestinal resections or enterostomies. 

In case of severe digestive involvement during 

Schönlein–Henoch purpura, CEN can be used as 

nutritional support in the absence of occlusion. 51 

Neonatal abdominal surgery 

In neonatal abdominal surgery for congenital or 

acquired disease, CEN, usually combined with PN, 

offers prolonged nutritional support. This has 

transformed the prognosis in many conditions and 

is particularly important in the following situations: 

reduction of the absorptive surface with 

enterocutaneous fistulae or extensive intestinal 

resection; and functional disorders of gut motility, 

such as malfunctions of a duodenojejunal anastomosis, 

‘plastic’ peritonitis after repeated interventions, 

gastroschisis and omphalocele. 

Chronic intestinal pseudo-obstruction syndrome, 

with neonatal onset, is a special condition in which 

EN is rarely tolerated and usually does not allow 

PN and/or a surgical procedure such as ileostomy 

to be avoided. 52–54 

Other malabsorption syndromes 


Failure to thrive is common in children with cystic 

fibrosis (CF), and results from several factors, 

including malabsorption from pancreatic insufficiency, 

bile salt abnormalities, anorexia, increased 

energy expenditure, protein catabolism from 

pulmonary infections and/or fever. 55 Even with an 

optimal approach to oral feeding, some patients fail 

to respond to conservative nutritional therapy. EN 

is proposed as a second-stage intervention and can 

help to restore and maintain nutritional status. 56–58 

EN is in most cases easily performed at home. It is 

generally performed during the night over 8–10h; 

CF patients are asked to eat and drink as much as 

possible during the day. Nasogastric tube feeding is 

generally used as a first step. The tube is passed 

every night, 1–2h after dinner, and removed in the 

early morning before physical therapy so that 

patients are not disturbed during the day for school 

attendance. In some children, a nasogastric tube 

becomes increasingly uncomfortable because of 

nausea, vomiting and nasal discomfort as a result of 

nasal polyposis or dislodgement during coughing 

in cases of pulmonary exacerbation. Thus, percutaneous 

endoscopic gastrostomy (PEG) has become 

the method of choice for performing long-term 

home nocturnal EN. A button device can be placed 

2–3 months after PEG tube placement, thus improving 

the physical and psychological tolerance of EN. 

It is important to look for glucose tolerance as well 

as for gastroesophageal reflux before starting EN. 

Psychological support of the patient is essential, 

since body image and self-esteem are frequently 

altered in CF patients, especially in cases of weight 

loss and/or failure to thrive. Nutritional support by 

EN, even recognized as necessary, is rightly considered 

by patients and/or parents as a new constraint.

Thus, the usefulness of EN must be precisely 

explained in order for it to become part of clear 

global therapeutic management. EN is required in 

malnourished children with decreased growth 

velocity, especially when transplantation is 

planned. Adequate EN, using either an intact 

formula with pancreatic enzyme extract or a semielemental 

diet can be achieved through either nasogastric 

or PEG tubes. Finally, it should be stressed 

that in CF nutritional supplementation improves 

not only nutritional status but also respiratory function. 

58–60 

Cholestatic liver disease 

Mechanisms leading to protein–energy malnutrition 

in infants and children with chronic liver disease 

are incompletely known. 61–63 They include reduced 

biliary secretion and intraluminal bile concentration 

resulting in malabsorption of lipid and fatsoluble 

vitamins. Energy requirements are 

increased by different mechanisms including 

portosystemic shunting and ascites, abnormal intermediary 

metabolism and the energy demands of 

complications such as sepsis or variceal bleeding. 

Anorexia is common in children with chronic liver 

disease resulting from organomegaly, abdominal 

pressure effects of ascites, congested gastric 

mucosa, reduced motility from portal hypertension, 

central effects of unidentified toxins, dietary manipulations 

such as fluid restriction or use of unpalatable 

feeds. Several factors contribute to long-chain 

polyunsaturated fatty acid (PUFA) deficiency 

including low PUFA intake, malabsorption and 

disturbed metabolism of long-chain PUFAs. Finally, 

the interaction of growth hormone with insulin-like 

growth factor (IGF)-I and its binding proteins constitute 

an important mechanism linking nutrition and 

growth. 

The most common cause of cirrhosis in infants is 

biliary atresia. Since orthotopic liver transplantation 

(OLT) is the only effective treatment, the role 

of nutritional support preceding transplantation is 

of importance. 63,64 Nutritional support has a direct 

impact on survival and suitability as candidates for 

OLT, while the effect of preoperative nutritional 

support on outcome after OLT is a matter of 

debate. 65,66 

Oral food intake is most of the time insufficient in 

these children. EN providing MCT-rich feeds is 

Indications in children with normal intestinal function 543 

recommended and should be associated with an 

adequate fat-soluble vitamin supply. 67,68 Many 

currently available commercial nutritional products 

are suitable for infants with chronic liver 

disease but none are ideal for all situations. 

Additives are usually necessary in infants and 

children with persistent failure to thrive. 

Ordinarily, nutritional management can be carried 

out at home. However, two issues remain controversial. 

First, children with portal hypertension 

may have esophagal varices with the risk of bleeding 

due to the nasogastric tube; in this circumstance, 

the use of a silicone tube is mandatory and 

home EN is contraindicated. Second, the use of 

branched-chain amino acids to feed children with 

chronic encephalopathy is debated. 69 

Indications in children with normal 

intestinal function 


EN is required in cases of inability to eat normally, 

i.e. in those situations that are secondary to structural 

or functional abnormalities of the upper GI 

tract or neurological impairment of the processes 

involved in sucking and/or swallowing (see also 

Chapter 15). 

Esophageal diseases including esophageal atresia, 

fistula or stenosis, can result from sequelae of 

epidermolysis bullosa. These conditions often 

need EN, usually through gastrostomy or duodenal 

tubes. 70 The choice of feeding through a gastrostomy 

or a transpyloric tube must be assessed 

according to the patient’s age, disease and condition. 

Children with chronic diseases inducing immaturity 

or inability to feed orally, especially with 

sucking and swallowing troubles as seen in neurologically 

impaired children, with neuromuscular 

chronic diseases or cerebral palsy also require EN, 

using gastrostomy tubes. 71–73 

Other indications 

Indications for EN have been extended in recent 

years to include several extraintestinal conditions.

544 


Hypermetabolic states 

Patients with acute hypermetabolic conditions, 

such as those resulting from head injury or burns, 

should receive an adequate nutrient supply, which 

should be given enterally in most cases. 74 EN has 

been used successfully in children with cancer, 

bone marrow transplantation or AIDS. 75–78 

All chronic diseases inducing both an increase in 

protein–caloric needs and anorexia, such as 

chronic renal failure 79,80 with or without hemodialysis 

awaiting transplantation, or congenital heart 

disease, 81,82 often induce malnutrition and failure 

to thrive. Children with these disorders benefit 

from EN, since improvement of nutritional status 

is expected to influence the outcome positively 

after transplantation. 

Inborn errors of metabolism 

EN is part of the treatment of numerous inherited 

metabolic diseases, which induce hypoglycemia 

(glycogen storage disease) 83–85 or increase protein 

catabolism, e.g. enzymatic deficiencies of the urea 

cycle. 86,87 CEN is required to avoid neurological 

consequences of these metabolic disorders. 

Premature infants 

EN is commonly used in premature infants, and in 

small-for-gestational age neonates with sucking 

and swallowing troubles. Mother’s milk can be 

given, sometimes into the duodenum rather than 

into the stomach in low-birth-weight infants (less 

than 1000g). All the factors discussed earlier must 

be carefully monitored in this high-risk group. 

Some physicians prefer to stop CEN in infants 

with respiratory disease, and to use total PN (see 

also Chapter 34). 

Miscellaneous conditions 

Miscellaneous indications for EN include primitive 

difficulties of eating behavior, including 

anorexia nervosa, 88–91 and chronic idiopathic 

failure to thrive. Failure to thrive may be due to a 

poor parent–child relationship leading to insufficient 

food intake. In such circumstances, tube 

feeding can be used to demonstrate that growth 

can be achieved if adequate nutrients are 

provided. 88,89 In older children and adolescents 

with anorexia nervosa, EN can be used according 

to the opinion and experience of the psychiatric 

team. 90,91 

Techniques 

Material 

Nasogastic tubes 

The route of EN administration should be individually 

tailored, depending on the underlying condition. 

The intragastric route of administration is the 

more used in children, since it is the more physiological 

route. It permits the action of salivary and 

gastric enzymes, the bactericidal action of gastric 

acid and better mixing with biliary and pancreatic 

juice. Therefore, the duodenal or jejunal route is 

used in few circumstances in children. For intragastric 

EN, nasogastric tubes or gastrostomy tubes 

may be used. Nasogastric tube feeding is the best 

initial approach to EN, to evaluate the tolerance of 

EN before placing a permanent gastrostomy tube, 

and/or when a brief period of EN support is anticipated. 

The nasogastric tube may be made of 

polyvinylchloride (PVC), polyurethane or silicone. 

The tube size is chosen according to the weight 

and age of the child, with an external diameter as 

small as possible. The nasogastric tube is inserted 

nasogastrically by using the nose–umbilicus 

distance as a reference point. Its position is 

routinely checked by epigastric auscultation 

during the injection of air and the aspiration of 

fluid with a pH less than 3. Duodenal or jejunal 

tube placement is more difficult; the patient 

should be placed in the right lateral position and, 

if necessary, after intramuscular injection of metoclopramide. 

The position of the distal end of the 

tube is then checked by X-rays. Careful nasal fixation 

of the tube is used to avoid displacement; it is 

taped to the upper lip, the ipsilateral cheek and the 

external ear. In some particular indications for EN, 

the feeding tube may also be introduced through 

the mouth, especially in premature babies. The 

placement of the nasogastric tube made of PVC is 

easier, but these tubes should be changed every 

2–4 days. Indeed, the tube becomes rigid if left 

longer, whereas the silicone or polyurethane tube 

may be used over 3-week periods or more. On the 

other hand, silicone and polyurethane tubes are 

more flexible and are more easily displaced by

vomiting; they are preferentially used for transpyloric 

and long-term EN. When the child requires 

prolonged EN (more than 2 or 3 months) and when 

EN is well tolerated, a gastrostomy should be 

considered. 

Percutaneous gastrostromy 

The PEG technique has revolutionized the placement 

of enteric feeding tubes in children. It is now 

a widely used and well-tolerated technique in children. 

92–95 This relatively simple and fast procedure 

can be performed during upper-GI endoscopy in 

an endoscopy suite with the use of conscious sedation 

and local anesthesia or under general anesthesia. 

Several techniques have been developed 

with the common basic principle that the endoscope 

locates the site of tube placement from 

within the stomach. The transillumination of the 

light from the endoscope through the abdominal 

wall identifies the site of skin incision. The ideal 

site is on the greater curvature of the stomach with 

the stoma sited on the anterior abdominal wall, 

below the costal margin with consideration to the 

axis of bending and to the clothing. To reduce the 

risk of infection at the stoma site, perioperative 

antibiotic prophylaxis is recommended. The tube 

can be used within 12–24h, while post-insertion 

edema at the stoma site is closely monitored. Care 

should be taken not to pull the bolster too high. 

The initial PEG tube is changed after 2–3 months, 

by which time a good tract has formed. Buttonreplacement 

gastrostomy devices provide patients 

a cosmetic advantage in case of long-term EN. PEG 

is contraindicated only in a few patients with 

previous abdominal surgery, abnormal abdominal 

anatomy, or severe deformities of the chest and 

spine that modify the position of the stomach. In 

such cases, a surgical gastrostomy tube should be 

placed. The implantation of a jejunal feeding tube, 

via PEG, is a possible method for the treatment of 

inadequate oral feeding in patients who are 

affected by gastroesophageal reflux and is thus an 

alternative to fundoplication and drugs. 96,97 

Special PEG techniques have also been developed 

for ICU patients. 98 

EN may be delivered by bolus or pump-controlled 

techniques, but should not be administered by 

gravity in children. Pumps recommended for pediatric 

use have to provide clear flow rate display 

and alarms. Miniaturized and battery-powered 

Techniques 545 

pumps are specially designed for home and ambulatory 

EN. 

Nutrients 

Nitrogen The absorption of amino acids is more 

rapid and efficient when given in the form of short 

peptides rather than free amino acids. 99,100 In addition, 

the quality, in terms of digestion and intestinal 

absorption of protein hydrolysates, depends on 

the type of hydrolysate; for example, lactalbumin 

is superior to casein. 101,102 Thus, the initial 

formula should be based on polypeptides, with a 

lower osmolality, rather than on a mixture of free 

amino acids. Nitrogen needs vary depending on 

tolerance, and range from 350 to 500mg/kg per 

day, or even more in some highly catabolic situations. 

The nitrogen/calorie ratio must be considered; 

protein intakes should represent 10% of the 

energy intake, especially for premature infants. 103 

Carbohydrates Disaccharidase enzymatic activities 

are depressed in disease involving the small-intestine 

mucosa. Lactase appears to be the most sensitive 

to injury and the last of the disaccharidases to 

recover. In addition, certain drugs such as 

neomycin or colchicine depress the intestinal 

disaccharidases. Therefore, it is important to avoid 

dietary sources of lactose. Other disaccharides 

should also be omitted from the solution used for 

initial feeding, as their corresponding brushborder 

enzymatic activities are reduced. The only 

carbohydrate allowed during the initial days of EN 

should be glucose, but its high osmolality 

(5.5mOsmol/g) limits the rate of infusion, and thus 

the total amount given. The later addition of fructose 

may lead to an increase of disaccharidase 

activity, so making it easier to substitute maltose 

and sucrose for glucose. The subsequent introduction 

of low-osmolality oligosaccharides may allow 

the intake to reach 20 or even 24g/kg per day, especially 

in infants, without resulting in a final solution 

osmolality higher than 350mOsm/l. 

Lipids The behavior of MCTs within the intestinal 

lumen and their absorption characteristics are 

primarily due to their greater water solubility. 

104,105 MCTs are hydrolyzed faster than LCTs in 

the small intestine by pancreatic lipase; they are 

converted almost exclusively into free fatty acids 

and glycerol and directly reach the portal circulation 

and the liver. Nevertheless, in case of pancre-

546 


atic insufficiency, MCTs may be absorbed intact. 

The excessive use of a MCT-containing diet can 

lead to osmotic diarrhea as a result of their rapid 

hydrolysis. Dicarboxylic aciduria has been 

described in infants supplemented with MCT-rich 

formulas without any evidence of a deleterious 

effect. 106 The provision of essential fatty acids 

(EFA) must be considered since MCTs contain no 

EFA. Furthermore, MCTs decrease the absorption 

of LCTs; therefore, supplementation with linoleic 

acid must be provided. However, its addition to a 

formula based on MCTs may be insufficient to 

prevent EFA deficiency, thus making it necessary 

to provide EFA parenterally. Nevertheless, most 

formulas containing MCTs include up to 50% of 

lipid as LCTs. By stimulating biliary and pancreatic 

secretions, LCTs promote increased intestinal 

motility; LCTs in excess in the intestinal lumen, 

especially if they are hydroxylated by bacteria, 

reverse the rate of water and electrolyte absorption 

and increase malabsorption. In those conditions, 

the addition of cholestyramine associated with 

EFA supplementation may be appropriate. Finally, 

a lipid intake of 3–4g/kg per day may be achieved, 

depending on the absorption capacity and digestive 

tolerance. 

Other components In infants and children, the 

recommended energy intake varies from 70 to 

100kcal/kg per day, and water rarely exceeds 

80ml/kg per day. The recommendations for 

average supplies of vitamins and trace elements 

are shown in Tables 33.2 and 33.3. Competition 

between trace elements such as copper and zinc 

has been taken into account in these recommendations; 

the daily supplement should be higher in 

premature than in full-term infants. 

Choice of a formula 

Enteral feeding formulas are divided into several 

families. The choice of a formula is made according 

to numerous parameters, such as 

protein–caloric needs, digestive function and tolerance 

to fluid intake – all obviously dependent on 

the age and on the underlying disease. 

(1) In newborns and young infants with normal 

or nearly normal intestinal function, breast or 

humanized milk may be used, while commercial 

polymeric diets are available for older 

children. Blenderized diets can be prepared 

Table 33.2 Vitamin requirements 

Infants Children 

Vitamin A (µg) 300–750 450–1000 

Vitamin D (IU) 400–1000 200–2500 

Vitamin E (mg) 3–10 10–15 

Vitamin K (µg) 50–75 50–70 

Vitamin Bl (mg) 0.4–0.5 1.5–3 

Vitamin B2 (mg) 0.4–0.6 1.1–3.6 

Vitamin B5 (mg) 2–5 0.5–5 

Vitamin B6 (mg) 0.1–1.0 1.5–2 

Vitamin B12 (µg) 0.3–3 3–100 

Vitamin C (mg) 25–35 20–100 

Folic acid (µg) 20–80 100–500 

Biotin (µg) 35–50 150–300 

Niacin (mg) 6–8 5–40 

Table 33.3 Trace element requirements 


Element (/kg/day) (/day) 

Iron (mg) 50 100–2500 

Zinc (mg) 100–250 1000–5000 

Copper (mg) 20–30 200–300 

Selenium (µg) 2–3 30–60 

Manganese (µg) 1–10 50–250 

Molybdenum (µg) 0.25–3 50–70 

Chrome (µg) 0.25–2 10–20 

lodine (µg) 1–5 50–100 

Fluoride (µg) 20 500–1000 

using food from the kitchen, but are usually 

replaced by polymeric formulas containing 

‘intact’ proteins with or without fibers, which 

are commercially available; they are indicated 

in most non-stressed patients, with 

normal gut function. These formulas contain 

1kcal/ml (standard) to 1.5kcal/ml (calorically 

dense). 

(2) In case of GI disease, the choice of the nutritive 

solution must take into account not only the 

child’s age and nutritional status but also the 

underlying digestive disease, e.g. the presence 

of anatomical and functional changes in the

intestine, whether due to an extensive reduction 

of the absorptive surface, to enteropathy 

or to pancreatic insufficiency. Limiting factors 

in such cases are impairment of gastric, biliary 

and pancreatic secretions, disturbances of the 

intestinal flora and malabsorption. The osmolarity 

of enteral formulas should be kept below 

320mOsmol/kg, nutrients should be rapidly 

transferred across the intestine and they 

should not leave an intraluminal residue. 

Substrates requiring intraluminal hydrolysis 

(proteins, starches, LCTs) should be excluded, 

as should potentially highly antigenic 

substrates (cow’s milk proteins, gluten and 

soy). Oligomeric or ‘semi-elemental’ diets are 

designed for use in patients with malabsorption, 

such as in short-bowel syndrome, CF, 

cholestasis or food allergy. These diets include 

dipeptides, tripeptides and a few free amino 

acids, combined with LCTs and MCTs, and 

carbohydrates including glucose polymers and 

maltodextrins. Powder formulas enable progressive 

adaptation of the concentration to the 

clinical condition (for example, to increase the 

concentration progressively from 0.65kcal/ml 

up to 1kcal/ml or more). Ready-to-use formulas 

usually contain 1kcal/ml. 

(3) Free amino acid-based formulas tend to have a 

higher osmolality. For instance, the amino 

acid-based formula Neocate ® specifically designed 

for infants under 1 year of age, has an 

osmolality of 360mOsm. The lipid component 

is a mixture of safflower, coconut and soy oils 

to provide essential and non-essential fatty 

acids. The carbohydrates are from corn syrup 

solids or maltodextrins, both derived from 

corn starch and differing in the size of glucose 

polymers. They are indicated especially in 

children with severe food allergy who do not 

tolerate even the peptide-based formulas. 

Children with severe malabsorption or shortbowel 

syndrome unable to tolerate peptidebased 

formulas (protein hydrolysates) might 

benefit from the free amino acid-based formulas. 

107,108 

(4) Special formulas are proposed for some indications 

such as renal failure, liver failure, 

pulmonary disease, diabetes and metabolic 

diseases. On the other hand, special formulas 

have been developed for preterm infants, who 

Techniques 547 

are characterized by the following factors: 

decreased energy and glycogen stores, limited 

gastric capacity, reduced intestinal peristalsis, 

reduced bile salt pool and delayed enzymatic 

development. The main differences in the 

composition of premature and term infant 

formulas include: partial substitution of 

oligosaccharides for lactose; increased protein 

content to support rapid growth; 60:40 

whey/casein ratio to increase essential amino 

acid intakes and protein digestibility; partial 

substitution of LCTs by MCTs; and adapted 

concentrations of vitamin E, calcium, phosphorus 

and iron. 

(5) Nutritional formulas in which each of the 

constituents is modified independently are 

mostly used in special conditions, e.g. selective 

malabsorption. In that case, glucose may be 

given initially as the calorie source, the amount 

being increased progressively and controlled 

according to the stool volume, pH and absence 

of reducing substances in the stools. In the first 

days of feeding, at least, a molar ratio of glucose 

and so-dium is maintained. Then, protein 

hydrolysates are gradually introduced according 

to digestive tolerance. The caloric enteral 

intake usually increases from 10–15 to 

70–80kcal/kg per day over the first week. In a 

second step, qualitative and quantitative 

changes are gradually made: fructose is added 

to the glucose, and then disaccharides are 

introduced, starting with maltose. Nitrogen and 

lipids are simultaneously increased. During 

this period, the introduction of oligosaccharides 

precede that of a commercially available 

semi-elemental diet. 

Regulation of intakes and rhythm of enteral 

nutritional delivery 

EN should be progressively introduced, depending 

on the child’s nutritional status and the indications 

for EN. In case of digestive disease, CEN can 

be used after a prolonged period of PN or simply 

after a brief phase of peripheral venous infusion. 

The first step includes the progressive reduction of 

the parenteral intake and the stepwise increase of 

EN according to the digestive tolerance. The semielemental 

diet (protein hydrolysates) can be used 

early, by progressively increasing the volume as

548 


well as the concentration, according to digestive 

tolerance and until optimal energy and nitrogen 

intakes are achieved. The water and sodium 

supply should be increased to compensate for the 

intestinal losses generally induced by the start of 

EN; the tolerance is estimated from the weight of 

the child, from the volume and osmolality of urine 

samples and from the plasma osmolality. The 

tolerance and needs are estimated from 24-h urine 

analysis, while attempting to maintain natriuresis 

of 2–3mmol/kg per day. At the same time, potassium 

intake is adjusted as a function of the nitrogen 

and energy intakes. 

The rhythm of EN delivery depends on the underlying 

disease. Intermittent feeding using a bolus is 

more physiological and well tolerated when the 

digestive function is normal. Continuous cyclic 

nocturnal EN is better tolerated in some patients 

who do not tolerate bolus feeding, and provides 

less interference with daytime oral intake. 

However, a continuous 24/24h rhythm of delivery 

is indicated in case of impaired digestive function. 

The weaning period varies from a few days to 

several weeks or months. Eating disorders can be 

avoided by the maintenance of sucking and swallowing 

functions during the period of CEN. It has 

also been demonstrated that non-nutritive sucking 

during CEN enhances growth and intestinal maturation 

in premature babies. 109,110 Weaning includes 

a period of continuous night-time feeding 

supplemented by several meals in the daytime 

until the latter account for 50% of the total intake. 

Oral feeding must be carefully increased because 

of the relatively low intestinal activity due to longterm 

CEN. 

Complications of enteral therapy 

These are rare but serious. Strict adherence to the 

procedure indicated and careful supervision are 

essential to prevent them. 111,112 

Gastrointestinal complications 

Vomiting and aspiration are the most threatening 

complications associated with tube feeding, at 

home as well as in the hospital, while its incidence 

seems to be low in children on home EN. 113 

Irregular flow rate of infusion, delayed gastric 

emptying due to the underlying disease or to the 

drugs, gastroesophageal reflux and tube placement 

or migration into the distal esophagus, behavioral 

vomiting and formula intolerance are risk factors 

for vomiting and aspiration. The possible preventive 

effect of a semirecumbent position has been 

discussed. 114 

Diarrhea is the most common complication of EN, 

and can occur in about 30% of patients. It might 

result in dehydration and hypoglycemia. It may be 

due to multiple causes, especially intraduodenal 

infusion, high osmolarity, excess or irregular infusion 

rate and bacterial contamination of the 

formula. Increased stool losses occur when the 

combined absorptive capacity of the small bowel 

and the salvaging capacity of the colon are 

exceeded. 

Mechanical complications 

Tube-related complications such as nasal trauma 

due to placement of a nasogastric tube, laryngeal 

ulceration or stenosis, esophageal stricture or 

perforation mainly if an introducer is used, gastric 

or duodenal perforation, intestinal bleeding and 

bowel intussusception are exceptional in children, 

but have been described with PVC tubes left for 8 

days or more. 115–117 Pyloric stenosis has been 

reported after prolonged duodenal feeding in 

premature babies; this is probably due both to the 

presence of the transpyloric tube and to spasm of 

the pylorus caused by the direct infusion of lipid 

into the duodenum. 

Ear, nose and throat complications are frequent in 

children who receive EN through a nasogastric 

tube. The incidence of these complications must be 

taken into account when making a decision for a 

gastrostomy. 

Complications from PEG placement include worsening 

of gastroesophageal reflux, dumping 

syndrome (if the PEG is to close to the pylorus) and 

gastrocolic fistula. Local skin problems include 

infection, cellulitis, granulomas and leaking. 

Leaking of formula, which may be the consequence 

of lack of adequate inflation of the 

balloon, or to malfunction of the antireflux valve, 

induces a vicious cycle with enlarging stoma and 

skin problems.

Infectious complications 

EN tubes have been associated with outbreaks of 

antimicrobial-resistant organisms. The enteral 

feed administration sets become colonized externally 

by microbes grown from the enteral tube 

hub, and therefore serve as a reservoir of organisms 

that can be cross-transmitted. 118–125 

Adherence to standard precautions is critical 

when handling enteral feeding apparatuses. 

Bacterial contamination of the nutritive solution 

with enterotoxin-producing bacteria such as 

coliforms or Enterobacter cloacae, 122 at the time of 

preparation, storage or delivery to the patient, 

leads to gastroenteritis and/or septicemia. 123–125 

The relationship between bacterial contamination 

of enteral formula and diarrhea may be a matter of 

debate when EN is delivered into the stomach, 

because of the protective role of gastric acid, the 

risk of bowel contamination being theoretically 

higher when EN is delivered below the pylorus. 

Furthermore, in hospitalized patients, bacteriological 

monitoring of formula samples is mandatory; 

manipulation of the tubing and feed reservoirs 

must be careful. Ready-to-use commercial formulas 

are therefore recommended for home EN and 

in hospitals. 

Since necrotizing enterocolitis may occur in 

premature infants and neonates suffering from 

hypoxia and infections, the abdomen must be 

checked daily very carefully. Because of the risk of 

infectious complications and necrotizing enterocolitis, 

some teams prefer PN to this technique for 

premature babies weighing less than 1500g, who 

require respiratory assistance. Prevention of such 

complications requires the use of the gastric route 

as far as possible, strict limitation of duodenal 

infusions and safe preparation of solutions. 

Metabolic complications 

Metabolic complications of EN are rare when 

compared to those of PN. However, especially in 

severely malnourished children, water overload 

or electrolyte imbalance should be avoided by 

careful monitoring. In those particular patients, 

phosphatemia should be monitored and phosphate 

supplementation provided. 

Dehydration and hypernatremia may occur in 

case of diarrhea or vomiting, which may result 

Home enteral nutrition 549 

from a formula that is hyperosmolar or too 

concentrated. Hypoglycemia may be due to 

sudden discontinuation of infusion, especially in 

infants, in malnourished children or when EN is 

used to prevent hypoglycemia in metabolic 

diseases such as glycogenosis. In children on 

cyclic EN who do not eat orally, a progressive 

decrease in infusion rate is recommended to 

prevent hypoglycemia. 

Home enteral nutrition 

Indications 

Home EN is a logical alternative to long-term hospitalization 

when long-term EN support is necessary 

(more than 1 month) in a patient in stable clinical 

condition. Home EN has been shown to be an effective 

and safe method, compatible with the best 

possible quality of life. 126–129 Major cost savings 

induced by home EN as compared to hospitalization 

have been demonstrated. The importance of 

families’ teaching and medical follow-up to prevent 

somatic and psychological complications should 

not be underestimated. 

Prevalence and incidence 

The origins of home EN are much older than those 

of home PN. In North America, 20000 patients 

received home EN in 1985 and 150000 in 1992 

(about 500 per million population). Based on an 

estimated growth rate of 25% per year, about 

500000 patients may have been on home EN in 

the USA in 1997. 130,131 The British Association of 

Enteral and Parenteral Nutrition estimated that 

the number of patients on home EN was about 40 

per million population, about ten-fold the number 

of home PN patients in the same country at the 

same time. Children accounted for 30–40% of 

home EN patients in Britain, compared to about 

20% in the USA. 130,132,133 However, the lack of 

national registers in most European countries 

makes estimation difficult. 

Organization 

The quality of home EN programs depends on the 

organization of multidisciplinary nutrition

550 


support teams, based on a tight collaboration 

between the different professionals including 

physicians, home care nurses, dietitians, pharmacists 

and social workers. In some countries, 

pumps, disposable equipment and nutrients for 

home EN are mainly delivered by hospitals, while 

in others, such as the USA, where they are the 

most developed, home care companies participate 

in patients’ training and provide a delivery 

service and a 24-h emergency phone contact. 

With expansion of the home care industry, it is 

important to ensure that adequate standards of 

care are provided. The American Society of 

Parenteral and Enteral Nutrition and the British 

Association of Parenteral and Enteral Nutrition 

have produced such standards. 132,133 

Parents’ teaching 

Tolerance and efficacy of EN have to be demonstrated 

at the hospital before home EN is organized. 

As for home PN, home EN in children is feasible 

only when the family is highly motivated and able 

to deal with technical aspects. Parents’ teaching is 

based on a nutrition multidisciplinary hospital team 

including a physician, nurse, dietitian and pharmacist. 

Parents are taught not only about technical 

aspects but also about risks, complications and their 

prevention. The hospital team ensures a 24/24h 

phone contact and regular follow-up, in close cooperation 

with the general practitioner. The help of 

a community nurse may be required, especially in 

case of placement of a nasogastric tube. 

Results 

Quality of life 

Although home EN, like home PN, is usually 

considered by children and families as an 

improvement of their quality of life, psychological 

consequences of this technique have to be 

carefully estimated and prevented. The placement 

of a nasogastric tube is distressing to 

parents and children. A tube in situ for continuous 

24/24h infusion is a major problem, particularly 

in older children and adolescents, because it 

induces an unwelcome public interest. These 

problems are solved by the use of gastrostomy. 

Children and families may also suffer from the 

suppression of meals taken together, which are 

usually considered as an important time in family 

life. Adequate psychological preparation and 

follow-up improve the tolerance in children and 

parents of home EN. 134,135 

Outcome 

Outcome studies in home EN patients have been 

fewer than those in patients on home PN. 

Improvement of the nutritional status and low 

mortality rate (always related to major underlying 

diseases) are usually described in children on 

home EN. 136–138 However, few data have been 

given about the outcome of such pediatric 

patients in the long term. 

Cost and funding 

Home EN is far from being as expensive as home 

PN. The total cost per day of home EN was about 

$35 in the USA in 1992, when the cost per day of 

home PN was about $300. 131 The cost savings 

associated with providing home EN estimated by 

the British Association for Parenteral and Enteral 

Nutrition in 1994 were about 70%. 126 In most 

countries, patients on home EN are funded by the 

National Health Service, although in the USA 

they are mostly paid for by insurance companies. 

130,139

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34 

Introduction 

Parenteral nutrition in infants 

and children 


In the late 1960s in the USA, Dudrick and Wilmore 

demonstrated that long-term administration of 

hypertonic nutrient infusates through a catheter 

inserted into the superior vena cava was feasible, 

with immediate dilution of the hypertonic solution, 

preventing damage to the vein. 1,2 By infusing a 

hypertonic mixture of glucose, protein hydrolysate, 

electrolytes, minerals and vitamins, they proved 

that it was possible to achieve normal growth and 

development in an infant with multiple smallbowel 

atresia. 1,2 Indeed, parenteral nutrition (PN), 

since its introduction in clinical practice during the 

late 1960s has enabled many patients to survive and 

has reduced the incidence of malnutrition related to 

a variety of digestive and non-digestive diseases. 

With antibiotics, antitumoral chemotherapy and 

organ transplantation, PN can be considered as one 

of the most important therapeutic advances over the 

past 50 years since it has demonstrated its potential 

for changing the course of both medical and surgical 

patients. 

Technical aspects, psychological consequences of 

feeding ‘deprivation’ and a high rate of complications 

led to suspicion of this therapeutic strategy at 

the early phase of its development. However, 

continuous clinical and basic research has allowed 

improvements in its efficiency and reduction in the 

rate of complications. PN is now widely used in a 

variety of indications as reviewed below. PN 

provides macro- and micronutrients and calories 

directly through the systemic circulation. Although 

such delivery short circuits the portal circulation, 

macronutrients such as lipids, glucose and amino 

acids, and micronutrients, can be infused in high 

concentrations without causing harmful effects and 

these are sufficient for nutritional maintenance and 

normal growth in children. Nevertheless, in some 

situations, such as those encountered in neonatol- 

ogy, gastroenterology or hematology, PN could be 

better adapted to the clinical condition by providing 

specific nutrients. This chapter will briefly review 

the indications, modalities, intakes and complications 

of PN for infants, children and adolescents. A 

specific chapter in this book is dedicated to 

parenteral nutrition in the newborn. Many references 

to reviews are provided and the reader is 

invited to refer to these for further details. 

Indications of parenteral nutrition 

Digestive and extradigestive indications 

PN is indicated in children for prevention or treatment 

of malnutrition, whatever its cause, as soon as 

it becomes impossible to use the enteral route. The 

range of PN indications, related both to digestive 

and non-digestive diseases (Table 34.1), has greatly 

increased during the last few years. However, 

because of the iatrogenic risk of the technique, especially 

when its use is prolonged, each indication 

should be discussed while PN should be, as often as 

possible, performed in specialized units, such as 

intensive care, hematology–oncology or gastroenterology 

units. 

Gastrointestinal (GI) indications for PN can be 

subdivided into three main situations: malabsorption 

syndromes, 3–5 indications of bowel rest (e.g. 

Crohn’s disease), 6,7 and congenital or acquired 

neonatal pathology of the GI tract. Short-bowel 

syndrome is the oldest and one of the most classic 

indications for long-term PN. 8–13 Some congenital or 

acquired metabolic diseases, such as severe hepatic 

or renal failure with Gl complications may benefit 

from PN with appropriate amino acid solutions. An 

increasing area of use of PN is represented by the 

management of children with malignant disease. 

555

556 

Parenteral nutrition in infants and children 

Table 34.1 Indications for parenteral 

nutrition 


Malabsorption medical and/or surgical 

Protracted and intractable diarrhea 


Enterocutaneous fistula 

Proximal enterostomy 

Intestinal bacterial overgrowth 

Immune deficiency 

Indication of bowel rest 

Inflammatory bowel disease (Crohn’s disease, 

ulcerative colitis, unidentified colitis) 

Necrotizing enterocolitis 

Intestinal lymphangiectasy 

Acute pancreatitis 

Systemic disease: Schönlein–Henoch, periarteritis 

Radiation enteritis 

Congenital or acquired neonatal pathology of the 

GI tract 

Gastroschisis 

Omphalocele 

Meconial ileus 

Extensive small-bowel resection 


Complicated Hirschsprung’s disease 

Chronic intestinal pseudo-obstruction syndrome 

Extradigestive indications 

Neonatology: premature baby

is the only way in which PN can be delivered at 

home. 

Home parenteral nutrition 

Home PN is the only alternative to prolonged hospitalization 

for patients requiring long-term PN. 32–36 

Such patients certainly need to be managed by a 

specialized center, from which a home PN program 

can be organized. 37 Nutrition is generally mixed 

parenteral and enteral, but it may be exclusively 

parenteral, lasting for months or years. Indications 

include total or subtotal resection of the small 

bowel; chronic intestinal pseudo-obstruction 

syndromes; intractable diarrhea caused by refractory 

atrophy of the intestinal mucosa with severe 

and persistent malabsorption, either alone or in 

association with an immune deficiency; and some 

cases of inflammatory bowel diseases (IBDs), especially 

severe Crohn’s disease, either extensive 

and/or with multiple surgery, with growth retardation 

or that have not responded to other therapy. 

The objective of long-term PN in these cases is to 

ensure normal growth of the child while the inflammatory 

syndrome subsides or while waiting for the 

residual intestinal condition to become stable. 

Whatever the duration of PN and the prognosis of 

the disease, home PN offers the patients and their 

families the best possible quality of life. 37 In addition, 

home PN reduces the cost of care, when 

compared to prolonged hospitalization. 36 Cyclic 

infusion, adequate and appropriate provision of 

macro- and micronutrients, and improvements in 

central venous catheters (CVCs) and nutritional 

mixtures have all played a major role in making 

home PN possible. The development of an infrastructure 

for patient training and follow-up, a PNsolution 

compounding unit, and an efficient domiciliary 

delivery service are required to organize 

home PN. Over the past 25 years, more than 300 

children treated at Necker-Enfants Malades 

Hospital have been discharged on home PN. Most 

home PN indications were primary digestive 

diseases: short-bowel syndrome accounted for 47% 

of the indications, the other main indications being 

IBD (11%), chronic intestinal pseudo-obstruction 

syndrome (10%) and intractable diarrhea of infancy 

(8%). Fifty-four per cent of the patients have been 

weaned from PN, 26% are still on home PN, and 

16% have died. Survival rates at 2 and 10 years 

Parenteral nutrition in clinical practice 557 

were 97% and 81%, respectively. Most of the PNrelated 

complications were from infection, with 

about two CVC-related infection for 1000 home PN 

days (Colomb et al. Submitted for publication). 

However, the most life-threatening home PN-related 

complication is liver disease. The French results, as 

well as those of other teams (Boston), suggest that 

home PN is the best option for children in need of 

long-term PN. 

Ethical dilemmas may arise for children with extensive 

GI resection, microvillous atrophy or persistent 

villous atrophy who are never able to tolerate full 

enteral feeding. In such patients, in whom intestinal 

autonomy cannot be achieved, intestinal transplantation 

may represent the only alternative to lifelong 

PN. 38–41 Indications for intestinal transplantation 

are not only extreme short-bowel syndromes but 

also all situations in which the small intestine is 

unable to achieve nutritional requirements; this 

includes intractable diarrhea of infancy (chronic 

villous atrophy, microvillus inclusion disease) or 

severe motility disorders such as chronic intestinal 

pseudo-obstruction syndrome. 

Parenteral nutrition in clinical 

practice 

Vascular access 

Central venous access for the purpose of supplying 

parenteral nutrition to the pediatric age group 

requires a careful definition of the patient’s caloric 

need, estimated duration of therapy, and an assessment 

of available sites. Peripheral venous administration 

is the easiest and least hazardous method, 

requiring rigorous asepsis, especially in malnourished 

children. However, only iso-osmolar solutes, 

providing insufficient protein-energy intake, can be 

used because of the risk of superficial phlebitis. In 

some cases, a further limiting factor can be that 

access to superficial veins is restricted or impossible. 

Peripherally inserted central catheters offer a 

new technology for accessing central veins while 

obviating the risk of central vein access. 42 

Infusion into the superior vena cava with a CVC is 

often necessary. 43 However, the use of a CVC is 

accompanied by specific complications, such as 

thrombosis or sepsis. There are several routes of

558 


central vein access and there are a variety of 

catheters available for placement. Tunneled percutaneous 

placement of silicone rubber-cuffed 

catheters via the subclavian vein approach is the 

most commonly used technique, the size of the 

catheter being selected according to the child’s 

weight and age. 44–46 A CVC with a Dacron ® cuff, 

ensuring efficient anchoring, may be inserted either 

percutaneously or surgically. In each case the cutaneous 

and venous entry sites should be separated 

by a 5–10-cm subcutaneous tunnel; one must be 

careful since subcutaneous tissue is particularly 

thin in severely malnourished children. 43 The risks 

of such access catheters include the mechanical 

risks of placement, venous thrombosis of the access 

sites and, most importantly, catheter-related infections, 

either at the exit site or at the subcutaneous 

tunnel or pouch, or even generalized sepsis. The 

cutaneous exit site should be given meticulous 

daily care using iodinized disinfectants and be 

protected by an occlusive dressing, which is 

changed every day. Implantable devices for longterm 

vascular access are also used in children, especially 

in those with cancer requiring intravenous 

chemotherapy. 47 The exclusive use of these devices 

for long-term home PN is rare and, in our experience, 

not well accepted by the children. In longterm 

home PN patients who have received many 

CVCs, we create an arteriovenous fistula. 48 With a 

full knowledge of the spectrum of access techniques, 

access materials and risks, safe total 

parenteral nutrition can be safely delivered to the 

children in need. 

The use of a 0.22-mm antibacterial membrane filter 

between the catheter and the administration tubing 

during perfusion remains recommended. The 

choice of pump is important, satisfying three criteria: 

reliability at low flow rates; ease of use; and 

fitted with a safety alarm capable of signaling a 

change in flow rate, an air bubble or a blockage 

leading to increased pressure. Solutions for 

parenteral nutrition must be prepared under strict 

asepsis by using antibacterial filters under a laminar 

flow hood. 

Parenteral nutrition supplies 

After a period of development of the technique and 

of improvement in prevention of complications, PN 

is now widely used in a variety of indications in 

pediatric patients. Macro- and micronutrients given 

exclusively through the central vein for prolonged 

periods are sufficient for nutritional recovery and 

maintenance as well as long-term growth in children. 

One of the current objectives is to adapt the 

PN intakes to the clinical and nutritional situation. 

Indeed, it is essential that the composition of the 

intravenous feeding solution be adjusted according 

to age and disease as well as to the clinical and 

biological criteria and as a function of the progressive 

transition from parenteral to enteral feeding. 

Energy requirements 

Defining energy requirements is mandatory to 

achieve adequate energy intake and to avoid overfeeding 

or underfeeding. Basal metabolic rate (BMR) 

and resting energy expenditure (EE) may be used for 

achieving adequate energy intake. BMR is the EE of 

a recumbent patient in a thermoneutral environment 

after a 12–18h fast just when the individual 

has awakened, but before starting daily activities. 

BMR reflects the EE required for vital processes. 

Resting EE refers to the EE of a person at rest in a 

thermoneutral environment. BMR and resting EE do 

not usually differ by more than 10%. Equations 

may be used for calculating BMR or resting EE. 49–51 

Most of them are based on body weight, height, age 

and sex. None of them will predict energy requirements 

with acceptable precision for daily clinical 

use. 49 The resting EE of a stable hospitalized child 

requiring PN may be measured by using indirect 

calorimetry. 52 However, energy intake must cover 

total EE, that is the sum of requirements for basal 

metabolism, thermic effect of food, thermoregulation 

and physical activity. In older children, physical 

activity may account for a large proportion of 

total EE, especially when he is able to be on cyclic 

PN. On the other hand, requirements for a malnourished 

child who requires catch-up growth, or the 

requirements for a critically ill patient are a matter 

of debate. Some data are available in infants or children 

after surgery 53–55 or in an ICU. 56–60 It has been 

thought that aggression, such as surgery, inflammation 

state or sepsis, increases energy requirements 

proportionally to the severity of the illness. 

However, the increased EE is short-lived. Newborns 

have a 20% increase in resting EE after major 

surgery, but this elevation returns to baseline within 

12–24h. 53 Another study performed by Jaksic et al 

failed to show any difference in EE between non-

ventilated surgical neonates (gastro-schisis, atresia, 

volvulus) on postoperative day 16 (±12 SD) 

compared with infants on extracorporeal life 

support studied at 7±3 days of age. 54 

Finally, these studies suggest that postoperative or 

critically ill infants and children do not require 

much more than their resting EE. Overestimation of 

the energy requirements for the entire postoperative 

period, or for any protracted period of time, may 

result in overfeeding and subsequent metabolic 

impairment. In addition, there may be significant 

interindividual variations in EE. 

Measuring resting EE in critically ill infants and 

children is difficult because of the expensive equipment 

and the expertise required. Nevertheless, 

Pierro et al and White et al proposed formulas for 

estimating EE in intensive care patients. 61,62 On a 

daily clinical practice, energy intake may be 

adapted and monitored according to the patient’s 

weight gain, the absence of water overload and 

evidence of overfeeding. In premature babies and 

infants, supplies vary from 150kcal/kg per day to 

100kcal/kg per day, and are reduced to 

60–80kcal/kg per day in older children and adolescents. 

Energy sources 

Glucose 

Glucose is the unique carbohydrate used during 

total PN. Few data are available for establishing the 

optimal glucose intake for children receiving PN 

and thus avoiding overfeeding from glucose. From 

the estimation of glucose utilization by the brain, 

which varies according to age, it is possible to 

discuss two issues: the contribution of gluconeogenesis 

in the glucose supply; and the glucose oxidation 

capacity on total body level. 63 Gluconeogenesis 

provides a significant amount of glucose (even in 

preterm infants) and suggests that not all the 

glucose has to be provided exogenously. 64,65 

The rate of parenteral glucose delivery must be kept 

constant without exceeding the maximum rate of 

glucose oxidation (RGO), which differs strongly 

among patients according to age and clinical status. 

In critically burned children, the maximal RGO has 

been found to be 5mg/kg per min. 66 In appropriatefor-gestational-age 

preterm infants, the RGO does 

not exceed 6–7mg/kg per min (9.5g/kg per day), 67 


while in term surgical infants or infants on longterm 

total PN, the maximal RGO is about 12mg/kg 

per min (18g/kg per day). 68–70 Data collected in 

stable adult patients on long-term PN show a 

maximal RGO much lower than in children and 

infants. 71,72 By excluding the preterm infants and by 

taking into account the brain to total body weight 

ratio, and according to glucose brain consumption, 

one could consider that maximal RGO is continuously 

decreasing from birth to adulthood. Thus, the 

rate of glucose administration should be adapted to 

age and clinical situation, e.g. premature babies, 

critically ill patients, severe malnutrition (Table 

34.2). 

Consequences of excessive glucose intake 

(Table 34.3) 

When glucose is administered in excess of the 

amount that can be directly oxidized for energy and 

glycogen production, the excess is directed to lipogenesis73,74 

and promotes fat deposition, which may 

be a nutritional goal in some clinical situations. 

This conversion probably accounts, in part, for the 

increase in EE observed with high rates of glucose 

infusion. 71 Excessive glucose intake is thought to 

increase CO2 production and minute ventilation but 

few relevant data are available to support this 

evidence. 75–77 Total energy delivery, as well as 

amino acid intake, are responsible for increased 

CO2 production and minute ventilation. 76,77 

Excessive glucose intake may also impair liver function, 

especially by inducing steatosis, while its 

Table 34.2 Recommended range of glucose 

intake for infants and children 

Glucose/kg body Day 1 Day 2 Day 3 Day 4 

weight per 24h 

Infant

560 


Table 34.3 Consequences of excessive 

glucose intake 

Hyperglycemia 

Increased CO2 production and minute ventilation 

Increased energy expenditure 

Lipogenesis and fat tissue deposition 

Steatosis and liver dysfunction (increased 

transaminases) 

Increased production of VLDL triglycerides 

VLDL, very low-density lipoprotein 

contribution to the development of cholestasis is 

not clearly established. 78,79 Studies in normal adult 

volunteers suggest that high carbohydrate feeding 

leads to an increase in total very low-density 

lipoprotein (VLDL) triglyceride secretion rate from 

de novo synthesis primarily due to stimulation of 

the secretion of preformed fatty acids. 80 The results 

imply that the liver derives all its energy from 

carbohydrate oxidation as opposed to fatty acid 

oxidation, such that fatty acids taken up by the liver 

are channeled into VLDL triglycerides. 80 Hepatic 

steatosis results when export of the VLDL triglycerides 

does not keep pace with production. 80,81 

It is obvious that PN is associated with an increased 

risk of infectious complications compared with 

enteral feeding or no nutritional support. 82–85 

Nevertheless, data suggest that hyperglycemia 

might be a risk factor for infection, 86–88 especially in 

critically ill patients. 89 These data have to be 

confirmed. Total PN may be associated with insulin 

resistance, due to both the substrate infusion and 

the underlying disease. 32 Therefore, particular 

attention must be paid to glucose tolerance (hyperglycemia, 

glucosuria) at the time of starting cyclic 

PN, when decreasing the duration of infusion may 

lead to excessive increase in the glucose rate of 

delivery. In patients on stable long-term total PN, 

glucosuria may reveal a stressful event, particularly 

infection, which impairs sensitivity to insulin. 

Recommendations for glucose administration 

during cyclic PN are provided in Table 34.4. 

Lipids 

Intravenous fat emulsions (IVFEs) are usually 

added to the PN regimen because they provide 

Table 34.4 Cyclic parenteral nutrition (PN) 

Cyclic PN is well tolerated and may be used from 

3–6 months of age 

Advantages of cyclic PN 

achieves insulin/glucagon balance 

improves protein synthesis 

prevention of liver disease 

physical and psychological 

home parenteral nutrition 

Hyperinsulinic response prevents hyperglycemia 

even with a rate of glucose infusion as high as 

1.4g/kg/h 

Safety recommendations 

use maximum rate of infusion

anabolism, because of adequate energy and nitrogen 

intakes, can lead to onset of essential fatty acid deficiency. 

A linoleic acid supply of about 2–3% of the 

total energy input is recommended in children on 

total PN. 98 A daily supply of 4% or 450mg of 

linoleic acid per 100kcal is often necessary to 

correct a pre-existing deficiency. IVFEs also include 

α-linolenic acid (C18:3 n-3). Although its function 

and requirements are still poorly defined, an intake 

of about 40–50mg/kg per 24h, equal to about 0.5% 

of the total energy intake, is normally provided. 

Administration of IVFEs is required as soon as 

possible in a patient on total PN, according to the 

clinical status. Two important issues have to be 

considered for IVFE administration: the rate of IVFE 

delivery is a major determinant of the rate of fat 

clearance from the bloodstream and the optimal 

glucose/lipid ratio for optimal energetic substrate 

utilization (oxidation) and avoidance of fat overload. 

Intravascular metabolism of lipids 

Clearance of lipid emulsions 

The composition of IVFEs results in a mixture of 

artificial chylomicrons having physicochemical 

characteristics very similar to those of the natural 

chylomicrons produced by enterocytes. They are 

hydrolyzed by lipoprotein lipase (LPL) in capillaries 


Figure 34.1 Metabolism of intravenous fat emulsions. NEFA, non-essential fatty acids; TG, triglycerides; PL, 

phospholipids; LPL, lipoprotein lipase; CETP, cholesterol ester transferase. 

of adipose tissue and muscle. This step determines 

the rate at which fatty acids from the emulsion are 

transported into the tissue for storage or oxidation. 

Like many other key enzymes, LPL can be regulated 

both in amount and in activity. The amount of LPL 

at the capillary endothelium is under hormonal 

control, while its activity is regulated by the specific 

activator apo CII 99 (Figure 34.1). 

Lipid clearance tests have been developed in the 

past but are not used routinely in clinical practice. 

They allow understanding of the factors determining 

the elimination of exogenous fat emulsions from 

the circulation. 100 Patients with moderate trauma, 

for example after cholecystectomy, have an 

increased fractional elimination rate in comparison 

with healthy controls. Critically ill patients on the 

other hand have an elimination rate which is lower 

or close to that of healthy controls. 101 

The composition of an exogenous fat emulsion is 

also important in determining its elimination from 

the circulation. The emulsifying agent is one important 

factor in this respect. The egg yolk phospholipids 

that are mostly used, give emulsions that are 

eliminated very rapidly. IVFEs with high concentrations 

of phospholipids, i.e. 10% emulsions, should 

be avoided as they carry a higher risk of producing 

high serum levels of triglycerides, cholesterol and 

phospholipids than other emulsions, i.e. 20% and 

30% emulsions. 102,103

562 


Interaction between drugs and fat elimination has 

frequently been discussed. With this regard, 

heparin remains controversial. Heparin acts by activating 

and releasing LPL from the endothelial 

surface and, when given together with exogenous 

fat emulsions, causes a sharp increase in circulating 

LPL activity and free fatty acid levels. Sometimes 

this might be a positive effect, but in patients with 

already high free fatty acid levels an increase in 

lipolysis may lead to extremely high free fatty acid 

values. There is no place for routine administration 

of heparin together with the fat emulsion as 

proposed in the past. 104 

Interactions with lipoproteins 

Lipoproteins play a key regulatory role in the metabolism 

and elimination of exogenous lipids. 

Endogenous VLDL particles undergo degradation to 

LDL in plasma under the action of LPL. These particles 

contain apo CII which acts as an activator of LPL. 

Exogenous triglyceride particles are hand-led in the 

same way but have to acquire apo CII mainly from 

the high-density lipoprotein (HDL) fraction before 

they can be hydrolyzed. During the degradation of 

VLDL particles there is a continuous exchange of 

apolipoproteins and surface material. The serum 

HDL concentration is positively correlated to the fractional 

elimination rate of exogenous fat emulsions. 

Routine assessment of patients receiving IVFEs 

should include, before and during the course of 

treatment: fasting plasma triglycerides, total cholesterol, 

and plasma LDL and HDL cholesterol. A 

normal plasma triglyceride level does not mean that 

exogenous triglycerides are adequately used (oxidation) 

or stored (adipose tissue). Indeed, part of the 

exogenous lipid may be cleared by other mechanisms, 

especially capture by the reticuloendothelial 

system (RES). In contrast, high plasma triglyceride 

levels suggest impaired clearance related to excessive 

infusion rate and/or decreased LPL activity. 

Reduced LPL activity may be due to prematurity, 

malnutrition, acidosis, hyponatremia, hypoalbuminemia-related 

high free fatty acid plasma levels, 

high plasma phospholipid levels, or cytokines such 

as tumor necrosis factor-α (TNF-α). 

Contraindictions to the use of IVFEs 

Despite the advantages of IVFEs and the need to 

correct any essential fatty acid deficiency, there are 

restrictions to the administration of lipids to 

malnourished patients. The lower the capillary 

tissue mass (a situation found in preterm infants 

and malnourished patients), the slower is the rate of 

intravenous fat emulsion clearance. Therefore, the 

longer the infusion time, the less is the risk for the 

patient to develop hypertriglyceridemia. 105,106 In 

very malnourished patients, LPL activity reappears 

rapidly with the onset of anabolism. The substrate 

itself also stimulates LPL synthesis. It is therefore 

recommended that IVFEs should not be administered 

until a few days after the start of parenteral 

nutrition in severely malnourished patients. 

There may also be several classic contraindications 

to the use of IVFEs during the initial phase, such as 

sepsis, thrombocytopenia, disseminated intravascular 

coagulation, respiratory distress syndrome or 

metabolic acidosis. Furthermore, administration of 

IVFEs during neonatal jaundice must be handled 

carefully as there is a risk of displacing non-conjugated 

bilirubin from albumin with free fatty acids. 

Finally, inadequate clearance of IVFEs may result in 

RES overload as suggested by the so-called ‘fat overload 

syndrome’ (see below). 

Optimal glucose/fat ratio 

In the past, total PN for adults, children and infants 

provided most of the energy as glucose, although it 

was not precisely known how much of the intravenously 

administered glucose was oxidized. 

Glucose-based total PN has been shown to cause 

adverse effects related to glucose storage, particularly 

as fat. This might account for the extensive 

lipid deposition reported both in liver and adipose 

tissue. 107,108 In these conditions, fat infusion further 

increases fat deposition and may result in fat overloading. 

Thus, substitution of part of the glucose 

calories avoids the undesirable effects reported with 

glucose-based total PN. Studies performed in 

infants or neonates have assessed glucose and fat 

utilization. 109 By using five isocaloric total PN regimens 

differing in their glucose/lipid ratio, it was 

possible to assess for the optimal glucose infusion 

rate. 110 Fat infusion aiming at a significant contribution 

to the coverage of energy expenditure requires 

that glucose oxidation be equal to or lower than 

maximal oxidative glucose disposal. Hence, glucose 

infusion rates should not exceed 18g/kg per day. A 

study in malnourished infants and young children 

showed that the amount of infused lipid mmust be

adapted to lipid oxidation capacity. 110 There is a 

maximal lipid utilization rate of about 3.3–3.6g/kg 

per day. Above these values there is an increased 

risk of fat deposition secondary to the incomplete 

metabolic utilization of infused lipid. Pierro et al 

showed similar results in a short-term study 

performed in surgical neonates on total PN. 111 

Fat overload syndrome 


IVFEs have been thought to impair immune function, 

but no relevant data are available suggesting an 

impairment. 112 Acute clinical and biological expression 

was described as mimicking septic syndrome 

but related to macrophage activation. Symptoms 

include high fever, hepatosplenomegaly, jaundice, 

respiratory distress syndrome, bleeding, thrombocytopenia, 

disseminated intra-vascular coagulation, 

metabolic acidosis and hypoalbuminemia. 113 This 

so-called ‘fat overload syndrome’ is thought to be 

related to the capture of exogenous particles by the 

RES. Cessation of lipid administration is insufficient 

most of the time for improving a patient’s 

condition. Steroids may stop the process of 

macrophage activation. More recently we reported 

several cases of severe cholestasis apparently 

related to long-term administration of intravenous 

lipids. 114 

Mechanisms of lipid toxicity 

Although lipids are necessary in patients on PN, 

they are strongly suspected to be toxic in some 

cases. The metabolism of their oxidized fraction is 

relatively well known; far less is known about the 

Table 34.5 Recommendations for lipid 

administration 

Use of 20% lipid emulsion 

Maximal daily amount of 2–2.5g/kg (

564 


shown to be cleared more rapidly and are now 

widely used in adult and pediatric patients. 118–120 

Fatty acids from the hydrolysis of MCTs are the 

primary substrate for ketogenesis. Carnitine is 

needed to transport long-chain fatty acids into the 

mitochondria, but malnourished and seriously ill 

patients may be carnitine-depleted. An energy 

source able to bypass this route into the mitochondria 

would in theory, be useful for such patients. 

The MCT/long-chain triglyceride (LCT) lipid emulsion 

(B. Braun, Germany) contains 50% LCTs to 

avoid any possible side-effects from excessive 

amounts of MCTs and to provide essential fatty 

acids. Medium-chain fatty acids can enter the mitochondria 

by simple diffusion, independent of the 

carnitine enzyme, and produce an elevation of 

plasma ketones. 118,119 MCTs have been shown to 

improve nitrogen balance in postoperative patients 

but this positive effect remains controversial 

according to several other studies. 120–122 There have 

been several published studies in children using 

MCTs. 123–126 Their use in malnourished infants after 

15 days on total PN indicates that they are well 

tolerated and could provide advantages in terms of 

nitrogen metabolism by supplying the equivalent of 

25% non-protein energy intake. 124 MCT emulsions 

have also been used in home PN pediatric patients 

with beneficial effect in reducing cholestasis. 125 

Structured triglyceride emulsion 

To improve the safety and the efficiency of MCTcontaining 

fat emulsions, a structured triglyceride 

emulsion, containing both long-chain and mediumchain 

fatty acids bound to the same carbon skeleton, 

has been synthesized. Such structured triglyceride 

emulsions have been shown to improve 

nitrogen retention and muscle protein synthesis in 

animal models and in humans. 127,128 There is is no 

study currently available in pediatric patients. 

Fish oil-based emulsions 

Fish oil triglycerides are also now being considered 

for PN either as pure fish oil particles or incorporated 

into MCT/LCT emulsions. Fish oil is now 

proposed as a component of lipid emulsions. By 

providing a high amount of long-chain polyunsaturated 

fatty acids (PUFAs), they are reported to have 

anti-inflammatory effects. 129,130 There is a study 

currently being carried out in pediatric patients. 

Olive oil-based IVFEs 

It is well known that a high intake of monounsaturated 

fatty acids in the form of olive oil is associated 

with a lower incidence of cardiovascular morbidity. 

131 In patients dependent on long-term PN, the 

availability of intravenous fat emulsions containing 

lower amounts of unsaturated fatty acids could be 

of interest. 132,133 New 20% fat emulsions containing 

17% olive oil and only 3% soybean oil are now 

available. 133 It has been shown in a long-term pediatric 

study that olive oil-based emulsion preserves 

essential fatty acid status and fatty acid elongation 

and decreases total cholesterol. 133 The olive oil 

group showed better measurements of antioxidant 

activity against lipid peroxidation. The same olive 

oil- and vitamin E-enriched emulsion was recently 

reported as a valuable alternative for PN of preterm 

infants who are often exposed to oxidative stress, 

while their antioxidative defense is weak. 134 

Carnitine and α-tocopherol 

Carnitine plays a central role in metabolism especially 

for optimal oxidation of fatty acids. 135 

Carnitine, in the form of acylcarnitine transfers free 

fatty acids into mitochondria, where they are 

recombined with co-enzyme A (CoA) to form acyl- 

CoA. 135 Plasma levels of carnitine decrease rapidly 

in premature newborns and small-for-gestationalage 

neonates during the first days of life if no exogenous 

carnitine is provided. 136 Available studies did 

not assess the use of carnitine during long-term PN, 

a situation that is more likely to result in carnitine 

deficiency. Some authors have raised the question 

of carnitine supplementation for children on total 

PN. 137 As yet, in the absence of specific recommendations, 

a supplement of 2mg/kg per day may be 

advisable. 138 Supplementation with α-tocopherol as 

antioxidant, added to IVFEs at a dose of 0.6mg/g of 

unsaturated fatty acids is also recommended. 

Nitrogen intake 

Energy supply should be closely correlated with 

that of nitrogen. Nitrogen intake obviously depends 

on the age and degree of malnutrition. 140 In premature 

babies the intake varies from 400–500mg to 

650mg/kg per day. 141 In infants, the intake varies 

from 400mg 142 to 800mg/kg per day in the case of 

great nitrogen losses from the GI tract. In older chil-

dren, 300mg/kg per day is usually sufficient. Such 

intakes, which are higher than the growth requirement, 

cover excessive nitrogen losses induced by 

catabolism. Greater amounts are unsuitable, 

because with a constant caloric intake there is a 

negative correlation between nitrogen intake and 

the amount retained and the subsequent danger of 

hyperaminoacidemia, metabolic acidosis or isoosmolar 

coma. Such intakes may also be responsible 

for excessive urinary losses of calcium and 

phosphorus and subsequent bone mineralization 

impairment. 143 Finally, usual nitrogen/energy ratio 

varies around 1g of nitrogen for 200–250kcal. 

Nitrogen sources 

Nitrogen sources available for PN come from 

various mixtures of crystalline L-amino acids. They 

have been shown to be effective in clinical use, 

providing appropriate nitrogen utilization and 

retention. Amino acid solutions for use in PN are 

selected according to the following criteria: 144,145 

(1) Whether the solution contains all or only some 

of the naturally occurring amino acids; 

(2) Total amino acid nitrogen content; 

(3) Osmolality and electrolyte content; 

(4) Amount of essential amino acids per gram of 

total nitrogen (E/T); 

(5) Non-nitrogen nutrient content (glucose, fructose). 

New pediatric solutions have been developed 

which appear to be better suited for use in 

newborns, premature babies or malnourished 

infants (Primene, Clintec ® ; Vaminolac, Pharmacia 

® ). Such products have an E/T ratio greater than 

3 and differ from standard solutions in having a 

higher percentage of branched-chain amino acids; 

modified aromatic amino acid content (a one-third 

reduction in phenylalanine); modified sulfur amino 

acid content, with methionine reduced by 50% and 

an increase in cysteine content (both solutions also 

contain taurine, which is absent from standard solutions); 

and increased lysine content. 

Other sources of nitrogen 

Protein-energy malnutrition secondary to chronic 

disease, as well as acute illness such as injury or 


infection, are associated with loss of body fat and 

skeletal muscle mass. The loss of body tissue may 

be minimal and of little consequence in patients 

with normal nutritional status and a brief, self-limiting 

illness lasting a few days. However, when the 

disease is prolonged and the patient is malnourished, 

a variety of clinical events may occur in association 

with the catabolic state. These alterations 

include immunosuppression, delayed wound 

healing and tissue repair, and loss of muscle 

strength. 146 The accelerated breakdown of body 

protein can be slowed by the administration of 

adequate quantities of energy, protein (amino acids) 

and other essential nutrients. However, measurements 

of body composition and substrate-flux 

studies indicate that it is extremely difficult to 

maintain or replenish body protein during catabolism. 

146 Thus, reducing the debility associated with 

the catabolic process could potentially enhance 

recovery and decrease the consequences of illness 

on protein retention and height–growth velocity. 

Because the efficacy of nutrition cannot be 

improved easily by quantitative modifications, 

attention has focused in recent years on qualitative 

improvments. The addition of specific amino acids 

or other sources of nitrogen to the feeding formulas 

might be logical in critically ill children (sepsis, 

burns, trauma) or in patients with chronic inflammatory 

processes such as severe Crohn’s disease. 

Glutamine 

Glutamine is the most abundant amino acid in the 

body. 147 However, glutamine is absent from the 

currently available amino acids solutions. Indeed, 

glutamine is considered as unstable in aqueous 

solutions and during heat sterilization with the 

formation of pyroglutamic acid and ammonia. 

Although glutamine is a non-essential amino acid, 

the nutritional requirement for this amino acid 

during catabolic illness may differ greatly from that 

during health. 147 During starvation or stress, the 

concentration of free glutamine in the intracellular 

amino acid pool of skeletal muscle rapidly 

decreases. Glutamine exported from the muscle is 

used primarily by visceral organs; in the kidney it 

serves as an ammonia donor; in the gastrointestinal 

tract it serves as a primary oxidizable fuel source for 

enterocytes and colonocytes. 148,149 Glutamine also 

supports other rapidly proliferating tissue, such as 

fibroblasts or lymphocytes. Glutamine-supple-

566 


mented total PN has been shown to preserve gut 

structure and to improve gut immune function in 

animal models. 150 Studies have shown the clinical 

benefits of glutamine-supplemented total PN in 

adult patients undergoing bone marrow transplantation. 

151–154 The use of glutamine-containing 

dipeptides is proposed because of the instability of 

free glutamine. Improved nitrogen balance has been 

shown in patients receiving alanyl-glutaminesupplemented 

total PN. 155 In addition, glutamine 

dipeptide-supplemented PN prevents intestinal 

atrophy and increased permeability in critically ill 

adult patients. 156 

Ornithine α-ketoglutarate 

Another source of nitrogen for patients on PN is 

represented by ornithine α-ketoglutarate (OKG). 

This is a salt formed with two molecules of 

ornithine and one molecule of α-ketoglutarate. OKG 

has been successfully used by the enteral and 

parenteral route in burn, traumatized and surgical 

patients and in chronically malnourished 

patients. 159,160 According to the situation, OKG 

administration decreases muscle protein catabolism 

and/or increases protein synthesis. The mechanism 

of action of OKG is not fully understood, but it was 

clearly demonstrated that it is a precursor of glutamine. 

162,163 In addition, the secretion of anabolic 

hormones (insulin, human growth hormone) and 

the synthesis of metabolites (polyamines, arginine, 

ketoacids) may be involved. 160,161 In prepubertal 

children on PN, administration of OKG (15g/day) 

reversed growth retardation and increased insulinlike 

growth factor I (IGF-I) plasma levels. 161 

Finally, it seems likely that, in the near future a 

more specific therapeutic approach to protein 

metabolism might be achieved. This prospect is of 

great importance for children with regard to the 

consequences of inadequate protein metabolism on 

growth velocity. 

Other components of PN solutions 

Water and electrolyte intake must be varied according 

to the age and condition of the child, needing 

adjustment, for example, if there are intestinal 

losses. Premature babies need 150–200ml water per 

kilogram body weight daily to maintain equilibrium; 

infants require 120–140ml/kg and older 

Table 34.6 Vitamin requirements 


Vitamin A (µg) 300–750 450–1000 

Vitamin D (IU) 100-1000 200–2500 

Vitamin E (mg) 3–10 10–15 

Vitamin K (µg) 50–75 50–70 

Vitamin Bl (mg) 0.4–0.5 1.5–3 

Vitamin B2 (mg) 0.4–0.6 1.1–3.6 

Vitamin B5 (mg) 2–5 0.5–5 

Vitamin B6 (mg) 0.1–1.0 1.5–2 

Vitamin B12 (µg) 0.3–3 3–100 

Vitamin C (mg) 25–35 20–100 

Folic acid (µg) 20–80 100–500 

Biotin (µg) 35–50 150–300 

Niacin (mg) 6–8 5–40 

Table 34.7 Trace element requirements 

Element Infants Children 

(/kg/day) (/day) 

Iron (mg) 50 100–2500 

Zinc (mg) 100–250 1000–5000 

Copper (mg) 20–30 200–300 

Selenium (µg) 2–3 30–60 

Manganese (µg) 1–10 50–250 

Molybdenum (µg) 0.25–10 50–70 

Chrome (µg) 0.25–2 10–20 

lodine (µg) 1–5 50–100 

Fluoride (µg) 20 500–1000 

children 80–100ml/kg per day. All normal babies 

and children need 3–5mmol chloride, sodium and 

potassium per kilogram per day. When there are 

losses due to vomiting or gastric aspiration 8mmol 

sodium, 1mmol potassium, 6mmol H + ions and 

12mmol chloride should be added to each 100ml of 

water. In the case of an enterostomy, 15mmol 

sodium, 1mmol potassium, 10mmol of chloride 

and 5mmol bicarbonate should be added to each 

100ml of water. 

With a nitrogen intake of 400mg/kg per day and a 

calcium intake of 1.7mmol/kg per day, the daily 

requirement of phosphorus is 2.3mmol/kg for bone 

growth and nitrogen anabolism. If the phosphorus 

intake is lower or the intake of nitrogen and/or

calcium is higher, severe phosphorus depletion 

results. Magnesium requirements are usually satisfied 

by 1mmol/kg per day. 

Vitamin and trace element intakes are provided as a 

function of the intake of the respective nutrients 

and their anabolism. For infants and older children, 

adherence to the recommendations in Tables 34.6 

and 34.7 helps to prevent depletion or excess. These 

intakes should be adjusted in cases of catabolic 

stress, such as an infection or intestinal losses. 

All-in-one mixture 162–168 

Administration of IVFEs together with the glucose 

amino acids in a three-in-one mixture is now widely 

used in children. There are a number of potential 

advantages to PN admixtures but also some drawbacks. 

In addition to reducing cost, use of a PN 

admixture simplifies the patient’s life in that only a 

single infusion pump with less tubing and other 

accessories is needed. 162 There is also evidence that 

it reduces the risk of bacterial growth in intravenous 

fat emulsion even after 24h. 163 

Stability is directly related to the concentration of 

the components, and is dependent on pH and 

temperature. If the mixture is not compatible, the 

fat emulsion will break, forming an oil–water 

interphase that can be seen floating on top of the 

mixture. Because the admixture is a physical mix 

of naturally incompatible substances (oil and 

water, calcium and phosphorus), their utilization 

requires strict attention to pharmaceutical guidelines 

for preparation, storage and use. 164,165 

Particulate matter (mobile, undissolved substances 

such as precipitates of calcium and phosphorus 

that are unintentionally present in products) 

resulting from inappropriate preparation or storage 

can be life-threatening. To reduce the risk of 

precipitates reaching the patient an in-line filter 

should be used. This should be a 1.2µm aireliminating 

filter (in contrast to the 0.22µm aireliminating 

filter recommended for non-lipidcontaining 

PN). A PN admixture is considered 

inappropriate for administration if >0.4% of the 

total fat contains particles >5µm in size. 166 Some 

drugs are compatible with PN admixtures but not 

with traditional PN, and vice versa. 167 

It is possible to formulate total PN mixtures that 

have good short-term stability and that satisfy the 

Refeeding syndrome 567 

nutritional requirements of most patients. Several 

companies produce a three-in-one mixture with 

good long-term stability. Retention of long-term 

stability in a mixture containing electrolytes is more 

difficult, although advances are being made in this 

area. The development of complete total PN 

mixtures with long-term stability will be assisted by 

advances in our understanding of the fundamental 

physical chemistry of colloid mixtures, particularly 

the interaction between emulsions and amino acids. 

Indeed such a ternary solution may lead to lipid 

instability, and/or catheter obstruction. PN admixtures 

should only be used in patients who are clinically 

stable. Solutions may be stable when refrigerated 

and become unstable at room temperature. 

Changes in the formulation of PN admixtures are 

more costly than changes in traditional (two-in-one) 

PN because of the wastage of both the dextrose 

amino acid and its components, and the intravenous 

fat emulsion. A number of questions remain 

about PN admixtures. These include the appropriate 

dosing of some vitamins, the true risks related to 

particulate matter and fat-droplet size, and drug 

compatibilities. 

Refeeding syndrome 


If PN is required because of severe malnutrition and 

inability of the GI tract to cover the protein-energy 

requirements, it has to be provided very carefully. 168 

Indeed, refeeding syndrome may be observed in 

severely malnourished patients receiving concentrated 

calories via PN. 169 This syndrome includes 

the metabolic and physiological consequences of 

the depletion, repletion, compartmental shifts and 

inter-relationships of the following: phosphorus, 

potassium, magnesium, glucose metabolism, 

vitamin deficiency and fluid resuscitation. 170,171 

The net effect of the hormonal and metabolic 

changes of starvation is to facilitate survival by a 

reduction in basal metabolic rate, conservation of 

protein and prolongation of organ function, despite 

the preferential catabolism of skeletal muscle tissue. 

Infants and children who have suffered from 

malnutrition for weeks or months will also experience 

a significant loss of visceral cell mass. 

Refeeding the malnourished child disrupts the 

adaptative state of semi-starvation.

568 


As refeeding is initiated there is a rapid reversal 

in insulin, thyroid and adrenergic endocrine 

systems. Basal metabolic rate increases and 

glucose becomes the predominant cellular fuel. 

The body immediately begins the process of 

rebuilding lost tissue. Anabolism is accompanied 

by a positive balance of intracellular minerals. 

As minerals shift to intracellular spaces, 

serum levels may plummet. Body fluid compartments 

redistribute as intracellular fluid 

increases; extracellular fluid may increase or 

decrease depending on the previous intake, the 

persistent digestive losses and the refeeding 

regimen. These rapid changes in metabolic 

status can create life-threatening complications, 

so the nutritional regimen must be chosen wisely 

and monitored closely. Several potential metabolic 

complications of the refeeding syndrome 

are listed in the Table 34.8. 

To reduce the risk of refeeding complications, 

several conditions are required at the initial 

phase of renutrition of severely malnourished 

infants and children. 

Table 34.8 Metabolic disorders associated with refeeding syndrome 

Prevention of water and sodium overload 

It is necessary to reduce the patient’s water and 

sodium intake, depending on the hydration state, 

to prevent water and sodium overload resulting 

from their excessive retention, accentuated by 

increased secretions of vasopressin and aldosterone. 

Early weight gain may be the consequence 

of fluid retention. The monitoring of water and 

electrolyte intake must include uncontrolled 

losses as well as those from the Gl tract. One of the 

difficulties in such situations is the need to take 

into account a third factor, such as intraperitoneal 

or intestinal fluid retention. Monitoring of body 

weight changes, urine collection, and assessment 

of blood and urinary electrolytes are essential. 

Oncotic pressure restoration 

The infusion of macromolecules aims to restore 

oncotic pressure and to minimize hemodynamic 

problems, worsened by a water–electrolyte imbalance. 

Albumin is the best infusate, but fresh-frozen 

Hypophosphatemia 

Cardiac: altered myocardial function, arrhythmia, congestive heart failure, sudden death 

Hematological: altered red blood cell morphology, hemolytic anemia, white blood cell dysfunction, 

thrombocytopenia, depressed platelet function, bleeding 

Hepatic: liver dysfunction 

Neuromuscular: acute areflexic paralysis, confusion, coma, cranial nerve palsies, diffuse sensory loss, 

Guillain–Barré-like syndrome, lethargy, paresthesias, rhabdomyolysis, seizures, weakness 

Respiratory: acute ventilatory failure 

Hypokalemia 

Cardiac: arrhythmias, cardiac arrest, increased digitalis sensitivity, orthostatic hypotension, ECG changes (T-wave 

flattening or inversion, U waves, ST segment depression) 

Gastrointestinal: constipation, ileus, exacerbation of hepatic encephalopathy 

Metabolic: glucose intolerance, hyporeftexia, paralysis, paresthesias, respiratory depression, rhabdomyolysis, 

weakness 

Renal: decreased urinary concentrating ability, polyuria and polydypsia, nephropathy with decreased glomerular 

filtration rate, myoglobinuria (secondary to rhabdomyolysis) 

Hypomagnesemia 

Cardiac: arrhythmias, tachycardia, torsade de pointes 

Gastrointestinal: abdominal pain, anorexia, diarrhea, constipation 

Neuromuscular: ataxia, confusion, fasciculations, hyporeftexia, irritability, muscle tremors, painful paresthesias, 

personality changes, positive Trousseau's sign, seizures, tetany, vertigo, weakness

plasma or blood may be required in cases of anemia 

and/or coagulation disorders. Artificial ventilation 

may be required in those, generally few, cases 

having a poor cardiorespiratory status. 

Intake of carbohydrates 

Constant administration of carbohydrate is required 

to maintain blood glucose homeostasis as the 

reserves are very low; parenteral administration of 

glucose requires care because of the risk of hyperglycemia 

with osmotic diuresis and hyperosmolar 

coma. 

Potassium repletion 

Correction of potassium depletion is of great importance, 

but should be achieved progressively with 

monitoring of renal and cardiac functions. It can be 

dangerous to try to correct the deficiency too 

rapidly at a stage where the capacity for fixing 

potassium remains low because of reduced protein 

mass; excessive intake leads to the cardiac risk of 

hyperkalemia. 

Body temperature monitoring 

It must be monitored, since protein-energy malnutrition 

(PEM) can lead to hypothermia, often associated 

with hypoglycemia and bradycardia. On the 

other hand, hyperthermia or excessive reheating 

increases water loss as well as energy expenditure. 

Maintenance of a stable body temperature between 

36°C and 37°C by appropriate warming techniques 

is essential. Careful daily nursing to prevent cutaneous 

lesions and musculotendinous retractions is 

also very important. 

Prevention of infection 

The infective, metabolic and GI problems must be 

constantly borne in mind during treatment of pediatric 

patients with severe PEM. The risk of infection, 

an expression of both specific and non-specific 

immunity depression, may jeopardize the prognosis 

and aggravate nutritional problems at any time. 

Clinical and paraclinical investigations must be 

performed repeatedly, to look for widening foci of 

infection (respiratory, GI, skeletal and urinary) and 

Refeeding syndrome 569 

for their systemic spread. When a localized or 

systemic infection is identified, specific treatment is 

urgently required. The routine use of antibiotics in 

the absence of bacteriological evidence in a 

malnourished child is inadvisable; antibiotics 

should only be given if sufficient indirect evidence 

points to the likelihood of infection. Active intestinal 

parasitosis should, of course, be vigorously 

treated. Evidence or suspicion of an infection is an 

essential factor in modifying water, electrolyte and 

nutrient intake and also in the choice of the feeding 

technique. 

Protein and energy intake 

It is difficult to suppress protein catabolism under 

these conditions of stress and low-energy intake. 

Excessive nitrogen intake may lead to hyperammonemia 

and/or acidosis by exceeding the renal 

clearance capacity for H + and phosphate ions. An 

intake of 0.5–1g/kg of parenteral amino acids or oral 

peptide is sufficient to maintain the plasma amino 

acid pool. The protein-energy deficiency and other 

related disorders must be corrected during the days 

following the initial period of stress. This type of 

correction should be made carefully and gradually 

since the deficits are profound and of longstanding. 

It is essential to provide both nitrogen and calories 

simultaneously and in the correct ratio. The 

increase in energy intake, if progressive, avoids 

acute episodes of sodium and water retention 

accompanied by oliguria and a fall in urinary 

sodium and potassium output. It is likely that these 

changes are carbohydrate dependent, since their 

occurrence and equally rapid reversal develop with 

changes in glucose rate of glucose infusion. This 

antinatriuretic effect of glucose appears to be 

similar to the antinatriuresis observed during 

feeding after a phase of experimental fasting. The 

insulin secreted induces sodium tubular reabsorption, 

and the alkalosis that develops might be due to 

increased tubular absorption of bicarbonate. 

Micronutrients 

The provision of appropriate nutrient solutions 

requires an understanding of the nutritional relationships 

between nutrients electrolytes, vitamins 

and trace elements. It is during this initial phase 

that any deficit due to incorrect intake will become

570 


apparent through either clinical or laboratory signs. 

These deficits can usually be prevented by giving 

them in the following proportions: 200–250kcal, 

nitrogen 1g, calcium 1.8mmol, phosphorus 

2.9mmol, magnesium 1.0mmol, potassium 

10mmol, sodium and chloride 7mmol, zinc 1.2mg. 

Similarly, it is essential to adapt the intake of 

copper, manganese, chromium, iron, iodine, cobalt 

and fluoride, and the group B vitamins in particular; 

also, the intakes of essential fatty acids, tocopherol 

and selenium. 

Adaptation of intake 

After the initial phase of renutrition, most complications 

can be prevented by careful supervision and 

the provision of appropriate intakes. It is essential 

that the infusion rate, body temperature, cardiac 

and respiratory function, urinary volume, twice 

daily weight and digestive output are continuously 

monitored. During the first 5 days and also when 

the osmotic load is increased, urine should be 

checked for osmolality, pH, glucose and protein. 

The plasma and urinary ion data, plus the calcium, 

phosphorus, magnesium, glucose and hematocrits 

should be obtained twice during the first week, and 

then once weekly; plasma proteins, albumin, bilirubin, 

alkaline phosphatase and transaminase values 

should be assessed routinely. These data, and 

knowledge of the patient’s state and age, should 

make it possible to progressively regulate and 

control the intake and avoid problems of overload 

or depletion. 

Complications of parenteral nutrition 

(Table 34.9) 

Catheter-related sepsis 

In hospital as well as at home, catheter-related 

sepsis is one of the most serious complications 

which can arise during parenteral nutrition. 172–175 A 

2-year prospective study of 185 CVCs showed a 

sepsis rate of 0.26%, with an overall incidence of 

one catheter-related sepsis per 278 days of total 

PN. 176 Systemic antibiotics provided sepsis control 

in 88% of the cases while CVC removal was 

required in the other cases. The factors significantly 

correlated with sepsis were: age (1–5 years); CVC 

Table 34.9 Complications during parenteral 

nutrition (PN) 

Infectious 

Local skin infections 

Catheter-related sepsis 

Complications of catheter-related sepsis: 

endocarditis, osteomyelitis 

Metabolic 

Water and/or sodium overload 

Hyperosmolar coma 

Excessive urinary losses 

Hyperglycemia with glycosuria–hypoglycemia 

Metabolic acidosis 

Hyperazotemia–hyperammonemia 

Hypokalemia 

Hypophosphatemia 

Hypercalcemia–hypercalciuria 

Hypertriglyceridemia–hypercholesterolemia 

Nutritional deficiencies 

Essential fatty acid deficiency 

Carnitine deficiency 

Trace element deficiency: Fe, Zn, Cu, Se, Mo, etc. 

Vitamin deficiency: A, E, B, B12, folates, etc. 

Long-term total PN 

Total PN liver disease 

Total PN bone disease 

Hematological and coagulation disorders 

type (surgically inserted CVCs were more frequently 

infected); local hemorrhage following CVC insertion; 

and local suppuration at the skin exit site. 

Prevention of catheter-related sepsis requires strict 

asepsis during both CVC insertion and changes of 

filter and infusion sets. Daily care of the CVC skin 

exit site is of great importance. All PN solutions 

must be prepared under a laminar flow hood and 

filtered. The care of the child should be undertaken 

by physicians and nurses who have been specifically 

trained in this technique. Fever or clinical 

signs suggestive of catheter-related sepsis should 

lead to a thorough search for a source of sepsis, 

together with a white blood cell count, C-reactive 

protein and coagulation tests. Samples for blood 

culture should be taken via the catheter and from a 

peripheral vein. If fever persists, antibiotic therapy 

should be started early and include antibiotics

against Staphylococcus. Coagulase-negative staphylococci 

(CoNS) is the most frequent blood culture 

isolate from neonates, infants and children with 

CVCs. 172,176 Clinicians vary in their management of 

suspected line sepsis, particularly that caused by 

CoNS. A vancomycin-containing regimen is widely 

used in infants and children suspected of having 

line sepsis. Procedures to prevent CoNS-positive 

blood cultures and to differentiate CoNS contaminants 

from pathogens are needed. For safely 

decreasing vancomycin use, clinical practice guidelines 

should be developed, implemented and evaluated. 

The guidelines should include optimal skin 

antisepsis and catheter disinfection before obtaining 

blood for culture, obtaining two blood cultures 

and using adjunctive tests and information to help 

differentiate contaminants from pathogens, and 

restriction on empiric vancomycin use. 

Both catheter removal and infection dissemination 

may be avoided by starting antibiotics soon after 

onset of fever. However, removal of the catheter is 

systematically considered in case of fungal infection, 

infection due to Staphylococcus aureus with 

cutaneous infection, or if the patient continues to 

deteriorate even when appropriate antibiotic 

therapy had been started. In neonates who were 

infected with Staphylococcus aureus or with nonenteric 

Gram-negative rods, it was shown that 

delayed removal of the CVC was associated with 

complicated bacteremia. 174 

Otherwise, removal of the catheter is considered 

when blood cultures remain positive after several 

days of optimal antibiotic treatment, or when the 

PN program is close to completion. With good technique, 

displacement or obstruction of the catheter, 

or thrombosis of large vessels are rare. Careful technique 

should also help prevent superficial venous 

thrombophlebitis and the risk of dissemination of 

septic emboli. 

Parenteral nutrition-related bone disease 

The so-called PN-related bone disease resembles 

rickets, with fractures of the limbs which are sometimes 

asymptomatic and are only discovered after 

routine X-ray examination. 177 The most constant 

laboratory features are an elevated alkaline phosphatase 

activity and hypercalciuria, with normal or 

subnormal levels of vitamin D metabolites and 

parathyroid hormone. Bone histology shows osteo- 

Complications of parenteral nutrition 571 

malacia-like changes with reduced mineralization 

and excess of osteoid tissue. The etiology of these 

bone lesions is probably multifactorial: excess 

vitamin D or disorders of its metabolism mean that 

it must be given very carefully on long-term 

parenteral nutrition. It is also possible to reduce the 

hypercalciuria by ensuring that the supplies of 

phosphorus, nitrogen and energy are properly 

balanced, while reducing the supply of amino acids, 

especially the sulfur-containing amino acids. 178 

Finally, it is necessary to ensure that the solutions 

used for children during long-term PN are not contaminated 

with alum-inum. 179,180 Prevention of this 

‘bone disease’ depends primarily on regular 

measurements of urinary calcium, which should 

not exceed 5mg/kg per 24h, and serum alkaline 

phosphatase activity. Measurement of bone mineral 

content is now widely performed using dual X-ray 

absorptiometry (DEXA) scan. 181 

Parenteral nutrition-related liver disease 

Liver disease is a major side-effect of long-term PN. 

Fifteen years after the first reports its pathogeny is 

not completely understood. 182 Disruption of bile 

acid enterohepatic circulation in case of ileal amputation, 

impairment in choleresis in the absence of 

oral feeding, bacterial overgrowth due to bowel 

obstruction, stasis and lack of ileocecal valvula, are 

patient-dependent factors thought to contribute to 

PN-associated cholestasis. 183 One mechanism might 

be an increase in bile concentration of lithocholic 

acid. 184 Bacterial infections were also proposed as a 

co-factor in PN-related cholestasis, since the sepsisassociated 

cholestasis has been well described, both 

in human and animal models. 185–187 Duration of PN 

is also a known risk factor. Qualitative aspects of PN 

are also a matter of debate. It was experimentally 

demonstrated that an excess in total energy delivered 

induces liver lesions, reversible when decreasing 

the energy supply. 188 The role of amino acids 

was suspected, either an excess or a lack of 

them, 189,190 and an excessive glucose supply might 

induce steatosis through the increase in de novo 

lipogenesis. 191 Hepatobiliary complications of PN 

are now well recognized and documented. Such 

liver involvement may result in some cases in endstage 

liver disease within a few months or years. 

Many PN-related and patient-related risk factors are 

involved in those hepatobiliary complications. 

Since the underlying digestive disease plays a

572 


prominent role, some pediatric patients requiring 

long-term PN are at high risk of developing liver 

disease. Short-bowel syndrome may be associated 

with disruption of bile acid enterohepatic circulation 

due to ileal amputation, impairment in 

choleresis when oral feeding is impossible, bacterial 

overgrowth due to bowel obstruction, stasis and 

lack of ileocecal valvula, which are all factors 

thought to contribute to PN-associated cholestasis. 

Recurrent septic episodes either catheter-related 

(Gram-positive bacteria) or digestive-related (Gramnegative 

sepsis from in-traluminal bacterial overgrowth) 

also contribute to liver injury. 192–197 

Prematurity itself might be an associated factor. In 

addition, inadequate PN may have an additional 

deleterious effect on the liver because of metabolic 

disorders or micronutrient overload. Indeed, 

continuous PN infusion with excessive glucose 

intake is associated with hyperinsulinism and 

subsequent steatosis. 144 Inad-equate amino acid 

supply is thought to be responsible for metabolic 

dysfunction of the liver. Excessive aluminum, iron, 

or chromium intake might be responsible for liver 

injury. 179,180,198,199 

The earliest and most sensitive, but not specific 

laboratory markers are serum alkaline phosphatase 

and γ-glutamyl transferase activities, while hyperbilirubinemia 

is the latest marker of cholestasis to 

appear. Steatosis is the first non-specific histological 

abnormality. Steatosis may result either from 

excessive glucose supply leading to lipogenesis, or 

from the deposition of exogenous IVFE. Clinical 

liver enlargement, confirmed by ultrasonography, 

may appear within a few days after PN onset. 

Cholestasis together with portal and periportal cell 

infiltration leads to fibrosis. This indicates severe 

liver disease, which can lead to cirrhosis and liver 

failure, but is fortunately rare if PN is performed 

correctly. More recently, the association of 

cholestasis with thrombocytopenia has been 

described in patients on PN, 114 but the link 

between liver disease and the RES overload needs 

to be better understood. 

Careful monitoring of hepatic function is extremely 

important in order to minimize factors responsible 

for liver disease. Some measures have been found to 

limit or reverse liver disease and may include: 

(1) The stimulation of the entero-biliary axis by 

ingestion of LCTs or breast milk, or by injection 

of cholecystokinin analogs; 200 

(2) The reduction of intraluminal bacterial overgrowth 

caused by intestinal stasis by giving 

metronidazole and/or performing tapering 

enteroplasty; 201 

(3) The use of ursodesoxycholic acid (10–20mg/kg 

per day) or tauroursodeoxycholic acid could 

contribute in decreasing liver injury; 202,203 

PN intake should be adapted by: 

(1) Limiting glucose intakes to reduce hepatic fat 

accumulation; 204–207 

(2) Using the appropriate type and amount of 

intravenous fat emulsion, which provides 

essential fatty acids, reduces glucose load and 

limits peroxidation; 133,196,208 

(3) Controlling the lipid supply and rate of delivery 

and/or stopping IVFEs as soon as thrombocytopenia, 

hyperbilirubinemia and/or jaundice 

appear; 114 

(4) Using the new pediatric-adapted amino acid 

solutions which provide appropriate amino 

acids as well as taurine; 144,209 

(5) Performing cyclic PN, which helps to reduce 

hyperinsulinism and liver steatosis; 25–32 

(6) Adapting the iron intake and decreasing 

aluminum content of the PN solution. 210,211 

When cholestasis occurs, biliary obstruction, infection 

or drug toxicity should be ruled out by appropriate 

investigations. Decrease in platelet count 

below 150 000/mm 3 associated with an increase in 

plasma transaminases, and a further increase in 

plasma bilirubin, should lead to strong suspicion of 

lipid toxicity when all other explanations are ruled 

out. Bone marrow aspiration, liver biopsy and 

temporary suspension or decrease in lipid infusion 

should be discussed. Lipid infusion should be 

stopped until normalization of bilirubin level and 

platelet count. Essential fatty acid deficiency must 

be carefully checked. In case of persistent cholestasis 

after a 2-month suspension of lipid infusion, an 

irreversible course of the liver disease should be 

suspected. Reintroduction of lipid emulsions 

should be attempted under strict supervision, below 

the previous dosage, beginning with 1 or 2 perfusions 

per week. Medium-chain-based emulsions 

(50% MCT) might help to minimize the LCT load 

and theoretically their hepatic deposition and longterm 

toxicity, but neither the current study nor

other clinical data have demonstrated any effects of 

MCT-based emulsions to prevent or to reverse longterm 

PN-associated cholestasis or hematological 

complications. Emulsions based on olive oil might 

also reduce the risk of lipid toxicity due to peroxidation, 

by decreasing the amount of linoleic acid. 

Conclusions 

Parenteral nutrition has become a widely used therapeutic 

option in clinical nutrition. One of the goals 

of PN is to have the same nutritional efficacy as that 

of normal oral feeding. Clinical research in the field 

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35 

Introduction 

Gastrointestinal problems of 

the newborn 

Moti M Chowdhury and Agostino Pierro 

The birth of a newborn in most cases marks a 

joyous occasion for a family. However, occasionally 

it is dampened by the tragedy of a congenital 

anomaly or illness within the first few weeks of 

life, a period that accounts for most childhood 

fatalities. In this chapter we endeavor to outline 

some of the acquired problems relating to the 

gastrointestinal (GI) tract. Whilst it is acknowledged 

that almost all acquired GI problems of 

childhood may present within the neonatal period, 

most are rare events in newborns (e.g. appendicitis, 

intussusception, inflammatory bowel disease), 

and it would be beyond the scope of this chapter 

to discuss all such problems exhaustively. In this 

chapter we focus instead on the four common GI 

problems encountered in the first few weeks 

of life: necrotizing enterocolitis (NEC), gastroesophageal 

reflux (GER), infantile hypertrophic 

pyloric stenosis (IHPS) and inguinal hernia. 


NEC is a disease predominantly of premature 

infants characterized by a variable degree of 

intestinal necrosis, which may or may not be 

complicated by perforation and fulminant sepsis. 

Epidemiology 

NEC is the most common surgical emergency in 

the neonatal period, 1 affecting 0.5% of all live 

births and 3–5% of low-birth-weight live births. 

Although primarily a disease of the preterm infant, 

6–13% are in full-term infants. 2–4 There is a male 

preponderance of 2:1. 3 

Etiology 

Whilst the precise mechanism of NEC remains 

unclear, a number of predisposing risk factors 

have been identified: low birth weight, prematurity, 

enteral feeds and sepsis. 

Low birth weight 

Low birth weight (

580 

Gastrointestinal problems of the newborn 

hyperosmolar feeds has the potential to contribute 

large quantities of hydrogen gas to the pneumatosis 

intestinalis. 

Sepsis 

Although a number of organisms (see Pathophysiology 

below) have been cultured in pathological 

specimens of NEC, many are from the bowel 

flora, suggesting a mechanism involving an imbalance 

between the host and the organism rather 

than direct virulence of the organism. 14,19 

In addition to these recognized risk factors, a 

number of other weak associations have been 

reported with the development of NEC (Table 

35.1). 


The precise pathophysiology of NEC remains 

unclear, but it is considered to be multifactorial in 

origin – the culmination of microbial colonization 

and inflammatory insult with mucosal injury to an 

intestine that is compromised by hypoxic ischemia 

and/or immaturity. 1,20 Hypoxia and circulatory 

ischemia result in preferential distribution of the 

limited blood supply to vital organs such as the 

heart, brain and kidney, at the expense of compromising 

blood flow away from non-vital regions 

including the splanchnic circulation of the intesti- 

Table 35.1 Risk factors for development of 


Low birth weight 

Prematurity 

Enteral feeds 

Sepsis 

Intrauterine growth restriction 11,188,189 

Fetal distress 190 

Exposure to antenatal or postnatal glucocorticoids 7 

Premature rupture of membranes 191,192 

Birth asphyxia 14 

Respiratory disease, 191 e.g. hyaline membrane disease 

Congenital heart disease, e.g. coarctation, patent 

ductus arteriosis 193 

Maternal cocaine abuse 194,195 

Umbilical artery catheterization 196 

nal tract (the Herring–Breur reflex). Intestinal 

ischemia and bacterial colonization stimulate proinflammatory 

mediators (including interferonγ, 

21,22 tumor necrosis factor (TNF)-α 23 and platelet 

activating factor (PAF) 24,25 ), which through multiple 

cascades may lead to variable degrees of coagulative 

and ischemic necrosis of the bowel. 20 

Furthermore free radicals released from inflammatory 

cascades following ischemia and reperfusion 

contribute to the tissue necrosis by causing lipid 

peroxidative damage to cellular membranes. 26 

Diffusion of free radicals and the effect of gasforming 

organisms within the gut wall result in the 

pathognomonic pneumatosis intestinalis that is 

seen on radiographs in 90% of cases. 27 

Transmural necrosis with bacterial translocation 

across the gut wall may result in perforation with 

peritonitis, bacteremia or septicemia. Up to 35% of 

patients with NEC have positive cultures, 28 with 

the most common implicated pathogens being 

Klebsiella, 29 Escherichia coli, 29 Clostridium difficile 

30,31 and Streptococcus faecalis. 32 

The increased propensity of premature infants to 

develop NEC injury is attributed to a number of 

additional factors. These include a deficient 

intestinal microbial host defense, poor development 

of the mucosal barrier, 33,34 an immature 

mucosa at greater susceptibility to hyperosmolar 

feeds 18 and an accentuated pro-inflammatory 

response. 35,36 If the intestinal injury is short-lived, 

the pathological course may be followed by 

healing with fibrosis, with or without a resulting 

stricture in the affected bowel. The disease most 

commonly involves the terminal ileum and 

ascending colon, but it may affect variable 

segments of the small and large intestine, being 

isolated (30%), multifocal (55%) or pan-intestinal 

(15%) (Figure 35.1). 37 


The clinical course of NEC is variable, with twothirds 

of patients developing the condition within 

the first week of life. 38 The severity of the disease 

may be categorized clinically using the original 

Bell’s staging system for NEC 39 outlined below, a 

classification later modified by Walsh and Kliegman. 

40

(a) (b) (c) 

Complications 

Necrotizing enterocolitis 581 

Figure 35.1 Intraoperative illustration of (a) isolated necrotizing enterocolitis (NEC), (b) multifocal NEC, (c) pan-intestinal NEC. 

Stage I 

Suspected NEC. At the early stage, symptoms and 

signs are usually non-specific, e.g. irritability, 

fever, apneas and bradycardias, and poor toleration 

of feeds. Many of these children are more 

likely to be suffering from feeding intolerance 

commonly associated with prematurity or low 

birth weight, but nonetheless they should be 

regarded as at risk of developing more fulminant 

disease. 

Stage II 

Established NEC. These babies will have established 

clinical and radiographic signs of NEC with 

moderate–profound systemic illness, including 

metabolic acidosis and thrombocytopenia. 

Vomiting/aspirates are usually bilious or bloodstained 

whilst stools are likely to be blood-stained. 

Abdominal distension, abdominal wall erythema 

and edema are usual, and there may or may not be 

evidence of perforation clinically and/or radiologically. 

A clinically palpable intra-abdominal mass 

(reported in 11% 38 ) may indicate the presence of 

persistently dilated bowel loops or, if the disease is 

localized, an intraperitoneal abscess. 

Stage III 

Advanced NEC with systemic instability. As well as 

features of stage II disease, these babies have 

cardiovascular instability (hypotension), severe 

metabolic acidosis and coagulative derangements. 

There will usually be abdominal and radiological 

evidence of perforation, peritonitis and ascites 

with generalized sepsis. 

At least 10% 41 of NEC cases develop one or more 

of the following complications, with their incidences 

being significantly more common in 

preterm infants. 37 

(1) Metabolic disorders including metabolic 

acidosis and disseminated intravascular coagulation 

(DIC); 

(2) Perforation with peritonitis and septicemia; 

(3) Localized intraperitoneal abscess formation; 

(4) Healing by fibrosis with stricture formation 

(20% in term infants and 31% in preterm 

infants 37 ); 

(5) Massive gut involvement that requires resection 

may result in short-bowel syndrome, 42,43 

with resultant failure to thrive or, worse still, 

pan-intestinal involvement that is incompatible 

with life; 

(6) Recurrence of the disease (9–14% 37 ); 

(7) Infants with stage II or III disease are 

commonly at risk of developing psychomotor 

retardation, 44–49 although this may be more 

attributed to the high incidence of prematurity 

than a direct effect of NEC. 


The differential diagnoses of NEC are outlined in 

Table 35.2. Investigations for diagnosis of NEC 

include the following.

582 


Table 35.2 Differential diagnosis of 


Feeding intolerance of prematurity 

Spontaneous intestinal perforation 

Malrotation/volvulus 

Neonatal sepsis with ileus 

Congenital intestinal obstruction (intestinal atresia, 

Hirschsprung’s disease) 

Neonatal pseudomembranous colitis (rare) 

Neonatal appendicitis (rare) 

Abdominal X-ray (Figure 35.2) may demonstrate 

dilated bowel loops, edematous bowel wall, 

ascites, intramural gas (pneumatosis intestinalis), 

portal vein gas and free air in the peritoneal cavity 

(pneumoperitoneum). Signs of a pneumoperitoneum 

include the ‘football sign’ (central collection 

of free air outlining the falciform ligament and 

umbilical arteries), localized gas in the right upper 

quadrant (the ‘right upper quadrant gas sign’), or 

gas on both sides of the bowel wall (‘Rigler’s sign’). 

The presence of a single/multiple loops of bowel 

retaining the same shape or position for 24–36h 

(‘fixed-loop sign’) may suggest full-thickness bowel 

necrosis. 

In metabolic acidosis, the hemoglobin level may 

fall, owing to hemorrhage and sepsis, whilst leukocyte 

and platelet counts 37,50 may be depressed, 

particularly in association with DIC. 37 

Bacteriological screening should include blood 

culture and collection of swabs from the nose, 

throat, umbilicus and rectum. 


The initial management of NEC consists of stabilization 

of the infant and resting of the intestinal 

tract by means of discontinuation of enteral feeds 

for 10 days, total parenteral nutrition, decompression 

of the stomach by a nasogastric tube, fluid 

resuscitation, intravenous antibiotics for 7–14 

days and correction of any metabolic derangement. 

However, up to 50% of neonates with NEC 

Figure 35.2 Abdominal X-ray demonstrating 

pneumoperitoneum from perforated necrotizing 

enterocolitis. 

develop advanced disease that requires surgery. 51 

Indications for surgery include: 

(1) Clinical deterioration despite maximal 

medical treatment; 

(2) A pneumoperitoneum, indicating perforated 

NEC; 

(3) An abdominal mass with persistent intestinal 

obstruction or sepsis; 

(4) The development of an intestinal stricture. 

The options for surgery are between primary peritoneal 

drainage or laparotomy. However, the optimum 

choice between primary peritoneal drainage 

and laparotomy remains controversial, 

particularly in low-birth-weight infants (1000g who have 

no associated morbidities and are clinically stable, 

are preferentially treated by primary laparotomy. 52 

The principal surgical objectives of laparotomy in 

acute NEC are to control sepsis, to remove 

gangrenous bowel and to preserve as much bowel 

length as possible. 53–55 Within these objectives, a

Figure 35.3 An infant with a peritoneal drain (arrow) 

inserted into the right iliac fossa. 

number of options exist, including: resection with 

enterostomy; resection with primary anastomosis; 

proximal jejunostomy; the ‘clip and drop’ technique; 

or to ‘patch, drain and wait’. The option 

exercised is highly variable between surgeons 

9,56–59 and is often influenced by the site and 

extent of the disease. An algorithm of the authors’ 

preferred surgical approach for the management of 

advanced NEC is illustrated in Figure 35.4. 

Prognosis 

The outcome from NEC is highly variable, with the 

postoperative complication and mortality rates 

ranging between 10 and 70%. These depend on: 

Stable 

Focal 

Resection and 

anastomosis 

Unstable 

Viable 

distal bowel 

Stoma Resection and Stoma ± 

anastomosis resection 

NEC findings at laparotomy 

Proximal 'Clip and 

enterostomy drop' 

(1) Stage of the disease; 14,49,60,61 

Gastroesophageal reflux 583 

(2) Extent of disease involvement, with 

the lowest survival in pan-intestinal disease; 

5,8,11,37,42,49,62–65 

(3) Birth weight; 5–10,14,49 

(4) Gestational age, 5,14,37,49,63,66,67 with 77% survival 

in term infants compared to 66% in 

preterm infants; 

(5) Presence of associated medical co-morbidities; 

7,49,68 

(6) Modality of operative treatment. This affects 

the postoperative complication rate for 

multifocal NEC (85% survival after resection 

and primary anastomosis compared to 50% 

with enterostomy alone) but not isolated 

NEC. 37 

Contrary to popular belief, the loss of the ileocecal 

valve is not associated with increased complication 

or mortality rates, 37,69,70 suggesting that these 

neonates adapt rapidly to the loss of the ileocecal 

valve. 

Gastroesophageal reflux 

GER is a physiological process characterized by 

the involuntary passage of gastric contents into the 

lower esophagus not induced by noxious stimuli. 

The phenomenon is considered as GER disease 

only when it causes the patient to be symptomatic 

or results in pathological complications. 

Multifocal Pan-intestinal Total intestinal 

gangrene 

Questionable distal bowel or 

bleeding at bowel dissection or 

unstable 

Proximal 

jejunostomy 

'Clip and 

drop' 

Consider withdrawal 

of teatment 

Figure 35.4 Algorithm of the authors’ preferred operative management of advanced necrotizing enterocolitis (NEC) 

(reproduced with permission from Seminars in Perinatology 2003).

584 


Epidemiology 

Most newborns have some degree of GER, but the 

majority resolve spontaneously, with the prevalence 

decreasing to 18% in childhood. 71 The 

male/female ratio is 1.6. 72 The incidence of GER is 

highest in neurologically impaired children (70%), 

who comprise 44–67% of children undergoing 

anti-reflux surgery. 73–75 


A number of physiological and anatomical factors 

normally contribute to prevent chronic reflux of 

gastric contents into the lower esophagus. The 

combination of esophageal motility and gravity 

facilitates esophageal clearance of refluxed material 

as well as of saliva, which is rich in bicarbonate, 

that coats the esophagus. These esophageal 

clearance mechanisms are usually developed by 

31 weeks’ gestation. 76 Other physiological barriers 

to GER include antral contractions facilitating 

gastric emptying, and the production of mucus, 

prostaglandin and epithelial growth factors, which 

help to prevent damage to the esophageal mucosa. 

Anatomically the length of the intra-abdominal 

esophagus, the phrenoesophageal ligaments, the 

gastric mucosal ‘rosette’ and the esophageal hiatus 

(which is a sling formed by the crura of the 

diaphragm causing a pinchcock effect) all 

contribute to a higher-pressure zone in the lower 

esophagus. This high-pressure zone forms the 

lower esophageal sphincter (LES), a physiological 

rather than a true anatomical sphincter. Pressures 

at this gastroesophageal junction (10–30mmHg) 

are greater than gastric luminal pressure 

(5mmHg), thereby preventing retrograde passage 

of gastric contents. In addition, the acute angle of 

His (made by the esophagus and the axis of the 

stomach) and the above physiological factors 

cumulatively contribute to limit the volume and 

frequency of gastric contents refluxing into the 

lower esophagus. Much of these anatomical 

features, however, are poorly developed in the first 

weeks of an infant’s life, predisposing it to a higher 

risk of GER within this period. For instance, the 

angle of His is obtuse in newborns and decreases 

only as the infant grows; also, the length of the 

intra-abdominal esophagus is shorter, only 1cm at 

birth, compared to 3cm by 3months of age. Other 

abnormalities that predispose to GER include 

disruption of the gastroesophageal junction (with 

resulting hiatus hernia), weakness or incompetence 

of the LES and poor clearance of acid from 

the esophagus. 77 

Etiology 

A mean intra-abdominal pressure of less than 

10mmHg is necessary for the LES to remain 

competent. GER is made more likely in groups 

with raised intra-abdominal pressure for example 

following repair of omphalocele (43% 78 ), congenital 

diaphragmatic hernia 79 and chronic respiratory 

infections. 

Neurologically impaired children have the highest 

incidence of GER (65–70% 80 ). This is due to a 

combination of poor esophageal and gastric motility 

(due to vagal nerve dysfunction), chronic 

supine positioning, abdominal spasticity, 

diaphragmatic flaccidity, scoliosis, retching and 

increased use of gastrostomy for feeding. 

Insertion of gastrostomy tubes has been reported to 

be associated with the development or worsening 

of pre-existing GER. The gastrostomy, which fixes 

the stomach to the anterior abdominal wall, potentially 

opens the angle of His 81 and lowers the LES 

pressure 82 thereby predisposing to GER. 

GER occurs in 30–80% of children treated for 

esophageal atresia, the incidence being related to 

the length of the atresia gap. The GER is attributed 

partly to poor esophageal motility in these patients 

and partly to a shortened esophagus. The shortened 

esophagus, from the original anomaly and 

compounded by the surgical repair, results in 

upward displacement of the gastroesophageal 

junction. 


The infant with GER typically presents with 

vomiting or poor toleration of feeds, made worse at 

night during the supine position. Those with associated 

esophagitis may manifest clinically with 

Sandifer’s syndrome, a voluntary dystonic contortion 

of the head, neck and trunk. These movements 

have been shown to improve peristalsis in 

the lower esophagus. If GER is left untreated,

failure to thrive from calorie deprivation may 

ensue. Reflux of gastric contents into the airways 

may result in coughing and choking, and chronic 

aspiration may cause the infant to present with 

complications of GER, including laryngospasm 

with apneic and bradycardia spells (particularly 

during sleep), stridor or pneumonia. 

Complications 

(1) Failure to thrive secondary to calorie deprivation 

occurs in up to 20–52% of children. 83,84 

(2) Iron deficiency anemia, seen in 31%, 83 may 

indicate significant reflux esophagitis with 

blood loss. 

(3) Aspiration of gastric contents may cause 

laryngospasm and subsequently obstructive 

apneas and bradycardias (17% 84 ), particularly 

during sleep, or be complicated by pneumonia 

(in 31% 83 ) or subglottic stenosis. 

(4) Bronchopulmonary dysplasia (60% 84 ), bronchiectasis, 

bronchitis and asthma. The mechanism 

of these complications is not clear. One 

hypothesis is that reflux of gastric contents 

may stimulate vagal afferents in the distal 

esophagus which may cause a reflex vagovagal 

bronchoconstriction. 85,86 

(5) Persistent GER may result in esophagitis, 

which in turn may lead to sticture with 

dysphagia or, in older children, Barrett’s 

esophagus, a recognized pre-malignant condition. 


The differential diagnoses of an infant with clinical 

features of GER are outlined in Table 35.3. 

Investigations used for diagnosis of GER include 

the following. 

Twenty-four-hour pH monitoring is currently the 

most sensitive and specific test available for diagnosing 

GER. Monitoring is performed for 24 

continuous hours, during which time the patient is 

fed only breast milk, formula or apple juice. The 

juice is preferable, as the alkaline content of milk 

feeds may neutralize the gastric acid reflux and 

thereby potentially produce a false-negative result. 


Table 35.3 Differential diagnosis of 

gastroesophageal reflux 

Infantile hypertrophic pyloric stenosis 

Overfeeding/feeding disorders 

Malrotation 


Neonatal sepsis 

Neurological pathology (e.g. raised intracranial 

pressure from hydrocephalus) 

Laryngeal cleft 

Acid reflux is defined by pH 50% of the radioisotope in 

the stomach after 90min, in the absence of 

mechanical obstruction, indicates delayed gastric 

emptying. 

Esophagoscopy allows visualization of the gastroesophageal 

mucosa. However, only 40% of cases of 

GER will demonstrate unequivocal esophagitis. 

Endoscopy is therefore a poor tool for diagnosis of 

GER, and is more useful in the assessment of 

complications of reflux (e.g. esophagitis or stricture) 

and in obtaining biopsies (e.g. Helicobacter 

pylori infections or development of Barrett’s 

esophagus). 

Esophageal manometry enables measurement of 

the LES tone. However, the LES tone is low at 

birth, rising to a mean pressure of 10–15mmHg by

586 


Figure 35.5 Upper gastrointestinal contrast study 

demonstrating gastroesophageal reflux. 

6 months of age. Thus, sphincter tone will be 

physiologically low in neonates, and therefore has 

little application in diagnosing GER in this age 

group. 

Chest X-ray may identify pulmonary complications 

of GER. 

Lipid-laden alveolar macrophages in tracheal aspirates/bronchoalveolar 

lavage may indicate aspiration 

secondary to GER. However, the sensitivity 

and specificity for detecting GER are as low as 38% 

and 59%, respectively. 87 Furthermore, elevated 

levels of lipid-laden macrophages are found in a 

number of pulmonary disease without any 

evidence of aspiration. 88 


The two main aims of treatment are to prevent the 

respiratory complications of GER and to improve 

the nutritional status of the child from resumption 

of normal feeding. 


Conservative measures for GER in infants are 

frequently advocated. They include the avoidance 

of medications that reduce LES tone (caffeine, 

theophylline, anticholinergics), dietary modifications 

(changing the feed pattern with use of 

frequent, small-volume feeds) and positioning 

maneuvers. However, many of these have no 

confirmed efficacy. Thickening of formula feeds 

(e.g. with carob bean gum, or rice flour) may 

reduce frank emesis but does not reduce GER 

measurably compared to placebo. 89–92 Furthermore, 

there are no quality data to support the 

opinion that more frequent but smaller-volume 

feedings reduce GER. 93 With respect to positioning 

maneuvers, positioning at a 60º head elevation 

increases GER compared to the prone position. 94 

However, the association of the prone position 

with sudden infant death syndrome has brought 

controversy with this maneuver. No significant 

difference has been found between the flat and 

head-elevation prone positions. 95 

Pharmacotherapy forms the main first-line treatment 

modality of GER. A wide spectrum of agents 

is now available (Table 35.4), aimed at decreasing 

acid secretion and increasing gastric emptying. 

Detailed descriptions of the pharmacological 

mechanisms of these agents can be found elsewhere. 


Whilst medical therapy serves to decrease the acid 

content of the refluxate, other components of the 

refluxate (e.g. bile pepsin, trypsin) remain unaffected. 

Surgery therefore becomes indicated in 

infants who do not respond to medical treatment, 

or who experience apparent life-threatening events 

(e.g. laryngospasm and apneas), or have anatomical 

problems such as hiatus hernias or esophageal 

strictures. Operative options available for treatment 

of GER are Nissen’s fundoplication (used in 

64% 74 ) and Thal (34% 74 ), Toupet (1.5% 74 ), Dor, 

Boerema, Boix–Ochoa, Collis–Belsey and Hill 

procedures. Nissen’s fundoplication (Figure 35.6) 96 

is the most popular method, and involves a 360º 

wrap of the fundus of the stomach, brought round 

the posterior aspect of the esophagus. It controls 

GER by increasing the acuteness of the angle of His 

and lengthening the intra-abdominal esophagus,

Table 35.4 Pharmacotherapy of gastroesophageal reflux (GER) 

Antacids, e.g. Gaviscon ® 

thereby increasing the high-pressure zone at the 

LES. A concurrent gastrostomy is frequently 

placed, particularly in neurologically impaired 

children, those with feeding difficulties and poor 

weight gain, or slow gastric emptying. The Thal 

procedure 97 is an anterior fundoplication with a 

partial (180–270º) wrap of the fundus of the 

stomach to the intra-abdominal esophagus. The 

benefit of the Thal procedure is that it allows the 

patient to belch and release any bloating, which is 

not feasible with Nissen’s fundoplication. 

Fundoplication procedures may be performed by 

the open or laparoscopic method. Reliable data 

comparing outcomes between the two approaches 

are, however, limited in children. Non-randomized 

studies suggest that the laparoscopic approach 

offers better cosmesis and, if not favorable, is at 


H2 blockers, e.g. ranitidine 

Proton pump inhibitors, e.g. omeprazole 

Prokinetic agents, e.g. dopamine antagonists (e.g. metoclopramide), postganglionic 5-HT4 agonist/acetylcholine 

agonists (e.g. cisapride), erythromycin, bethanecol or domperidone. Prokinetics increase LES tone and esophageal 

peristalsis thereby improving gastric emptying. However, concerns regarding the safety of cisapride on the 

myocardium, with reports of arrhythmias and prolonged QT interval, has restricted its clinical use 

γ-Aminobutyric acid (GABA) agonists, e.g. baclofen, are agents that inhibit GER episodes by inhibition of transient 

relaxations of the LES, 197,198 and are currently being considered for clinical trials 

LES, lower esophageal sphincter 

Figure 35.6 Nissen’s fundoplication 1, Mobilization of the fundus of the stomach by division of short gastric vessels. 2, 

Fundus folded round the posterior aspect of the esophagus. 3, A loose wrap formed, using interrupted sutures. 4, The 

completed stomach wrap. (Adapted with permission from reference 187). 

least comparable with respect to operative time, 

postoperative pain, time to feeds and complication 

rate. 98–101 

Recently, two further endoscopic techniques have 

been described for the treatment of GER. The first 

is endoscopic radiofrequency energy delivery to 

the gastroesophageal junction around the LES. 

Early data suggest that this can achieve resolution 

of symptoms of GER in 87% of patients, 102 but is 

associated with significant mortality and morbidity, 

including aspiration, pleural effusion and 

atrial fibrillation. 103 The second is endoscopic 

gastroplication, 104 which involves internally plicating 

the stomach on itself approximately 1cm 

below the gastroesophageal junction to alter the 

angle of His and thereby decrease reflux of gastric

588 


contents. Early results indicate poorer outcomes 

compared to fundoplications, with 75% still 

requiring adjuvant medical treatment and 6% 

undergoing fundoplication due to therapeutic 

failure. 105 Furthermore, the data reported with 

both these procedures have so far been limited to 

adult populations, and their application in pediatrics 

remains unclear. 

Prognosis 

The prognosis of infants with GER is highly variable, 

depending on the presence of associated 

anomalies (e.g. esophageal atresia, congenital 

diaphragmatic hernia, neurological disorders), 

anatomical problems (e.g. hiatus hernia), prematurity 

of the infant, or the presence of established 

complications of GER. Approximately 80% of 

patients with symptomatic GER are treated 

successfully without surgery. Infants undergoing 

anti-reflux surgery demonstrate clinical improvement 

in 90%, if GER is isolated, compared to 64% 

of infants with associated anomalies. 106 Fundoplication 

is more effective in improving emesis 

(76%) and respiratory symptoms (66%) than affecting 

the nutritional status, with persistence of 

failure to thrive in 62% of patients. 

Complications following fundoplication repairs 

(Table 35.5) occur in up to 24%, with the neurologically 

impaired having up to six-fold increased 

incidence compared to those neurologically 

normal. 73–75,106–113 A repeat fundoplication is 

required in up to 24% of cases, due to either failure 

of the wrap (disruption, herniation or excessive 

tightness) or recurrence of GER. Recurrence of GER 

symptoms after fundoplication is more frequent in 

infants, particularly those with previous esophageal 

atresia repair (42%), with half of these requiring 

a second procedure. 106 

Infantile hypertrophic pyloric stenosis 

IHPS is the second most common condition in 

infancy that requires surgery. The treatment of 

pyloromyotomy was first described by Fredet in 

1907, and then my Ramstedt 4 years later. 114 

Table 35.5 Complications following 

fundoplication 

Disruption of the wrap with recurrence of GER 

(8–12%) 

Dysphagia from an excessively tight wrap (2–12%) 

Herniation of the wrap (2–10%) 

Gas bloating (4–10%) particularly with Nissen’s 

fundoplications 

Adhesive intestinal obstruction (2–10%) 

Poor esophageal clearance (in patients with 

esophageal atresia) 

Splenic injury (0.5%) 

Mortality (0–13%) 

GER, gastroesophageal reflux 

Epidemiology 

IHPS affects 1 in 500 Caucasian children and fewer 

than 1 in 1000 Asian and African infants. 115–118 

There is a male preponderance – a gender discrepancy 

that has been widening recently, reported 

between 4:1 and 10:1. 119–125 Firstborn males are 

most often affected, accounting for 40–60% of all 

cases. 

Etiology 

In spite of IHPS being one of the most common and 

earliest recognized surgical problems in infants, its 

precise etiology remains unclear. Two proposed 

risk factors are breast feeding and a positive family 

history. Twenty per cent of infants with IHPS have 

a positive family history. Although more common 

in males, a positive family history is four times as 

common from affected mothers than fathers. 126 

Overall, there is a 15–20-fold increase in risk of a 

child of an affected parent developing pyloric 

stenosis compared to the general population. 126,127 

It is also more common in multiple births. 128,129 

The incidence of Smith–Lemli–Opitz syndrome 

diagnosed in infants with IHPS is 150-fold higher 

than in the general population. 117 This, and other 

congenital gastrointestinal and urinary tract 

malformations that are more common with 

IHPS, 118 suggest a genetic role in its etiology. The

mode of inheritance is likely to be multifactorial, 

although evidence of reduced expression of the 

neuronal nitric oxide synthase (nNOS) gene, which 

is responsible for the smooth-muscle relaxant nitric 

oxide (NO), has been found. 130,131 The influence of 

breast feeding on IHPS is more controversial. A 

number of groups have found that infants with 

IHPS were twice as likely to have been breast 

fed. 116,132,133 However, Hitchcock et al 134 found no 

such link whilst Pisacane et al 135 found a protective 

effect from breast feeding. 


Whilst the precise mechanism of IHPS remains 

unclear, a number of causative factors have been 

reported. 

First, is failure of relaxation of the pylorus. The 

circular layer of smooth muscle of the pylorus is 

stimulated by the myenteric plexus, whilst its 

relaxation is dependent on non-adrenergic, noncholinergic 

(NANC) inhibitory motor neurons. 

Depletion of these nerves (either primary absence 

or degeneration) in pyloric muscle may be the 

cause of the excessively contracted hypertrophic 

circular pyloric muscle. 136 This hypothesis is 

further supported by the demonstration of reduced 

expression of the nNOS gene (responsible for NO 

synthesis, a mediator of NANC inhibitory nerves) 

in animals models 130 and depleted nNOS mRNA in 

the pyloric muscle of patients with IHPS. 131 The 

influence of uncompensated pylorus contractility 

may also explain why neonates receiving 

erythromycin, which induces the activity of migrating 

motor complexes in the stomach 137 and 

increases pyloric contraction, 138 have up to a 

seven-fold increased risk 139,140 of developing IHPS. 

It is suggested that this marked increase in motility 

may lead to hypertrophy of the pylorus. 139 

Increased expression of insulin-like growth factor- 

Ι 141,142 and transforming growth factor-β 143 found 

in hypertrophic pyloric muscle, may indicate a 

hormonal role in smooth-muscle hypertrophy in 

IHPS. 

Increased amounts of extracellular matrix proteins, 

particularly collagen, have been reported within 

the circular muscle wall of the pylorus in IHPS. 

This may account for the hypertrophic wall of the 

pylorus. 144,145 

Infantile hypertrophic pyloric stenosis 589 

Hypertrophy of the circular smooth muscle wall of 

the pylorus up to four-fold results in pyloric 

luminal outflow obstruction. The infant vomits 

obstructed milk feeds and with it gastric acid 

contents (hydrochloric acid), resulting in dehydration 

with a hypochloremic, hypokalemic metabolic 

alkalosis. 


The infant with IHPS typically presents with 

vomiting, usually at 3–6 weeks of age, although up 

to one-third start vomiting within the first week of 

life. 121,146 Vomiting may initially be effortless, but 

with time it becomes forceful, described as ‘projectile’. 

The vomitus is usually milk feeds, practically 

never bilious, and if severe may contain some 

‘coffee-ground’ flecks of altered blood from 

secondary gastritis in 15–20%. 133 The infant is 

frequently hungry for further feeds, despite the 

vomiting. Constipation is common. Jaundice may 

occur in 3%, and is attributed to the adverse effect 

of starvation on hepatic glucuronyl transferase 

activity. 133 Clinically, dehydration from severe 

vomiting, loss of weight and failure to thrive may 

ensue. Abdominal examination may reveal visible 

peristalsis of the obstructed pylorus (from left to 

right) in 75–95% of cases, and a pyloric ‘tumor’ 

mass, felt like an ‘olive’, representing the hypertrophic 

pylorus, usually in the epigastrium or 

upper quadrants of the abdomen. Successful palpation 

of the pyloric tumor can be achieved in up to 

90% of cases, 147 and may be aided by maneuvers 

such as nasogastric decompression of the stomach 

(which is usually distended with gas swallowed by 

a hungry crying child), palpation through the 

midline gap between the two rectus muscles or at 

the lateral margins of the recti, flexing the hips, or 

allowing the child to suck on a passifier or a ‘test 

feed’ of dextrose solution (which should be aspirated 

back from the nasogastric tube). 

Complications 

(1) Dehydration and metabolic imbalance; 

(2) Intraoperative duodenal perforation. This may 

occur in 3–4%; 148,149 

(3) Postoperative complications. These include 

transient persistence of vomiting in 3–19% 122,148

590 


(particularly those with a protracted preoperative 

history of vomiting); wound infection 

(1–4%); 148 or wound dehiscence (1.4%). 149 

With experience and earlier diagnosis, mortality 

fell from 59% in 1925 to almost nil by 

1975. 121,148,150 


The differential diagnosis of a vomiting child in 

this age group is usually an overfed child or GER. 

Less commonly, the following should be considered: 

incarcerated inguinal hernia, malrotation of 

the bowel (particularly if vomiting is bilious), 

congenital causes of gastric outlet obstruction (e.g. 

webs or duplications), or medical conditions (e.g. 

sepsis, raised intracranial pressure). 

Over the past 30 years, increased reliance on 

imaging has decreased clinical diagnosis from up to 

90% of cases 147,151,152 to as little as 23%. 152 

Ultrasound diagnosis, which has a sensitivity and 

specificity for detecting IHPS of 95–100%, 153,154 is 

the most popular mode of imaging, but some 

groups continue to use upper GI contrast studies 

(Figure 35.7). At least one imaging study is now 

performed in 96%, with diagnosis by radiological 

means alone having increased to up to 65%. 155 The 

criteria for ultrasound diagnosis of IHPS (Figure 

35.8) in a term infant include a pyloric diameter of 

>11mm, muscle wall thickness of >3mm and 

pyloric canal length of >16mm. However, overreliance 

on imaging of a clinically obvious palpable 

tumor is cost-ineffective, and may delay treatment 

unnecessarily, particularly if a false-negative result 

is reported, 156 and should be discouraged. 

Infants with suspected IHPS should routinely 

undergo analysis of serum electrolytes and 

acid–base status, which will typically demonstrate 

a hypokalemic, hypochloremic metabolic acidosis, 

secondary to loss of gastric acid and dehydration 

from vomiting. 


Initial management of IHPS is rehydration and 

correction of biochemical derangements. Various 

fluid regimens are advocated; one such is an infusion 

of 0.45% saline with dextrose solution (10% 

Figure 35.7 Upper gastrointestinal contrast study 

demonstrating narrowed gastric outlet from pyloric 

stenosis (‘string sign’). 

for neonates and 4% for older infants) with 

10mmol potassium chloride. Only after correction 

and adequate rehydration is the definitive 

surgery performed. The operation, Fredet– 

Ramstedt’s pyloromyotomy, may be performed by 

the open or laparoscopic method. Whilst the 

laparoscopic approach offers better cosmesis, 

clinical outcomes appear comparable. 157,158 The 

open method may be performed using a vertical 

midline, right upper quadrant transverse, or an 

umbilical incision. No difference in complications 

were found between the right upper quadrant 

and vertical incisions. 159 The hypertrophic 

pyloric muscle (Figure 35.9) is split longitudinally, 

releasing the mucosal tension within. The 

optimum timing of re-commencing feeding postoperatively 

following an uncomplicated pyloromyotomy 

remains controversial. Advocates of 

early feeding ad libitum immediately following 

recovery from anesthesia report shorter time to 

full feeds and shorter hospital stay. 160 Others, 

who report higher incidence of emesis from such

Figure 35.8 Ultrasound scan demonstrating pyloric 

stenosis. 

a regimen, favor delaying feeding for 6–12h. 161 

Feeding is usually delayed for 24h in those 

complicated with an intraoperative mucosal 

perforation. 

Inguinal hernia 

A hernia is defined as an abnormal protrusion of a 

viscus or part of a viscus through its coverings into 

an abnormal anatomical site. Inguinal hernia is the 

most common condition requiring surgery during 

childhood. Almost all are indirect, i.e. they pass 

through the internal inguinal ring and through the 

inguinal canal. 

Epidemiology 

Inguinal hernias affect one in 50 term male infants 

and up to 30% of premature infants. 162 There is a 

male preponderance, reported between 4:1 and 

9:1. 163–169 In males, 60% of hernias occur on the 

right, 30% occur on the left and 10% are bilateral. 170 

Bilateral herniais are more common in females and 

in premature infants (15–24%). 166,169,171,172 A contralateral 

hernia is found in 50–60% of infants 

Figure 35.9 Ramstedt’s pyloromyotomy. 

Inguinal hernia 591 

under 6 months of age, although the majority of 

these are not manifested clinically. 

Pathogenesis 

The processus vaginalis is a peritoneal diverticulum 

that passes through the internal inguinal ring 

at 3 months in utero. During the 7th month in utero, 

the testis descends from its intra-abdominal position 

at the urogenital ridge, into the scrotum, and 

as it does so it takes part of the processus with it 

into the scrotum. The processus is usually obliterated 

shortly before birth, leaving only the portion 

of the processus surrounding the testis, which is 

now called the tunica vaginalis. In 10–20% of the 

population the processus remains patent throughout 

life. 173 Failure of obliteration of the processus 

leaves a potential communicating sac that allows 

passage of peritoneal fluid (hydrocele) or abdominal 

contents (hernia) into the groin or scrotum. The 

hernial sac may contain bowel or, additionally in 

girls, ovary or Fallopian tube. The descent of the 

right testis and the subsequent obliteration of its 

processus vaginalis occur later than the left. For 

this reason right-sided hernias are twice as 

common. In girls, the canal of Nuck undergoes the 

same obliteration as the processus vaginalis in 

boys, but the obliteration is more likely to be 

complete, explaining the lower incidence of 

inguinal hernias in girls. If the hernia becomes irreducible 

(incarceration), the sac contents are at risk 

of injury. Incarceration of bowel within the hernia

592 


is most common, and it may lead to the development 

of intestinal obstruction or strangulation. 

Etiology 

A number of patient populations have been identified 

with increased incidence of inguinal hernias. 

Premature infants have the highest incidence (up 

to 30% 162 ) of inguinal hernias, owing to the premature 

birth preceding full completion of the obliteration 

of the processus vaginalis. Cystic fibrosis 

patients have a 15% incidence of inguinal 

hernias. 174 This increased risk is thought to be 

related to an altered embryogenesis of the Wolffian 

duct structures that also leads to an absent vas 

deferens in male infants with cystic fibrosis. 

Increased incidence is also found in patients with 

connective tissue disorders (e.g. Ehlers–Danlos 

syndrome 175,176 ) and mucopolysaccharidosis 

(Hunter–Hurler syndrome 177 ); children with 

ventriculoperitoneal shunt; 178 children receiving 

chronic peritoneal dialysis; 179,180 and children 

with congenital dislocation of the hips. 181 


The hernia is often noticed by parents, for example 

on changing the infant’s diaper, as a swelling, 

either in the groin (inguinal hernia) or scrotum 

(inguinoscrotal hernia; Figure 35.10). In most 

cases the infant is asymptomatic. The hernia may 

become prominent on straining or crying. 

However, a child in discomfort, or who is vomiting, 

particularly bile, should alert to the possibility 

of an obstructed or strangulated inguinal hernia. 

Features of intestinal obstruction include bilious 

vomiting, constipation and abdominal distension. 

A strangulated hernia will cause severe discomfort 

from ischemic bowel or testis and tenderness of 

hernial contents. It may cause passage of blood in 

the stools, with or without features of obstruction. 

Occasionally the only clinical evidence of a 

hernial sac may be a thickened spermatic cord 

compared to the contralateral cord. 

Complications 

Of infants with an inguinal hernia, 20–50% 182,183 

present with incarceration, the risk being highest 

Figure 35.10 Bilateral inguinoscrotal hernias. 

in the first 6 months of life. The main complications 

associated with incarceration (most 

frequently bowel contents) are intestinal obstruction 

or strangulation with testicular necrosis 

and/or bowel necrosis. 


The primary differential diagnosis in boys is 

between a hernia and a hydrocele. The latter is 

cystic in consistency and easily transilluminates. 

Other differentials include an undescended or 

retractile testis, inguinal lymphadenopathy and 

rarely inguinal abscess. The ability to delineate the 

upper margin of the swelling distinguishes it from 

an inguinal hernia. The diagnosis is almost exclusively 

clinical; rarely, ultrasound confirmation 

may be used where there is reason for doubt. The 

presence of an intestinal obstruction complicating 

an incarcerated inguinal hernia may be confirmed 

by plain abdominal X-ray, which will demonstrate 

dilated loops of bowel.


Surgery is indicated in all cases, because of the 

danger of incarceration and strangulation of 

hernial sac contents. The timing of surgery is 

determined by three factors: the age of the child, 

its clinical condition, and whether the hernia has 

become complicated. In infants, in whom strangulation 

is most common, the hernia operation 

should be performed at the earliest possible date, 

even if the infant is asymptomatic, provided the 

infant’s clinical status allows it. Premature, ventilated 

and critically ill infants with an uncomplicated 

hernia may have it repaired once they are 

stable. An irreducible hernia with or without 

strangulation or obstruction requires immediate 

surgery, irrespective of age. An incarcerated hernia 

that has been reduced successfully but with great 

difficulty may benefit from delayed repair of the 

hernia after 24–48h, to allow edema of bowel 

contents that is usually present to settle preoperatively. 

The hernia may be repaired by the open or laparoscopic 

method, although the optimal approach 

remains unproven. At surgery, if the hernia is 

uncomplicated, the PPV is mobilized and ligated at 

the internal ring. If the hernia is complicated by 

non-viable bowel within the sac, resection of the 

affected bowel with end-to-end anastomosis is 

performed. The decision as to whether the 

contralateral groin should be explored routinely 

under the same anesthetic remains controversial. 

163,169,184 This practice is generally not favored, 

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36 

Introduction 

Enteral nutrition in preterm 

infants 

Mario De Curtis and Jacques Rigo 

Currently, there is little consensus among neonatologists 

on the optimal way to initiate, proceed 

with or maintain enteral feeding in preterm 

infants. Most routines in neonatal intensive care 

units derive more from an empirical approach 

than from controlled studies. Nevertheless, the 

enormous number of studies conducted in this 

field over the past few years have greatly 

contributed to our knowledge of the nutrition of 

preterm infants, even if many doubts still remain. 

The gastrointestinal tract of preterm infants 

and especially of very-low-birth-weight (VLBW) 

infants is immature at birth and initially incapable 

of performing full digestion and absorption. 

Immature gastrointestinal motility manifests itself 

in so-called ‘feeding intolerance’, which is characterized 

by delayed gastric emptying, abdominal 

distension, water stool passage or constipation. 1 

The advent of intensive care and the increased 

survival of premature infants led to the problem of 

necrotizing enterocolitis (NEC), which almost 

always occurred in infants who were fed. 

Consequently, enteral feeding was avoided as a 

strategy to prevent NEC. The introduction of 

enteral feeding was delayed, often for prolonged 

periods and parenteral nutritional was considered 

as the best nutrition route for VLBW infants in the 

first period of life. 

Enteral nutrition during the early 

adaptive period 

More recent studies have suggested that associating 

parenteral nutrition and early postnatal enteral 

feeding with small amounts of human milk or 

formula (called ‘minimal enteral feeding’, 

‘gastrointestinal priming’, ‘trophic feeding’ and 

‘hypocaloric feeding’) could help improve the 

development of the gastrointestinal tract, gut 

hormone release and gut motility. 2 Results of clinical 

trials in premature infants support the opinion 

that minimal enteral feeding has some clinical 

benefits, such as reducing the time to start full 

enteral feeding and length of hospitalization 

without increasing the risk of NEC. 3 The precise 

impact of minimal enteral feedings is still difficult 

to evaluate, because the studies carried out, aside 

from being based on a limited number of infants, 

considered different criteria of inclusion, feeding 

protocols and outcome measures. Thus, the metaanalysis 

is a less effective tool for reaching clear 

conclusions, whereas a larger trial with a single 

uniform protocol could clarify many of these 

issues. 

In VLBW infants, the preferred early feeding 

regimen is human milk, which can be initiated, 

according to clinical conditions, even on the day of 

birth, or the following days, in small quantities, 

e.g. 1–2ml colostrum every 6h, progressively 

increasing the volume and frequency. Feeds 

should be given with a continuous infusion pump 

or by gavage. A recent review showed that there 

was no significant difference in somatic growth, 

days to discharge or the incidence of NEC for 

infants fed by continuous versus intermittent 

bolus tube feeding. 4 In any case the tube should be 

aspirated regularly in order to determine feeding 

tolerance. Gastric residues are usually measured 

every 3h in infants aged less than 32 weeks and 

even more frequently in smaller and sick infants. 

The aspirate is reinfused to reduce the loss of 

enzymes and electrolytes. There is little rationale 

for the practice of diluting milk; the dilution does 

not promote maturation of gut motility. 5 

599

600 

Enteral nutrition in preterm infants 

The ideal rate of progression of milk volume given 

to VLBW infants is controversial. While a Cochrane 

Review has concluded that a rapid rate of 

advancing feeds was not associated with a higher 

risk of NEC, 6 a recent study suggested that rapid 

advancement of enteral feeding might increase the 

risk of NEC. 7 Although additional studies are 

needed, a small progressive increment of 10ml/kg 

per day after a few days of stabilization can be 

recommended. 

Nutrition during the intermediate and 

stable growth period 

Transition from the early adaptive to an intermediate 

and stable growing period is related to stable 

clinical and metabolic conditions and tolerance of 

minimal enteral feeding. During this period enteral 

feeding can be slightly increased, up to 

140–180ml/kg per day, whereas the amount of 

parenteral fluid is progressively reduced and interrupted 

as soon as 100–120ml/kg per day is well 

tolerated. 

Nutrient needs during enteral feeding 

Water 

Total fluid intake is related to ingested calorie and 

protein intake as well as to the renal solute load. 

During the early phase there is a progressive cornification 

of the epidermidis causing a significant 

reduction of perspiratio insensibilis and an 

improvement of renal function. 8 The goal of fluid 

administration is to replace water loss, maintain 

water and electrolyte homeostasis and provide 

extra water and electrolytes to build up new 

tissues. Renal solute load (RSL) plays a major role 

in the water balance of enterally fed preterm 

infants. It can be defined as water-soluble waste 

products excreted through the kidney. The excretion 

of these products requires a given amount of 

water, which affects the net water balance. As the 

RSL increases, the minimal urinary water excretion 

increases, owing to the relative immaturity of 

the premature kidney to concentrate urine. The 

RSL is closely related to the nitrogen and electrolyte 

content of the diet, and its potential RSL 

can be estimated according to the following 

formula, expressed in millimoles (mmol, or 

milliosmoles, mOsm): Potential RSL=N/28+Na+ 

Cl+K+P, where N/28 indicates the excretion, in 

mg, of nitrogenous substances such as urea (urea 

contains two nitrogen atoms, atomic weight 14), 

Na is sodium, Cl is chloride, K is potassium and P 

is available phosphorus which is the same as total 

phosphorus in milk-based formulas. 9 The 

potential RSL of mature human milk is 

14mOsm/100kcal, 10 whereas that of currently 

available premature infant formulas is about 

26mOsm/100kcal, 11 Maximum amounts of solutes 

in a formula providing 81kcal/100ml has been 

estimated in non-growing preterm infants as 

32mOsm/100kcal, 12 taking into account a formula 

intake of 150ml/kg per day, skin and lung water 

loss of 75ml/kg per day and stool loss of 8–11ml/kg 

per day. 13 In such conditions, at least 64ml/kg per 

day are available for urinary excretion, considering 

that the great majority of preterm infants without 

renal disease can concentrate urine to 

600mOsm/l. 14 

Because the growing infant incorporates into new 

tissue a portion of the substances present in the 

diet (protein, potassium, phosphate, etc.), which 

in the non-growing subject would be presented to 

the kidney for excretion, an ‘osmolar equivalent of 

weight gain’ was removed from the calculated 

potential renal solute load. A theoretical estimate 

of the size of this sparing effect, based on the body 

composition of the newborn infant, in a study on 

relatively large premature infants (mean birth 

weight 1787 g and gestational age 33 weeks), 

suggested an osmolar equivalent of 0.9mmol/g 

weight gain and half the expected true osmolar 

load of adapted formulas. 15 In the stable growing 

period, the water requirement, accounting for 

security levels, is 130–160ml/kg per day. 

Protein 

The goal in estimating the protein requirements of 

preterm infants is to provide the quantity and 

quality of protein needed to obtain a growth 

similar to that observed in the fetus during the 

third trimester of intrauterine life, and to obtain an 

early postnatal catch-up growth, keeping in mind 

that the accretion of lean body mass needs to be 

considered more than absolute weight gain. 16 

Protein utilization is influenced by several factors 

such as quality and quantity of the protein supply,

dietary protein energy ratio, gut immaturity and 

nutritional status. Dietary protein needs for 

preterm infants have been estimated by two different 

methods. The first, the empirical approach, 

measures biochemical or physiological responses 

to graded intakes. The second method, the factorial 

approach, considers the requirements as the 

sum of the essential losses (e.g. urine, feces, skin), 

plus the amount incorporated into newly formed 

tissues. 

The empirical approach evaluates physiological 

and biochemical variables to determine minimum 

and maximum protein needs in the growing 

preterm infant. The measures used in these types 

of study are: anthropometry (weight, length, head 

circumference, skinfold thickness); nitrogen 

balance or retention; metabolic or chemical 

indices (plasma and urinary amino acids, serum 

albumin, total protein, immunoglobulin, retinal 

binding protein and transthyretin – most of which 

provide an indirect reflection of protein synthesis); 

indirect calorimetry, to evaluate energy balance 

and – in combination with nitrogen balance – the 

composition of weight gain; isotope studies of 

whole-body nitrogen kinetics (used as indirect 

measures of protein synthesis rates); body composition, 

by dual energy X-ray absorptiometry; and 

development assessment, studying the effect of 

quality and quantity of protein on neurological 

development through various neurometric tests 

such as the Neonatal Behavioral Assessment scale 

and the Bayley Scales of Infant Development. 17 

In the factorial approach, compositional analysis 

of fetal tissues has been a valuable source of data 

for our understanding of the nutrient needs of the 

fetus and, by extension, those of the growing 

preterm infant. Fetal accretion rates have been 

obtained from compositional analyses of aborted 

fetuses or stillborn infants. 18 From these data, the 

protein increment for growth has been estimated 

as approximatly 2.3g/kg per day, 19 but more recent 

data seem to indicate a value closer to 2.5g/kg per 

day. Protein requirement is thus calculated by 

adding to this value the obligatory losses, and the 

amount needed for the additional catch-up 

growth. In a large population of preterm infants 

receiving a controlled energy intake, the minimal 

protein supply necessary to obtain a zero nitrogen 

balance (to cover all nitrogen losses) was calculated 

to be 0.74g/kg per day. 20 A similar value was 

Nutrition during the intermediate and stable growth period 601 

estimated to cover the need for catch-up growth. 21 

Thus, the protein requirements in VLBW infants, 

so calculated, reach 3.8–4g/kg per day. The recommended 

dietary protein allowance needs to be 

adapted to the fractional absorption rate and 

protein efficiency as well as to individual 

variations. 

Nitrogen absorption and utilization were recently 

reviewed on 226 metabolic balances performed in 

recent years in preterm infants fed human milk, 

human milk fortifiers and various preterm formulas. 

22 Data are summarized in Table 36.1. 

Nitrogen absorption rate (absorbed/intake) differs 

significantly according to the feeding regimen. It 

was higher with powder whey-predominant 

protein preterm formulas (90.7%) than with 

human milk supplemented with fortifiers (82.7%), 

powder protein hydrolyzed formulas (84.3%) or 

ready-to-use liquid whey-predominant preterm 

formulas (86.0 %) (Table 36.1). Those differences 

result from the nature of the various types of 

protein supply. In human milk, non-nutritional 

protein content (lactoferrin, sIgA, lysozyme) or 

non-protein nitrogen content (oligosaccharides) 

are absorbed less than the nutritional protein 

content (whey proteins, caseins) and contribute to 

a significant part of fecal excretion. An interesting 

observation is the relatively lower absorption rate 

of ready-to-use liquid preterm formulas or protein 

hydrolyzed preterm formulas, where the technical 

process seems to impair nitrogen absorption in 

relation to heat treatment – inducing some Maillard 

reaction – or to preliminary hydrolysis, altering 

the physiological absorption process in the 

lumen or at the border of the gastrointestinal 

tract. 23 

The efficiency of protein gain, estimated by the 

ratio between retained and metabolizable nitrogen 

(absorbed), differs also according to the feeding 

regimen (Table 36.1). The highest values were 

obtained in preterm infants fed powder (77.7%) 

and liquid (77.5%) preterm formulas. It was significantly 

lower in those fed protein-hydrolyzed 

formulas (74.0%) and fortified human milk 

(72.1%). 22 The lower value obtained with fortified 

human milk may be related to non-protein nitrogen, 

which represents 20–25% of total nitrogen 

content of human milk, but still 13.5–17% of total 

nitrogen content of fortified human milk. As

602 


Table 36.1 Nitrogen balances according to feeding regimen in preterm infants (from reference 22) 

Powder whey- Liquid whey- Powder 

predominant predominant protein- 

Amount Fortified preterm preterm hydrolyzed 

(mg/kg per day) human milka formulasb formulasc formulasd (n=88) (n=49) (n=58) (n=31) 

Intake 517±86 d 522 ± 70d 506 ± 58 553 ± 56ab Fecal excretion 90±28 bc 49±19acd 71±28abd 87±26bc Absorbed 428±76 bd 474±75ac 434±52 bd 466±51 ac 

Urinary excretion 121±45 c 106±36 98±21ad 122±39 c 

Retained 307±56 bcd 368±57acd 337±46 ab 343±42 ab 

Absorption (%) 82.7±4.8bc 90.7±3.3acd 86.0±5.0ab 84.3±4.0b Net protein utilization* (%) 59.7±7.7bc 71.5±6.5acd 66.6±5.8abd 62.4±6.5bc Protein efficiency † (%) 72.1±7.6bc 77.7±6.4ad 77.5±4.4ad 74.0 ± 6.9bc * Nitrogen retention/nitrogen intake 

†† Nitrogen retention/nitrogen absorption 

abcd Values with like letters p < 0.05 

demonstrated for urea nitrogen, the contribution of 

this metabolizable non-protein nitrogen fraction to 

protein gain is lower than that of the α-lactalbumin 

or the casein content of human milk. 

Therefore, regarding the net protein utilization (N 

retained/N intake), preterm formulas appear to be 

more efficient than human milk with or without 

protein supplementation. However, the net protein 

utilization of formulas can be altered by some 

technical processes, such as those required for 

hydrolysis. 23 Thus, adapted for fractional absorption 

rate and protein efficiency, the recommended 

protein allowance could reach 4.5g/kg per day in 

extremely-low-birth-weight (ELBW) infants with 

significant catch-up growth requirements. 16 

The potential risk of such an aggressive nutritional 

strategy is a metabolic stress resulting from protein 

overload or unbalanced amino acid supply. 

Therefore, the most recent technologies will be 

necessary to improve nitrogen bioavailability, 

reduce Maillard reactions and provide the most 

balanced amino acid composition. 

The whey/casein ratio significantly influences 

individual amino acid intakes and plasma amino 

acid concentrations. Plasma threonine is increased 

and tryptophan relatively decreased in infants fed 

a whey-predominant formula, whereas methionine 

and aromatic amino acids are increased in those 

fed a casein-predominant formula. 24,25 The high 

plasma threonine concentration, observed in 

preterm infants fed whey-predominant formulas, 

is related to the glycomacropeptide obtained from 

casein by enzymatic casein precipitation of cow’s 

milk proteins. Acidic precipitation, by contrast, 

removes the glycomacropeptide rich in threonine 

from the soluble phase. 26 Today it is possible to 

design whey-predominant formulas with a lower 

threonine content. 27–29 In 14 preterm infants 

receiving either an enzymatic or an acidic wheypredominant 

formula, a significant reduction 

in plasma threonine concentration was observed 

in acidic whey-protein formula-fed infants 

(27.9±8.5µmol/dl), compared to those receiving 

conventional enzymatic whey-protein formula 

(37.5±8.4µmol/dl). All other plasma amino acid 

concentrations were similar, with the exception of 

valine, which was slightly reduced in acidic whey 

protein formula-fed infants. 27 

In addition to these technological treatments, 

performed to remove the glycomacropeptide and 

reduce the threonine content, the ratio between 

different cow’s milk protein contents was modified

to increase the relative percentage of α-lactoalbumin. 

Indeed, this protein fraction is naturally rich 

in tryptophan and helps normalize the low levels 

of this amino acid frequently observed in wheypredominant 

formula-fed infants. 30,31 

Formulas based on hydrolyzed proteins have been 

recently proposed for the feeding of preterm 

infants to reduce gastrointestinal problems such as 

delayed gastric emptying, abdominal distension, 

hard stools and feeding intolerance. 32,33 The technological 

processes necessary to perform hydrolysis 

and reduce protein antigenicity may, however, 

modify the amino acid content and/or amino acid 

bioavailability. 34 The use of a higher percentage of 

whey in protein-hydrolyzed formulas further 

worsens the plasma amino acid pattern previously 

observed with the use of whey-predominant 

formulas by increasing threonine and decreasing 

aromatic amino acid concentrations. 32 Moreover, a 

significant decrease of plasma histidine and tryptophan 

concentrations, probably due to a relative 

reduction in amino acid bioavailability, was also 

observed. Using a more appropriate technology, 

these formulas have been corrected for the threonine 

content and supplemented with histidine and 

tryptophan. 35–37 

Formulas do not contain any of the biologically 

active immune substances, nor enzymes, 

hormones or growth factors found in human milk. 

The long-term implications of this deficiency has 

not been determined. Several studies have been 

performed to evaluate the functional properties of 

non-nutritional compounds, such as nucleotides, 

polyamines, growth factors or prebiotics, which 

could potentially improve the quality of these new 

formulas, although no definitive conclusions are 

currently available. 17 

Considering the revised protein recommendations, 

large multicenter randomized studies need to evaluate 

the improvement in growth and in body 

composition, as well as the reduction in incidence 

of postnatal growth restriction expected from an 

aggressive nutritional policy in preterm infants. 

Further studies are also needed to identify more 

sensitive markers of protein toxicity, to determine 

the safety and efficacy of such a high protein 

supply and to evaluate the beneficial impact on 

short- and long-term growth and development. 


Energy 

The energy demands for preterm infants depend 

on many factors including fetal and neonatal 

development, genetically determined metabolic 

rate, thermal environment, activity, sleep status, 

nutritional status, nutrient intake, body composition 

and occurrence of illness. Energy intake 

recommendation for preterm infants, calculated 

for 150ml/kg per day of formula, by different nutrition 

committees, range between 98 and 139kcal/kg 

per day, while the more recent recommendations 

range between 110 and 135kcal/kg per day. 11,17,38,39 

Energy retention, in premature infants, after the 

first 2–3 days of life, is about 85–90% of energy 

intake. The remainder is lost in stool and a small 

quantity as urea in the urine. Energy retained is in 

part stored in tissues as protein and mainly as fat, 

and in part lost as energy expenditure. After birth, 

fat deposition represents a higher proportion of 

weight gain than in utero. 40 Rapid accretion of 

body fat appears to be unavoidable, although it can 

be altered considerably by dietary manipulation of 

the protein/energy ratio. 40.41 A fat deposition of 

20–25% of weight gain has been proposed as a 

reasonable goal for preterm infants but there are, 

however, no long-term data to justify this limit. 42 

Protein/energy ratio 

Protein and energy needs are reciprocally limiting, 

the intake of one affecting the ability of the infant 

to assimilate the other. A suboptimal range of the 

protein/energy ratio leads to untoward consequences. 

43 If energy intake is inadequate, protein 

is used as an energy source and the nitrogen 

balance becomes less positive. Increasing the 

caloric intake will spare protein loss and improve 

nitrogen retention. If there is a surfeit of energy 

with limited protein intake, the protein retention 

reaches a plateau and the energy excess is used 

only for fat deposition. 43 Nevertheless, when the 

protein supply is satisfactory (close to 4.0g/kg per 

day), the effect of energy increase from 130 to 

155kcal/kg per day on protein retention appears to 

be minimal – about 0.1g of protein/kg per day. 44 

An additional issue concerns the partition of 

energy intake between fat and carbohydrates. It 

seems that carbohydrates are slightly more effective 

than fat in sparing protein oxidation. At the 

same two levels of energy supply the advantage of

604 


a diet containing 65% of non-protein energy as 

carbohydrate versus 35% on nitrogen retention 

represented about 0.15g of protein/kg per day in 

enterally fed low-birth-weight (LBW) infants. 44 

Analysis of various studies in preterm infants fed 

human milk, 45–51 human milk fortifiers 46,49,52–57 

and various preterm formulas 45,47,50–52,55,56,58–61 

allows the evaluation of the main determinant of 

weight gain, nitrogen retention and fat mass deposition. 

From these data, the major determinants of 

weight gain, lean body mass gain, fat accretion and 

protein retention may be determined using 

stepwise regression analysis. Protein intake and 

protein/energy ratio are the main determinants of 

weight gain. Protein intake is the only determinant 

of lean body mass gain in contrast to fat mass gain, 

which is positively related to energy intake and 

negatively to protein/energy ratio. 16 Protein gain 

and lean body mass gain increase significantly 

with protein intake without any additional significant 

influence of energy intake and protein/energy 

ratio. According to these data, as well as to the 

factorial approach, new recommendations for 

protein and protein/energy ratio can be suggested 

(Table 36.2) in relation to post-conceptional age 

and the need for catch-up growth. 16 Thus, according 

to this calculation, recommended intakes for 

preterm infants at 26–30 weeks’ postconceptional 

age should have 3.8–4.4g of protein/kg per day 

with a protein/energy ratio between 3.0 and 

3.3g/100kcal, according to their relative postnatal 

growth restriction. These values are in the range of 

the recent suggestion from an Expert Panel of the 

Life Sciences Research Office and the American 

Society for Nutritional Sciences who suggested 

3.4–4.3g of protein/kg per day with an energy 

intake of 120kcal/kg per day and a protein/energy 

ratio between 2.5 and 3.6g/100kcal. 17 

Fat 

Fat provides the major source of energy in growing 

preterm infants, representing approximately 50% 

of the non-protein energy content of human milk 

and current infant formulas. Although a mainly 

carbohydrate-based diet appears beneficial in 

terms of sparing protein oxidation, enhancing 

growth and protein accretion as well as to improve 

quiet sleep and influence the distribution of 

behavior activity states in VLBW infants, it is 

generally accepted that metabolizable long-chain 

fat should be at least equal to the fat deposition in 

growing tissues. 62 Accordingly, a fat intake of 

5.4–7.2g/kg per day (or 40–54% of energy content) 

has been recommended. 38 

The newborn’s capability of digesting triglycerides 

is not fully developed in premature infants. Lipid 

malabsorption is the result of low levels of pancreatic 

lipase and bile salts. The bile acid pool is only 

half the size of that of a full-term infant. In premature 

infants there is an alternative mechanism for 

digestion of dietary fat, represented by intragastric 

lipolysis, due to lingual and gastric lipases, 

secreted by the 25th week of gestation, that 

compensate for the low concentration of pancreatic 

lipase. Human milk provides additional 

Table 36.2 Revised recommended protein intake and protein/energy ratio for preterm infants 

according to post-conceptional age (PCA) and need for catch-up growth (from reference 16) 

Without need for With need for 

catch-up growth catch-up growth 

26–30 weeks’ PCA: 16–18g/kg per day 3.8–4.2g/kg per day 4.4g/kg per day 

LBM 14% protein retention PER: ±3.0 PER: ±3.3 

30–36 weeks’ PCA: 14–15g/kg per day 3.4–3.6g/kg per day 3.6–4.0g/kg per day 

LBM 15% protein retention PER: ±2.8 PER: ±3.0 

36–40 weeks’ PCA: 13g/kg per day LBM 2.8–3.2g/kg per day 3.0–3.4g/kg per day 

17% protein retention PER: 2.4–2.6 PER: 2.6–2.8 

LBM, lean body mass; PER, protein/energy ratio

lipases: lipoprotein lipase, bile salt-stimulated 

esterase and non-activated lipase, which improves 

intestinal lipolysis. 63 

Lipid digestion and absorption are also affected by 

fatty acid composition, the triglyceride structure 

and the calcium content of the milk. Fatty acid 

absorption is related to chain length and degree of 

unsaturation. Thus, medium-chain triglycerides 

(MCTs) with 8–10 carbon atoms are hydrolyzed 

more readily than long-chain triglycerides (LCTs), 

and fatty acids with more double bonds are 

absorbed more efficiently. In order to improve fat 

absorption, commercial formulas contain a significant 

quantity of MCTs that are more easily 

absorbed than LCTs and transported directly to the 

liver via the portal vein as non-esterified fatty 

acids. The use of MCTs instead of LCTs in preterm 

infant formulas can reduce the formation of 

calcium and magnesium soaps with unabsorbed 

long-chain saturated fatty acids and, thereby, 

increase calcium and magnesium absorption. 

However, it needs to be stressed that the energy 

content of MCTs corresponds to about 85% of that 

of LCTs. In addition, the use of MCTs in formulas 

induces an increase in plasma ketones as well as in 

urinary excretion of dicarboxylic acids, suggesting 

that MCT metabolism could be slightly limited. 64 

Moreover, since MCTs do not contain essential 

fatty acids, a high MCT intake can reduce the 

availability of the essential long-chain fatty acids 

necessary for normal growth and development. It 

is recommended that the maximum MCT intake in 

preterm formula be limited to 40–50% of total fat 

content. 17,38 

In human milk, long-chain fatty acids are preferentially 

positioned in the sn-2 position on the glycerol 

and are thus directly absorbed as monoglyceride. 

The use of formulas with palmitic acid 

with preferential esterification in the sn-2 position 

(β-palmitate) induces a minimal positive effect on 

energy balance but increases mineral absorption, 

leading to a significant reduction of insoluble 

calcium soap formation with free palmitic acid 

(16:0) and stearic acid (18:0). In preterm infants 

the rate of calcium absorption was markedly 

increased from 42% in a control formula to 57% in 

a formula containing 74% of palmitate esterified in 

the triglyceride sn-2 position (as β-palmitate). 65 It 

is noteworthy, however, that for commercial 

reasons, some preterm infant formulas available 


today with β-palmitate contain lower proportions 

of this structured triglyceride than those evaluated 

in previous clinical trials. 

A fraction of fat must be provided as essential fatty 

acids; these are necessary to ensure optimal fatty 

acid composition and function of growing tissue 

and for normal eicosanoid synthesis. In preterm 

infants linoleic acid intakes of 3.2–12.8% energy 

intake have been recommended. 17 

Because humans cannot insert double bonds at the 

n-3 and n-6 positions, fatty acids with double 

bonds in these positions cannot be synthesized 

endogenously. Therefore, either specific n-3 and 

n-6 fatty acids or the precursor of each series such 

as linoleic acid (18:3n-3) and α-linolenic acid 

(18:2n-6) must be provided as a component of the 

diet. Both linoleic and α-linolenic acid are metabolized 

by a series of desaturation and elongation 

reactions to more unsaturated longer-chain fatty 

acids. Important metabolites of these two fatty 

acids include 20:5n-3 eicosapentaenoic acid (EPA), 

22:6n-3 docosahexaenoic acid (DHA) and 20:4n-6 

arachidonic acid (AA). 

The biochemistry and metabolism of the essential 

fatty acids is complex, involving differences in 

metabolism and competition between the various 

n-6 and n-3 fatty acids. The desaturase enzymes 

show substrate preference in the order n-3>n- 

6>n-9, and are inhibited by products of either the 

n-6 or n-3 fatty-acid series. 66,67 Consequently, the 

rate of desaturation of linoleic acid (18:2n-6) to 

arachidonic acid (20:4n-6) and of α-linolenic acid 

(18:3n-3) to docosahexaenoic acid (22:6n-3) depends 

on the quantities of linoleic acid (18:2n-6) 

and α-linolenic acid (18:3n-3) substrate and 

preformed arachidonic acid (20:4n-6, AA) and/or 

docosahexaenoic acid (22:6n-3, DHA) in the diet. 

Accordingly, a linoleic/α-linolenic acid ratio of 5- 

16:1 wt/wt is currently recommended. 17 

Eicosapentaenoic acid (20:5n-3, EPA), which is 

found predominantly in fish oil, may also inhibit 

synthesis of arachidonic acid (20:4n-6). Thus, the 

infant’s ability to maintain tissue arachidonic acid 

(20:4n-6, AA) levels may be lost if inappropriately 

high amounts of eicosapentaenoic acid (20:5n-3, 

EPA) or a high ratio of 22:6n-3 and 20:5n-3 to 

20:4n-6 are provided by the diet. 68 In addition, the 

rate of precursors and long-chain polyunsaturated 

fatty acids (PUFAs) oxidation for energy

606 


production differs for each fatty acid and may 

influence biological activities and their multiple 

interactions. 68 

Considering that endogenous synthesis of longchain 

PUFAs is limited in preterm infants, these 

fatty acids were considered as semi-essential or 

essential for preterm infants, and numerous 

studies evaluated the consequences of early 

neonatal deficiencies as well as the need of 

formula supplementation. Available sources of 

essential fatty acids are vegetal oils, whereas those 

of long-chain PUFAs include egg yolk lipid, phospholipid 

and triglyceride, fish oils and oils 

produced by single-celled organisms (microalgal 

and fungal oils). 

Several studies have suggested that the long-chain 

PUFAs supply in preterm infants has a beneficial 

effect on growth, visual and cognitive function, as 

well as on the immune system. Although some 

methodological limits of these studies do not allow 

definitive conclusions to be drawn, most of the 

formulas in Europe and the USA are currently 

supplemented with long-chain PUFAs. However, 

as membranes enriched with PUFAs are particularly 

susceptible to oxidative damage, concern 

over the use of long-chain PUFAs in infant formulas 

might suggest the need for a higher vitamin E 

intake. 

Several expert groups have recommended the 

routine addition of DHA and AA to LBW infant 

formulas. 17,38,69 Based on biochemical analyses, 

comparison with estimated intrauterine accretion 

rates, and the ranges of intakes with human milk 

feeding, a consensus group of experts on perinatal 

fatty-acid metabolism recently recommended the 

supplementation of formulas for preterm infants 

with DHA in the range of 0.35–0.5% of the fatty 

acids, and with AA in an AA/DHA ratio of 1.2–2 

wt/wt. 14,63 

Carbohydrates 

Carbohydrates represent approximately 40% of the 

energy intake of infants ingesting human milk or 

infant formulas. By virtue of their important 

biological effects, they improve nutritional status 

and function of the intestine and colon via the 

stimulatory effects of short-chain fatty acids on 

cell proliferation and ion absorption, stimulate 

insulin secretion and metabolism and growth and 

enhance the metabolic response to growth 

hormone and calcium absorption. Thus, they are 

essential to the overall health of the gastrointestinal 

tract and the fulfillment of energy requirements. 

The predominant carbohydrate in mammalian 

milk and in term infant formula is lactose; after 

digestion by lactase, lactose is absorbed as glucose 

and galactose, which utilize the same carrier 

mechanism. In the human fetus, intestinal lactase 

activity is measurable by 10–12 weeks of gestation. 

There is a gradual increase in lactase activity with 

advancing gestation, although the activity remains 

low until about 36 weeks of gestation, when it 

reaches the levels seen in full-term neonates. 70 

Based on the low lactase activity in early gestation 

and the estimated length of the bowel, it was 

calculated that a preterm infant weighing 

1300–1400g might be expected to have nearly 

50–70% of the lactose ingested passing unabsorbed 

into the colon 71 where, under the action of 

bacterial flora, it is transformed into short fatty 

acids and then absorbed. No difference in fecal 

carbohydrate loss was found in preterm infants fed 

formulas containing either 100% lactose or 50% 

lactose and 50% glucose. 72 Lactose not fully 

digested in many preterm and term infants could 

serve as a source of nutrition for beneficial bacterial 

flora in the colon. Through the process of 

fermentation, this not only facilitates colonic 

water and electrolyte absorption but also stimulates 

cell turnover of both the colon and the small 

intestine. In premature infants early exposure to 

lactose seems to induce intestinal lactase. 73 

Regarding the relationship between lactose intake 

and calcium absorption, data in human adults 

seem to indicate that, in lactose-tolerant subjects, 

lactose does not appear to have any beneficial 

effect on calcium bioavailability. 74 In lactoseintolerant 

subjects, such as preterm infants, there 

is a significant level of uncertainty. Whether 

lactose in the distal bowel increases or impairs 

calcium absorption in preterm infants has yet to be 

defined. 17 

Quantitatively, other than lactose, oligosaccharides 

are the largest carbohydrate component in 

mature human milk and represent the third largest 

solute load after lactose and fat. 75,76 The

concentration of oligosaccharides in human milk 

has been observed to change with the duration of 

lactation, being highest in the colostrum (about 

20–23g/l), about 20g/l on day 4 and about 13g/l on 

day 120 of lactation. 77 Many of the protective 

effects of human milk against diarrheal diseases, 

respiratory and ear infections, documented from a 

number of clinical epidemiological studies in 

developed and developing countries have been 

attributed to oligosaccharides. 

In preterm formula a significant part of the carbohydrate 

is given as glucose polymers. These sugars 

have the advantage of providing a higher caloric 

intake without a corresponding rise in osmolarity. 

Glucose polymers are pure carbohydrates prepared 

by controlled acid/enzyme hydrolysis of cornstarch. 

They consist of polymers of glucose of 

varying chain length, although the majority are of 

medium (6–10 glucose units) chain length with a 

small amount (usually

608 


Table 36.3 Mineral balance in very-low-birth-weight infants fed human milk or preterm formulas 

Calcium Calcium Calcium Phosphorus Phosphorus Phosphorus 

intake absorption retention intake absorption retention 

(mg/kg per (%) (mg/kg per (mg/kg per (%) (mg/kg per 

Diet Reference day) day) day) day) 

HM (n=10) 80 58±11 71±14 25±12 24±6 92±4 21±5 

HM + Ca+P (n=8) 80 90±11 73±13 63±12 62±5 93±2 53±4 

HM + HMF (n=7) 80 101±19 66±7 65±14 78±13 94±2 62±9 

HM + HMF2 (n=9) * 170±13 57±17 91±27 87±6 94±2 61±12 

PTF1 (n=39) 32 91±14 51±17 45±18 63±9 89±6 42±8 

PTF2 (n=12) * 103±16 43±18 41±22 64±8 92±3 40±7 

PTF3 (n=7) 80 118±10 65±14 68±11 72±3 92±2 60±6 

PTF4 (n=19) 32 120±21 44±16 48±22 70±9 78±12 43±11 

PTF5(n=8) * 120±19 46±18 50±20 75±12 88±6 45±10 

PTF6 (n=7) 83 135±4 46±13 59±17 88±3 91±5 53±7 

PTF7 (n=7) * 161±11 41±13 58±22 90±5 59±8 50±8 

PTF8 (n=6) 84 162±5 49±6 78±11 78±2 92±2 49±3 

PTF9 (n=6) 84 162±5 64±5 100±8 75±2 92±2 58±3 

PTF10 (n=9) 83 164±13 55±13 85±18 93±4 90±4 63±8 

PTF11 (n=8) * 172±11 34±12 54±25 95±6 60±6 51±10 

PTF12 (n=11) 85 225±6 36±6 76±13 120±4 64±5 64±5 

HM, human milk; HMF, human milk fortifier; PTF, preterm formula 

* Unpublished data 

calcium absorption is usually lower than with 

powder formulas. With the use of formulas with a 

well-absorbed fat blend of about 85%, the formation 

of a calcium soap is of minimal interest in 

clinical practice. Owing to the poor solubility of 

calcium salts, especially calcium phosphate, the 

calcium content measured in the formula could be 

significantly lower than the claimed value, and 

additional loss due to precipitation may occur 

before feeding. Therefore, the actual amount of 

calcium provided by feeding needs to be chemically 

measured in each infant during metabolic 

balance studies. As shown in Table 34.3, a calcium 

retention close to 90mg/kg per day could currently 

be expected in preterm infants fed preterm 

formula with a highly soluble calcium content. 

Nevertheless, these values are still lower than the 

values estimated during the last trimester of gesta- 

tion (100–120mg/kg per day) and still considered 

as the target mineral accretion for VLBW infants. 

Accordingly, it could be recommended that the 

calcium intake in preterm infants range between 

130 and 170mg/kg per day with a calcium/phosphorus 

ratio close to 1.8, as long as the calcium 

absorption rate is 45–60%. 

Iron 

Preterm infants require iron for erythropoiesis, brain 

development, muscle function and cardiac function. 

The symptoms of iron deficiency are due to tissuelevel 

losses of iron containing enzymes and 

iron–sulfur proteins, not just to anemia. Oski has 

estimated that, in the absence of iron supplementation 

and blood loss, the VLBW preterm infant has 

enough iron stores to last 2 months and becomes 

anemic before liver stores are completely depleted. 86

Table 36.4 Recommended enteral micromineral 

intakes (µg/kg per day) for preterm 

infants (from reference 87) 

Transitional 

period Stable/post- 

(0–14 days) discharge periods 

Iron 0 2000–4000 

Zinc 500–800 1000–2000* 

Copper 120 120–150 

Selenium 1.3 1.3–4.5 

Chromium 0.5 0.1–2.25 

Molybdenum 0.3 0.3–4.0 

Manganese 0.75 0.75–7.5 

Iodine 11–27 10–60 

*Post-discharge supplement of 0.5mg/kg per day for 

infants fed human milk 

Preterm infants need supplemental iron after 2 

weeks of age. The enteral route appears safest. Iron 

can be supplied by preterm formula, human milk 

fortifier or medicinal iron drops. The enteral dose 

for the preterm infant not receiving erythropoietin 

ranges from 2 to 4mg/kg per day depending on the 

degree of prematurity and the amount of uncompensated 

phlebotomy. The recent introduction of 

erythropoietin puts a greater stress on iron 

balance, forcing the infant to mobilize endogenous 

iron stores at a faster rate. For infants receiving this 

medication, an enteral dose of 6mg/kg per day is 

recommended. No study has demonstrated oxidative 

toxicity from enteral iron given at conventional 

doses in preterm infants. 

Studies are currently addressing the need for iron 

after discharge in preterm infants. Their iron needs 

will probably remain greater than those of term 

infants because of their more rapid relative rate of 

growth and therefore blood volume expansion. 

Given their lower endogenous iron stores, it would 

be prudent to screen these infants earlier (e.g. 2 

months post-discharge) than term infants. 

Other trace elements 

Trace elements contribute less than 0.01% of total 

body weight. They function as constituents of 


metalloenzymes, cofactors for metal ion-activated 

enzymes, or components of vitamins, hormones 

and proteins. Because the fetus accumulates stores 

of trace elements, especially during the third 

trimester of pregnancy, premature infants have 

low stores at birth and are at risk of developing 

mineral deficiencies if intakes are inadequate for 

their growth requirements. 

Trace minerals with established physiological 

importance in humans include zinc, copper, selenium, 

manganese, chromium, molybdenum, fluoride 

and iodine. The recommended oral intakes for 

infants are listed in Table 36.4. 87 Potentially toxic 

trace minerals for pediatric patients are lead and 

aluminum. 

Oral vitamin requirements 

Vitamins are organic compounds that are essential 

for metabolic reactions but are not synthesized by 

the body. Vitamins are classified as water soluble 

or fat soluble, based on the biochemical structure 

and function of the compound. The recommended 

oral intakes of vitamins for infants are shown in 

Table 36.5. 11 

Water-soluble vitamins that cannot be formed by 

precursors (with the exception of niacin from tryptophan) 

and do not accumulate in the body (with 

the exception of vitamin B12) include B complex 

vitamins and vitamin C. They serve as prosthetic 

groups for enzymes involved in amino acid metabolism, 

energy production and nucleic acid synthesis. 

A daily intake is required to prevent deficiency. 

Excretion occurs in the urine and bile. 

Altered urinary losses due to renal immaturity 

during the first week of life predispose a preterm 

infant to vitamin deficiency or excess. 

Fat-soluble vitamins include vitamin A, D, E and 

K. These vitamins function physiologically in the 

conformation and function of complex molecules 

and membranes and are important for the development 

and function of highly specialized tissues. 

They can be built from precursors, are excreted 

with difficulty and accumulate in the body, and 

therefore they can produce toxicity. They are not 

required daily and deficient states develop slowly. 

Fat-soluble vitamins require carrier systems, 

usually lipoproteins, for solubility in blood, and 

intestinal absorption depends on fat absorption.

610 


Table 36.5 Recommended oral intake of vitamins for preterm infants (from reference 

11, American Academy of Pediatrics, Committee on Nutrition, 1998) 

AAPCON Consensus 

Recommendations Recommendations 

Vitamin (amount for premature infants for infants with 

per 100 kcal) (1998) VLBW (1993) 

Fat soluble 

Vitamin A (IU) 75–225 583–1250 

Vitamin D (IU) 270 125–333 

Vitamin E (IU) >1.1 5–10 

Vitamin K (µg) 4 6.66–8.33 

Water soluble 

Vitamin B6 (µg) >35 125–175 

Vitamin B12 (µg) >0.35 0.25 

Vitamin C (mg) 35 15–20 

Biotin (µg) >1.5 3–5 

Folic acid (µg) 33 21–42 

Niacin (mg) >0.25 3–4 

Pantothenate (mg) 0.3 1–1.5 

Riboflavin (µg) >60 200–300 

Thiamine (µg) >40 150–200 

AAPCON, American Academy of Pediatrics Committee on Nutrition; VLBW, very low birth weight 

Practical aspects of enteral nutrition 

Breast milk 

Benefit of human milk 

The American Academy of Pediatrics has acknowledged 

the advantages of human milk feeding with 

the statement that it is the preferred feeding for all 

infants, including those born preterm. 88 The benefits 

of human milk for gastrointestinal function, 

host defense and neurodevelopmental outcome are 

well known. The amino acid composition of 

human milk is suitable for the nutritional requirements 

of preterm infants who are, because of 

incomplete development of some amino acid 

metabolic pathways, at risk of developing a deficit 

or an overload of essential and semi-essential 

amino acids. 

Clinical studies performed in various parts of the 

world have shown that preterm infants fed human 

milk have fewer infections than those fed on 

formula. 89 This effect has been observed with both 

fresh and pasteurised human milk. There are 

studies showing a protective effect of breast milk 

on the incidence of NEC. A meta-analysis of 

randomized controlled trials was performed to 

determine whether enteral feeding with donor 

human milk, compared with formula, reduced the 

incidence of NEC in preterm infants. They found 

that feeding with donor human milk was also associated 

with a significantly reduced risk of NEC; 

infants who received donor human milk were 

three times less likely to develop NEC and four 

times less likely to have confirmed NEC. 90 

The protective effect of human milk has been 

attributed to several factors, such as macrophages, 

lymphocytes, sIgA, lysozyme, lactoferrin, oligosaccharides, 

nucleotides, cytokines, growth factors 

and enzymes. Immune defense can be provided by 

an interaction between these factors. Human milk 

can play a protective role through the enteromammary 

immune system. The mother’s presence in

the neonatal nursery, particularly the premature 

infant’s skin-to-skin contact with the mother, may 

induce the production of specific antibodies 

against the nosocomial pathogens present in the 

nursery. 88 Breast milk enhances the growth, motility 

and maturity of the gastrointestinal tract; 

compared to formulas it induces faster gastric 

emptying. 91 

Preterm infants with a birth weight below 1850g, 

fed human milk during hospitalization, showed 

better neurological development. At 7.5–8 years 

they showed a higher intelligence quotient 

compared to those fed formula, even after controlling 

for the mother’s education and social class. 92 

Higher mental developmental index scores were 

reported in VLBW (

612 


Table 36.6 Composition of various human milk fortifiers (expressed per gram of protein) 

BMF EHMF1 SHMF WHMF EHMF2 EHMF3 

Eoprotin FM-85 (Nutricia) (M-J) (Abbott) (Wyeth) (M-J) (M-J) 

(Milupa) (Nestlé) bag bag bag bag bag bag 

powder powder 1.5g 0.9g 0.9g 2g 0.8g 0.8g 

Protein (g) 1 1 1 1 1 1 1 1 

Fat (g) 0 0 0 0 0.36 0 0.58 0.91 

Carbohydrate (g) 3.48 4.3 2.86 3.9* 1.8 2.0 1.0 0.2 

Sodium (mg) 3.3 32.3 8.7 10.3 15.0 15.0 1.0 15.0 

Potassium (mg) 4.0 13.8 5.7 23.0 62.9 20.0 18.2 26.0 

Calcium (mg) 62 61 87 136 117 80 82 82 

Magnesium (mg) 3.5 2.4 8.6 1.5 7.0 2.0 0.9 0.9 

Phosphorus (mg) 42.3 40.7 58.4 66.8 67.2 40.0 41.0 45.0 

Chloride (mg) 24.9 22.2 10.1 26.0 37.9 14.0 8.2 12.0 

Energy (kcal) 31.7 21.4 14.3 20.7 14.0 13.0 12.7 12.7 

Osmolality (mOsm) 90 96 85 177 90 136 59— 

* Including the carbohydrate content of calcium glycerophosphate 

titatively. In general, they contain bovine whey 

protein (intact or hydrolyzed), carbohydrates 

(mainly or exclusively glucose polymers or 

maltodextrins), minerals and electrolytes such as 

sodium, calcium, phosphorus and magnesium and 

some also contain micronutrients (zinc and 

copper) and vitamins. 

The properties of human milk may be changed by 

nutrient fortification. For example, the addition of 

human milk fortifiers induces a rapid and clinically 

significant increase in osmolality, frequently 

above 400mOsm/kg H2O, a value at least 40% 

higher than that of human milk. 99 This is the result 

of the osmotic content of the fortifier but also of 

the rapid and continuous activity of human milk 

amylase on the dextrin content of fortifiers. Such 

an increase in osmolality may at least partly 

explain some minimal clinical disturbances, such 

as abdominal discomfort and delayed gastric 

emptying, but in some cases it might increase the 

risk of NEC in preterm infants. 100 Recently, in 

order to avoid these problems, fortifiers with 

whole proteins, reduced carbohydrate content and 

fat supplementation have been proposed. 101 The 

presence of fat in fortifiers has the advantage of 

increasing the energy intake of human milk 

without increasing osmolality values. However, 

this needs further technological studies, because 

the action of human milk lipase on triglycerides of 

fortifiers could produce instability in human milk. 

Many studies have evaluated growth, metabolic 

balance and weight gain composition in preterm 

infants fed fortified human milk. 49,98,102–108 The 

addition of multinutrient fortifiers to human milk 

resulted in short-term improvements in weight 

gain and increments in both length and head 

circumference growth during hospital stay. For 

ethical reasons, it is now unlikely that further 

studies evaluating fortification of human milk in 

comparison with no fortification will be 

conducted. Although the fortification of human 

milk improves the growth of preterm infants, 

growth both in general and referred to specific 

parameters (such as lean body mass, fat mass and 

bone mineral content) is significantly lower in 

fortified human milk-fed infants than in those fed 

preterm formula (Table 36.7). These differences 

could be related to the lower protein content but 

also to the reduction in metabolizable protein and 

energy available for new tissues synthesis. 

Questions have been raised as to whether the addition 

of bovine-derived human milk fortifiers can

affect feeding tolerance in premature infants. No 

differences in feeding tolerance were reported in a 

meta-analysis comparing premature infants fed 

fortified human milk or unfortified human milk. 109 

In contrast, fortifiers have recently been considered 

as risk factors for NEC in VLBW infants. 100 

When compared with premature infants fed 

preterm formula, infants fed exclusively fortified 

human milk had a significantly lower incidence of 

NEC and/or sepsis, had fewer positive blood 

cultures and required less antibiotic administration. 

89 

The effect of nutrient fortification on some of the 

general host defense properties of milk have been 

evaluated. Fortification did not affect the concentration 

of IgA in milk. 110 When fortified human 

milk was evaluated under simulated nursery 

conditions, bacterial colony counts were not 

significantly different after 20h of storage at refrigerator 

temperature, but increased from 20 to 24h 

when maintained at incubator temperature. 110 

Early use of a human milk fortifier up to 1.3g of 

protein/100ml is recommended for more immature 

or smaller preterm infants, beginning from the 

time when they are able to tolerate 50–70ml/kg per 

day of milk. Preference should be given to fortifiers 

with higher protein density and lower osmotic 

load. Additional studies are required to define the 

Practical aspects of enteral nutrition 613 

Table 36.7 Nutritional intake, growth and weight gain in preterm infants fed fortified human milk 

(HMF) and preterm formula (PTF) (from reference 16) 

Amount (/kg per day) HMF (n=48) PTF (n=86) p Value 

Volume intake (ml) 164±12 152±12

614 


Nevertheless, according to more recent data, a 

general profile in macronutrients could probably 

be suggested. Energy content could be slightly 

higher than at present (80–90kcal/100ml in order 

to provide 130–135kcal/kg per day with a volume 

intake close to 160ml/kg per day). According to the 

protein requirements, the protein content would 

represent 3.3g/100kcal, i.e. 2.6–3.0g/100ml. Wheypredominant 

protein with reduced glycomacropeptide 

and α-lactalbumin enrichment 

could be used to optimize the amino acid profile. 

Up to now the use of protein-hydrolyzed formulas 

have not been recommended. Their amino acid 

pattern is relatively unbalanced and the net 

protein utilization and protein efficiency are relatively 

impaired in comparison to whole protein, in 

contrast to the minimal clinical advantages 

observed, such as an improvement in gastric 

emptying or a reduced transit time. 32,111 The partition 

of the non-protein energy supply would favor 

the carbohydrate content up to 50–60% in view of 

its suggested benefits in sparing protein oxidation, 

enhancing growth and protein accretion as well as 

improving quiet sleep and influencing the distribution 

of behavioral activity states in VLBW infants. 

According to the relatively reduced intestinal 

lactase activity, the lactose content could be relatively 

reduced and substituted with glucose polymers 

with the characteristic of maintaining the 

low osmolality of the formulas. The remaining 

energy supply would be covered by fat with a fat 

blend carefully designed to reduce the long-chain 

saturated fatty acid content, and provide the essential 

fatty acids (linoleic and α-linolenic acid) in an 

appropriate ratio as well as the long-chain PUFA 

such as DHA and AA. In order to improve fat 

absorption, an important quota of fat could be 

given as MCT with a maximum of 30–40%. Highly 

metabolizable (50–60% absorption rate) calcium 

content would be limited to 100–120mg/100ml. A 

higher calcium supply does not seem useful. 

According to the expected nitrogen and calcium 

retention, the phosphorus content of this formula 

would represent 55–65mg/100ml, considering a 

phosphorus absorption close to 90%. 

Additional components of human milk, such as 

nucleotides, polyamine prebiotics and glutamine, 

are currently under investigation, and the results 

need to be available before their use in preterm 

formulas. 17 

Preterm formulas are available as powder or liquid 

in glass bottles or cans. Liquid formulas have the 

advantage that they provide sterile feeding thereby 

reducing possible infections reported in pre-term 

infants fed powder formulas such as the 

Enterobacter sakazakii. 112 Nevertheless, it worth 

remembering that with liquid formulas, there is 

frequent discordance between claimed and available 

content of several nutrients. For instance, part 

of the calcium content of liquid formula may 

precipitate on the wall of the container reducing 

the calcium truly available to the preterm infants. 

In addition, the heat treatment necessary to sterilize 

the liquid formulas reduces the bioavailability 

of various nutrients such as proteins, calcium or 

copper. The impaired bioavailability is directly 

related to the importance of heat treatment and is 

probably lower in the ultra heat treated (UHT) 

brickpack formula. In summary, powder formulas 

allowing adaptation of nutrient density and being 

of higher nutritional value, remain the formulas of 

choice for the feeding of VLBW infants when 

human milk is not available. 

Post-discharge nutrition in preterm infants 

Protein- and mineral-enriched formulas have been 

proposed to feed preterm infants after discharge 

with the aim of minimizing as much as possible, 

postnatal growth restriction during the early weeks 

of life, inducing early catch-up growth and reducing 

the adult adverse effects of early malnutrition. 

In most neonatal units, the discharge of VLBW 

infants usually occurs usually when premature 

infants reach a corrected gestational age of 35–36 

weeks and a weight of about 1800–2100g. By that 

time, they have accumulated energy, protein and 

mineral deficits and still present higher nutrient 

requirements than healthy infants appropriate for 

gestational term. The potential benefits of 

enriched formula on growth have been investigated 

following the first study of Lucas et al in 

1992 who introduced the concept of the postdischarge 

formula. 113 

Although the various studies differed in design 

and reported conflicting results, they allow a 

global analysis to be made. Comments follow: 

(1) Among the VLBW infants, not all preterm 

infants are at similar risk of later growth

failure. Small-for-gestational-age infants 

and those appropriate for gestational age 

developing postnatal growth restriction 

seem to be the population at higher risk, 

while infants appropriate for corrected age 

at the time of discharge from the hospital 

subsequently continue to maintain appropriate 

growth. 114 

(2) Energy intakes were the main determinant 

of milk volume intakes. Compared to regular 

(standard) formula, an increase in energy 

density had no influence on energy supply, 

in contrast to the increase in protein density 

that influences protein intake, and protein 

metabolism. 

(3) A positive effect of growth parameters was 

not observed in all studies, but the benefit of 

the nutrient-enriched formula on growth, 

when observed, was mainly seen during the 

early post-discharge period (between discharge 

and term), in infants with very low 

birth weights. 115,116 In addition, the growth 

benefit could be related to the preterm 

infants without a postnatal growth deficit at 

the time of discharge. 117 

(4) There is a strong gender influence on the 

result of diet manipulation during the postdischarge 

period. The main positive results 

are limited to boys. 

(5) The safety of prolonged high-protein intake 

during the early period of life in preterm 

infants after discharge has not been established, 

in contrast to the minimal benefits 

suggested by the various studies. Highprotein 

intake, by inducing an increase in 

biochemical parameters of nitrogen metabolism 

(urea, amino acids, ammonia), could 

enhance the development of several diseases, 

such as obesity and hypertension 

later in life. 118 

Since early nutrition should not be considered 

simply in terms of providing immediate nutritional 

needs but also for the biological effects with 

Practical aspects of enteral nutrition 615 

possibly lasting or lifelong significance, it seems 

prudent to suggest an enriched formula only in 

infants at risk of future growth failure. 119 

Mothers of infants at low risk of longitudinal 

growth restriction should be encouraged to feed 

them their own milk. Careful attention is necessary 

to evaluate the appropriateness of intakes 

and growth just before and in the first week after 

discharge. In early discharge a supplementation 

with fortified human milk or formula might be 

necessary in order to improve the nutrient 

supply in relation to the remaining state of 

prematurity. 

In infants with a low risk of longitudinal growth 

restriction, fed on formula at the time of discharge, 

a regular formula with relatively low protein 

density (2.2g/100kcal) should be provided with 

particular attention to its long-chain PUFAs, 

mineral and trace element content. 

Infants at high risk of longitudinal growth restriction, 

should be breast fed or should receive human 

milk supplemented with fortified human milk or 

formula, in order to improve the nutrient supply 

and promote catch-up growth. An evaluation of 

nutrient intakes and growth should be done 

frequently to optimize growth and biological parameters. 

In infants at high risk of longitudinal growth 

restriction, on formula at the time of discharge, a 

specific post-discharge formula with higher 

protein and mineral density but also adapted in 

long-chain PUFAs and trace elements should be 

provided. Intakes and growth would also be 

recorded weekly and thereafter monthly to ensure 

that nutrient supplementation is in agreement 

with growth and biological results. 

Further research should be initiated in order to 

determine the specific nutritional needs of growthrestricted 

preterm infants in order to design more 

specific post-discharge formulas and evaluate their 

effect on the long-term incidence of growth restriction 

as well as somatic and neurodevelopmental 

outcomes.

616 


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on nutrient intake and growth. Pediatr Res 1998; 

43: 355–360. 

117. De Curtis M, Pieltain C, Rigo J. Body composition in 

preterm infants fed standard or enriched formula after 

hospital discharge. Eur J Nutr 2002; 41: 177–182. 

118. Rolland-Cachera MF. Early adiposity rebound is not 

associated with energy or fat intake in infancy. 

Pediatrics 2001; 108: 218–219. 

119. De Curtis M, Pieltain C, Rigo J. Nutrition of preterm 

infants on discharge from hospital. In Raiha NCR, 

Rubaltelli FF, eds. Infant Formula: Closer to the 

Reference. Nestlè Nutrition Workshop Series, Nestec 

Ltd. Vevey/Lippincott Williams & Wilkins Philadelphia, 

2002; 47 (Suppl): 149–163.

37 

Introduction 

Parenteral nutrition in 


Jacques Rigo and Mario De Curtis 

Over the past decades there has been a dramatic 

increase in the survival of preterm infants, especially 

very-low-birth-weight (VLBW) infants. 

Prenatal steroids to enhance pulmonary maturation, 

the use of exogenous surfactant for the treatment 

of the respiratory distress syndrome, and 

better prenatal obstetric and postnatal neonatal 

intensive care have all played a major role in 

improving survival rate in these infants. 1–3 

With the major advances in life-support measures, 

nutrition has become one the most debated issues 

in the care of low-birth-weight infants; in this 

regard, several reports have shown the important 

effect of nutrition during the first period of life on 

early and late outcome. 4 

Although the general objective of a nutritional 

regimen for preterm infants is to support life and 

achieve a growth rate sufficient to fulfill the individual’s 

genetic potential, there are many controversies 

on how to attain this goal. In this chapter 

we discuss the most important features regarding 

the nutrition of preterm, and particularly VLBW 

infants, outlining the main aspects of parenteral 

nutrition. 

Nutritional requirements 

While the nutritional reference standard for fullterm 

newborns is an exclusively breast-fed infant, 

no similar standard is available for preterm 

infants. In the neonatal period, preterm infants 

and especially VLBW infants have greater nutritional 

needs in order to achieve optimal growth 

than at any other time in their life. Preterm birth is 

associated with decreased nutrient storage, and 

the clinical conditions after birth may increase 

nutrient needs. 

The recommended nutrient intakes of preterm 

infants are still a matter of debate, arising from the 

lack of consensus on the short- and long-term 

objectives for early nutrition. Current nutritional 

recommendations from various international 

committees (American Academy of Pediatrics, 

European Society for Pediatric Gastroenterology, 

Hepatology and Nutrition, Canadian Academy of 

Pediatrics) are based on healthy preterm infants 

and designed to provide postnatal nutrient retention 

during the ‘stable-growing’ period equivalent 

to the intrauterine gain of a normal fetus. They do 

not take into consideration the relatively long transitional 

period that induces the cumulative nutritional 

deficit and the need to obtain an early catchup 

growth. 5–7 

The postnatal use of the gastrointestinal tract, 

instead of placental transfer, and the metabolic 

changes that occur immediately after birth, do not 

allow provision of the quantitative or qualitative 

supply of all the nutrients needed to approximate 

fetal growth of the comparable corrected age. 

Additional nutritional deprivations can also arise 

from neonatal illnesses such as metabolic stress, 

infectious diseases, necrotizing enterocolitis or 

bronchopulmonary dysplasia, which often further 

decrease nutrient supply. 

In practice, the shorter the gestation of a neonate 

the more challenging are the influences of immaturity 

and the accompanying morbidity on nutritional 

supply during the early weeks of life. As a 

result of this cumulative nutritional deficit during 

early life, most growth parameters remain subnormal 

by the time the preterm infant reaches a 

corrected age of 40 weeks (Figure 37.1); this 

phenomenon worsens in the case of VLBW and 

619

620 

Z Score compared to Usher & McLean (SD) 

1.5 

0.5 

-0.5 

-1.5 

-2.5 

-3.5 

-4.5 

Parenteral nutrition in premature infants 

At birth 

At discharge (± 7 weeks) 

Body weight Body length 

Figure 37.1 Z score of body weight, body length 

determined in healthy very-low-birth-weight infants (birth 

weight 2g amino acids/kg per day) and the use of intravenous 

lipids (0.5–1.0g lipid/kg per day), from the 

first day of life, associated when necessary, with 

the use of insulin to improve carbohydrate tolerance 

during the early adaptive period. 10,11 

Nutrition during the ‘stable-growth’ period on PN, 

is given exceptionally, when preterm infants are 

recovering from severe gastrointestinal problems, 

to prevent or limit the use of the gastrointestinal 

tract. In most preterm infants, nutritional supplies 

are provided using the mother’s milk supplemented 

with human milk fortifiers or preterm 

formulas specially designed for VLBW infants. 

The objective of nutrition in this period is to minimize 

postnatal growth deficit, maximize longitudinal 

growth and induce catch-up growth. 

Although the optimal nutritional supply is still 

controversial, more recent studies suggest that, in 

order specifically to enhance lean mass growth 

and improve the early catch-up growth in preterm 

infants, the use of a high-protein regimen 

combined with a high protein-energy density 

regimen (4.0–4.4g of protein/kg per day with a 

protein/energy ratio up to 3.3g/100kcal) promotes

growth without metabolic stress in VLBW 

infants. 12,13 

Parenteral nutrition 

PN provides the infant’s requirements for growth 

and development when the infant’s size or clinical 

conditions preclude enteral feeding. PN in 

preterm infants is prescribed especially for those 

with respiratory distress, before starting enteral 

feeding, and can be increased slowly to avoid 

overloading the immature gastrointestinal tract 

while continuing to satisfy nutritional requirements. 

A recent report indicates that in the USA, even 

though over the last 15 years, there has been a 

decrease in the length of days of PN in VLBW 

infants, most of these VLBW infants receive 

parenterally delivered nutrients as their major 

source of nutrition for the first few days to weeks 

of life. 14 

Today PN is seen by many neonatologists as a 

means of achieving rapid nutrition and administering 

nutrients that could be delayed and/or 

insufficiently absorbed via the enteral route, especially 

in the presence of conditions considered to 

be hazardous to the intestine and thus increasing 

the risk for necrotizing enterocolitis. PN allows 

infusion of concentrated hypertonic nutrient solutions 

without excessive fluid intake (which is not 

well tolerated by most VLBW infants), through an 

indwelling catheter, the tip of which is in the 

superior vena cava just above the right atrium. 

This technique was first described by Wilmore 

and Dudrick in 1968. 15 

Nowadays, in ELBW infants, PN is usually administered 

through the umbilical vessels for a limited 

number of days, followed by the use of a silastic 

catheter introduced percutaneously from a peripheral 

vein. Less frequently, in bigger preterm 

infants, a catheter is inserted surgically into either 

the internal or external jugular vein and tunneled 

subcutaneously. Currently, the use of direct infusion 

via peripheral veins has become less common 

because of the relatively high osmolarity of the 

solution that can lead to endothelial damage, 

frequent interruption of continuous feeding and 

relative reduction of the nutritional supplies. 

Fluids 

Parenteral nutrition 621 

A number of physiological changes and adaptive 

processes that occur at birth, immediately or 

subsequently affect water and electrolyte metabolism. 

In particular, placental clearance and placental 

supply of fluids, electrolytes and nutrients are 

discontinued, and a considerable insensible water 

loss and infant thermoregulation begin to occur. 

Compensatory regulative processes (such as renal 

adaptation, start of oral intake) need time to counteract 

these effects on body water pools. 

Just after the birth, there is a fall in urinary 

output due to a decreased glomerular filtration 

rate. This relative oliguria, which may last for a 

variable period (hours or days), is mainly determined 

by the presence of conditions and 

diseases, such as respiratory distress syndrome. 

Oliguria is then followed by a diuretic phase, 

during which a contraction of extracellular fluid 

volume occurs. The end of this transitional 

period is usually characterized by a urine volume 

3% to

622 


enormous, especially when the baby is under a 

radiant warmer and is undergoing phototherapy. 

A reduction of insensible water loss can be 

obtained by increasing the humidity of incubators. 

Increased fluid loss occurs when the infant 

is placed under radiant warmers or undergoes 

phototherapy. 16 Fluid requirements are decreased 

with the use of double-walled incubators, heat 

shields or plastic blankets and high-ambient 

humidity. 17,18 

The following intermediate phase is characterized 

by a decrease in insensible water loss from the 

skin, the increasing maturation of the epidermis, 

and improved renal function. In this period fluid 

and electrolytes have to be increased in order to 

cover the requirements (120–150ml/kg per day) 

and to allow adequate growth. During this period 

the amount of parenteral fluid can be reduced and 

enteral feeding can be augmented. Infants with 

bronchopulmonary dysplasia, patent ductus arteriosus, 

renal failure and respiratory distress 

syndrome, are very vulnerable to fluid overload. 

Energy 

Energy must be supplied by nutrient intake to 

cover two major components, energy expenditure 

and growth. A caloric intake of 40–60kcal/kg per 

day approximates energy expenditure and is a 

reasonable goal for the maintenance requirements 

of premature infants for the first days after birth. 

The energy cost of gaining 1g of new tissue is 

about 5kcal. This value is influenced largely by 

quantity of fat deposition ranging between 20 and 

40% of postnatal weight gain in premature infants, 

according to the feeding regimen. 19 The lower the 

fat deposition, the lower is the cost of growth; 

thus, energy cost of weight gain during the third 

trimester of intrauterine life, 16–20g/kg per day, 

with 15% fat, is lower than that for postnatal 

weight gain accounting for a higher fat deposition, 

up to 40%. 

In contrast to what is generally proposed, the 

energy requirement in PN approximates to that of 

enteral nutrition. In fact, the energy content of 

amino acid solutions in PN is lower than that 

provided by the protein in enteral nutrition 

(human milk or formulas). The gross energy, 

measured by calorimetric bomb, provided by 

glucose used in PN is less than that provided by 

the carbohydrate content of formulas. In contrast, 

while the metabolizable energy of amino acid solutions 

and glucose, given by the parenteral route, is 

identical to total intake, the metabolizable energy 

of dietary protein and carbohydrates represents 

about 90% of the intake. 20,21 Consequently, the 

recommendation for energy intake during the 

stable-growing period in VLBW infants on PN 

corresponds to 110–135kcal/kg per day. 

Carbohydrates 

Glucose is the most widely used intravenous 

carbohydrate for neonates, because it is readily 

available to the brain. The monohydrate form of 

dextrose is used for intravenous solutions; each 

gram provides 3.7kcal upon complete oxidation. 20 

As the solution concentration increases, so does 

osmolarity, ranging from approximately 

255mOsm/l for a 5% solution to 1020mOsm/l for a 

20% solution. Many other non-glucose carbohydrates 

have been tried, but with limited success. 

The newborn infant is often in a transitional stage 

of glucose homeostasis and is, therefore, subject to 

hyper- or hypoglycemia. Although the definition 

and the long-term consequences of neonatal hypoglycemia 

remain controversial, plasma glucose 

concentration should be monitored and corrected 

if it falls below 35mg/dl (1.9mmol/l) during the 

first days of life. 22 In the first few days of life, 

VLBW infants are more susceptible to hyperglycemia 

often associated with glucosuria, which 

seems to be caused by a persistent endogenous 

hepatic glucose production secondary to an insensitivity 

of hepatocytes to insulin. 23–25 The definition 

of hyperglycemia varies but is generally set at 

a plasma level above 150mg/dl (8.3mmol/l). 

However the upper ‘safe’ limit of blood glucose 

concentration in the neonate is not well defined 

and, as for hypoglycemia, there is a great variation 

in terms of the diagnosis and management of 

hyperglycemia. The increase in serum osmolarity 

induced by the increase in blood glucose has been 

associated with higher mortality and a higher rate 

of intracranial hemorrhage. Glycosuria associated 

with hyperglycemia results from the relatively low 

renal threshold for glucose excretion in the 

preterm infant compared with the adult and may 

increase the risk of dehydration. Risks for hyper-

glycemia and glycosuria increase with decreasing 

gestation and birth weight, and is estimated to be 

between 20% and 86% during the first few days of 

life in preterm infants who survive their first 

week. 26,27 

If hyperglycemia is detected early through 

frequent glucose monitoring, plasma glucose 

levels can be decreased by reducing insensible 

water loss, glucose infusion rate and by providing 

exogenous insulin supply. Decreasing volume 

intake and glucose concentration reduces energy 

supply and consequently growth and nitrogen 

retention. Insulin administration helps control 

plasma glucose concentration, achieve increased 

energy intake and promote nitrogen retention and 

growth, although there is need for more data on its 

safety and long-term consequences as a growthpromoting 

agent. More recently, it has been 

proposed that high amino acid intake, 2–3g/kg per 

day from the first day, in addition to preventing 

catabolism and promoting anabolism, may have 

several other beneficial effects including decreasing 

the frequency and severity of neonatal hyperglycemia 

by stimulating endogenous insulin secretion 

and stimulating growth by enhancing the 

secretion of insulin and insulin-like growth 

factors. 28 

In practice, 6g/kg per day of intravenous glucose 

are generally well tolerated (4–5mg/kg per min) 

even on the first day of life in VLBW infants. If this 

intake is tolerated, it may be increased to 8, 10 and 

up to 12–18g/kg per day. If it is not tolerated, 

progression of glucose intake will be stopped and 


insulin perfusion will be considered according to 

clinical and nutritional status with an initial dose 

of 0.05IU/kg per h. 29 

Protein 

In order to define the protein requirements for 

preterm infants more precisely, it has been 

suggested that lean body mass be taken into 

account instead of weight gain, also considering 

that preterm infants present a high fat deposition 

in the postnatal period. Table 37.1 shows the 

revised recommended protein intake and 

protein/energy ratio for preterm infants according 

to postconceptional age and the need for catch-up 

growth. 12 It should be stressed that these recommendations 

derive especially from studies on 

preterm infants greater than 1000g rather than on 

ELBW infants (

624 


therapy and by catabolic stress due to diseases or 

early neonatal surgery. 

Amino acid composition of solutions for 


Considerable improvements in parenteral amino 

acid solutions have been made since the 1960s 

when the source of intravenous protein was casein 

hydrolysate. The use of a crystalline amino acid 

mixture in the early 1980s helped to improve the 

nitrogen utilization whereas, more specific pediatric 

amino acid solutions were designed in the 

early 1990s with a high essential/non-essential 

amino acid ratio and conditionally essential amino 

acid content for use in preterm infants. Despite the 

new evidence, the reference optimal solution for 

PN has not yet been well defined because the 

optimal value for plasma amino acid concentrations 

in preterm infants is still a matter of debate. 

At least three different ‘gold standards’ have been 

proposed for premature infants: first, the amino 

Plasma concentration (µmol/100ml) 

65 

60 

55 

50 

45 

40 

35 

30 

25 

20 

15 

10 

5 

0 

GLN 

ASP 

LYS 

PRO 

GLY 

THR 

VAL 

TYR 

SER 

TAU 

acid concentrations from the umbilical cord 

obtained following fetal cord puncture or after 

birth; second, the amino acid concentrations of 

rapidly growing preterm infants receiving their 

mother’s milk or human milk supplemented with 

human milk proteins; and third, the amino acid 

concentrations of healthy breast-fed term infants. 

The amino acid concentrations observed in VLBW 

infants during the last trimester of gestation or in 

well-growing preterm infants fed an optimal intake 

of human milk protein appear to be safe. However, 

considering the large differences observed between 

fetal and postnatal values of some amino 

acids (THR, VAL, TYR, PHE, LYS and HIS), a 

combined reference has been proposed taking into 

account the mean ±1 SD of the values obtained in 

cord blood and in the postprandial serum of 

preterm infants fed human milk supplemented 

with human milk proteins (Figure 37.2). 31 

Nevertheless, despite the diverse composition of 

parenteral amino acid solutions used in pediatric 

care, nitrogen utilization does not change signifi- 

Figure 37.2 Plasma amino acid reference (adapted from reference 31). HMF, human milk fortified with human milk 

protein; Cord, cord blood concentrations. 

GLU 

HIS 

ORN 

LEU 

ARG 

HPR 

ASN 

ILE 

Cord 

HMF 

Reference 

PHE 

TRP 

CYS 

MET 

CIT 

ASP

cantly. 32,33 Nitrogen amino acid content is related to 

the amino acid composition and varies according to 

the solution, and is frequently lower than in enteral 

nutrition (160mg/g of protein). Therefore, it is probably 

preferable to consider nitrogen rather than 

amino acid intake in total PN. 

Analysis of a large number of nitrogen balances in 

preterm infants shows that a nitrogen retention of 

380mg/kg per day can be obtained with a nitrogen 

intake of 530mg/kg per day (Figure 37.3), 33–43 which 

corresponds to a net protein utilization (nitrogen 

retention/nitrogen intake) of 70%, a value quite 

similar to that recorded in oral nutrition (60–72%). 44 

These data indicate that the nitrogen requirement in 

PN is close to 95% of the enteral requirement, but 

corresponds to a similar amino acid versus protein 

requirement in parenteral and enteral nutrition. 

Parenterally fed preterm infants are at risk of toxicity 

from excessive amino acid intake, immature metabolic 

pathways, absence of first hepatic crossing and 

lack of small-intestinal metabolism. Therefore, 

optimal amino acid pattern for parenteral amino 

acid solutions in preterm infants still needs to be 

determined, and new solutions should be developed 

keeping in mind the following principles: 

Nitrogen retention (mg/kg per day) 

450 

400 

350 

300 

250 

200 

150 

100 

50 

0 

100 


(1) The requirement of essential amino acids in 

VLBW infants is greater than in term 

neonates or older infants; 45 

(2) The activity of phenylalanine hydroxylase as 

well as tyrosine aminotransferase and 4dioxyphenylpyruvate 

dioxygenase is considered 

to be immature during the neonatal 

period; 46 

(3) The activity of cystathionase in neonates is 

low and cysteine synthesis from methionine 

is reduced; 47 

(4) Nutritional supply of taurine is probably 

necessary during the neonatal period. 

Although cysteine sulphinic activity has been 

demonstrated in preterm infants, taurine is 

probably considered as a conditionally essential 

amino acid in neonates; 48 

(5) In addition to cysteine and tyrosine, histidine 

and arginine are categorized as semi-essential 

amino acids in neonates; 49 

(6) Organ dysfunction tends to occur when some 

amino acids are administered in high 

(methionine) or low (arginine, glutamine) 

amounts. 50,51 

150 200 250 300 350 400 450 500 550 

Nitrogen intake (mg/kg per day) 

Figure 37.3 Relationship between nitrogen retention and nitrogen intake in parenterally fed preterm infants. 12,33–43

626 


Table 37.2 Composition of commercially available parenteral amino acid solutions 12 

Aminoplasmal- Aminosyn Aminosyn-PF Aminovemos FreAmine III Neophan MPF 

Aminoped N-Pad (FAO/WHO) 

(Pfrimmer-kabi) (Abbott) (Abbott) (Fresenios) (McGaw) (Cutter) General use 

Trp 4 1.6 1.8 1.8 1.5 2.1 1.3 

Ile 5.1 7.2 7.6 6.4 6.9 4.7 5.6 

Leu 7.6 9.4 11.9 10.7 9.1 10.7 12.5 

Val 6.1 8 6.5 7.1 6.6 5.5 4.5 

Lys 8.8 7.2 6.8 7.1 7.3 8.6 8.8 

Met 2 4 1.8 4.3 5.3 2 3.5 

Phe 3.1 4.4 4.3 4.6 5.6 4.1 9.4 

Thr 5.1 5.2 5.1 5.1 4 5.5 6.5 

His 4.6 3 3.1 4.1 2.8 3.2 6 

Arg 9.1 9.8 12.3 6.4 9.5 6.3 7.9 

Orn 0 0 0 0 0 0 0 

Gly 2 12.8 3.9 4.1 14 3.2 10.7 

Ala 15.9 12.8 7 7.1 7.1 9.7 6.2 

Glu 9.3 0 8.2 0 0 10.9 6.5 

Asp 6.6 0 5.3 0 0 6.3 3.8 

Pro 6.1 8.6 8.1 16.1 11.2 8.6 3.3 

Ser 2 4.2 5 9 5.9 5.8 2.2 

Tyr 1.1* 0.4 0.6 1.6* 0.7 0.3 

Cys 1 0 0.6 0.2 1.5 1 

Tau 0.3 0 0.7 0 0 0 

AAA 46% 50% 49% 51% 49% 46% 58% 

BCAA 19% 25% 26% 24% 23% 21% 23% 

Nitrogen 160 167 165 152 162 153 165 

To date, the normalization of plasma amnio acid 

concentrations in PN has never been achieved due 

to the poor solubility of free tyrosine and cystine 

and the absence of an adequate and safe metabolic 

substitute. 52 

Table 37.2 shows some commercially available 

parenteral amino acid solutions. 

Amino acids for special purposes 

Arginine 

Arginine is a precursor of nitric oxide; inadequate 

availability has been implicated in various neonatal 

Continued 

diseases, such as persistent pulmonary hypertension 

and necrotizing enterocolitis. Recent evidence 

suggests that the de novo arginine synthesis in the 

neonate relies on small-intestinal metabolism, and 

that dietary arginine requirements could be higher 

in the parentally fed infants. 53 Currently, arginine 

content varies widely in pediatric parenteral solutions 

suggesting that the dietary requirement in 

parenteral and oral nutrition must be elucidated. 

Glutamine 

Glutamine is the most abundant amino acid in the 

human body and the main one supplied to the fetus


through the placenta. Glutamine is thought to be an 

important fuel for rapidly dividing cells such as 

enterocytes and lymphocytes. It is a regulator of 

acid–base balance via ammonium, as well as an 

important precursor of nucleic acids, nucleotides 

amino sugars and protein. There is, however, little 

information on the role of glutamine in children 

and infants or as to whether glutamine supplementation 

is beneficial in preterm babies. In ELBW 

infants and during critical illnesses glutamine could 

be a conditionally essential amino acid. 54 

Reviewing the available studies in preterm infants 

for the Cochrane database, Tubman and 

Thompson 55 did not find evidence to support the 


PED Pleamine-P Primene Travasol Trophamine VAMIN Infant 

(B. Braun) (Fuso, Japan) (Baxter) (Clintec) (Kendall–McGaw) (Kabivitrun) 

Trp 1 1.6 2 1.8 2 2.2 

Ile 2.8 10.5 6.7 6 8.2 4.8 

Leu 5 21 10 7.3 14 10.8 

Val 3.2 7.9 7.6 5.8 7.8 5.5 

Lys 9 6.3 11 5.8 8.2 8.6 

Met 1.6 2 2.4 4 3.3 2 

Phe 3.8 3.3 4.2 5.6 4.8 4.2 

Thr 6 3.2 3.7 4.2 4.2 5.5 

His 6 3.3 3.8 4.8 4.8 3.2 

Arg 4.4 13.2 8.4 11.5 12.1 6.3 

Orn 0 0 2.2 0 0 0 

Gly 9.8 2.6 4 10.3 3.7 3.2 

Ala 11.6 6.8 8 20.7 5.3 9.7 

Glu 19.6 1.1 10 0 5 10.9 

Asp 3.8 1.1 6 0 3.2 6.3 

Pro 5.4 7.9 3 6.8 6.8 8.6 

Ser 2 5.3 4 5 3.8 5.9 

Tyr 0.6 0.8 0.5 0.4 0.7* 0.8 

Cys 1.7 2 1.7 0 0.2 1.5 

Tau 0 0.2 0.6 0 0.3 0 

AAA 38% 59% 51% 45% 57% 47% 

BCAA 11% 39% 24% 19% 30% 21% 

Nitrogen 149 177 161 173 168 154 

All amino acid mixtures are in % amino acid content. Nitrogen expressed as mg/100 ml 

AAA, aromatic amino acid; BCAA, branched chain amino acid 

* Mixture of L-tyrosine and N-acetyl-L-tyrosine 

routine use of parenteral or enteral glutamine 

supplementation in preterm infants. A more 

recent, multicentric study on ELBW infants 

showed that parenteral glutamine supplementation 

can increase plasma glutamine concentrations, 

but the potential clinical effects of such glutamine 

supplementation remain to be elucidated. 56 

Intravenous lipids 

Intravenous lipid emulsions are important 

constituents of total PN as they provide energy and 

essential fatty acids to VLBW infants. Lipid 

emulsions consist of different oils, egg yolk

628 


phospholipids and glycerol. The fat particles in the 

emulsions resemble endogenously produced 

chylomicrons in terms of size, physicochemical 

properties and metabolism, and are hydrolyzed by 

lipoprotein lipase. The rate of infused triglyceride 

clearance is determined by the available lipase 

activity and by the uptake of unesterified fatty acid 

products related to the adipose tissue mass and/or 

fatty acid oxidation in muscles. Intravenous lipid 

emulsions provide high caloric, isotonic solutions 

of linoleic acid (18:2n-6) and linolenic acid (18:3n- 

3), as well as other fatty acids, and can also be 

given through peripheral lines. Traditionally, lipid 

infusions are prepared from soybean oil triglycerides 

emulsified with egg yolk phospholipids. 

Typical soybean oil contains about 45–55% 

linoleic acid (18:2n-6) and 6–9% linolenic acid 

(18:3n-3), but very little saturated or monounsaturated 

fat (Table 37.3). 57 There are considerable 

concerns over the effect of these emulsions on the 

composition of the fatty acids deposited in the 

developing tissues of preterm infants. 

Intravenous lipids play two separate roles in the 

PN of VLBW infants. One is the role of intravenous 

lipids as an energy substrate to be readily utilized 

by VLBW infants. There is some evidence that the 

supply of some of the energy as lipids is preferable 

over carbohydrate as the sole energy substrate. 58 

Amino acid oxidation and protein breakdown 

were significantly lower when lipids provided 

50% of the non-protein calories than when glucose 

alone served as the energy substrate. Advantages 

of lipids emulsions over concentrated glucose 

solutions also include their isotonicity and greater 

energy density, the latter meaning that less volume 

is required per calorie. This is particularly true for 

20% lipid emulsion, which is preferred over the 

10% emulsion because it leads to a more normal 

pattern of plasma phospholipid and cholesterol 

than the 10% intralipid. 59 This beneficial effect of 

the 20% emulsion is attributed to the lower phospholipid 

content (per gram of triglyceride), 

although for the lower phospholipid content, the 

20% emulsion delivers less long-chain polyunsat- 

Table 37.3 Commercial intravenous lipid emulsions currently used in preterm infants 57 

Soybean Soybean/MCT Olive/soybean Soybean/fish 

Product names Intralipid (Pharmacia) Lipofundin ClinOleic Lipovenous + 

Ivelip (Clintec) MCT(Braun) (Clintec) Omegavenös, 

Lipofundin (Braun) 9+1 parts mix 

Lipovenös (Fresenius) (Fresenius) 

Liposyn III (Abbott) 

Triglycerides (%) 10, 20 & 30 20 20 10 

Ratio of phospholipids/ 120, 60 & 40 60 60 66 

triglycerides (mg/g) 

Glycerol (%) 2.5 2.5 2.25 2.5 

kcal/ml 1.1–2.0 1.9 2.0 — 

Fatty acid composition (% wt/wt) 

Medium chain (8:0+10:0) n.d. 50 n.d. n.d. 

Palmitic (16:0) 9–11.2 5 13.5 10.8 

Stearic (18:0) 4–4.2 2 2.9 3.7 

Oleic (18:1n9) 20.4–26 12 59.5 19.9 

Linoleic (18:2n6) 52.4–54.5 27 18.5 49.7 

linolenic (18:3n3) 

linolenic (18:3n6) 

8–8.5 4 2 6.5 

Arachidonic (20:4n6) n.d.–0.2 n.d. 0.2 0.2 

Eicosapentaenoic (20:5n3) n.d. n.d. n.d. 2.4 

Docosahexaenoic (22:6n3) n.d.–0.1 n.d. 0.1 2.3 

MCT, medium-chain triglyceride, n.d. not determined

urated fatty acids (PUFAs) (contained in the phospholipid 

fraction) than the 10% emulsion. For this 

reason, it seems that, at least in the first days of 

life, until the lipid dose reaches 2.0g/kg per day, 

the 10% emulsion could be preferable over the 

20% emulsion. 10 The other role is as a source of 

essential fatty acids as well as long-chain PUFAs. It 

is well known that when preterm infants are maintained 

on lipid-free PN there is a rapid essential 

fatty acid deficiency. An essential fatty acid deficiency 

is known to interfere with normal lung 

surfactant synthesis, possibly further impairing 

pulmonary function in infants already at risk for 

respiratory problems. 60 Abnormalities in platelet 

function, which could have implications for clinical 

bleeding, have also been described. 61 Essential 

fatty acid deficiency is avoided by infusions of 

0.5–1.0g lipid per kg per day. 62 The importance of 

long-chain PUFAs for the development of the brain 

and the retina has also been recognized. Preterm 

infants are unable to form sufficient quantities of 

long-chain PUFAs from the respective precursor 

fatty acids (linoleic and α-linolenic acids) and thus 

depend on an exogenous source of long-chain 

PUFAs. 63,64 Intravenous lipid emulsions contain 

small amounts of these fatty acids as part of the egg 

phospholipid used as a stabilizer. 

More recently, new lipids emulsions containing a 

mixture of medium-chain and long-chain triglycerides 

(MCTs and LCTs), a mixture of MCTs, LCTs 

and fish oil, or based on olive and soybean oil, are 

receiving increasing attention. 65–70 All these solutions 

are designed to reduce the high linoleic and 

α-linolenic acid supplies provided by the classic 

soybean oil, improve the fatty acid composition of 

plasma lipids, reduce the risk of peroxidation and 

provide additional long-chain PUFAs with the use 

of fish oil. Infused MCTs are rapidly cleared, 65 

although studies of parenterally fed newborn 

infants have not confirmed a benefit of mixed 

MCT–long-chain fatty acid emulsions on protein 

accretion 66 and plasma fatty acid pattern. 67 The 

addition of fish oil to MCT and LCT solutions has 

not led to adverse effects, although a significant 

increase in plasma α-tocopherol and eicosapentaenoic 

acid in the high-density lipoprotein phospholipid 

68 was seen. The most promising appears 

to be the lipid emulsion based on olive and 

soybean oil. In preterm infants, it produces more 

physiological levels of linoleic and oleic acid and 

a better antioxidant status than the conventional 

soybean oil emulsion. 69,70 


Concerns had been raised in some retrospective 

studies, about the potentially adverse effects of 

early lipid infusion in preterm infants on later 

outcomes, such as increased rates of chronic lung 

disease and mortality. 71,72 However, a meta-analysis 

of the five prospective controlled trials in lowbirth-weight 

infants on this issue has shown that 

early lipid infusion within the first 5 days of life is 

not associated with an increased risk of adverse 

outcomes. 73 There is no credible evidence of 

potentially adverse effects of intravenous lipid 

emulsions when these are properly used. Proper 

use includes slow and continuous infusion rate 

(3g/kg per day). 74 It 

has been suggested that triglyceride concentrations 

should be maintained at around 150–200mg/dl as 

an upper limit in VLBW infants, especially in 

unstable clinical situations. 

Considering that even a short delay in adding fat to 

the PN of preterm infants leads to biochemical 

essential fatty acid deficiency, infusion of lipids 

should commence within 24h of birth for infants 

>28 weeks’ gestation and >1000g. The dose 

should be increased, as tolerated, at a rate of 0.5g 

every 1–2 days to a maximum of 3g/kg per day. In 

all cases, the triglyceride infusion dose should be 

adjusted to maintain a serum lipid level not 

exceeding 200mg/dl. Infants

630 


Electrolytes, minerals and trace elements 

Sodium 

Sodium exists predominantly as an extracellular 

ion, and its requirements are unaltered by PN. 

The normal sodium requirement is assumed to be 

3mmol/kg per day. During the first week of life, 

infants of less than 28 weeks’ gestation often 

receive additional sodium supply from sources 

other than the parenteral solution, i.e. blood 

transfusion, bicarbonate or drugs, and lose more 

water than sodium. Therefore, to prevent hyperosmolar 

hypernatremia, some authors suggest 

very close monitoring of sodium intake during 

the first week of life, while others recommend the 

complete exclusion of sodium during the first few 

days in ELBW infants. Frequent monitoring and 

customization of serum sodium and water/ 

sodium is mandatory especially in infants with 

congestive heart failure, acute renal failure or 

chronic diuretic therapy. 

Potassium 

The normal requirement for potassium for 

growing preterm infants is assumed to be 

1–2mmol/kg per day. It should be withheld in the 

first 3 days after birth in those who are extremely 

preterm because of the risk of developing nonoliguric 

hyperkalemia from immature distal 

tubular function. An adjustment of potassium 

intake is required if the infant is on diuretics or 

has poor urine output. 

Chloride 

The recommended intake is 2–3mmol/kg per day 

and the chloride maintenance intake must not be 

lower than 1mmol/kg per day. 

Calcium, phosphorus and magnesium 

Inadequate calcium and phosphorus intake has 

been associated with diminished bone mineralization 

in parenterally fed premature infants. 

This occurs when protein and energy are 

adequate for growth, but calcium and phosphorus 

are insufficient to sustain appropriate skeletal 

mineralization. 75–78 

Calcium and phosphorus cannot be provided 

through the same parenteral solution at concentrations 

needed to support in utero accretion, because 

of precipitation. The solubility of calcium and 

phosphorus in parenteral solutions depends on 

temperature, type and concentration of amino 

acid, dextrose concentration, pH of the calcium 

salt, the sequence of addition of calcium and phosphorus 

to the solution, calcium/phosphorus ratio 

and the presence of lipids. 79 More acidic pediatric 

amino acid solutions improve calcium and phosphorus 

solubility. With a range of fluid intake of 

120–150ml/kg per day, it is advisable to supply a 

calcium content of 50–60mg/dl (1.25–1.5mmol/l), a 

phosphorus content of 40–45mg/dl (1.25–1.5mmol/l) 

and a magnesium content of 5–7mg/dl (2.1–2.9mmol/l) 

corresponding to a calcium phosphorus ratio of 1.3:1 

by weight and 1:1 by molar ratio in the total PN 

solution. It must be underlined that this quantity 

of calcium provided by the parenteral route is 

about 60–75% of that deposited by the fetus during 

the last trimester of gestation (100–120mg/kg per 

day) but similar or higher than that obtained in 

enteral nutrition with the available preterm formulas. 

Administering sufficient amounts of calcium 

and phosphorus in PN solutions is no longer a 

problem in countries where organic phosphate 

preparations are available and the amounts of 

calcium and phosphorus available with PN could 

be theoretically higher than that absorbed using 

the enteral route. 80 However, information on bone 

mineralization of ELBW infants receiving what 

appears to be an adequate calcium and phosphate 

intake is still limited. 

The usual dose of magnesium is about 6 mg/kg per 

day (2.5mmol/kg per day), delivered as sulfate. 

This dose is rarely adjusted unless the infant has 

persistent hypocalcemia secondary to hypomagnesemia, 

or the infant has abnormally high magnesium 

levels due to maternal treatment with magnesium 

sulfate. Serum magnesium levels before 

magnesium supplementation with a PN solution 

should be checked in any small infant whose 

mother was treated for hypertension or preeclampsia. 

Trace elements 

Nine trace elements (or trace minerals) are nutritionally 

essential for humans: iron, zinc, copper,

selenium, molybdenum, chromium, manganese 

and iodine. Although trace elements make up a 

small fraction of the total mineral content of the 

human body, they play an important role in 

numerous metabolic pathways. The infant born 

prematurely is at increased risk of developing trace 

mineral deficiencies. Premature birth is associated 

with low stores at birth, because accretion of trace 

minerals takes place during the last trimester of 

pregnancy. Rapid postnatal growth, unknown 

requirements, and variable intake of trace minerals 

also put the preterm infant at risk for deficiencies. 

79 

During the early years of PN, it was thought that 

frequent plasma and/or blood transfusions 

provided the necessary trace minerals. Reports of 

zinc and copper deficiencies, even in infants who 

had received these transfusions, demonstrated the 

inadequacy of this approach and led to the availability 

of zinc and copper additives. The exact 

requirements of premature infants for most of the 

microminerals remain poorly defined because of 

the paucity of randomized controlled trials assessing 

their efficacy and safety. Recent studies have 

better delineated the range of suggested micromineral 

delivery to this population and Table 37.4 

shows the recommended enteral and parenteral 

intake of trace elements for preterm infants for the 

transition period from the first 2 weeks of life to 

the following stable and post-discharge period. 81 

Table 37.4 Recommended micromineral intakes for preterm infants on 

total parenteral nutrition 81 

Transitional period Stable/post-discharge 

(0–14 days) periods (>14 days) 

(µg/kg per day) (µg/kg per day) 

Iron 0 100–200 

Zinc 150 400 

Copper 0, 20 * 20 * 

Selenium 0–1.3 1.5–4.5 

Chromium 0–0.05 0.05–0.3 

Molybdenum 0 0.25–1.0 † 

Manganese 0, 0.75 * 1.0 * 

Iodine 0–1.0 1.0 

* Should be withheld when hepatic cholestasis is present 

† For long-term total parenteral nutrition only 


Research concerning the parenteral requirements 

of these nutrients by infants is, of course, hindered 

by the difficulties in both measuring plasma 

concentrations of the nutrients using small 

volumes of plasma, and interpreting the physiological 

significance of plasma concentrations. 

Accurate studies on the retention of these nutrients 

are also notoriously difficult. 

Intravenous vitamins 

Table 37.5 shows the recommended parenteral 

intake of vitamins for preterm infants. These 

guidelines, suggested in the past years by different 

committees provide a theoretical recommendation 

to obtain the optimal intake which is, however, 

unachievable with current commercial preparations. 

The delivery of vitamins from parenteral 

solutions can be lower than intended. Fat-soluble 

vitamins may be adsorbed into the storage bag and 

delivering tubing and may alter when exposed to 

light, oxygen or heat. As much as 80% of available 

vitamin A and 30% of vitamins D and E are lost 

during administration due to adherence to tubing 

and photodegradation especially during phototherapy82 

. 

Therefore, significant destruction may occur 

within the newborn intensive care unit environment, 

where higher environmental temperatures 

and light levels are commonplace. Vitalipid ®

632 


Table 37.5 Recommended parenteral intake 

of vitamins for preterm infants (dose/kg per 

day) 81 

Consensus 

Vitamins recommendations 

Fat Soluble 

Vitamin A (IU) 700–1500 

with lung disease 1500–2800 

Vitamin D (IU) 40–160 

Vitamin E (IU) 3.5 (max = 7) 

Vitamin K (µg) 8–10 (300 at birth) 

Water soluble 

Vitamin B6 (µg) 150–200 

Vitamin B12 (µg) 0.3 

Vitamin C (mg) 15–25 

Biotin (µg) 5–8 

Folic acid (µg) 56 

Niacin (mg) 4–6.8 

Pantothenate (mg) 1–2 

Riboflavin (µg) 150–200 

Thiamin (µg) 200–350 

(Kabivitrum, Stockholm), a lipid preparation available 

in Europe, is an intravenous soybean oil 

emulsion that contains vitamins A, D, E and K, 

thus reducing adsorption into the plastic tubing. 

Further clinical studies are needed to assess the 

vitamin status of VLBW and ill infants who receive 

parenteral solutions for prolonged periods and to 

evaluate the effects of the peroxide load induced 

by photo-exposed intravenous multivitamin solutions. 

83 

Complications of parenteral nutrition 

The main complications of PN, as shown in Table 

37.6, can be metabolic, infective or catheterrelated. 

Several complications (e.g. electrolyte 

imbalance, hypoglycemia, hyperglycemia, hypo/ 

hypercalcemia, hypophosphatemia) can be 

corrected and prevented by manipulating the 

components of the solution. Other potentially 

more serious complications (e.g. cholestasis) are 

less easily corrected. 

Table 37.6 Possible complications of 


Metabolic complications 

Cholestasis 

Electrolyte imbalance 

Essential fatty acid deficiency 

Hyperammonemia 


Hypocalcemia/hypercalcemia 

Hypoglycemia/hyperglycemia 

Metabolic acidosis 

Metabolic bone disease 

Prerenal nitrogen 

Vitamin, mineral and trace elements deficiencies 


Bacterial 

Fungal 

Catheter-related complications 

Vascular perforation 

Embolism 

Improper insertion resulting in extravasation, pneumothorax, 

hemorrhage, pleural effusion or pericardial 

tamponade 

Local irritation, infiltration 

Thromboses 

Cholestasis 

Cholestasis is a well-known complication associated 

with PN. 84,85 The initial lesion seen histologically 

is intracellular and intracanicular cholestasis, 

followed by portal inflammation. With 

prolonged administration, portal fibrosis and ultimately 

cirrhosis may develop. Cholestasis induced 

by PN is associated, initially with the elevation of 

serum bile acids and γ-glutamyl-transpeptidase 

(GGTP) and then with direct hyperbilirubinemia 

and jaundice. Elevation of hepatic transaminases, 

SGOT and SGPT is a late finding. Premature 

infants receiving PN for prolonged periods are at 

high risk of developing cholestasis. 86 

Incidence of cholestasis represents about 50% in 

infants with a birth weight

een suggested that hepatic dysfunction may be 

caused by the overgrowth of the intestinal flora in 

static gut. Fasting is also linked to development of 

cholestasis. This complication is less frequent 

when enteral feeding, even hypocaloric, is started. 

Abnormal amino acid pattern and taurine deficiency 

in some amino acid mixtures used as part of 

PN have been considered as possible etiological 

factors, but currently used solutions contain 

amino acids (including taurine), designed to maintain 

normal infant serum amino acid profiles. 89 

Usually cholestasis resolves with discontinuation 

of PN but there are some reports of advanced liver 

disease in infants parenterally fed for several 

months. 

Several measures have been suggested to prevent 

cholestasis induced by total PN such as: use of 

minimal enteral feeding, early introduction of 

enteral feeds to stimulate bile flow, use of 

balanced parenteral solutions, and reducing lipid 

infusion. In newborns and young infants with 

total PN-associated cholestasis who require 

continued PN, limiting the protein intake to 2g/kg 

per day may help minimize amino acid-related 

hepatic toxicity. Ursodeoxycholic acid treatment 

seems to improve the course of PN-associated 

cholestasis not only in children and adults but 

also in premature infants, leading to an early 

sustained decrease in bilirubin levels after 2 

weeks of therapy. 90 

Infection 

Bacterial and/or fungal infection is another complication 

of PN. The most common isolated agents are 

Staphylococcus epidermidis, Staphylococcus aureus 

and Candida albicans. The incidence of sepsis as a 

Table 37.7 Precautions taken to minimize the risk of sepsis 

Complications of parenteral nutrition 633 

complication of PN increases as gestational age 

decreases and the duration of PN increases. Even 

if infection is often a catheter-related complication 

it seems that the composition of solutions 

may predispose to sepsis. Intravenous lipid have 

been associated with coagulase-negative staphylococcal 

bacteremia and Malessezia furfur 

fungemia. 91 Table 37.7 shows the main precautions 

that should be taken to minimize the risk of 

sepsis. 

Catheter-related complications 

Preparation of individual aliquots of parenteral nutrition solutions in the pharmacy 

Manipulations carried out in the ward to be avoided 

Central venous silastic catheters must be placed under strict aseptic conditions 

Skin exit side for catheter placed in area which can be meticulously cleansed 

Proper care of the site and all the connectors and essential tubings 

Addition of heparin (1 unit/ml) to the infusate for peripheral/central venous catheters 

The main complications associated with venous 

catheter are usually the result of: improper insertion 

or placement; bacterial or fungal colonization 

of the catheter; and vessel irritation and/or thrombosis. 

Peripheral Teflon ® catheters are prone to 

infiltration in a short time and to be colonized 

with bacteria at a rate of over 30% when they have 

been in place for more than 3 days. 

Central venous catheters have a lower incidence 

of infiltration and deliver higher concentrations of 

the solution, but can be associated with severe 

complications. Broviac ® catheters are associated 

with a higher incidence of infection (5–60%) 

and/or thrombosis in the neonatal period. At 

present, with the small silastic catheters introduced 

percutaneously, the incidence of sepsis 

and/or thrombosis is lower than with Broviac 

catheters. Thrombosis in these small-bore 

catheters can be minimized by adding heparin to 

the solution. In order to obtain a correct intravenous 

nutrition and avoid the high risks of 

complications, the patient must be closely monitored. 

Table 37.8 shows the main parameters that 

need to be checked.

634 


Table 37.8 Monitoring during parenteral nutrition 

Measurement of body weight daily and body length and head circumference weekly 

Initially, during grading up of parenteral nutrients or during periods of metabolic instability: 

strict fluid balance 

6–12 hourly urine/blood glucose 

daily plasma sodium, potassium, calcium, urea and acid–base 

When on full parenteral nutrition and during metabolic steady state: 

strict fluid balance 

12–24 hourly urine/blood glucose 

plasma sodium, potassium, calcium, urea and acid–base once/twice weekly 

Plasma magnesium, phosphorus, alkaline phosphatase, albumin, transaminases and bilirubin weekly 

Plasma triglycerides, amino acids, trace elements and ammonia not usually routinely monitored 

Screening for infection or coagulation defects as indicated 

Practical aspects of parenteral 

nutrition in VLBW infants 

Tailored or standard parenteral solutions 

Parenteral solutions can be prescribed using either 

of two formats: tailored or standard. 92 Tailored 

solutions are formulated specifically to meet the 

daily nutritional requirements of the individual 

patient, whereas standard solutions are designed 

to provide a formulation that meets most of the 

nutritional needs of the stable biochemical and 

metabolic parameters. Both of these methods have 

advantages and disadvantages associated with 

their use. 

Tailored solutions are based on the principle that 

no single parenteral regimen can be ideal for all 

patients, for a wide variety of pathological 

processes, all age groups, or for the same patient 

during a single disease. The main advantage of 

tailored solutions is flexibility. Each solution is 

formulated for an individual patient and can be 

modified when the patient’s nutritional needs and 

metabolic, electrolyte or clinical status changes. 

The disadvantage of these solutions is linked to the 

time involved in calculation and label preparation, 

which today is nevertheless diminished with the 

use of specific computer programs. These solutions 

should be prepared with strict aseptic tech- 

niques, possibly in the pharmacy, not in the ward, 

and stored in a refrigerator at 4°C. The solutions 

thus prepared are stable for 96h and should be 

allowed to reach room temperature slowly and not 

warmed before infusion. 

Standard solutions contain fixed amounts of each 

component per unit volume. In some hospitals 

there are several types of fixed solutions to cover 

the nutritional requirements of premature infants 

more adequately. The advantages of these solutions 

is that they include all the essential nutrients 

in fixed amounts, which eliminates the chances of 

inadvertent omission or overload. The major 

disadvantage of standard solutions is their lack of 

patient specificity and the need of minimal adjustment 

particularly during the first days of life. 92 

Nutrient intake 

Table 37.9 shows the composition of a ready-to-use 

parenteral solution for VLBW infants and Table 

37.10 the daily nutrient intake (kg/day) given by 

total PN according to the new practice of ‘aggressive 

nutrition’ proposed to minimize the interruption 

of nutrient intake induced by premature birth. 

In any case, nutrient intakes are always indicative 

and have to be modified according to each patient, 

his/her clinical picture, biochemical data and 

tolerance to nutrient intake. Thus, this standard 

solution could be diluted with free water accord-

ing to fluid requirement and natrium chloride 

could be adapted after a few days of life. 

The following suggestions could be useful in the 

management of a parenterally fed VLBW infant. 

(1) In the first days of life fluid intake should be 

increased if daily weight loss is >5%, total 

weight loss is >12–15%, serum sodium is 

Table 37.9 Composition of a ready-to-use 

binary parenteral solution (per 100 ml) 

adapted for very-low-birth-weight infants 

Glucose (g) 12.0 

Amino acid (g) 2.7 

Calcium (mg) 56 

Phosphorus (mg) 43 

Magnesium (mg) 4 

Sodium (mmol) 1.6 

Potassium (mmol) 1.5 

Chloride (mmol) 2.0 

Energy (kcal)* 55 

* Energy (kcal) = amino acids (g)x3.75+glucose x 3.75 

Practical aspects of parenteral nutrition in VLBW infants 635 

>150mmol/l, urinary osmolality is 

>350mOsm/l and if the infant is under 

phototherapy or managed in a radian incubator. 

In contrast, fluid intakes should be 

reduced if daily weight loss is

636 


energy intakes reach about 70kcal/kg per day 

and there is no enteral protein intake, the 

dose should be increased progressively to 

3.5–4.4g/kg per day. 

(4) Although many neonatal intensive care units 

start lipid infusion only after the first few 

days, it seems logical to start parenteral lipids 

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38 

Introduction 

Approach to gastrointestinal 

bleeding 

Samy Cadranel and Michèle Scaillon 

Gastrointestinal (GI) bleeding, an uncommon 

phenomenon in infants and children, is most often 

felt, by parents and caregivers, as very dramatic, 

needing emergency treatment, regardless of the 

importance of the bleeding. Adequate management 

of the situation – which can obviously be 

life-threatening – requires experience, common 

sense and good co-ordination from the nursing 

staff and physicians in charge. 

Epidemiology 

In the general population, bleeding from the upper 

GI tract occurs with a prevalence of 100 in 100000 

adults per year, whereas lower GI bleeding is five 

times less frequent. The vast majority of hospitalizations 

occur in patients with concurrent illness 

and advanced age. 1 The overall incidence seems 

lower in Europe, for instance 45 in 100000 as 

reported in a Dutch study. 2 In childhood, bleeding 

is less frequent but potentially serious, and the 

proportion of upper and lower intestinal bleeding 

appears to be roughly similar to that reported in 

the adult literature. 3 However, the etiology can be 

different, largely depending on the age of the child. 

There are no reliable quantitative data about the 

epidemiology of GI bleeding in ambulatory pediatric 

patients. 4 Children are usually in better 

condition, with the notable exception of the 

newborn period, the critically ill child in an intensive 

care unit (ICU) and children with portal 

hypertension and end-stage liver failure. 5 Many 

medications used in adults have not been standardized 

in children and the devices available for 

emergency endoscopic treatment may sometimes 

be too large for the child’s limited GI tract caliber. 

Despite important technical and training improvements 

in the management of acute bleeding in the 

adult patient, occurring during the past 30 years, 

the morbidity and mortality has remained unchanged, 

at around 6–7%. 6 

This finding is probably biased, reflecting only a 

considerable decrease of the less dramatic bleedings 

related to relapsing gastroduodenal ulcers due 

to the active eradication of Helicobacter pylori. 

During the same period, the systematic use of 

medications that control gastric acidity (such as 

anti-H2 blockers or protein pump inhibitors (PPIs)) 

has succeeded in considerably reducing acute 

bleeding episodes in ICU patients (adults and children 

alike). 7 

Presentations and definitions 

GI hemorrhage may present in different fashions. 

Acute GI bleeding is obvious GI blood loss, and is 

often associated with hemodynamic compromise. 

Gross GI bleeding that occurs intermittently is 

defined as acute-recurrent bleeding. Occult blood 

loss is a chronic source of GI blood loss usually 

detected by either a positive fecal occult blood test 

or iron deficiency anemia. 

Regurgitations or vomiting of large quantities of 

red or digested brownish ‘coffee ground’ blood by 

mouth is called ‘hematemesis’; the source of the 

bleeding is located between the esophagus and the 

ligament of Treitz. This is not always a sign of GI 

bleeding, since it may sometimes be confused with 

‘hemoptysia’ which is triggered by cough, or with 

a bleeding from a nasopharyngeal origin. The 

brownish aspect of regurgitations can also be due 

to other causes such as cola or coffee drinks, sometimes 

misinterpreted by the family as blood. 

639

640 

Approach to gastrointestinal bleeding 

‘Melena’ describes black, tarry, foul-smelling 

stool, and its presence usually indicates an upper 

intestinal source. Rarely, a proximal colonic 

bleeding may present as melena. Melena associated 

with hematemesis again implies a voluminous 

upper GI source. 

‘Hematochezia’ (red blood passed per rectum) 

usually indicates a lower GI source, although 

voluminous blood loss from any location may 

present in this manner. In the unstable patient, 

presumption of an upper GI source dictates 

management, regardless of the color of blood per 

rectum. 

Streaks of fresh blood on the feces or after defecation 

are not a sign of a severe hemorrhage but 

of a benign light bleeding often overestimated by 

the family. In the pediatric patient, ‘occult’ bleeding 

is usually discovered during a work-up of 

side-ropenic anemia together with clinical manifestations 

of chronic blood loss: fatigue, pallor or 

lightheadedness. 

Practical approach 

Extensive and comprehensive descriptions of all 

possible situations generating GI bleeding (some 

of them very rare in childhood) and of the different 

causes, diagnostic procedures and treatments 

have been published elsewhere and especially in 

classical textbooks. 8–11 The purpose of the 

present chapter is to focus on a practical approach 

to GI bleeding in children and we have 

arbitrarily organized it in seven gradual steps 

(Figure 38.1). 

Is it a life-threatening emergency due to the 

blood loss? 

The symptoms such as pallor, agitation, sweating, 

tachycardia or low blood pressure (this is a severe 

but late complication) are usually very clear and 

should be evaluated accurately in order to initiate 

adequate resuscitation measures. Treating or 

preventing hypovolemia is the first step in stabilization. 

A secure large-bore intravenous access – 

or a central line for the monitoring of central 

venous pressure – is mandatory, since shock can 

develop at any time if uncontrolled bleeding 

1. Vital emergency? 2. Ongoing emergency? 

No Yes 

No 

Emergency measures 

Intravenous access 

Hemodynamic stabilization 

Clotting factors 

Cross-matching 

Laboratory 

3. Is it digestive? 

4. Upper or lower? 

5. Etiology and underlying factors 

6. Investigations 

7. Management and prevention 

Figure 38.1 Practical approach to gastrointestinal 

bleeding in children. 

persists. Blood should be drawn for blood typing 

and cross-matching. At this stage, extra blood 

samples for hematocrit, hemoglobin, coagulation, 

and red and white blood cell and platelet counts 

are necessary. A low mean corpuscular volume 

(MCV) suggests a chronic blood loss and an 

elevated blood urea nitrogen (BUN) due to the 

absorption of intestinal blood points mainly to 

upper GI bleeding. 12,13 It is also advisable, whenever 

possible, to initiate investigations for etiological 

factors (such as liver function tests) by 

drawing extra blood samples. Management by 

fluid and/or colloid infusion can then be started. 

Once the stabilization has been obtained these 

children must be admitted to an ICU, ideally 

connected with a pediatric surgery department. 

Is the bleeding still ongoing? 

Relevant familial or personal surgical or medical 

histories should be taken as soon as possible. 

Every effort should be made to obtain a complete 

list of all medications administered to the child. 

This may prove difficult to obtain from upset

parents: it is strongly recommended to use a 

locally adapted checklist of drugs, which should 

be available and ready in the emergency room. 

Invasive monitoring is not always necessary and 

should be reserved for such situations where an 

ongoing bleeding is obvious or whenever history 

or physical examination suggests a potential for 

re-bleeding. Early insertion of a large-bore nasogastric 

tube is helpful for assessing possible 

continuing bleeding from the upper GI tract. We 

use a double-lumen tube (e.g. Salem sump TM , 

Sherwood Medical, St Louis, MO, USA), which 

enables decompression, aspiration and also 

lavage using saline as preparation for a diagnostic 

endoscopic procedure. Attempts to stop an 

ongoing bleeding with iced saline lavage, a classical 

technique 14,15 once considered as helpful is 

no longer recommended, since it is rarely useful 

and potentially harmful. 16–18 

Is it a gastrointestinal tract bleeding? 

Hemoptysis is rare in children and usually associated 

with respiratory symptoms. Blood swallowed 

during an unrecognized epistaxis can mimic GI 

bleeding and present as hematemesis but also as 

melena. Previous episodes of epistaxis should be 

recorded. A rapid examination of the nasal cavity 

can easily diagnose the source of the bleeding. 

Not all vomiting or stools stained in red are blood. 

Additives coloring food, drink mixes or medicines 

can be mistaken for blood. Tomatoes, beets, cherries 

and cranberries may look like blood when 

vomited or passed per rectum by a child with diarrhea. 

Bismuth, iron supplements, spinach and 

dark chocolate can give a dark coloration to stools, 

which may be mistaken for melena. The very dark 

feces of constipated children are usually easy to 

distinguish from melena. Diapers can acquire a 

pink discoloration if some time elapses prior to 

their disposal. 

The testing for occult blood is usually performed 

on a stool specimen by a Guaiac reaction. Guaiac 

is a colorless compound that turns blue in contact 

with substances with peroxidase activity (e.g. 

hemoglobin) and hydrogen peroxide. This test is 

easy, inexpensive and convenient, but the reaction 

is not specific for blood. Many substances with 

peroxidase activity may yield a false-positive 

Practical approach 641 

result. Ingested red meat, certain fruits and vegetables 

such as cantaloupes, radishes, bean sprouts, 

cauliflower, broccoli and grapes have enough 

peroxidase activity to cause a positive reaction. 

Oral iron preparations may also cause falsepositive 

reactions. 

In the newborn, suspected GI bleeding can be due 

to swallowed maternal blood and should be ruled 

out by the Apt test. The test is based on the denaturation, 

in an alkaline milieu, of adult hemoglobin 

to a yellow-brown solution of alkaline globin 

hematin whereas fetal hemoglobin, resists and is 

colored to a pink solution. 

Is it an upper or a lower gastrointestinal 

bleeding? 

Logically, hematemesis or melena indicates bleeding 

from the upper GI tract, while hematochezia 

indicates bleeding from a colonic source. However, 

this simple distinction can be confusing in the 

newborn and in infants. The transit time can be 

very quick and undigested red blood hematochezia 

(instead of digested melena) may be the only 

symptom of a hemorrhage occurring in the upper 

segment of the GI tract. 

Similarly, in some instances, melena is the only 

manifestation of colonic blood trapped during 

sufficient time to permit the degradation of hemoglobin 

by the intestinal flora. Small-intestinal 

bleeding manifests as either melena or hematochezia. 

Simultaneous mixed digested black and 

undigested fresh red blood suggests a Meckel’s 

diverticulum or a large upper GI bleeding. 

The nasogastric tube, used as a tool for monitoring 

the continuity of bleeding, can also be used as a 

first-step investigation to distinguish between an 

upper or a lower GI bleeding origin; blood-stained 

gastric fluid indicates an upper GI source. 

However, a clear or bilious stained fluid does not 

exclude a duodenal origin of the bleeding. 

Guaiac testing for occult bleeding from gastric 

aspirates is not reliable. Needless to say, a 

complete and oriented history taking can provide 

useful clues, such as recent medication with 

non-steroidal anti-inflammatory drugs (NSAIDs), 

previous ulcer, familial history of polyposis, or 

liver disease. Associated symptoms such as bloody

642 


mucous diarrhea suggest a colonic or terminal 

small-bowel source. 

A careful physical examination looking for signs of 

portal hypertension, splenic or liver enlargement, 

cutaneous stigma of Peutz–Jeghers polyposis or 

syndromes associated with vascular abnormalities 

is essential. A thorough examination of the oral 

and nasal cavity as well as the anal region can rule 

out simple diagnoses. 

What are the etiology and underlying factors? 

GI bleeding occurs at all ages with similar etiologies 

and mechanisms. However, the frequency and 

presentation varies according to age (Table 38.1) 

and underlying factors. 

Neonatal period 

Bleeding from coagulation abnormalities due to 

vitamin K deficiency is becoming rare since this 

condition is corrected by systematic vitamin K 

supplementation at birth. 19,20 

The most frequent cause of upper GI bleeding in 

the neonatal period is the poorly understood 

‘neonatal esophagogastritis’ which affects acutely 

distressed newborns. The course is most often 

benign and self-limited. The availability of miniaturized 

fiberscopes has enabled the recognition of 

this condition as a cause of GI bleeding in a series 

of 14 out of 32 newborns published in 1989. 21 The 

same group reviewed their series of endoscopies 

performed in the neonatal period; 158 out of 219 

newborns presented with esophagitis. 22 Other 

authors reported findings in 17 full-term newborns 

and attributed the lesions to a traumatic origin, 

because of the distribution of the lesions (more 

severe in the upper esophagus), of the early onset 

(almost at birth) and the very rapid healing. 23 

Finnish authors drew attention to the presence of 

gastric lesions, highly prevalent in preterm infants 

in the ICU 24 and claimed that mechanical ventilation 

has the main risk factor, but factors included 

also the mode of delivery and hypotension after 

birth, which increase the risk of stress-induced 

gastric lesions. 25 Other French groups insisted on 

the extension of the lesions involving the esopha- 

Table 38.1 Main sources of gastrointestinal (GI) bleeding according to age and frequency 

Newborn 1 month to 2 years 2–16 years 

Upper GI bleeding 

Maternal blood (Apt test) esophagitis esophagitis 

Coagulation factors gastritis gastritis 

Esophagitis acute ulcer acute ulcer 

Gastritis Mallory–Weiss syndrome Mallory–Weiss syndrome 

Duodenitis varices varices 

Vascular malformation vascular abnormalities vascular abnormalities 

GI duplications GI duplications 

Lower GI bleeding 

Maternal blood (Apt test) anal fissures anal fissures 

Coagulopathy infectious colitis infectious colitis 

NEC vascular anomalies vascular anomalies 

Other enterocolitides allergic colitis polyp(s) 

Volvulus Meckel’s diverticulum IBD 

vasculitis 


hemolytic uremic syndrome 

hemorrhoids 

IBD, inflammatory bowel disease

gus and the stomach, or the stomach and the 

duodenum, or the whole upper GI tract. 26 

A case–control study concluded that there was a 

possible protection by breast feeding. 27 A recent 

case–control multicenter study in France pointed 

out the possible role of antacid drugs used by 

mothers during the last month of pregnancy, and 

emphasized the possible protective role of early 

breast feeding against severe lesions. 28 

In the neonatal period, rectal bleeding (sometimes 

from an upper GI source) is infrequent and differs 

little from rectal bleeding in older infants. 

However, necrotizing enterocolitis occurs early, 

especially in the preterm infant and after the first 

oral feedings. 29 Besides bloody stools, symptomatology 

includes abdominal distension, decreased 

activity and feeding difficulties. Radiological signs 

such as pneumatosis intestinalis and air in the 

biliary system are pathognomonic. The condition 

is severe and may result in sepsis. 

Infancy 

In infants, esophagitis due to gastroesophageal 

reflux disease is the most frequent cause of upper 

GI bleeding. In addition, although infrequent, it is 

sometimes an early complication of hypertrophic 

pyloric stenosis. 30 Gastroduodenal ulcers are rare, 

since Helicobacter pylori infection, an etiological 

factor in peptic ulceration, is not a common 

finding in this age group, at least in industrialized 

regions. Furthermore, interferon (IFN)-γ secretion 

in the stomach of H. pylori-infected patients is 

lower in children than in adults, and this could 

protect children from development of severe 

gastroduodenal diseases such as ulcer disease. 31 

Rectal red blood mixed with mucus and loose 

stools suggests an infectious cause. Viral infection 

is seldom the cause of rectal bleeding. However, 

many known pathogenic bacteria such as 

Salmonella, Shigella, Campylobacter jejuni and 

some strains of Escherichia coli can cause acute 

rectal bleeding through invasive colonic lesions. 

The role of Clostridium difficile is more 

debated 32,33 whereas we have observed Yersinia 

enterocolitica-associated colonic lesions that 

closely resemble those observed in inflammatory 

bowel diseases (S. Cadranel, personal communication). 

34 Rectal bleeding can also occur through 


colonic parasitic infections with Entamoeba 

histolytica and Dientamoeba fragilis. In this age 

group, cow’s milk is the most frequent cause of 

food allergy producing occult or even frank blood 

loss. It occurs mostly in formula-fed infants, 

although the same allergy can be induced indirectly 

through breast milk. Resolution of the symptoms 

usually occurs shortly after recognition of 

this condition and further avoidance of dairy products 

by the breast-feeding mother or switching to a 

non-allergenic formula. 

In this age group, because of potential severe 

complications and sequelae, intussusception 

needs early recognition and adequate management. 

34 It occurs more frequently in male infants 

(3:1) aged 3–24 months presenting with acute 

paroxysmal abdominal pain alternating with 

symptom-free periods and, later on, passage of 

‘currant jelly’ stools. An association between 

antibiotic use and primary idiopathic intussusception 

has been reported recently. 35 

Hirschsprung’s related enterocolitis may affect 

undiagnosed constipated infants, but also patients 

of any age who had undergone complicated operations. 

36 

Childhood 

In older children upper GI bleeding suggests an 

acid-related disease such as peptic esophagitis or 

gastritis. 

The Mallory–Weiss tear is a mucosal laceration at 

the level of the cardia following vomiting with or 

without symptoms of epigastric pain. 37–39 The 

bleeding is usually self-limited. Retching can also 

cause mild-to-moderate bleeding through superficial 

ecchymotic traumatic lesions of the fundic 

mucosa. 

In industrialized regions, upper GI bleeding due to 

Helicobacter pylori-associated gastritis or ulcer is 

seldom observed in children younger than 5 

years. 40 Nevertheless, systematic antral and fundic 

biopsies are recommended for histological study 

and microbiological culture. 41 Esophagitis is the 

most frequent cause of acute upper GI bleeding in 

children with brain damage. The complaints of 

these neurologically impaired children are often 

unrecognized during long periods of time result-

644 


ing in chronic occult blood losses and esophageal 

stenosis. 42 

In children mentally retarded or with behavioral 

abnormalities, the possibility of ingesting foreign 

bodies as a source of upper GI bleeding should be 

considered. 

Portal hypertension and deficient coagulation 

factors complicating liver diseases are the most 

dramatic causes of upper GI bleeding. The 

adequate management of esophageal varices and 

preventive treatment of portal hypertension need 

close collaboration between a skilled pediatric 

gastroenterology staff and a well-equipped ICU. A 

common complication of portal hypertension is 

the typical gastropathy in which the gastric 

mucosa from portal hypertensive patients exhibits 

a typical vascular dilatation and congestion that 

seems more extensive after endoscopic sclerotherapy 

of varices. 43 

In pediatric ICUs the systematic prophylaxis with 

H2-receptor blockers and, more recently PPIs, has 

resulted in a dramatic decrease of peptic stress 

ulcers affecting mainly children with severe 

burns, with acute neurological diseases or undergoing 

major surgical procedures. Ventilator-associated 

pneumonia and upper airway colonization 

with Gram-negative bacilli does not seem to be 

aggravated by these drugs. 44 

The Dieulafoy’s lesion is an unusually large 

mucosal ulcer eroding a submucosal artery. This 

unusual lesion is observed in children who 

present with massive hematemesis (sometimes 

hematochezia) without the usually associated 

symptoms of ulcer. In most cases the lesion is 

found in the proximal stomach, but it can occur at 

any site of the GI tract. 45 

One of the most frequent causes of upper GI 

bleeding in young children used to be acetylsalicylic 

compounds. These can cause acute gastric 

erosions but also deep extensive ulcers. 46 Stenotic 

scarring may develop in the pyloric region as a 

result of the healing of such ‘kissing ulcers’. 

Recently, ibuprofen has become widely used in 

children in the USA and also in continental 

Europe as an analgesic and antipyretic drug. 47,48 

Its innocuousness is controversial and, along with 

all NSAIDs, should be avoided in children with 

portal hypertension. 49 

Other drugs potentially causing upper GI bleeding 

include anticoagulants and antimitotics used in 

oncological patients and inducing esophageal and 

gastric mucitis. 

Hematemesis was the main symptom reported in 

an epidemic of dengue hemorrhagic fever in children 

in India. 50 

Juvenile polyps are the most common cause of 

rectal bleeding in this age group and affect 3–4% 

of the population in Mexico. 51 Rectal bleeding 

from juvenile polyps is usually mild and selflimited, 

although the relapsing episodes can cause 

emotional trouble in the child and family. Polyps 

are to be found mainly in the rectum and 

sigmoid. 52 However, in our personal series, 20% of 

all juvenile polyps occurred in other parts of the 

colon, including the cecum. Retrieval of polyps 

for histological study is strongly recommended, 

especially in case of multiple polyps (10% in our 

series). 

Meckel’s diverticulum is a congenital anomaly 

occurring in 2% of the population. While it 

commonly remains clinically silent, it may also 

present at any age, typically with intermittent, 

painless frank hematochezia in children. In a 

series of 164 children undergoing laparotomy 

between 1970 and 1989, a Meckel’s diverticulum 

was discovered at laparotomy. There were 120 

boys and 44 girls with a mean age of 5.2 years 

(range 0–18 years). Forty-seven cases were asymptomatic, 

representing an incidental finding at 

laparotomy, 25 were resected and ectopic gastric 

mucosa was present in seven specimens (28%). Of 

the 117 symptomatic patients, 49 (42%) presented 

with bowel obstruction, 45 (38%) had rectal 

bleeding, 16 (14%) had diverticulitis and seven 

(6%) had umbilical pathology. 53 In another more 

recent review, no sex ratio differences were 

observed. 54 

Duplication cysts containing gastric mucosa that 

may ulcerate and bleed represent other causes of 

bleeding from the small intestine. Of special interest 

are antral duplications that cause hypergastrinemia, 

with consequent ulceration and bleeding. 

55 Other lesions as a source of bleeding from 

the small bowel include infectious enteritis, 

lymphonodular hyperplasia, 56 typhlitis, 57 Crohn’s 

disease and several vasculitides.

In Henoch–Schönlein purpura, gastrointestinal 

bleeding has been reported in 33% of cases. 58 

Hemolytic uremic syndrome is another vascular 

complication following several strains of Shigatoxin 

producing Escherichia coli. 59–61 Other 

causes of GI bleeding have been described, such 

as cytomegalovirus (CMV)-associated hematochezia 

in HIV-infected children 62 and also 

complications of graft-versus-host disease after 

bone marrow transplant 59–63 and post-chemotherapy 

neutro-penic enterocolitis in children with 

cancer. 64 Acute major gastrointestinal hemorrhage 

is uncommon in inflammatory bowel disease and 

most cases are due to Crohn’s disease without a 

predilection for site of involvement. 65 Although 

rare, bacterial overgrowth may present as a cause 

of lower GI bleeding. 66 

Vascular anomalies are a rare cause of bleeding in 

children. The symptoms vary according to the site 

and size of the bleeding lesion. Hemangiomas are 

proliferative lesions with a tendency to regress 

spontaneously, whereas vascular malformations 

are non-proliferative and do not regress. These rare 

causes of GI bleeding include Osler–Rendu–Weber 

disease and Klippel –Trenaunay, Turner’s and bluerubber 

bleb nevus syndromes. 

How should diagnostic investigations be used? 

The introduction in pediatrics of fiberoptic endoscopes, 

some 30 years ago, 67–69 has progressively 

but radically changed the investigation of GI 

bleeding. GI bleeding implies a mucosal lesion 

that will always be better detected by endoscopy 

than by any other ‘indirect visualization’ means. 

Biopsies for further study of microscopic lesions 

and, more recently, endoscopic treatment has 

become possible; endoscopy has logically become 

the first diagnostic step (see below). Consequently, 

contrast radiology is seldom – if ever – 

used in upper GI bleeding, since barium contrast, 

even with double contrast, is too insensitive to 

detect superficial mucosal lesions. 

Imaging 

Has the plain abdominal X-ray film become obsolete? 

The main advantage of this simple procedure 

is that it is available almost everywhere. Plain 

abdominal radiographs may provide useful infor- 


mation in children with upper GI or rectal bleeding 

when pain or vomiting is present, and can 

clearly show bowel obstruction or perforation. 

Echography, with Doppler ultrasound, is one of the 

best diagnostic tools for visualizing the vascular 

system and evaluating the blood flow when portal 

hypertension is suspected. It can provide valuable 

information about vascular abnormalities. 

Echography is also able to detect bowel wall thickening, 

intussusceptions or, on some occasions, 

intraluminal masses. However, it can seldom be 

used as the first step in the investigation and has 

probably no utility as a first approach to a massive 

hematemesis. 

Computed tomography (CT) and magnetic resonance 

imaging (MRI) can be helpful for the detection 

of mass lesions or vascular malformations. An 

important limitation to these investigations is the 

fact that they require adequate sedation, in order 

to avoid unwanted movements of the child. 

The most popular form of scintigraphy is the 

‘Meckel’s scan’ using technetium-99m pertechnetate, 

which accumulates in functional gastric 

mucosa such as Meckel’s diverticulum; but also in 

other ectopic gastric mucosa, for instance in duplication 

cysts. However, this test is far from being 

accurate in all instances and as many as 20% falsepositive 

and 20% false-negative results are 

observed. 70 

The ‘bleeding scan’ is another scintigraphic technique 

that can be used to identify a bleeding site 

that cannot be reached by endoscopy. Technetium- 

99m-labeled red blood cells from a sample of the 

patient’s blood are re-injected into the bloodstream. 

Bleeding rates of 0.1ml/min are detectable 

through gamma camera images of the abdomen 

every 5min for the first hour and then at regular 

intervals for as long as 24h if needed. A minimum 

bleeding of 500ml is necessary to obtain a positive 

scan in cases of lower GI hemorrhage. 71–73 

Angiography detects active bleeding lesions or 

chronic recurrent blood losses if the estimated rate 

of bleeding exceeds 0.5ml/min. The disadvantages 

of this technique, besides its invasiveness requiring 

general anesthesia, are frequent false-negative 

results. Its main advantages are the correct identification 

of the bleeding site – for further surgery – 

and the possibility of using the catheter for therapy

646 


either with selective infusion of vasopressin or 

embolization. 74,75 

Endoscopy 

The considerable progress achieved in the miniaturization 

of endoscopes and also in the field of 

sedation and anesthesia has substantially changed 

the role of endoscopy in the handling of GI bleeding 

in children. 

The availability of instruments that can be used at 

any age, ranging from the slimmest 6mm outer 

diameter ‘neonatoscopes’ to the standard 9mm 

gastroscopes, has enabled pediatric gastroenterology 

to deal more easily with the diagnosis of GI 

bleeding. Also, modern video-endoscopes facilitate 

teamwork and training. However, the use of therapeutic 

probes usually requires the 2.8mm operating 

channel diameter of the standard adult endoscope 

which is difficult to employ in children younger 

than 2 years, even under general anesthesia. 

Prompt upper endoscopy guarantees a more accurate 

result, since identification of the bleeding site 

can vary from 82% when endoscopy is performed 

within 24h to 48% if done over 72h of an upper GI 

bleeding. 8 

For bleeding of the lower GI tract, rigid endoscopes 

are seldom used and are replaced by the most 

‘user-friendly’ flexible instruments. Miniaturized 

colonoscopes of 10mm in outer diameter can be 

easily used in children older than 5 years, properly 

sedated, and under the control of a trained pediatric 

anesthesiologist. In younger children the 

various pediatric gastroscopes can be used, taking 

into account that they are not designed with the 

same characteristics of colonoscopes (more stiff 

and less handy). Colonoscopy is not always an 

easy procedure and a clean intestinal lumen is 

sometimes difficult to obtain. In non-emergency 

conditions, a plain abdominal X-ray film permits 

assessment of the degree of stool retention and 

starting with the necessary steps to void the colon 

from its fecal contents. We recommend, when 

possible, a strict diet without residues for 4–5 days 

prior to the colonoscopy and a semi-liquid diet on 

the last day. Many preparations combining enemas 

with large quantities of oral polyethyleneglycol 

(PEG) solution (sometimes administered through a 

nasogastric tube) have proved disappointing and 

poorly tolerated. We prefer, at least in children 

older than 6 years, an oral preparation consisting 

of the combination of sodium phosphate (acting as 

an osmotic laxative within 2h), and bisacodyl 

(acting within 6–8h) (Prepacol “ Delpharm, 

Bretigny-sur-Orge, France). 

Enteroscopy and wireless capsule video-endoscopy 

Modern video-endoscopes have a working length 

of 100cm, enabling, in experienced hands, a 

thorough and accurate investigation of the upper 

GI tract as far as the ligament of Treitz. From the 

opposite side, investigation of the entire colon and 

10–20cm of the terminal ileum is also possible. 

However, bleeding originating from the small 

bowel is not accessible to conventional endoscopic 

instruments. The development of a long ‘enteroscope’ 

with easy maneuverability in order to 

explore the entire small bowel seems a futuristic 

dream; on some occasions peroperative endoscopy 

with the surgeon directing the progress of the 

instrument can be helpful. 

The wireless capsule endoscopy is currently the 

outstanding technical innovation in diagnostic 

gastrointestinal endoscopy. 76,77 Especially for 

small-bowel diseases, this new technique offers 

several potential advantages compared to traditional 

diagnostic tools. Capsule endoscopy is a 

painless procedure that can be performed as an 

ambulatory endoscopic examination. The first 

experimental studies showed good tolerance of the 

capsule endoscopy and the possibility of a 

complete visual investigation of the small bowel. 

Clinical studies have demonstrated possible fields 

of application in obscure chronic or intermittent 

GI blood loss and inflammatory bowel disease, 

with better results than with classical pushenteroscopy 

or radiological imaging. 78–80 The 

major risk of the procedure – intestinal obstruction 

by the capsule – may hinder its use in the diagnosis 

of polyps or tumors in the small bowel. It will 

probably progressively replace the cumbersome 

and disappointing push-enteroscopy. The capsule 

is relatively large but can be swallowed by children 

older than 8 years. 81,82 

Management and prevention 

Most GI bleedings are self-limited and need only 

close observation; others require medications or

even aggressive and invasive endoscopic management. 

Many treatments and techniques are theoretically 

possible, extrapolated from adult studies 

to the pediatric patient. The regimen implemented 

for a child should be individualized, taking into 

account the supposed or confirmed origin and 

etiology of the bleeding, the underlying medical 

condition and the age. Guidelines for pediatric 

situations need controlled trials in order to provide 

an evidence-based approach; thus, they are currently 

based on local competence and equipment. 

A local protocol should be available in order to 

improve the quality and efficacy of the management. 

83 

The two main and serious origins of clear upper GI 

bleeding are peptic and variceal. 

Peptic lesions 

Medical treatment is based on acid suppression 

and is often started empirically because a peptic 

origin is frequent in pediatrics (40% of the moderate 

or severe hematemesis in the series reported by 

Mougenot and Balquet). 84 Currently, H2-receptor 

antagonists and PPIs are widely used, and ranitidine 

and omeprazole are the most extensively 

studied molecules in each class, respectively. They 

can be given either intravenously or orally. The 

multiple-unit pellet system enables dispersion in 

water and an easier use in small children unable to 

swallow tablets. In bleeding peptic ulcers, the 

pharmacotherapy is aimed at improving the environment 

of the bleeding point by keeping the 

gastric pH above the proteolytic range for pepsin 

and curing the initial lesion. This kind of treatment 

is also indicated for preventing stress ulcers. 

Ranitidine Serum concentrations of ranitidine 

necessary to inhibit gastric acid secretion by at 

least 90% ranged between 40 and 60ng/ml in children 

aged 3–16 years. 85 The pharmacokinetics of 

ranitidine in critically ill children is variable. In a 

study in mechanically ventilated, critically ill children 

weighing at least 10kg, the proposed doses of 

ranitidine, needed to reach a gastric pH of >4 for 

stress ulcer prophylaxis, depended on the regimen 

by bolus or continuous infusion. The recommended 

bolus regimen is 1.5mg/kg administered 

every 8h. In continuous infusion, the recommended 

intravenous loading dose is 0.45mg/kg, 

followed by a continuous infusion of 0.15mg/kg 


per hour. Thereafter, gastric pH should be monitored 

and the dose of ranitidine adjusted accordingly. 

86 Children with acute central nervous 

system injury or pediatric risk of mortality 

(PRISM) scores of >20 show a poor control of 

gastric pH. 87 In another study, no significant differences 

were observed, regarding the raising of 

gastric pH values above 4, between a bolus 

regimen with 1mg/kg in two doses 6h apart or a 

continuous infusion regimen of ranitidine bolus of 

0.15mg/kg followed by continuous infusion at 

0.15mg/kg per hour for 12h. Proposed doses are 

shown in Table 38.2. There was no correlation 

between illness severity scores and gastric pH 

values. 88 Smaller volumes can be perfused with 

bolus infusions, whereas continuous infusions of 

ranitidine often need a second line, since many 

drugs are incompatible with ranitidine; however, 

continuous infusion decreases the variability of 

gastric pH in children in an ICU. 87 Critically ill 

children with normal renal and hepatic function 

should be treated with a minimum 3mg/kg per day 

of intravenous ranitidine and the dose should be 

titrated to a gastric pH of ≥ 4. 89 

In full-term newborns, with a stable renal and 

hepatic function treated with extracorporeal 

membrane oxygenation, ranitidine administered 

as a single 2mg/kg dose over 10min is able, within 

90min after administration, to increase the intragastric 

pH to >5 and to maintain it at >4 for a 

minimum of 15h. 90 

In a study in 30 full-term newborns treated for 

bleeding erosions during the first 2 days of life, a 

rate of less than 0.2mg/kg per hour seemed to be 

advisable for continuous ranitidine infusion, 

whereas the 5mg/kg twice a day regimen could be 

considered adequate for oral therapy. 91 Preterm 

infants need significantly smaller doses of ranitidine 

to keep their intraluminal gastric pH over 4. 

The required optimal dose of ranitidine is 

0.5mg/kg body weight twice a day and that for fullterm 

infants 1.5mg/kg body weight three times a 

day. 92 In premature infants with bronchopulmonary 

dysplasia, infusion of 0.0625mg/kg per 

hour of ranitidine during dexamethasone administration 

is sufficient to increase and maintain the 

gastric pH above 4. 93 The doses of ranitidine 

should be adjusted in patients with severe renal 

failure even when undergoing regular hemodialysis. 

94,95 The bolus injections ought to be slow

648 


Table 38.2 Proposed doses of ranitidine for critically ill newborns, infants and children 

Children 

References Bolus IV Continuous infusion Orally 

Lugo (2001) 86 1.5mg/kg tid loading dose 0.45mg/kg, 

followed by 0.15mg/kg/ per h 

Adults Marchant (1988) 139 loading dose 50mg, 

followed by 0.15mg/kg per h 

or 0.25mg/kg per h (high risk) 

Infants 

Full-term Kuusela (1998) 92 1.5mg/kg tid 

Fontana (1993) 91 0.2mg/kg per h 5mg/kg bid 

Wells (1998) 90 2mg/kg bid 

Preterm Kuusela (1998) 92 0.5mg/kg bid 

IV, intravenous; tid, three times a day; bid, twice a day 

because of the risk of bradycardia. The tolerance 

effect of ranitidine could lead, as reported in adults, 

to a rapid loss of antisecretory activity on days 2 and 

3. 96 

Oral doses reported in the literature vary from to 

6–10mg/kg per day, twice or three times a day 

during 8 weeks to cure esophagitis to 2.5–10mg/kg 

per day during 4–8 weeks for ulcers. 

Omeprazole The oral dose range of omeprazole for 

management of gastroesophageal reflux disease and 

acid-related diseases is 0.3–3.5mg/kg with a 

maximum of 80mg/day). Orally, 1mg/kg per day 

every 12 or 24h or simply tablets of 10mg under 

and 20mg above 20kg of weight are most often 

prescribed. 

In children aged 3 months to 19 years, the pharmacokinetics 

of intravenous doses from 36.9 to 

139mg/1.73m 2 were: systemic clearance of 0.23l/kg 

per hour; volume of distribution of 0.45l/kg; elimination 

half-life of 0.86h with a high individual variability. 

97 

In adults, after an initial bolus of 80mg of omeprazole, 

the infusion rate of 8mg/h is significantly 

superior to 40mg/6h. 96–98 

In nine adult patients with duodenal ulcers, a daily 

intravenous dose of 40mg omeprazole was not sufficient 

to keep the intragastric pH above 4 in all 

patients during the first day of treatment. After 5 

days, 1 single daily low dose of 10mg intravenously 

and 20mg orally were effective and dependable in 

reducing 24-h intragastric acidity. 99 In adults, the 

best regimen to raise the intragastric pH above 

levels alleged to allow hemostasis in patients with 

peptic ulcer bleeding (and subsequent healing of 

the ulcer) seems to be an initial bolus of omeprazole 

followed by a continuous infusion for 72h and then 

switching to a single oral dose. 100 

Prevention of stress ulcers or re-bleeding An evidence-based 

medicine review of published trials 

yields sufficient evidence to support the use of 

prophylactic acid suppression in critically ill 

patients with coagulopathies or in those who are 

receiving prolonged mechanical ventilation. Not 

enough data have accumulated to prove the superiority 

of intravenous PPIs to intravenous H2-receptor 

antagonists for the prophylaxis of clinically important 

stress ulcer bleeding. With respect to acute GI 

bleeding, intravenous PPI is significantly more 

effective than an intravenous H2-receptor antagonist 

in reducing the rate of re-bleeding after hemostasis 

in patients with bleeding peptic ulcer. 101 In adult 

patients, a recent placebo-controlled trial of highdose 

parenteral omeprazole after an initial endoscopic 

treatment of bleeding peptic ulcers demonstrated 

a substantial reduction in the risk of 

re-bleeding 102 and a meta-analysis showed a significant 

beneficial effect of acid-decreasing agents in 

lowering re-bleeding and surgery rates, but demonstrated 

no effect upon mortality. 103

Portal hypertension 

Esophageal variceal bleeding is one of the severe 

consequences of portal hypertension. However, 

the bleeding site may sometimes be otherwise than 

the cardiac regions, for instance at the level of a 

portoenterostomy anastomosis, in the rectal 

mucosa or in the gastric cavity as a consequence of 

a hypertensive gastropathy. The management 

becomes even more difficult, because of coagulation 

abnormalities, infection and cirrhotic 

encephalopathy needing their own specific treatments. 

Endotracheal intubation should be considered 

especially to protect against blood flow 

during hemesis. 

Variceal bleeding is the most common cause of 

severe GI bleeding in childhood. Biliary atresia 

and portal venous obstruction are the most 

common causes. Hemorrhages due to portal hypertension 

from pre-hepatic obstruction carry a better 

prognosis but are more precocious than those from 

an intrahepatic origin, as observed in cirrhosis or 

liver fibrosis. Varices in patients with biliary 

atresia are at high risk of bleeding and need careful 

preventive monitoring. 

A recent extensive literature search identified 13 

randomized control trials with a clear indication of 

the number of adult patients with ongoing bleeding 

and their clinical outcomes. Treatment of 

esophageal varices with band ligation appeared to 

be the most effective approach (91%), significantly 

(p

650 


together with endoscopic variceal band ligation or 

sclerotherapy; all children surviving variceal 

hemorrhage should undergo secondary prophylaxis 

with band ligation. 116 

A randomized controlled trial in cirrhotic adults 

has shown that a bolus injection of somatostatin 

caused an immediate and marked decrease of the 

hepatic venous pressure gradient and azygos blood 

flow. The decrease seemed more pronounced 

compared to the effect of octreotide, probably 

owing to a nitric oxide-induced mechanism. 117 

Continuous somatostatin infusions of 500–250µg 

per hour have no systemic effects, but a more 

pronounced effect on splanchnic hemodynamics 

than the recommended 250µg/h. 118 In patients 

with active bleeding at endoscopy, the 500µg/h 

infusion dose achieved a higher rate of control of 

bleeding (82 vs. 60%, p

Sclerotherapy is used in extrahepatic as well as in 

intrahepatic liver diseases with a reported efficacy 

of 90%. 129–131 Secondary esophageal strictures 

occur in 5–20%, whereas deep ulcerations and 

perforations are rare. We recommend a semi-liquid 

diet during 2 days following sclerotherapy or band 

ligation. Coughing and vomiting should also be 

prevented. 

Elastic band ligation of varices is currently used in 

most pediatric gastroenterology centers with 

success. It is a quick procedure requiring greater 

endoscopic skill because of the relatively large 

device used to release the elastic band. 132–134 

Recent devices allow multiple elastic ligations, 

although it seems difficult (and probably dangerous) 

to ligate more than two or three varices at the 

same time. Only large varices deserve band ligation 

and the complete cure of esophageal varices 

combines initial band ligation with subsequent 

sclerotherapy. 135,136 

Endoscopic treatment of the lower GI tract is 

primarily polypectomy. On rare occasions other 

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treatment of severe gastrointestinal bleeding in children. 


115. Tauber MT, Harris AG, Rochiccioli P. Clinical use of the 

long acting somatostatin analogue octreotide in pediatrics. 

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116. McKiernan PJ. Treatment of variceal bleeding. 

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712–718. 

120. Lui HF, Stanley AJ, Forrest EH et al. Primary prophylaxis 

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39 

Introduction 

Approach to the child with 

acute diarrhea 

Hania Szajewska and Jacek Z Mrukowicz 

In this chapter we present a pragmatic, evidencebased 

approach to the child with acute diarrhea, 

which is a result of an extensive review of several 

diagnostic and treatment options that have been 

studied in children. We searched MEDLINE for 

relevant, good-quality observational studies on 

etiology, epidemiology, risk factors, clinical presentation, 

complications and diagnostic work-up. 

To evaluate treatments for acute diarrhea, we 

focused on data from meta-analyses, systematic 

reviews and randomized controlled clinical trials 

in MEDLINE, the Cochrane Library and the 

Cochrane Central Register of Controlled Trials. 

Finally, we searched MEDLINE for published 

evidence-based clinical practice guidelines developed 

by respected scientific societies or expert 

groups. We included conclusions from these documents 

in our chapter, because they contain recommendations 

based usually on a process of balancing 

benefit and harm of available approaches and 

interventions, and are commonly used to improve 

the quality of health care in many countries. In all 

cases the last search date was May 2003. 

Background 

Management of a child presenting with diarrhea is 

a logical chain of clinical decisions guided by 

answers to the following main questions. 

(1) Does the patient have acute diarrhea? 

(2) What is the presumed etiology of diarrhea 

(infectious vs. non-infectious)? 

(3) Should the patient be treated in an ambulatory 

setting or in the hospital? 

(4) Are stool cultures or any other laboratory 

tests required? 

(5) How should the patient be rehydrated: orally 

or intravenously? 

(6) How should the patient be managed nutritionally? 

(7) Should the patient receive any antimicrobial 

drug, and – if yes – which one is the most 

suitable? 

(8) Should the patient be treated with any other 

drug or preparation (antidiarrheal, antimotility, 

antiemetic)? 

(9) Are there any complications or specific clinical 

situations that require modification of the 

recommended approach? 

Below, we provide readers with the information 

required to answer those questions and make the 

best decisions for each patient. 

Definitions 

In published clinical practice guidelines and 

consensus documents, diarrhea is defined as a 

change in bowel movement for the individual 

child, characterized by an increase in the water 

content, volume and – usually – frequency of 

stools. 1,2 This definition also applies to exclusively 

breast-fed infants, in whom patterns of bowel 

habits vary widely from several soft or loose stools 

per day in one group of infants to one or two soft 

stools every 4–5 days in the other. For practical 

purposes and epidemiological investigations, diagnostic 

criteria in children – except for exclusively 

breast-fed infants – include a decrease in consistency 

(loose or liquid) and increase in frequency of 

bowel movements to ≥ 3 per 24h. 1,3 Since the 

increased water content in stools is the most 

important criterion (frequent passage of formed 

stools is not diarrhea), some authors advise to 

diagnose diarrhea when the volume of loose stools 

655

656 

Approach to the child with acute diarrhea 

exceeds 10g/kg of body weight per 24h in children 

and 200g/24h in adolescents and adults. 2 Although 

this definition is more precise and may be 

used in a research setting, it is impractical and 

difficult to incorporate into daily medical practice. 

Depending on the duration of the diarrhea, the 

illness may be considered acute, persistent, or 

chronic. Acute diarrhea is an episode of less than 

14 days in duration (usually a few days). Diarrhea 

lasting longer than 14 days is called persistent 

diarrhea, and longer than 30 days – chronic. 3 This 

categorization is somewhat arbitrary, but longer 

duration of diarrhea (>14 days) significantly 

increases the probability that symptoms are 

caused by some specific pathogens (see below) or 

the etiology of the disease is non-infectious, and 

the risk of a poor outcome is greater. Therefore, a 

more detailed diagnostic work-up towards a different 

etiology and modification of management are 

required. Persistent diarrhea, often of presumed 

infectious etiology, complicated by malnutrition 

and a high risk of serious non-intestinal infections, 

is a significant problem in developing countries. 1 

In this chapter we will discuss exclusively the 

management of acute diarrhea in immunocompetent 

children. 

Prevalence, incidence and disease burden 

Acute diarrhea is one of the most common 

diseases in children, and the second leading cause 

of morbidity and mortality worldwide. Every child 

encounters at least one diarrheal episode. 3–6 The 

attack rate in developed countries ranges from 1.2 

to 1.9 illnesses per person annually in the general 

population, and is higher in the first 2–3 years of 

life (2.5 illnesses per child per year to even five in 

those attending day-care centers). 3 The incidence 

is greater in developing countries, and in some 

tropical areas may reach even 6–10 episodes per 

child annually in children aged

Table 39.1 Etiological agents of acute infectious diarrhea in immunocompetent children 

Bacterial 

Viruses* Bacteria* enterotoxins* † Parasites* 

Inflammatory diarrhea, characterized by gross 

(dysentery) or occult blood and/or an increased 

number of leukocytes (or increased level of their 

marker lactoferrin) in the stool, is the result of 

intestinal wall invasion by Salmonella, Shigella, 

Campylobacter, Yersinia enterocolitica, hemorrhagic 

E. coli (O157:H7), enteroinvasive E. coli 

(EIEC) or Clostridium difficile. 1,3 This classification 

is helpful in planning selective microbiological 

testing and selecting patients who may benefit 

from empirical antibacterial therapy. 3,25 For a more 

comprehensive and specific discussion of infectious 

diarrheas, see Chapters 9–12. 

Complications 

Introduction 657 

Group A rotavirus ‡ Salmonella spp. †‡ Staphylococcus aureus Cryptosporidium 

(toxins A, B, C, D, E) parvum 

Caliciviruses and Campylobacter jejuni, ‡ Clostridium perfringens Giardia lamblia 

Norwalk virus Campylobacter coli (toxins A, C) 

Astrovirus Shigella spp. Bacillus cereus (heat-labile Blastocystis hominis 

and heat-stabile toxin) 

Adenovirus (type 40/41) Escherichia coli: EPEC, ‡‡ EHEC, Entamoeba 

EIEC, ETEC, ‡‡ EAggEC, DAEC histolytica ‡‡ 

Group B rotavirus** Yersinia enterocolitica, Yersinia Balantidium coli 

Group C rotavirus** pseudotuberculosis 

Picobirnavirus** Clostridium difficile Isospora belli** 

Others (coronavirus, Vibrio cholerae ‡‡ Cyclospora spp.** 

norovirus, parvovirus, 

torovirus, Breda virus) †† 

Listeria monocytogenes † ** 

Vibrio parahaemolyticus** 

Plesiomonas shigelloides** 

Aeromonas hydrophila** 

EPEC, enteropathogenic E. coli, EHEC, enterohemorrhagic E. coli (also known as Shiga-toxin-producing E. coli); 

EIEC, enteroinvasive E. coli; ETEC, enterotoxigenic E. coli; EaggEC, enteroaggregative E. coli; DAEC, diffusely 

adherent E. coli 

*In order of decreasing prevalence in the particular category in developed countries; † implicated in food-borne 

illness; ‡ common in developed countries; ** rare cause; †† unknown role in children; ‡‡ found in developing 

countries and endemic regions 

The main complications of acute diarrhea are 

dehydration (leading to hypovolemic shock in 

severe cases) and – especially in developing countries 

– malnutrition (particularly in persistent diarrhea). 

1 The mainstay of management is therefore 

adequate rehydration and early resumed, appropriate 

feeding. 1,26–28 In more severe cases, especially 

in malnourished children and when clear 

fluids, broth or cow’s milk were used instead of 

oral rehydration solution for initial treatment of 

dehydration, electrolyte abnormalities (hyper- or

658 


hyponatremia, hypokalemia) may be present. 28–30 

Hyponatremia is especially common in children 

with shigellosis and in severly malnourished children 

with edema. 1 In developed countries, as 

shown in the UK, electrolyte derangement is rare, 

with 1% of admissions having hypernatremia and 

no reports of hypokalemia or hyponatremia. 28 

Awareness of typical signs of hypernatremia, 

including doughy, velvety skin, dry and beefy red 

mucous membranes, muscular signs such as 

twitching and hyper-reflexia and central nervous 

system symptoms such as lethargy, confusion, irritability, 

rigidity, generalized convulsions and 

coma, is of particular importance, although there 

are no published studies on the reliability of these 

signs in diagnosing hypernatremia. In most moderate-to-severe 

cases of diarrhea there is some degree 

of metabolic acidosis. In malnourished children 

hypoglycemia may be a serious complication 

contributing to increased case fatality. 31,32 Persistent 

diarrhea is a serious complication in young 

children in developing countries, since it results in 

severe malnutrition and increased risk of 

death. 31,33,34 Pathogens such as EPEC, EAggEC, 

Shigella, Cryptosporidium and Giardia are significantly 

correlated with persistent infectious diarrhea. 

35,36 Some bacterial causes of diarrhea result 

in other serious long-term sequelae: EHEC (or 

Shiga-toxin-producing E. coli; STEC) infection 

may be followed by hemolytic uremic syndrome 37 

and C. jejuni infection by Guillain–Barré syndrome. 

38 

Diagnosis 


Rapid onset of liquid stools with or without 

accompanying symptoms or signs such as nausea, 

vomiting, fever and abdominal pain comprise the 

clinical picture of acute diarrhea. As mentioned 

previously, for practical reasons, clinical 

syndromes of non-inflammatory and inflammatory 

diarrhea may be distinguished. 1,3,25 Watery diarrhea, 

sometimes with more prominent vomiting, 

and no blood or signs of an inflammatory response 

in the stool (leukocytes or lactoferrin) are features 

of the first diarrheal syndrome, whereas gross 

blood (dysentery) and an increased number of 

stool leukocytes and/or presence of lactoferrin, 

usually accompanied by fever and prominent, 

cramping abdominal pain and/or tenesmus, are 

characteristic of the second syndrome. The presence 

of gross blood or an inflammatory response in 

the stool significantly increases the chance for 

isolation of invasive enteric bacteria. 39–41 


If there are no signs and/or symptoms suggesting 

an alternative diagnosis (Table 39.2), an episode of 

acute diarrhea is considered presumably to be 

infectious. If symptoms and signs persist beyond 

10–14 days, the diagnosis should be revised, and a 

more detailed work-up is indicated focusing on 

complications and chronic conditions. 

Table 39.2 List of conditions that should be 

considered in the differential diagnosis of 

acute diarrhea in children 

Acute appendicitis 


Hypertrophic pyloric stenosis 

Malrotation 

Hirschsprung’s disease (enterocolitis variant) 

Ileus 



Food allergy or intolerance 

Malaria 

Measles (particularly in malnourished children) 

Sepsis 

Jejunal and ileal diverticula 

Diabetic ketoacidosis 

Staphylococcal toxic shock syndrome 

Celiac disease and other malabsorption syndromes 


Pneumonia 

Meningitis 

Urinary tract infection (pyelonephritis) 

Acute otitis media, mastoiditis 

Drugs (laxatives, antibiotics, potassium salts, 

antineoplastic agents) 

Congenital adrenal hyperplasia 

Münchausen and Münchausen per 

proxy syndromes 

Radiotherapy 

Lead intoxication 

Mushroom poisoning (Amanita)

Estimation of dehydration 

Assessment of dehydration is an essential step in 

evaluation of a child presenting with diarrhea, 

since the degree of dehydration is the criterion for 

deciding upon the route of rehydration (oral or 

intravenous), thus determining also the need for 

hospital admission. The gold standard is to 

compare the current body weight of a patient with 

a recent measurement before the onset of the 

disease. Dehydration is usually quantified from 

the percentage of total body weight loss, and 

categorized as mild (10%). Unfortunately, this method is not 

always possible in practice, especially in infants 

and young children who grow relatively fast. 

Therefore, the World Health Organization (WHO) 

has proposed a set of clinical symptoms and signs, 

which helps to approximate the degree of dehydration 

(volume of fluid loss; Table 39.3) 1 and to 

decide about an appropriate treatment plan (see 

below). In one prospective cohort study performed 

in a developing country, prolonged ‘skinfold’ (skin 

pinch going back slowly), altered neurological 

status, sunken eyes and dry oral mucosa were 

found to correlate best with the percentage of 

dehydration in infants. 42 A study in American 

children reported the capillary refill time to be 

closely correlated with the degree of dehydration, 

43 although this was not confirmed subsequently 

by others. 42,44,45 In another small prospective 

study performed in hospitalized American 

children conventional laboratory blood tests were 

found to be poorly predictive of fluid deficits. 46 

Laboratory testing 

Microbiological testing 

The majority of episodes of acute infectious diarrhea 

in children are mild and resolve spontaneously 

without any specific antimicrobial treatment, 

hence no in-depth diagnostic testing is 

usually required for managing an individual case. 

Antimicrobials are beneficial only in a small, 

selected proportion of cases (see below), and 

empirical antibiotic treatment should generally be 

avoided in acute diarrhea. 3 Routine stool cultures 

in acute diarrhea have a very low yield (1.5–5.6%) 

and relatively high cost. 3 On the other hand, 

Table 39.3 Assessment for dehydration in a patient with diarrhea (from reference 1) 

Degree of Mouth and Total body Estimated fluid 

dehydration Condition Eyes Tears tongue Thirst Skin pinch weight loss (%) deficit (ml/kg) 

Laboratory testing 659 

None or mild well, alert normal present moist drinks goes back 100 

unconscious; sunken or not able slowly * 

floppy* and dry to drink* 

*‘Major’ signs; to classify a patient into a particular category, at least two signs must be present, including one ‘major’

660 


organism-specific diagnosis may have great public 

health importance, allowing for outbreak detection 

and control, and prevention of spread of infection 

in the community. Selective testing is therefore 

recommended, since it improves the yield and 

cost-effectiveness of stool cultures. 3 

In cases of bloody (dysenteric) or inflammatory 

(see below) community-acquired or traveler’s diarrhea 

(especially if accompanied by fever) testing 

for Salmonella, Shigella, Campylobacter, E. coli 

0157:H7 (and other STEC) and Clostridium difficile 

toxin A and B is recommended, the latter particularly 

if the diarrhea is severe and the child was 

treated with antibiotics during the few preceding 

weeks. History suggesting food-borne disease 

should also prompt appropriate stool cultures. 3 

In children most cases of nosocomial diarrhea are 

of viral (mainly rotaviral) or non-bacterial etiology. 

47–49 In older children with nosocomial diarrhea, 

Clostridium difficile may be more prevalent 

than in infants and toddlers. 50 Therefore, older 

children with nosocomial diarrhea (i.e. with onset 

after 3 days in hospital), especially when disease is 

severe, should be tested for Clostridium difficile 

toxins. Routine stool cultures for standard bacterial 

pathogens are discouraged for episodes occurring 

after the third day in hospital, since the yield 

is very low, except for epidemics of bloody diarrhea 

or suspected food-borne disease. 3,51 

In diarrhea that persists for longer than 10–14 

days, especially in an immunocompromised 

patient, testing for Giardia, Cryptosporidium, 

Cyclospora and Isospora belli should be considered. 

3 In almost all cases of pediatric diarrheal 

diseases a single stool test is diagnostic, regardless 

of the type of pathogen isolated. 3,52 

Fecal screening tests 

Initial screening for inflammatory diarrhea may be 

helpful in identifying patients requiring stool 

cultures or tests. One systematic review evaluated 

several methods for the identification of patients 

with inflammatory bacterial diarrhea: Wright’s or 

methylene blue stain of fresh stool for fecal leukocytes, 

a test for fecal occult blood, an immunoassay 

for fecal lactoferrin (a neutrophil marker) 

and a stain for fecal leukocytes combined with 

clinical data. It was concluded that fecal lactoferrin 

appeared to be the most accurate and useful 

diagnostic test for initial screening for inflammatory 

diarrhea. 53 Five subsequent studies confirmed 

the utility of lactoferrin testing to determine 

patients infected with invasive enteric 

pathogens. 54–58 Disadvantages of lactoferrin testing 

include its additional cost and false-positive 

results in breast-fed infants. 3 Lactoferrin is often 

negative, despite blood in stool, in STEC infection 

and Entamoeba histolytica colitis. 3 

Electrolyte measurement 

Serum electrolyte measurements are generally 

unnecessary, as most episodes of dehydration 

caused by diarrhea are isonatremic (see above). 

The American Academy of Pediatrics recommends 

that electrolyte levels should be measured in 

moderately dehydrated children whose histories 

are inconsistent with straightforward diarrheal 

episodes and in all severely dehydrated children. 

Furthermore, electrolytes should be measured in 

children with features of hypernatremic dehydration 

that can result from ingestion of hypertonic 

liquids or the loss of hypotonic fluids in the stool 

or urine. 27 

Management 

The main objectives in the therapeutic approach to 

a child with acute diarrhea are: to prevent or treat 

dehydration; to promote weight gain following 

rehydration; and to reduce the duration of diarrhea 

and quantity of stool output. 

Rehydration 

Oral versus intravenous rehydration in mild to 

moderate dehydration 

One systematic review of six randomized controlled 

trials of unequal methodological quality in 

371 children in developed countries with acute 

gastroenteritis, mostly with mild-to-moderate 

dehydration, found no significant difference 

between oral versus intravenous fluids in duration 

of diarrhea, duration of hospitalization, or weight 

gain at discharge. 59 Furthermore, patients treated

with oral rehydration therapy were not found to be 

at higher risk of iatrogenic hypernatremia or 

hyponatremia. Failure of oral treatment defined as 

the need for intravenous treatment was reported in 

3.6% of patients. Similar findings were reported in 

two additional randomized controlled trials not 

included in the systematic review. 60,61 In view of 

the evidence from these clinical trials, oral rehydration 

therapy is generally recommended to 

replace fluid and electrolyte losses caused by diarrhea 

in infants and children with mild-to-moderate 

dehydration. 1,27,28,62 

Oral versus intravenous rehydration in severe 

dehydration 

One randomized controlled trial in 470 children 

with severe acute gastroenteritis aged 1–18 months 

found that oral rehydration compared with intravenous 

therapy reduced the duration of diarrhea 

and increased weight gain at discharge, and was 

associated with fewer adverse effects. 63 Failure of 

oral treatment occurred in 0.4%. No significant 

differences in the death rate were found. Although 

oral rehydration may be used even in severe dehydration, 

intravenous therapy is generally recommended 

if the patient is more than 10% dehydrated, 

as well as in case of shock, failure of oral 

rehydration therapy, if the patient is unconscious 

or ileus is present. 27,28,62 

Nasogastric tube versus intravenous fluids 

One randomized controlled trial comparing nasogastric 

and intravenous methods of rehydration in 

young children with acute dehydration due to 

vomiting and/or diarrhea found that rehydration 

through a nasogastric tube was equally efficacious 

as intravenous rehydration, and was associated 

with fewer complications and was cost-effective. 64 

The nasogastric route of rehydration may be suitable, 

particularly outside facility-based treatment 

centers when intravenous fluids are difficult to 

administer. 

Scientific background for using oral rehydration 

solutions 

Oral rehydration therapy, hailed as potentially the 

most important medical discovery of the 20th 

century, 65 is the mainstay of treatment of acute 


diarrhea in patients of all ages provided they are 

able to drink and that the dehydration is not 

severe. 1,27,62,66 The effectiveness of oral rehydration 

solutions depends on co-transport of sodium 

ions and glucose (or other organic solutes) across 

the brush-border membranes of enterocytes, 67 

which results in passive absorption of water and 

other electrolytes. It is now well established that 

this glucose–sodium co-transport system remains 

largely intact during nearly all kinds of acute infectious 

gastroenteritis, irrespective of their cause. 

The integrity of this mechanism during any diarrheal 

disease makes oral rehydration therapy 

appropriate for treatment of diarrhea associated 

with dehydration. Today, a number of different 

oral rehydration solutions (ORSs) are available. 

The major differences in these solutions are 

related to sodium concentration and the source 

of carbohydrates that affects osmolality (Table 

39.4). 68 

Despite the proven efficacy of oral rehydration 

therapy, it remains underused. 68,69 The main 

reason for this is that an ORS neither reduces the 

frequency of bowel movements and fluid loss nor 

shortens the duration of illness, which decreases 

its acceptance. Parents, but also health-care professionals, 

demand safe, effective and inexpensive 

agents as an additional treatment that will visibly 

reduce the rate of stool loss and the duration of 

diarrhea. Such a product could, perhaps, be 

helpful in efforts to reduce the common practice of 

treating diarrhea with ineffective antidiarrheal 

Table 39.4 Composition of World Health 

Organization (WHO) and European Society 

for Paediatric Gastroenterology, Hepatology 

and Nutrition (ESPGHAN) oral rehydration 

solutions 

WHO ESPGHAN 

Sodium (mmol/l) 90 60 

Potassium (mmol/l) 20 20 

Chloride (mmol/l) 80 60 

Base (mmol/l) 30 (bicarbonate) 10 (citrate) 

Glucose (mmol/l) 111 74–111 

Osmolality (mOsm/l) 331 225–260

662 


drugs or unnecessary antibiotics. In the following 

section we briefly summarize the results of clinical 

trials of improved oral rehydration solutions. 

Reduced-osmolarity oral rehydration solutions 

There is a significant body of literature indicating 

that osmolality is a major factor in determining 

ORS efficacy. 70 The reduction of the osmolarity of 

the ORS may be achieved either by reducing the 

concentration of sodium and glucose or by replacing 

glucose with a complex carbohydrate. 

The optimum sodium concentration of an ideal 

ORS that would preserve and/or correct the electrolyte 

balance in a child with acute diarrhea 

without carrying the risk of inducing hypo- or 

hypernatremia is controversial. For many years, 

WHO has recommended the standard formulation 

of a glucose-based ORS with 90mmol/l of sodium 

and 111mmol/l of glucose and a total osmolarity 

of 311mmol/l. This original WHO standard ORS 

was designed for patients with cholera or choleralike 

(toxigenic) diarrhea associated with large 

stool sodium losses. However, in developed countries, 

where diarrheal diseases are rarely associated 

with large stool sodium losses, the use of 

WHO standard ORS has led to hypernatremia, 

especially in infants

Amylase resistant starch oral rehydration solutions 

A novel approach to enhancing the clinical effectiveness 

of ORSs is the addition of ingredients that 

utilize the absorptive capacity of the human colon. 

When undigested carbohydrates, such as an 

amylase-resistant starch or guar gum, reach the 

colon they are fermented into short-chain fatty 

acids, which induce colonic absorption of sodium 

and water from both the normal and the secreting 

colon. 84 A small randomized trial in 48 adolescents 

and adults with watery diarrhea due to Vibrio 

cholerae showed that amylase-resistant starch 

added to the standard WHO ORS reduced stool 

output. Furthermore, the mean duration of diarrhea 

was shorter in the amylase-resistant starch 

group than in the rice-flour group and the standard 

WHO ORS group. 85 In a similarly designed trial in 

150 children, partially hydrolyzed guar gum added 

to the standard WHO ORS compared with the 

control group substantially reduced the duration 

of diarrhea and modestly reduced stool output in 

acute non-cholera diarrhea in young children. In 

contrast, a recent multicenter study by the 

ESPGHAN in 144 boys with acute non-cholera 

diarrhea with mild-to-moderate dehydration 

showed that a mixture of non-digestible carbohydrates 

(soy polysaccharide 25%, α-cellulose 9%, 

gum arabic 19%, fructo-oligosaccharides 18.5%, 

inulin 21.5%, resistant starch 7%) was ineffective 

as an adjunct to oral rehydration therapy. 86 Further 

trials are therefore needed. 

Other fluids 

A recent survey suggested that in some countries 

fluids other than ORS are used for oral rehydration, 

including tea, cola drinks, fruit juices or 

chicken broth. 69 Such beverages contain inappropriate 

electrolyte (low sodium and potassium) and 

glucose concentrations, are very often hyperosmotic, 

and are potentially dangerous as treatments 

in a dehydrated child. Homemade ORS prepared 

by parents is also not an optimal treatment, 

because its preparation may involve significant 

errors in composition and osmolality. 87,88 

Recommendations on management of dehydration 

See Table 39.5 for a summary of practical recommendations 

for management of dehydration in 

children with acute diarrhea. 

Criteria for hospital admission 

Nutritional management 663 

No studies were found in which out-patient and 

in-patient management of children with acute 

diarrhea was compared. However, in some clinical 

practice guidelines experts recently reached 

consensus and specified indications for hospital 

admission. 1,28,89 Management in the hospital is 

generally required in: severely dehydrated children; 

children whose parents are unable to 

manage oral rehydration at home; patients intolerant 

of oral rehydration; in case of failure of treatment, 

e.g. worsening diarrhea and/or progression 

of dehydration despite oral rehydration therapy; 

bloody or persistent diarrhea in a severely 

malnourished child; and other concerns, e.g. diagnosis 

uncertain, potential for surgery, child at risk, 

child irritable or drowsy, or child younger than 2 

months. 

Nutritional management 

Early versus late feeding 

For many decades it has been an established practice 

that children with acute diarrhea should be 

fasted for 24–48h. 90,91 In various forms, these erroneous 

practices persist today in many communities. 

69 However, several controlled trials have 

clearly shown the beneficial effect of early feeding 

in malnourished 92 as well as in adequately nourished 

children. 93–102 Based on these studies, the 

ESPGHAN recently recommended, in line with 

AAP and WHO recommendations, that the optimal 

management of mild-to-moderately dehydrated 

children should consist of oral rehydration with an 

ORS over 3–4h, and rapid reintroduction of normal 

feeding thereafter. 1,26,27 Early feeding may 

decrease the intestinal permeability induced by 

infection, minimize protein and energy deficits, 

and thereby maintain growth, reduce functional 

and morphological hypotrophy associated with 

bowel rest and maintain disaccharidase activity. 

103,104 

Breast feeding 

For infants who are breast fed exclusively, continuation 

of breast feeding at all times results in

664 


Table 39.5 Practical approach to management of a child with acute diarrhea based on published 

clinical practice guidelines (references 1, 26–28) 

Management of dehydration 

Estimate severity of dehydration (see Table 39.3). 

In mildly to moderately dehydrated children, initial oral rehydration with an oral rehydradtion solution (ORS) given 

over 3–4h should be the preferred treatment of fluid and electrolyte losses caused by acute gastroenteritis 

In developed countries use of a hypotonic ORS (sodium 60mmol/l, glucose 74–111mmol/l), instead of WHO 

standard ORS, is recommended 

Suggested intake of the ORS depends on the degree of dehydration: 

mild dehydration (10% dehydration 

signs of shock 

unconsciousness 

presence of ileus 

failure of oral replacement therapy 

inability to tolerate an ORS 

Prevention of further dehydration could be accomplished by supplementing maintenance fluids with an ORS for 

ongoing losses (10ml/kg per watery stool or approximate volume of vomits) 

Nutritional management 

Rapid reintroduction of an age-appropriate normal diet (including solids) should take place after successful 

rehydration for 3–4h with an ORS is accomplished 

Routine use of a special formula is unjustified 

Routine use of a diluted formula is unjustified 

Continuation of breast feeding at all times is recommended 

Pharmacological therapy 

Antiemetics and antidiarrheal drugs should not be routinely given to infants and children with acute gastroenteritis 

Stool cultures and tests should be performed selectively 

Antimicrobial therapy is generally recommended for: 

shigellosis 

suspected cases of cholera 

symptomatic infection with invasive intestinal Entamoeba histolytica 

laboratory-proven symptomatic infection with Giardia intestinalis 

suspected infection with enteroinvasive bacteria in patients with an increased risk of invasive disease, including 

infants younger than 6 months and persons with malignant neoplasms, hemoglobinopathies, HIV infection or 

other immunosuppressive illness or therapy, chronic gastrointestinal tract disease, or severe colitis 

decreased stool output, and is generally recommended. 

105,106 Importantly, as demonstrated by the 

results of three randomized controlled trials 107–109 

and some observational studies, 110–113 breast 

feeding protects against diarrhea, thereby this 

practice in addition may decrease the risk of recurrent 

diarrheal disease. 

Lactose-containing versus reduced lactose or 

lactose-free feeds 

Recurring diarrhea has been attributed to lactose 

intolerance that can occur for a short period of 

time after gastroenteritis, because of mucosal 

damage and temporary lactase deficiency. One

systematic review of 13 randomized controlled 

trials has found that lactose-free feeds versus 

lactose-containing feeds reduced the duration of 

diarrhea in children with mild-to-severe dehydration. 

114 Subsequent trials found conflicting results. 

Two found that lactose-free versus lactose-containing 

feeds significantly reduced the duration of 

diarrhea, 115,116 and the other two found no significant 

difference. 117,118 In Europe, where lactose 

intolerance appears to be uncommon, the 

ESPGHAN recommends that the normal diet can 

be resumed without restriction of lactose intake in 

most cases. However, if diarrhea worsens on the 

reintroduction of standard milk or formula, stool 

pH and/or reducing substances should be checked 

and lactose content reduced only if the stool is 

acid and contains >0.5% reducing substances. 26 

Diluted or full-strength milk or formula 

There is concern that feeding full-strength formula 

or animal milk to infants aged less than 6 months 

with diarrhea may have adverse consequences, 

although one randomized controlled trial has 

shown that diluting formula or milk as opposed to 

using full-strength formula over 48h did not 

reduce complications. 119 More recently, one 

randomized, unblinded, controlled study demonstrated 

that, in infants aged 3–12 months with 

acute diarrhea, decreasing the volume of each feed 

and increasing the frequency of feedings to 12 

times per day (while maintaining the same total 

daily energy intake) speeded recovery, reduced 

fecal frequency and fecal weight, and increased 

weight gain during the recovery period. 120 

Recommendations on nutritional management 


on nutritional management of a child 

with acute diarrhea. 

Pharmacological therapy 

Rational use of antibacterial drugs 

In the vast majority of children, acute infectious 

diarrhea is self-limited and antibacterial drugs are 

generally unnecessary, even when a bacterial 

Pharmacological therapy 665 

cause is suspected. WHO recommends routine use 

of antibacterial agents only for shigellosis, 

suspected cases of cholera, symptomatic infection 

with invasive intestinal Entamoeba histolytica and 

laboratory-proven symptomatic infection with 

Giardia intestinalis. 1 Although of unproven 

benefit, anitmicrobial therapy is generally recommended 

for suspected infection with enteroinvasive 

bacteria (e.g. Salmonella gastroenteritis) in 

patients with an increased risk of invasive disease, 

including infants younger than 6 months 

of age and persons with malignant neoplasms, 

hemoglobinopathies, HIV infection or other 

immunosuppressive illness or therapy, chronic 

gastrointestinal tract disease, or severe colitis. 121 

Furthermore, patients with bloody or inflammatory 

diarrhea accompanied by high fever, especially 

when the disease is moderate to severe, may 

benefit from empirical antibacterial treatment, 

modified subsequently on the basis of results of 

stool culture. 3 Antimicrobial treatment should be 

preceded by appropriate stool cultures or pathogen 

detection tests. One situation in which empirical 

antibiotics are commonly recommended without 

obtaining a fecal specimen is in cases of traveler’s 

diarrhea, in which ETEC or other bacterial 

pathogens are usually the likely cause. Prompt 

treatment with trimethoprim–sulfamethoxazole in 

children or fluorochinolone in adolescents and 

adults can reduce the duration of illness from 3–5 

days to less than 1–2 days. 3 Most of these episodes 

are self-limiting, and antimicrobial use should 

always be preceded by careful weighing of the 

benefits and potential harms of such treatment. 3 

Details of treatment of specific infections are 

summarized in Table 39.6. Because of changing 

patterns of antimicrobial resistance, recent local 

patterns are critical in making decisions about 

antimicrobial therapy. 3 Irrational prescribing of 

antibiotics may cause more harm than good (for 

example, it prolongs the excretion of Salmonella, 

leads to the emergence of drug resistance among 

some bacterial strains, and increases the risk of 

antibiotic-associated diarrhea and pseudomembranous 

colitis). 122,123 

Antiemetic drugs 

Vomiting is a common symptom in children with 

gastroenteritis. Metoclopramide, prochlorprezine 

and promethazine hydrochloride are effective

666 


Table 39.6 Drugs for treatment of enteric pathogens (adapted from reference 3) 

Pathogen Recommended treatment in immunocompetent patients 

Shigella species TMP–SMZ 5 and 25mg/kg, respectively, twice daily for 3 days (if susceptible) 

OR 

fluoroquinolone* for 5 days 185–190 

OR 

nalidixic acid 55mg/kg per day in four doses for 3 days 191 

OR 

ceftriaxone 100mg/kg per day in one or two doses 192 

OR 

azithromycin 189 

Non-typhi species not recommended routinely, 122,193,194 but advised if severe infection or in infants 

of Salmonella 8 years of age) 6mg/kg 

O1 or O139 OR 

TMP–SMZ 5 and 25mg/kg, respectively, twice daily for 3 days; 

OR 

single-dose fluoroquinolone* 223–227 

OR 

single-dose azithromycin (20mg/kg) 228 

Continued


Pathogen Recommended treatment in immunocompetent patients 

Toxigenic Clostridium offending antibiotic should be withdrawn if possible 229–231 

difficile metronidazole 30mg/kg per day in four doses for 10 days 232–234 

Giardia metronidazole 15mg/kg per day in three doses for 5 days235–237 OR 

tinidazole 50mg/kg single dose (maximum 2g) 238 

OR 

furazolidone 6mg/kg per day in four doses for 7–10 days 

OR 

paromomycin 25–35mg/kg per day in three doses for 7 days 

Cryptosporidium if severe, consider paromomycin 25–35mg/kg per day 

species in two or four doses for 7 days 

Isospora species TMP–SMZ 5 and 25mg/kg, respectively, twice daily for 7–10 days 

Cyclospora species TMP–SMZ 5 and 25mg/kg, respectively, twice daily for 7–10 days239,240 antiemetics. However, troublesome side-effects, 

including sedation and extrapyramidal reactions, 

occur frequently with standard doses. 124–126 

Therefore, these drugs should be avoided in young 

children with vomiting associated with acute diarrhea. 

Two recent studies have suggested that intravenous 

or oral ondansetron, a specific serotonin 

(5HT3) antagonist, decreases vomiting in children 

with gastroenteritis managed in the emergency 

room and reduces the need for intravenous fluid 

administration and hospital admission, and thus 

may have a valuable role as an antiemetic 

therapy. 127,128 

Antimotility or antiperistaltic drugs 

There is a wide variety of drugs that alter intestinal 

motility, including loperamide hydrochloride, 

diphenoxylate with atropine, tincture of opium, 

Pharmacological therapy 667 

Microsporidium species not determined 

Entamoeba histolytica metronidazole 35–50mg/kg per day in three doses for 7–10 days plus either diloxanide 

furoate 20mg/kg per day in three doses for 10 days 

OR 

paromomycin 25–35mg/kg per day in two or four doses for 7days241–243 TMP–SMZ trimethoprim–sulfamethoxazole 

*Fluoroquinolones (i.e. ciprofloxacin, ofloxacin, norfloxacin) are not approved for treatment of children in some 

countries 

† Antibiotics are most effective if given early in the course of illness 

camphorated tincture of opium and codeine. 

These drugs are widely used for the relief of symptoms 

during diarrheal episodes and are regarded as 

safe for adults and older children, 129,130 excluding 

those with bloody diarrhea or documented infection 

with Shiga toxin-producing E. coli (STEC). 3 

However, antimotility treatment should not be 

given for acute diarrhea in infants and young children, 

1,27,28 as numerous reports have documented 

severe and potentially life-threatening adverse 

effects, including lethargy, ileus, respiratory 

depression and coma. 131–134 

Adsorbents 

In several countries dioctahedral smectite, a 

natural adsorbent clay capable of adsorbing 

viruses, bacteria, bacterial toxins and other intestinal 

irritants, is commonly used for the treatment of

668 


acute infectious diarrhea. 69 Three small randomized 

trials in children 135–137 have suggested that 

smectite compared with placebo was associated 

with moderately reduced duration of diarrhea, 

although there was no significant effect on total 

stool output. Other adsorbents such as 

kaolin–pectin, fiber, attapulgite (anhydrous aluminum 

silicate) and activated charcoal have not 

been shown to be of value in the treatment of acute 

diarrhea in children. Adsorbents are not recommended 

in the routine treatment of acute diarrhea 

in children. 1,27,28 

Antisecretory drugs 

Bismuth subsalicylate, or other bismuth salt 

preparations, are common constituents of overthe-counter 

medications for diarrhea. Although 

the precise mechanism of their action remains 

unknown, antisecretory and antimicrobial properties 

have been suggested. 138–140 Three randomized 

controlled trials that compared bismuth subsalicylate 

with placebo in infants with acute watery diarrhea 

found that bismuth subsalicylate modestly 

reduced the duration and severity of diarrhea. 

141–143 In addition to harmless and temporary 

side-effects (e.g. darkening of the tongue and 

stool), salicylate toxicity from bismuth subsalicylate 

use in children has been reported. 144 The 

routine use of bismuth subsalicylate is not recommended 

in the management of children with acute 

diarrhea. 1,27,28 

Racecadotril (acetorphan), is a newer antisecretory 

drug that exerts its antidiarrheal effects by inhibiting 

intestinal enkephalinase, thus preventing the 

breakdown of endogenous opioids (enkephalins) 

in the gastrointestinal tract, thereby reducing the 

secretion of water and electrolytes into the gut. 145 

In two recent randomized placebo-controlled trials 

conducted in hospitalized children in developed 

and developing countries, racecadotril was effective 

in reducing the volume and frequency of stool 

output and in reducing the duration of diarrhea 

(particularly in children with rotavirus or E. coli 

diarrhea). 146,147 Although these data are interesting, 

the cost-effectiveness as well as safety needs 

to be defined before this drug is recommended in 

the routine management of children with acute 

diarrhea. 

Probiotics 

Probiotics are living micro-organisms that, upon 

ingestion in certain numbers, exert health benefits 

beyond their inherent general nutrition. 148 The 

most commonly used as probiotics are lactic acid 

bacteria, such as lactobacilli or bifidobacteria, and 

the non-pathogenic yeast Saccharomyces boulardii. 

The rationale for the use of probiotics is 

based on the assumption that they modify the 

composition of the colonic microflora and act 

against enteric pathogens. The evidence from two 

systematic reviews 149,150 and two subsequent 

randomized controlled trials 151,152 suggest a statistically 

significant effect and moderate clinical 

benefit of some probiotic strains in the treatment 

of acute gastroenteritis, mainly rotaviral, in infants 

and young children. Lactobacillus GG shows the 

most consistent effect. Other probiotic strains may 

also be effective, but should be evaluated in 

randomized controlled trials to prove their clinical 

utility, since not all products marketed as ‘probiotic’ 

are effective. 153 So far, the beneficial effects of 

probiotics in acute diarrhea in children seem to be: 

moderate; strain-dependent; dose-dependent 

(greater for doses >10 10 –10 11 CFU); significant in 

watery diarrhea and viral gastroenteritis, but not 

existing in invasive (inflammatory) bacterial diarrhea; 

and more evident when treatment with 

probiotics is initiated early in the course of diarrhea. 

154 

Homeopathy 

The role of homeopathic remedies in the treatment 

of acute childhood diarrhea is still controversial. A 

recent meta-analysis from three randomized 

controlled clinical trials involving 242 children 

aged 6 months to 5 years has suggested that some 

homeopathic treatment decreases the duration of 

acute diarrhea in children. 155 The exact mechanism 

by which homeopathic remedies could have 

exerted their activity is unclear. 

Herbal medicine 

No systematic review or randomized controlled 

trial was found on herbal medicine for the treatment 

of acute diarrhea in children.

Micronutrients (zinc, folic acid) 

Zinc deficiency, which is common in young children 

in the developing world, is associated with 

impaired water and electrolyte absorption, 156–159 

decreased brush-border enzymes, 160–162 and impaired 

cellular and humoral immunity. 163–166 As 

intestinal losses of zinc are considerably increased 

during acute diarrhea, 167,168 a number of 

trials have evaluated the effect of zinc supplements 

on diarrheal diseases. The findings suggest 

that in developing countries zinc supplementation 

results in clinically important reductions in the 

duration and severity of acute diarrhea when given 

as an adjunct to oral rehydration therapy, 169–174 or 

mixed with an ORS. 175 Further work is needed to 

clarify whether zinc supplementation would also 

be of benefit in developed countries in children 

with diarrhea without pre-existing zinc deficiency. 

Previous reports have suggested that there is a 

therapeutic effect of folic acid in the treatment of 

acute diarrhea in children. 176 However, a recent 

well-designed double-blind randomized controlled 

trial in 106 males aged 6–23 months found no 

significant effect of folic acid compared with 

placebo in the treatment of acute watery diarrhea. 

177 

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222. Scavizzi M. Yersinia enterocolitica. In Yu VL, Merlgan 

TC, Barriere SL, eds. Antimicrobial Therapy and 

Vaccines. Baltiomore: Williams & Wilkins, 1999: 

481–488. 

223. Alam AN, Alam NH, Ahmed T et al. Randomised 

double blind trial of single dose doxycycline for treating 

cholera in adults. BMJ 1990; 300: 1619–1621. 

224. Bhattacharya SK, Bhattacharya MK, Dutta P et al. 

Double-blind, randomized, controlled clinical trials of 

norfloxacin for cholera. Antimicrob Agents Chemother 

1990; 34: 939–940. 

225. Gotuzzo E, Seas C, Echevarria J et al. Ciprofloxacin for 

the treatment of cholera: a randomized, double-blind, 

controlled clinical trial of a single daily dose in 

Peruvian adults. Clin Infect Dis 1995; 20: 1485–1490. 

226. Khan WA, Begum M, Salam MA et al. Comparative trial 

of five antimicrobial compounds in the treatment of 

cholera in adults. Trans R Soc Trop Med Hyg 1995; 89: 

1036. 


227. Khan WA, Bennish ML, Seas C et al. Randomised 

controlled comparison of single-dose ciprofloxacin and 

doxycycline for cholera caused by Vibrio cholerae 01 or 

0139. Lancet 1996; 348: 296–300. 

228. Khan WA, Saha D, Rahman A et al. Comparison of 

single-dose azithromycin and 12-dose, 3-day 

erythromycin for childhood cholera: a randomised, 

double-blind trial. Lancet 2002; 360: 1722–1727. 

229. Fekety R. Guidelines for the diagnosis and management 

of Clostridium difficile-associated diarrhea and colitis. 

American College of Gastroenterology Practice 

Parameters Committee. Am J Gastroenterol 1997; 92: 

739–750. 

230. Gerding DN, Johnson S, Peterson LR et al. Clostridium 

difficile-associated diarrhea and colitis. Infect Control 

Hosp Epidemiol 1995; 16: 459–477. 

231. Teasley DG, Olson MM, Gebhard RL et al. Prospective 

randomised trial of metronidazole versus vancomycin 

for Clostridium difficile-associated diarrhoea and colitis. 

Lancet 1983: 1043–1046. 

232. Olson MM, Shanholtzer CJ, Lee JT Jr, Gerding DN. Ten 

years of prospective Clostridium difficile-associated 

disease surveillance and treatment at the Minneapolis 

VA Medical Center, 19821991. Infect Control Hosp 

Epidemiol 1994; 15: 371–381. 

233. Teasley DG, Olson MM, Gebhard RL et al. Prospective 

randomised trial of metronidazole versus vancomycin 

for Clostridium difficile-associated diarrhoea and colitis. 

Lancet 1983; 2: 1043–1046. 

234. Wenisch C, Parschalk B, Hasenhundl M et al. 

Comparison of vancomycin, teicoplanin, metronidazole, 

and fusidic acid for the treatment of Clostridium 

difficile-associated diarrhea [published erratum appears 

in Clin Infect Dis 1996; 2: 423]. Clin Infect Dis 1996; 22: 

813–818. 

235. Bassily S, Farid Z, Mikhail JW et al. The treatment of 

Giardia lamblia infection with mepacrine, metronidazole 

and furazolidone. J Trop Med Hyg 1970; 73: 1518. 

236. Lerman SJ, Walker RA. Treatment of giardiasis: literature 

review and recommendations. Clin Pediatr (Phila) 

1982; 21: 409–414. 

237. Levi GC, de Avila CA, Amato NV. Efficacy of various 

drugs for treatment of giardiasis. A comparative study. 


238. Zaat JOM, Mank ThG, Assendelft WJJ. Drugs for treating 

giardiasis (Cochrane Review). In The Cochrane Library, 

Issue 2. Oxford: Update Software. 

239. Gerding DN, Johnson S, Peterson LR et al. Clostridium 

difficile associated diarrhea and colitis. Infect Control 

Hosp Epidemiol 1995; 16: 459–477. 

240. Madico G, McDonald J, Gilman RH et al. Epidemiology 

and treatment of Cyclospora cayetanensis infection in 

Peruvian children. Clin Infect Dis 1997; 24: 977–981. 

241. Rubidge CJ, Scragg JN, Powell SJ. Treatment of children 

with acute amoebic dysentery. Comparative trial of 

metronidazole against a combination of dehydroemetine, 

tetracycline, and diloxanide furoate. Arch Dis Child 

1970; 45: 196–197. 

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Engl J Med 2003; 348: 1565–1573.

40 

Introduction 

Approach to the child with 

acute abdomen 

Luigi Dall’Oglio, Paola De Angelis and Giovanni Federici di Abriola 

‘Acute abdomen’ is a loose concept, referring to a 

medical emergency involving signs and symptoms 

pertaining to the abdomen and whose therapeutic 

option is usually surgery. 

In this chapter we review the clinical signs and 

symptoms of various gastrointestinal disorders 

that have an acute onset and can progress dramatically 

to involve the parietal or visceral peritoneum. 

Our aim is to help the pediatrician realize 

when a gastrointestinal condition changes from an 

indolent to an acute course, and when a surgeon 

should be consulted. We also describe some 

simple but important strategies that are helpful in 

reaching a diagnosis without delay, and in 

adequately preparing patients for either surgery or 

for one of the newer effective and less invasive 

non-surgical treatments. 

Symptoms and signs 

The symptoms and signs of an acute abdomen vary 

widely depending on the patient’s age and the clinical 

course of the disease. An early, efficient and 

accurate diagnosis depends crucially on a meticulous 

review of the patient’s medical history, focusing 

on the symptoms, their time of onset, and their 

intensity and character. To avoid a misdiagnosis of 

other extraintestinal diseases, the history taking 

must include symptoms apparently unrelated to 

the digestive tract. For example, a history of excessive 

thirst, increased urination and lack of appetite 

preceding the abdominal pain, accompanied by 

deep sighing and rapid breathing, and severe 

dehydration, may suggest diabetic ketoacidosis 

mimicking an acute abdomen. 1 

The most important elements to evaluate in a 

patient with an acute abdomen are: 

(1) Abdominal pain; 

(2) The presence and characteristics of vomiting; 

(3) The presence and characteristics of fever; 

(4) The characteristics of the stools; 

(5) The findings from a detailed physical examination. 

Abdominal pain 

Whereas in older, co-operative children, close 

observation and a detailed diagnostic work-up of 

abdominal pain will usually identify various possible 

causes of an acute abdomen, in infants and 

newborns, abdominal pain is often a poorly 

specific symptom. Young infants with functional 

abdominal colic, at times very painful, need only 

be kept under clinical observation, whilst those 

with abdominal pain of organic origin should 

undergo aggressive diagnostic and therapeutic 

procedures. In newborns and infants, a true acute 

abdomen is rare and is generally related to congenital 

malformation. It should be suspected when the 

patient presents with abdominal tension, paradoxical 

diarrhea and vomiting, sometimes accompanied 

by a surprisingly rapid decline in general 

condition followed by shock. Circumstances such 

as these require therapy for shock, along with 

diagnostic investigations. 

In older children, a complete medical history and 

description of the symptoms can generally be 

obtained. The suspected diagnosis can then be 

confirmed with standard clinical examinations 

and laboratory tests. 

677

678 

Approach to the child with acute abdomen 

The assessment of abdominal pain should include 

the intensity of pain, the type (continuous or colic) 

and the site – whether the pain affects a specific 

site or the entire abdomen, and whether it 

irradiates to the back, chest, or shoulders. The 

chronological pattern of the pain, the rapidity of 

onset and the progression and duration of 

symptoms can be useful in the diagnosis; pain 

with sudden and severe onset is generally due to 

perforation or mesenteric infarction. In gastroenteritis, 

pain is self-limited; in appendicitis, or in 

other peritoneal inflammations, pain is progressive. 

Infants with bowel occlusion typically have 

evident colicky pain and even more evident postcolic 

seediness. 

As a general rule, visceral pain (noxious stimuli in 

the intestinal wall) is located in the epigastrium, 

mid-abdomen and hypogastrium; the pain is 

generally crampy, burning or gnawing in quality. 

Parietal pain (noxious stimuli in the parietal peritoneum) 

is generally more intense and more 

precisely localized to the site of the lesion, and it 

is often aggravated by movement or coughing. The 

onset of pain differs in the various diseases. For 

example, in patients with perforated ulcers or 

ruptured abscess, pain has a sudden (instantaneous) 

onset; in strangulated bowel and intussusception, 

it has a rapid onset (minutes); and in 

appendicitis, bowel obstruction, cholecystitis, and 

Meckel’s diverticulitis, it has a gradual onset (a few 

hours). 2 Close observation, absolutely crucial in 

infants to gain information on the pain, is also 

necessary in the older child. A patient lying still in 

bed, in the fetal position, neither moving nor 

speaking, with a distressed facial expression, is 

likely to have peritonitis; conversely, a patient who 

has short periods free of pain, recognizable by 

normal appearance and behavior, could have 

visceral pains due to gastroenteritis or bowel 

occlusion. 3 Intestinal volvulus generally starts 

with intense abdominal pain and, after possible 

vascular torsion, the most important symptom is 

the worsening of the general condition; vomiting 

and blood in stools are frequent, without other 

characteristic clinical indications. 

Vomiting 

An important symptom in clarifying the severity 

and type of disease, vomiting is an early sign of 

peritoneal inflammation or bowel obstruction. 

Initially, vomit is mixed with food; after minutes or 

hours, it can become bile-stained, as in intestinal 

obstruction. Vomiting can be highly dangerous, 

owing to the risk of aspiration; especially in 

newborn or in unconscious infants, a nasogastric 

tube must be inserted for adequate gastric suction. 

Fever 

An unspecific symptom, fever, when present, can 

be helpful in suspected peritonitis. As a general 

rule, a temperature that rises slowly and progressively 

in parallel with the abdominal signs 

indicates peritoneal infection. Conversely, a 

temperature that rises rapidly, despite acute 

abdominal pain, indicates other, and often selflimited, 

non-surgical diseases. 

Characteristics of the stools 

The rule that adults with acute abdomen usually 

have no passage of stools does not hold true in 

infants and young children. The important signs to 

note in infants are: mucousy or bloody diarrhea, 

and the time elapsing after the last bowel movement 

and flatus. Bloody diarrhea is a common 

symptom of bowel occlusion with vascular 

damage due to strangulation. Diarrhea often 

accompanies peritoneal inflammation in small 

children. Older children with pelvic abscess also 

often have repeated small bowel movements. 

Complete information about stool habits before the 

onset of the acute abdominal symptoms is useful. 

For instance, a history of alternating diarrhea and 

constipation may be an indication of aganglionosis, 

while a history of bloody and mucousy 

stools could raise a suspicion of inflammatory 

bowel disease (IBD). 

Findings from the physical exam of the 

abdomen 

A careful physical examination, looking for the 

various signs of extra-abdominal systemic disease, 

is of paramount importance. For example, cutaneous 

petechiae can raise a suspicion of 

Henoch–Schönlein purpura and possible bowel 

involvement with intussusception. The abdomen

must be meticulously inspected, looking for 

distension; visible veins; visible loops of bowel, 

with or without peristaltic waves; superficial nonabdominal 

breathing; and flexion of lower limbs 

over the abdomen. All these signs can be more or 

less evident, and can differ in intensity, depending 

on the patient’s age, the disease and its severity. 

The same problems arise during abdominal palpation. 

In a newborn, insufficient muscular mass 

and muscle activity makes rigidity from muscular 

guarding difficult to detect. The only way to obtain 

information from abdominal palpation in a child is 

to approach the child carefully, and begin palpation 

at the least tender site; light finger percussion 

over an area of tenderness often elicits the same 

information as deep palpation and is less disturbing 

to infants and children. 4 Abdominal palpation 

with the child lying on the side, with one or both 

legs on the abdomen itself, is a helpful maneuver 

for obtaining muscular relaxation, thus gaining 

more information. Percussion can be useful to 

elicit tympany from intraluminal abdominal gas, 

as in obstruction, or from extraluminal gas, as in 

intestinal perforation. 

Careful rectal examination yields a great deal of 

information about anal or rectal malformations, 

stools, gas, blood, mucus and pelvic tenderness or 

masses. 

Laboratory examination, imaging and 

other techniques 

Laboratory examination 

All patients with suspected acute abdomen should 

have a complete blood count with differential, Creactive 

protein (CRP) and urinalysis. Analysis of 

serum electrolytes, blood urea nitrogen, creatinine 

and glucose levels is useful in determining fluid 

and acid–base status, renal function and metabolic 

status. In newborns and infants the standard laboratory 

tests sometimes have poor sensitivity and 

specificity, but they are important for identifying 

pre-shock signs early, before the clinical status 

becomes critical. 

The patient’s clinical history and physical examination 

may indicate the need for special tests (e.g. 

liver function tests and amylase in patients with 

upper abdominal symptoms). 

Laboratory examination, imaging and other techniques 679 

Imaging 

Symptoms of acute abdomen generally arise from 

bowel occlusion or peritoneal inflammation. Plain 

abdominal X-rays and ultrasonography are the two 

most common imaging techniques. Plain abdominal 

X-rays visualize free air, as in perforation, and 

the possible presence of air–fluid levels, pathognomonic 

for occlusion. They also provide evidence 

of various pre-surgical problems, such as pneumatosis 

in necrotizing enterocolitis, and toxic 

megacolon which need to be recognized early, in 

order to avoid delaying surgery. 

Plain abdominal series must always be taken in 

supine, upright and side views; in patients unable 

to stand in this position, a lateral decubitus film 

with the left side down (or cross-table lateral) can 

be useful to identify abnormal gas distribution. A 

chest X-ray must be obtained to exclude possible 

respiratory disease; lung-base pneumonia is a 

well-known cause of acute abdominal symptoms, 

whereas acute abdominal disease can give rise to 

chest problems, as it does in pancreatitis or 

subphrenic abscess. No recently published trials 

have addressed the diagnostic value of plain 

series, but in accordance with Glasgow and 

Mulvihill, 3 ‘it is a readily available and inexpensive 

examination and in most circumstances 

should be obtained’. 

Ultrasound gives rapid, non-invasive, accurate, 

repeatable and inexpensive information. Unlike 

plain series, the ultrasound technique needs an 

experienced examiner who knows precisely which 

information to seek in the abdomen and how to 

look for it. Ultrasound allows accurate detection of 

localized or diffuse liquid and its density; it also 

defines the morphology of other structures, 

including the biliary and pancreatic tree. This 

technique accurately estimates the intestinal wall 

thickness, and visualizes peristaltic activity. In 

conjunction with color and pulsed Doppler 

imaging, ultrasound provides a new tool for diagnosing 

an acute abdomen, depending on the 

child’s age. 5 It has a well-known role in IBD and in 

other inflammatory diseases, including intestinal 

localizations in Henoch–Schönlein purpura. It also 

visualizes hydrostatic reduction of intussusception 

with saline enema. 6 The primary imaging 

procedure 7 in abdominal emergency in childhood 

is: plain X-ray film of the abdomen followed by

680 


ultrasound. The findings from these initial studies 

dictate the need for further imaging. 

The role of computed tomography (CT) and 

magnetic resonance imaging (MRI) remains less 

clear. These techniques are expensive and, in 

uncooperative children, deep sedation is needed to 

obtain the clear images necessary for a meaningful 

assessment. 

In suspected biliary or pancreatic disease, MRI 

cholangiography gives full information about 

morphology 8,9 and, with secretin stimulus, about 

pancreatic activity. 10 Other invasive diagnostic 

procedures, including peritoneal lavage or diagnostic 

laparoscopy, are occasionally useful but are 

more often used in post-trauma acute abdomen. 

Digestive endoscopy is generally contraindicated 

in acute abdomen, although it may have a diagnostic 

or therapeutic role in special circumstances. 

These include decompression, reduction and 

sigmoidopexy of sigmoid volvulus, 11,12 or clip 

closure of cardia perforation in Mallory–Weiss 

tears, after dilatations 13,14 or after a lap Nissen 

procedure. 

General considerations about 

treatment 

A good strategy for avoiding misdiagnosis or surgical 

delay is to contact the surgeon as soon as an 

acute abdomen develops and maintain full and 

timely collaboration. While awaiting the surgeon, 

the pediatrician must complete the diagnostic 

work-up and start medical treatment. Recent 

advances in diagnosis and therapy mean that 

many patients who hitherto would have undergone 

surgery can now be treated medically. 

Surgical intervention must be scheduled only after 

the patient’s status has been fully stabilized and 

only if the non-surgical therapeutic strategy is 

unsuccessful. In doubtful circumstances, the pediatrician 

along with the surgeon should observe 

how the disease evolves clinically, in order to 

identify the correct timing for diagnostic procedures 

and to decide between conservative therapeutic 

options or surgical intervention. Should the 

diagnosis remain unclear and a life-threatening 

risk develop, then the surgeon may proceed to an 

exploratory laparotomy or, as in recent years and 

in selected cases, laparoscopy. 

The management of an acute abdomen also has to 

be cost-effective. Therefore, surgeons must be 

involved early in the evaluation phase of patients 

with an acute abdomen, and follow the patient 

during the observation period, so that unnecessary 

laboratory or diagnostic tests can be avoided and 

the costs reduced. 15,16 The goal in treating an acute 

abdomen is to reach an early diagnosis and to 

establish the correct surgical indications and 

timing to allow effective surgery. 

Unfortunately, these goals are not always 

achieved. Far more often, the clinical presentation 

and the indications for surgery are unclear. In 

these cases, the pediatrician must, in strict collaboration 

with the surgeon, do everything necessary 

to reach a diagnosis, and at the same time start 

supportive therapy before the patient’s general 

clinical status takes a downhill course. The following 

simple but essential procedures can help. 

Evaluation of fluid loss 

This is obtained by the use of nasogastric suction 

with a tube of adequate caliber. A simple report on 

the number of vomits and the presumed amount 

vomited does not give a precise evaluation of fluid 

loss. The evaluation requires adequate urine 

collection and diaper weight for fecal volume. 

Placement of an adequate intravenous line 

Especially in newborns and infants, a vein catheter 

must be installed in time to avoid difficult venous 

puncture under conditions of collapse. In patients 

whose clinical status is more severe, a central 

venous catheter can be useful, not only for infusion 

but also for measuring central venous pressure. 

This measurement is essential in ensuring a 

proper fluid intake. 

Consideration of pharmacological therapy 

Antibiotic therapy is always necessary in patients 

with clinically evident sepsis and is useful in those 

with well-diagnosed peritonitis before surgery. In 

other less clear circumstances, antibiotics might

hide the clinical evolution of the disease, thus 

delaying the definitive diagnosis and proper surgical 

therapy, and should therefore be avoided. 

The usefulness of H2-antagonists or proton pump 

inhibitors in the prevention of acute peptic disease 

is unclear in children and debated in adults. 

Persistent vomiting attempts can provoke prolapse 

of the gastric wall through the cardia, thus causing 

blood in the vomit, despite the absence of a 

specific gastric disease. 17,18 In patients whose clinical 

status worsens, 10 mg/kg per day of ranitidine 

or 1–1.5 mg/kg per day of omeprazole are useful in 

preventing acute peptic disease. 

Specific diseases 

Some specific diseases resulting in acute abdomen 

(such as appendicitis, intussusception, Meckel’s 

diverticulum, Hirschsprung’s disease or chronic 

intestinal pseudo-obstruction) are discussed in 

detail in their respective chapters. Here we focus 

only on some conditions that may atypically 

present the clinical picture of acute abdomen, 

offering some suggestions pertinent to their diagnosis 

and treatment. 

Foreign body ingestion 

Foreign body ingestion is rarely described as a 

cause of acute abdomen; children can ingest everything 

and these objects, 19 even button batteries, 20 

often pass naturally. 

Acute abdomen was described in patients who had 

ingested bezoars 21,22 especially in mentally 

retarded children, or in cases where multiple 

magnets were attracted to each other across the 

bowel wall, leading to pressure necrosis, perforation, 

fistula or intestinal obstruction. 23 Ingestion of 

pins has been described as a cause of gastric perforation. 

24 

In our experience of ingested foreign bodies, an 

acute abdomen occurred twice: duodenal perforation 

from a hairpin and sigmoid perforation from a 

fragment of glass from the top of a cola bottle. The 

first patient, who presented in the pre-endoscopy 

period, with the foreign bodies embedded in the 

third duodenal portion, died of pancreatitis and 

Specific diseases 681 

septic complications. In the second case, the 

foreign bodies passed naturally with a small 

amount of blood in the stools as a lucky warning 

sign, in a patient without abdominal pain; radiological 

evidence of free abdominal gas suggested 

the surgical direct suture of the 3-cm long sigmoid 

lesion, with a good outcome. Refer to Chapter 41 

for further information. 


Acute surgical emergencies in children with IBD 

need a team approach, involving gastroenterologists 

and surgeons, avoiding an unnecessary or 

delayed surgical strategy. If the team chooses the 

correct time for surgery, acute abdomen from toxic 

colitis with megacolon, perforation, abdominal 

abscesses and bowel obstructions can have a good 

outcome, with morbidity and mortality rates of 

15% in childhood. 25 The goal of this team is to 

make sure that unduly prolonged medical therapy 

does not result in an emergency operation. 

Emergency surgery, not being planned in advance, 

may be performed by a surgical team to which the 

patient is unknown, and often involves a multistep 

operation. 

Toxic colitis 

Toxic colitis is an emergency life-threatening 

complication of IBD. Crohn’s disease was once 

thought to be secondary only to ulcerative colitis, 

but we now know that it may cause up to 50% of 

the cases. 26 

The pathophysiology in Crohn’s disease and 

ulcerative colitis is similar, with transmural vascular 

congestion, muscular disintegration with 

consequent colon atony and dilatation, and with 

very thin, deeply ulcerated walls. Histologically, 

the inflammation involves all layers of the colon, 

with myocyte degeneration, necrosis and the 

formation of granulation tissue, infiltrated by 

neutrophils, lymphocytes and plasma cells. 27 The 

etiology seems to be related to colonic muscle 

paralysis, secondary to the inflammatory infiltrate 

and destruction of the myenteric plexus. More 

recent case reports have described toxic megacolon 

involving nitric oxide, generated by 

macrophages and smooth muscle cells. 27,28 Once 

the diagnosis is suspected for worsening general

682 


conditions, abdominal distension and tenderness, 

plain abdominal series may confirm the colonic 

distension and must be repeated every 12h in order 

to provide a close monitoring of its evolution. 

Medical treatment consists of antibiotics 

(ciprofloxacin, metronidazole), to avoid bacterial 

translocation through the bowel wall, high-dose 

intravenous corticosteroids and cyclosporin or, 

more recently, tacrolimus. A higher incidence of 

postoperative complications was described in nondeferrable 

surgery and high-dose corticosteroid 

therapy. 25,29,30 If the dilated colon persists, free 

perforation develops, or the clinical conditions fail 

to improve within 2 or 3 days, prompt surgery is 

indicated. 31 Mortality related to perforation may 

exceed 40%, but if surgery is completed before 

perforation, the mortality decreases to 2–8%. 27 

Perforation 

Perforation occurs in approximately 2% of patients 

with ulcerative colitis, and is generally associated 

with toxic colitis and megacolon. In a patient with 

toxic colitis without megacolon, Crohn’s disease 

must be suspected. 32 The diagnosis may be delayed 

because high-dose corticosteroids may mask the 

signs of peritonitis. The transmural damage in 

Crohn’s disease creates an inflammatory adhesion 

between the affected bowel segments and local 

structures with consequent sealed perforation. 32 

Owing to these adhesions, pneumoperitoneum is 

present in only 20% of patients with perforated 

Crohn’s disease, and in a smaller percentage of 

those with ileal perforations. 33,34 The surgical 

procedure in colon perforation with or without 

toxic colitis must be limited to total colectomy and 

terminal ileostomy, avoiding proctectomy because 

of the risk of blood loss, pelvic sepsis and pelvic 

nerve damage. 26 This strategy removes the diseased 

bowel and avoids anastomosis in critically ill 

patients. 35 

In Crohn’s disease, gastroduodenal perforations 

need debridement and primary repair; jejunal–ileal 

perforations require resection and primary anastomosis 

with associated intestinal diversion in unfavorable 

conditions. 36 

Intra-abdominal abscess 

Characteristic of Crohn’s disease, intra-abdominal 

abscess can give rise to an acute abdomen if the 

abscess ruptures into the peritoneal cavity. Often 

the abscesses are associated with a fistula, 

secondary to a distended loop of proximal bowel, to 

a distal stricture or to transmural ulceration of the 

diseased bowel. Ultrasound and CT are useful for 

identifying the type of abscess and its location. 

Because surgical drainage of an abscess leads to 

numerous severe complications, it should be 

avoided. The best options are medical treatment or 

percutaneous drainage guided by ultrasound or CT. 

If surgery cannot be deferred, and in patients with 

intestinal damage, it should aim only at draining 

the abscess and diverting the fecal stream, avoiding 

resection or other useless and dangerous maneuvers. 

37 

Intestinal obstruction 

Intestinal obstruction, generally in the small 

bowel, is the most common complication requiring 

surgical correction in Crohn’s disease, but is rarely 

related to acute abdomen; improved medical and 

nutritional treatment has now reduced the indications 

for surgical emergencies for bowel obstruction. 

If acute obstruction cannot be managed 

otherwise, surgery must be as conservative as 

possible, avoiding wide resection. In accordance 

with the conservative strategy for surgery in 

Crohn’s disease, the newer stricturoplasty techniques 

are providing increasingly good results and 

fewer complications than resective surgery, avoiding 

the risk of short-bowel syndrome due to 

repeated resections. 38–42 

Biliary and pancreatic diseases 

Biliary diseases 

Biliary diseases are uncommon in children and 

especially rare as a possible cause of acute 

abdomen. Suppurative cholecystitis or cholangitis, 

from malformations and cholelithiasis, must be 

suspected in patients who present with acute 

abdomen and pain in the right upper quadrant that 

irradiates to the right shoulder, and laboratory 

blood findings indicating biliary stasis. Also, jaundice 

is not an early symptom of biliary and pancreatic 

disease. Ultrasound, in skilled hands, can be 

useful in showing common bile duct or gallbladder 

dilatation with stones or biliary sludge; it will also 

identify choledochal malformations.

MRI cholangiography gives full information about 

morphology. 8,9 Endoscopic retrograde cholangiopancreatography 

(ERCP) can be helpful for 

morphological evaluation of the biliary and pancreatic 

ducts and for therapeutic options such as 

sphincterotomy, stone removal and drainage. 43–45 

Percutaneous transhepatic cholangiography, 

drainage and stenting of the biliary tree is another 

non-surgical diagnostic and therapeutic option. 

However, an urgent surgical strategy for biliary 

drainage must be considered if antibiotic, endoscopic 

or radiological treatment fails. Depending on 

the degree of inflammation, surgery generally 

involves simple biliary drainage through a cholecystotomy. 

In patients with choledochal malformation, 

definitive surgery must be postponed until the 

peritoneal infection has resolved, because of the 

high risk of complications (including anastomosis 

leak) in patients with active biliary peritonitis. 

Spontaneous perforation of the bile duct 

This is a rare pediatric cause of biliary peritonitis46,47 

that has been described in newborns and 

infants, frequently associated with a choledochal 

cyst or anomalous pancreaticobiliary union. 48,49 In 

the absence of a dilated biliary duct, diagnosis is 

difficult; sometimes, biliary peritonitis is an 

occasional finding at exploratory laparotomy. The 

presence of bile-like fluid at abdominal puncture 

nevertheless suggests this disorder. Patients 

without malformations or peritonitis should 

undergo primary repair, with biliary and abdominal 

drainage. Otherwise, the best choice is simple 

biliary and abdominal drainage, postponing definitive 

surgery. 

Acute pancreatitis 

Acute pancreatitis is a dramatic cause of acute 

abdomen; it is uncommon in children and, in the 

past, has been an occasional finding in acute 

abdomen operated upon for suspected appendicitis. 

50 In acute pancreatitis, abdominal pain, 

referred to the middle or epigastric abdomen, has 

an acute onset and is deep-seated, requiring 

adequate analgesic treatment; abdominal parietal 

tenderness is generally evident. A major decision in 

the management of severe acute pancreatitis is 

whether and when surgery is necessary for 

Infectious and parasitic disease 683 

pancreatic necrosis (see Chapter 21). ERCP, sphincterotomy 

and drainage can be useful as diagnostic 

and therapeutic options if hepatic enzyme 

abnormalities suggest biliary pancreatitis due to 

stones or sludge. 51,52 Somatostatin and octreotide 

are widely used but their efficacy is not 

proven. 53–55 The course of pancreatitis can be 

assessed by monitoring the patients’ general condition, 

fever, hematological variables (white blood 

cell (WBC) count, CRP, lactate dehydrogenase, 

calcium and albumin), and imaging findings (ultrasound, 

CT). 56 In patients with necrosis and, in 

particular, septic necrosis, surgical intervention 

must be considered for drainage of the peripancreatic 

space. 57 

Infectious and parasitic disease 

Typhoid perforation 

Typhoid perforation is a well-known surgical 

complication of Salmonella typhi infection, 58–61 

whose outcome is related to the number of perforations 

and to the severity of peritonitis. 58 This last 

point is obviously related to the timeliness of diagnosis. 

Because no specific warning signs are known for 

identifying a pre-perforation state, the diagnosis 

rests on close clinical observation. Unspecific laboratory 

indexes include elevated WBC count and 

CRP; plain abdominal series will usually identify 

pneumoperitoneum. Multiple therapeutic protocols 

and surgical strategies have been proposed, 

depending on the intensity of peritoneal involvement. 

Antibiotic therapy consists of aminoxide, 

metronidazole and the third-generation 

cephalosporins. 60 In patients without advanced 

peritonitis, and with a single perforated lesion, 

excellent results can be achieved by excising the 

edges followed by direct suture and, in multiple 

perforations, by segmental resection followed by 

end-to-end anastomosis. Patients presenting with 

severe peritonitis must be invariably treated by 

bowel diversion. 59 The most common postoperative 

complications are wound infection and enterocutaneous 

fistula. In a prospective study, the ideal 

treatment for typhoid enteric perforation was found 

to be resection anastomosis with copious peritoneal 

lavage. 62

684 


Non-typhi Salmonella 

In this intestinal infection, toxic megacolon can 

occur. Patients with toxic megacolon have a toxic 

appearance, diarrhea, high fever (>39°C) and 

marked colon dilatation with maximal diameter 

>1.5 times the width of the vertebral body of the 

first lumbar vertebra (L1-VB). A retrospective 

analysis identified as the most significant factors 

associated with intestinal perforation: age >1 year, 

serum CRP >200mg/l; colon diameter >2.5 times 

the width of L1-VB; inadequate early hydration; 

and delay in inserting a rectal tube. 63 

Entamoeba histolytica 

Entamoeba histolytica is another infectious cause 

of colonic involvement; acute abdomen due to 

perforation is rarely reported and related to perforated 

appendicitis. The most frequent manifestations 

are acute intestinal symptoms and bleeding. 

64 In severely ill patients, with acute bleeding 

and general septic signs, misdiagnosis of fulminant-onset 

IBD could result in unnecessary colectomy. 

Intestinal tuberculosis 

This is now widespread and must be suspected in 

patients who present with perforation or occlusion-like 

symptoms, as well as in cases of 

suspected Crohn’s disease, given the similarities 

between these two conditions. Intestinal perforation 

and fistulae were described in 7% of tuberculosis 

patients in a large retrospective series. 65 The 

diagnosis of perforation, due to adhesion between 

the bowel loops, is not easy. In a retrospective 

series, most patients presented with non-specific 

clinical features; pneumoperitoneum on abdominal 

radiographs was present in only 48.3% of 

cases. 66 Surgery consists of resection, end-to-end 

anastomosis and peritoneal drainage. 


Intestinal parasites (besides Entamoeba histolytica) 

are rarely a cause of perforation or occlusion. 

Anisakiasis can be a surprising finding at surgery 

for bowel obstruction; these parasites can be 

suspected in children with acute abdomen caused 

by bowel obstruction, who have eaten raw or 

undercooked fish. Typical ultrasound findings in 

patients with suspected anisakiasis are ascites, 

small-bowel dilatation, focal edema of Kerckring 

folds, 67 markedly thickened bowel loops associated 

with luminal narrowing and decreased peristalsis. 

68 Cytological examination of a specimen 

obtained from ascites by abdominal puncture 

showed a dense infiltration of eosinophils. 68 If the 

foregoing ultrasound features are found, the diagnosis 

of intestinal anisakiasis must be considered, 

because medical treatment has a good outcome 

and will avoid unnecessary surgery. 

Mucormycosis 

Mucormycosis is an increasing concern in 

immunocompromised patients, in whom mortality 

exceeds 60%. The multiple mycotic localizations 

(intestinal wall, liver, kidneys, sinuses, lower 

respiratory tract, or skin) give a dramatic clinical 

picture with acute abdomen secondary to occlusion 

and multiple perforations. The last are due to 

vessel thrombosis. 69,70 The standard treatment is 

amphotericin B combined with surgical debridement 

if necessary, depending on occlusion or 

perforations. In our experience, in one patient with 

fourth-degree neuroblastoma, after the histological 

diagnosis of mucormycosis in the gastrointestinal 

tract (surgical treatment for multiple perforations) 

and the echographic detection of multiple mycotic 

localizations in the liver and kidneys, the treatment 

was high-dose amphotericin B. At the same 

time, to prevent the growth of hyphae, we avoided 

the development of anaerobiosis and/or acidosis, 

as well as hyperglycemia. This therapeutic strategy 

successfully prevents spreading of the infection 

and encourages complete healing. 70 

Acute abdomen caused by 

endoscopic and other diagnostic 

procedures 

Endoscopic procedures, even in skilled hands, can 

be dangerous and provoke complications sometimes 

resulting in acute abdomen. Many of these 

events can be prevented by using strictly pediatric 

instruments, by suspecting a complication before

it becomes irreversible and by instituting specific 

treatments without delay. 

Polypectomy 

Simple rules can help in preventing perforation 

that may become manifest during the procedure or 

some hours later. Delayed perforation is caused by 

deep scalding of the intestinal wall due to the use 

of an inappropriate blend of cutting and hemostatic 

current and excessively high current intensities. 

Incomplete snare closure with its tip hidden by the 

polyp can perforate the intestinal wall. Sometimes 

the perforation becomes evident during the procedure 

because of bleeding and, moreover, because 

insufflation of air fails to distend the bowel, thus 

causing abdominal tension with respiratory 

distress. In cases like this, the complication can be 

resolved by immediate surgical intervention with 

direct suture and drainage. Deep scalding can 

occur during multiple polypectomies or during 

resection of polyps with a large pedicle, especially 

those sited in the right colon or jejunum, where 

the wall is thinner than the gastric or left colon 

wall. Abdominal pain, fever, leukocytosis and 

abdominal wall tenderness can be evident even 

without perforation. In patients with radiological 

evidence of a large, increasing quantity of free 

abdominal gas, surgery might be necessary. If 

surgery is avoided, the lesion may still have a good 

outcome in 2 or 3 days, after treatment with broadspectrum 

antibiotics, metronidazole (22mg/kg per 

day) and strict observation with fasting. 

Colonoscopy in inflammatory bowel disease 

In IBD, an attempted total colonoscopy can be 

hazardous for the patient, owing to the fragility of 

the colonic wall. In our experience, in an infant 

with acute ulcerative colitis careful insufflation 

into the sigma caused perforation of the transverse 

colon. In order to prevent peritoneal infection, the 

patient must undergo emergency surgery to 

attempt a direct suture of the lesion; if the colon is 

extensively damaged a fecal diversion (ileostomy) 

may be required, with or without colectomy. 

In colonic strictures from Crohn’s disease, surgical 

resection or stricturoplasty is increasingly avoided 

Acute abdomen caused by endoscopic and other diagnostic procedures 685 

in favor of palliative therapy with pneumatic 

endoscopic dilatations. 71,72 Because of the wall 

thickness, perforations are rare and the surrounding 

scar tissue hinders the diffusion of gas and 

intestinal contents into the peritoneal cavity. 

Peritoneal involvement is therefore less severe but 

the diagnosis can be delayed. Helpful ways of 

preventing further peritoneal complications 

include diagnostic ultrasound or CT scans, and 

conservative treatment with antibiotic prophylaxis 

and strict observation. 

Percutaneous endoscopic gastrostomy 

To avoid complications related to percutaneous 

endoscopic gastrostomy (PEG), the operator must 

be familiar with its contraindications, relative and 

absolute. The most frequent cause of a PEG-related 

acute abdomen is air, gastric juice or food in the 

peritoneal cavity due to incomplete adhesion of 

the gastric to the abdominal wall. 73–75 During the 

procedure, especially in infants with bowel distension, 

inserting the needle can provoke an 

intestinal perforation that might require surgical 

intervention. 76 In psychiatric and neurologically 

impaired children, premature tube removal can 

provoke peritonitis requiring surgery for peritoneal 

drainage. In patients without peritonitis, surgical 

intervention can be avoided by carefully inserting 

a pigtail wire and replacing the drainage tube, 

under radiographic control, with a slimmer 

gastrostomy Foley catheter (Medical Innovation 

Corporation, Milpitas, CA; Bard Interventional 

Products, Tewksbury, MA, USA). During substitution 

of the PEG with a low-profile device, the 

gastric wall can become detached from the abdominal 

wall. In our experience, in a patient with 

cystic fibrosis, this complication developed after a 

sports injury to the abdomen, which caused 

dramatic invasion of food into the peritoneum and 

required open surgery. 

In certain clinical settings, such as peritoneal dialysis, 

this type of complication can be avoided by 

placing the gastrostomy surgically 77 or by using a 

special kit (Cliny, Create Medic Co, Ltd, Yokohama, 

Japan) which, under endoscopic control, 

allows adhesion between the gastric and abdominal 

wall. Previous abdominal surgery can expose 

patients to a high risk of gastrocolic fistula, and 

surgery is necessary only in cases of dramatic

686 


disruption of the gastric or colonic wall, with peritoneal 

fecal contamination; otherwise antibiotic 

therapy and gastric drainage resolves the problem 

within days. 

Cardia and esophageal dilatations 

Pneumatic or semi-rigid endoscopic dilatations in 

achalasia, or congenital esophageal strictures, can 

provoke perforation of the cardia or of the abdominal 

esophagus and possible acute abdomen. In 

children with esophageal perforation and mediastinum 

involvement, current opinion favors the 

following standard management protocol: nasogastric 

and pharyngeal suction, wide-spectrum antibiotics, 

proton pump inhibitors, total parenteral 

nutrition and daily testing of CRP and WBCs. 

Endoscopic clip closure of the perforation and 

transesophageal drainage can be attempted to 

avoid surgery 13,14 (and D. Fregonese, personal 

communication). The main indications for surgery 

are worsening sepsis and insufficient drainage, 

with diffuse or localized multiple purulent collections. 

The general rule that purulent infection of 

the peritoneum contraindicates resections and 

reanastomosis is even more applicable in these 

cases. In cardia or abdominal esophageal perforation, 

an attempt to suture the lesion may require 

gastrostomy (in order to obtain full gastric 

drainage), jejunostomy (for early enteral nutrition) 

and multiple drainage in the subphrenic and 

posterior mediastinum on both sides of the 

abdomen. In non-responders, esophagostomy and 

esophagogastric disconnection can be life-saving 

maneuvers. 

Duodenal hematoma 

Symptomatic intramural duodenal hematoma 

secondary to duodenal biopsies obtained at 

endoscopy is a rare but sometimes dramatic complication 

leading to possible perforation, pancreatitis 

and occlusion-like symptoms. 78,79 The resulting 

obstruction is self-limited and typically 

resolves spontaneously within a week. Conversely, 

perforation and pancreatitis progress to acute 

abdomen. In a patient with suspected perforation, 

because the posterior duodenal wall lies in the 

retroperitoneal cavity, plain abdominal series 

cannot show free abdominal gas. Nor are abdomi- 

nal pain and muscular tenderness as obvious as 

they are in children with gastric or anterior 

duodenal wall perforation. Ultrasound shows the 

hematoma and, if present, improvement in pancreatic 

thickness, and a CT scan allows the diagnosis 

of perforation to be made. In patients with massive 

infected necrosis of the pancreatic parenchyma or 

retroperitoneal infection, surgical drainage is 

required. 

Endoscopic cholangiopancreatography 

Complications after ERCP are well known in children 

as in adults; their incidence, in diagnostic 

ERCP, is higher in children. 43 The therapeutic 

options are the same in both age groups. 44 Post- 

ERCP pancreatitis is also more frequent in children 

than in adults (8% vs. 3–7%). 45 Its main 

causes are papillary swelling owing to repeated 

cannulations; and pancreatic parenchymography 

due to excessive contrast injection. 80 A transient 

rise in serum amylase level, unaccompanied by 

pain or elevated WBC count or CRP level, is not 

diagnostic of pancreatitis. True pancreatitis with 

acute abdomen generally responds to conservative 

management; in our experience we have observed 

only one case of severe pancreatitis, which was 

conservatively managed but complicated by a 

pancreatic pseudocyst. 

Biliary tree or duodenal perforation is a rare 

complication that can be managed conservatively 

but needs strict clinical surveillance. In a newborn 

with suspected biliary hypoplasia we observed a 

post-ERCP duodenal perforation, near the papilla, 

that responded well to non-surgical therapy. 

Rectal suction biopsy 

This well-known diagnostic procedure is the reference 

standard in the diagnosis of Hirschsprung’s 

disease. The diagnostic role of rectal suction 

biopsy, first described by Noblett, 81 has improved 

with the availability of acetylcholinesterase staining. 

Complications of this procedure are bleeding 

and, especially in newborns, rectal perforation. 

Rectal perforation was described in 0.2% of 1340 

consecutive rectal suction biopsy procedures, 

including one case of buttock gangrene. 82 In our 

experience, we have observed one case of bleeding 

in a patient who received a blood transfusion, and

a case of rectal perforation in a patient with acute 

abdomen and pneumoperitoneum that needed 

laparotomy, surgical suture and drainage. If a deep 

suction biopsy specimen has to be taken below the 

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41 

Introduction 

Management of ingested 

foreign bodies 

Yvan Vandenplas, Said Hachimi-Idrissi and Bruno Hauser 

The first report of a foreign body in a child dates 

from 1692 when Frederick the Great who, at the 

age of 4 swallowed a shoe buckle that passed 

without incident. 1 Accidental ingestion of a 

foreign body occurs frequently in children, and 

accounts for a significant number of emergency 

room visits. In general, accidental ingestion causes 

little or no morbidity. 2–4 In the majority of cases 

that come to medical attention, the ingestion was 

witnessed or is strongly suspected by the child’s 

caretaker. A significant number of accidental 

ingestions are likely to remain asymptomatic, 

since most objects pass without any incident. 

Sometimes the foreign object is discovered by accident 

in the stools 5 . 

Epidemiology 

Ingestion of foreign bodies is mainly a pediatric 

problem, since about 80% of cases occur in children 

between the ages of 6 and 36 months. 6–9 In 

our series of 325 children, the median age of the 

children was 2.8 years (Table 41.1). 6 According to 

reported series, the median age is less than 5 years. 

In adults, ingestion of foreign bodies may be intentional, 

as can be the case in adolescents. 

Intentional ingestion occurs most frequently in 

psychiatrically impaired individuals and prisoners. 

10 The largest series ingested by one individual 

was reported by Chalk and Foucour in 1928 and 

was an assortment of 2533 pins, needles and 

bobbins. 11 We had an adolescent girl who was a 

pencil-swallowing recidivist (unpublished). 

Amongst the miscellaneous foreign bodies 

observed in our series, one developmentally 

retarded child managed to ingest a large plastic bag 

(the type used in supermarkets); the plastic bag 

caused decreased food intake as single symptom. 6 

During recent years, a number of large pediatric 

series have been reported in the literature. The 

series of Weissberg included 70 patients (children 

and adults), 12 Kim et al reported 104 Korean pediatric 

cases, 13 and Olives report a series of 395 children. 

8 Athanassiadi et al reported a series of 400 

cases, 14 and Lam and et al reported as many as 

5240 ingested foreign bodies. 15 In the USA, about 

200000 accidental ingestions occur yearly in children 

and adolescents. 16 In 1997, there were more 

than 21000 emergency room visits by children in 

the USA for coin ingestions alone. 17 The incidence 

Table 41.1 Age distribution of 325 children 

with foreign body ingestion 

Age (years) No. of patients % 

0–1 36 11 

1–2 64 20 

2–3 78 24 

3–4 55 17 

4–5 27 8 

5–6 29 9 

6–7 12 4 

7–8 10 3 

8–10 6 2 

10–18 8 2 

Total 325 100 

Mean age 2.8 years (range 5 months to 18 years) 

Boys/girls, 58/42% 

691

692 

Management of ingested foreign bodies 

Table 41.2 Nature and number of foreign 

bodies ingested 

n % 

Coins 89 27 

Sharp objects (needles, pins, etc.) 51 16 

Batteries 43 13 

Toy parts 38 12 

Bones (fish, chicken) 38 12 

Large food bags 37 12 

Jewellery 19 6 

Miscellaneous 10 3 

Total 325 100 

and type of foreign body ingested depends on the 

geographic region (and reports depending on the 

specialty of the author). In our department, during 

a period of 15 years, 325 pediatric cases were seen 

because of ingestion of a foreign body or symptoms 

of acute esophageal obstruction. In general, coins 

are the most common foreign bodies ingested, and 

account for 27–70% of all cases 6,10,18-21 (Tables 

41.2 and 41.3, and Figure 41.1). History in determining 

coin denomination is unreliable. 22 In 

seaside regions, fish bones tend to be the most 

important. 23 The incidence of accidental ingestion 

of fish bones in China seems very high, with an 

incidence reaching 84%. 24 In the children of this 

series, fish bones accounted for 43% and coins for 

39%. 24 Other frequently ingested objects are sharp 

objects such as needles and pins, batteries, toy 

parts, chicken or fish bones. Each accounts for 

5–30%, depending on the series. 6,10,23 In adults, 

unintentional ingestions most frequently involve 

meat or fish bones. Gastric (tricho-) bezoars can be 

considered as a special group of foreign bodies, 

most of the time needing surgical removal. 25 In 

young infants, lactobezoars can cause gastric 

outlet obstruction. 26 Some candies contain a gel 

that may become compact in the intestinal lumen 

and cause obstruction. 27 

Table 41.3 Comparison between our data 

and the study reported by Olives 8 

In our series of 325 children, 12 children had 

ingested more than one foreign body. Ten children 

were ‘recidivists’, and were seen twice because of 

ingestion of a foreign body. 6 Overall, natural elimination 

occurred in 46% of the patients. 6 


Location of the object 

Present study Olives 8 

Number of 325 395 

patients 

Age distribution 5 months 2 months 

to 18 years to 18 years 

Boy/girl ratio (%) 58/42 60/40 

Radio-opaque 60 64 

foreign body (%) 

Asymptomatic (%) 46 20 

Dysphagia, 24 59 

restrosternal pain (%) 

Coins most frequent most frequent 

(27%) (40%) 

Endoscopic 25 85 

removal (%) 

Success rate (%) 99 64 

Perforation (n) 0 0 

Most swallowed foreign bodies do not come to 

medical attention as they do not cause symptoms. 

Sometimes foreign bodies are discovered by coincidence, 

on a standard X-ray that was performed 

for other indications. 6 The majority of coin ingestions 

are asymptomatic. 6,23 The symptoms of 

obstruction caused by a foreign body depend on 

patient age, object size and its location. Symptoms 

in young children are non-specific and can include 

choking, drooling and poor feeding. There may be

Symptomatic 

endoscopy and 

• FB trapped in esophagus: push into stomach 

• attempt at removal 

(fasting if symptoms allow waiting time) 

Symptomatic 

endoscopy and 

• FB trapped in esophagus: push into stomach 

and in pharynx, esophagus: removal/push into 

stomach 

• attempt at removal 

(fasting if symptoms allow waiting time) 

Normal 

X-ray neck, chest (anterior–posterior, lateral) 

normal: wait and see 

FB: removal 

a time interval between ingestion and development 

of (respiratory) symptoms in infants. 10 

Children may alter their diet to consume liquids or 

a soft diet. Older children and teenagers with a 

foreign body in the esophagus typically complain 

of dysphagia, odynophagia and chest pain. 

Depending on the organization of medical care, 

approximately 5–10% of patients will have the 

foreign body located in the oropharynx, 20% in the 

esophagus, 60% in the stomach and 10% distal to 

the stomach. 28 Where fish bone ingestion is 

History of radio-opaque foreign body (FB) 

Fluoroscopy or X-ray neck, chest, stomach (abdomen) 

History of radiolucent swallowed foreign body 



Asymptomatic 

FB In pharynx, esophagus: removal/push into stomach 

FB in stomach: removal if sharp, battery, large (> 3–4 cm 

in length) 

(magnet probe vs. endoscopy) 

FB beyond stomach: wait and see if after 1–2 weeks, FB 

not observed in stools: control X-ray 

Asymptomatic 

X-ray with contrast (visualizes FB if trapped in 

esophagus, diagnostic possibly therapeutic) 

if FB remains in esophagus: endoscopy when fasting 

if FB not in esophagus: wait and see (observe stools) if 

after 1–2 weeks, FB not observed in stools: control 

X-ray 

History of choking spell (acute onset of severe onset cough, difficulty 

breathing, anxiety) 

Abnormal 

X-ray neck, chest (anterior–posterior, lateral) 

FB: removal 

Figure 41.1 Proposed recomendations for a child who has possibly swallowed a foreign body or presents the symptoms 

suggesting esophageal obstruction. 

common, a higher percentage of patients will have 

the foreign body located in the oropharynx. In 

general, foreign bodies in the oropharynx are 

symptomatic and cause dysphagia. 6–10 In our 

series, 22 of the 28 (79%) foreign bodies in the 

oropharynx were bones from fish or poultry. The 

rest were glass and there was one metal object. 6 

These foreign bodies were visible on physical 

examination of the oropharynx. 6 Additionally, it 

should be mentioned that there were 17 children 

who became symptomatic during the eating of fish 

or poultry, but with a negative inspection and no

694 


visualization of a bone on X-ray. Because symptoms 

persisted in these children, endoscopy was 

performed and a (small) laceration of the pharyngeal 

or esophageal mucosa could be observed in 

eight of them. 6 

In our experience, 54% of the children had transient 

symptoms immediately after the ingestion. 6 

In the patients in whom the ingestion was not 

witnessed (32 out of 176; 18%), the sudden onset 

of symptoms (such as acute and severe coughing, 

pain, etc.) and the circumstances of this sudden 

onset made the diagnosis of accidental ingestion 

suspected. Symptoms were in almost all cases pain 

or discomfort at the pharyngeal or retrosternal 

region, excessive saliva production, nausea and 

vomiting, acute coughing and difficulties in 

breathing. In 28 out of 325 patients (9%), the event 

was accompanied by more severe manifestations 

such as cyanosis or severe dysphagia. 6 

Approximately 60–70% of foreign bodies that 

become stuck in the esophagus are located in the 

proximal esophagus at the level of the upper 

esophageal sphincter. 10,28 Twenty per cent of the 

obstructions occur at the lower esophageal sphincter; 

the rest occur in the mid-esophagus at the level 

of the aortic notch. Patients with underlying 

esophageal disease are at greater risk for the 

foreign body being entrapped in the esophagus. 

Especially children with congenital esophageal 

atresia, tracheoesophageal fistula or fundoplication 

are at risk. Coins are relatively frequently 

trapped in the esophagus, although the reported 

incidence varies from 5 to 60%, mostly at the level 

of the upper or lower esophageal sphincter. 29,30 

The history of the child does not help to understand 

the pathophysiological reason of this trapping. 

Manometric measurements of the sphincters 

have not been performed in these patients. 

Respiratory symptoms such as wheezing, stridor 

and speech impairment may be the only symptoms 

of a foreign body in the esophagus. Respiratory 

symptoms can be the consequence of 

paraesophageal soft tissue swelling 10 . Isolated 

respiratory symptoms are more frequent in infants 

and toddlers. 

In our published series, the vast majority of the 

foreign bodies (196; 60%) were located in the 

stomach at the time of presentation. 6 Thirty-six 

(11%) foreign bodies were already located in the 

small intestine at first presentation. 6 All these, 

except three, were eliminated spontaneously. 

Three foreign bodies were very long sharp metal 

objects (screws of >5cm) located in the duodenum 

at presentation. In order to avoid complications, 

they were endoscopically removed under 

anesthesia. Gastric and intestinal foreign bodies 

may cause obstruction and perforation. 

Complications 

Yearly, approximately 1500 deaths occur in the 

USA secondary to foreign body ingestion 31 . 

Foreign bodies impacted in the oropharynx are 

usually sharp and cause symptoms, and may cause 

life-threatening complications such as retropharyngeal 

abscess and perforation. 23,32–35 

Perforation is one of the most dangerous complications, 

but occurs in less than 1% of cases. Sharp 

objects are associated with a much higher perforation 

rate than dull objects. 36 Pins can cause gastric 

perforation and migrate into the thorax. 36 The 

notion that ‘advancing points perforate and trailing 

points do not’ dates back to 1937, based on the 

evidence provided by analysis of 3266 accidental 

ingestions and inhalations. 37 A foreign body 

entrapped in the esophagus may initially be 

asymptomatic, but cause ulceration of the 

esophageal mucosa due to pressure necrosis in 

case of a dull object. Sharp objects may perforate, 

and cause aortic–esophageal fistula, mediastinitis, 

tracheo-esophageal fistula and bronchoesophageal 

fistula. 23 Esophageal diverticula or 

pseudodiverticula may develop secondary to pressure 

by a dull object. 

Death because of multiple perforations occurred 

within 2 months in an individual who had swallowed 

over 500 pins. 38 No child in our series or in 

Olives’ series presented with perforation. 6,8 In the 

series reported by Weissberg, 15 perforations 

occurred in 70 patients. 12 Differences and similarities 

between the reported series are likely to be 

related to the selection of the patients. 39 

Perforation can result in extraluminal migration of 

the foreign body. Perforations occur most 

frequently in the region of the ileocecal valve. 

Congenital malformations such as Meckel’s diverticulum 

or prior intestinal surgery are sites of

increased risk for foreign body entrapment and 

perforation. 28 

Foreign bodies only rarely cause jejunal, ileal or 

colic obstruction, although it has been reported to 

occur. 40 Obstruction of the appendix with a foreign 

body is extremely rare. 41 

Metallic foreign bodies such as coins that remain 

for several weeks in the stomach could cause toxicity, 

especially with zinc-predominant coins. 17 

Diagnosis and differential diagnosis 

Rapid diagnosis and treatment of foreign bodies 

trapped in the gastrointestinal tract will decrease 

morbidity and length of hospital stay. 42 A foreign 

body not discovered in all patients with symptoms 

suggests the presence of an object in the oropharynx. 

In the series of Olives, 11% of the swallowed 

foreign bodies were not found in the gastrointestinal 

tract. 8 

Oral fluids make coins move easily into the 

stomach. 30 Therefore, a 5-day observation at home 

is advised. 30 Whether X-ray is recommended in 

every child who is suspected of having swallowed 

a foreign body has been a topic of controversy for 

many years. 43 Between 60 and 90% of ingested 

foreign bodies are radio-opaque. 6,10,18 Although 

most foreign body ingestions remain asymptomatic, 

when ingestion is witnessed it is recommended 

to perform a roentgenogram because the 

object may be lodged in the esophagus and pose a 

risk to the patient even if asymptomatic. 28 An anterior–posterior 

X-ray demonstrates the location of a 

coin. A lateral radiograph may be helpful in case of 

ingestion of a sharp object such as a needle or a pin 

to exclude asymptomatic location in the airways. 

Since esophageal trapping of a foreign body may 

remain asymptomatic, and since chronic 

impaction may cause ulceration and necrosis of 

the mucosa, fluoroscopy or X-ray is advised. 

Unnecessary exposure to radiation is less harmful 

than the consequence of chronic impaction. A 

simple X-ray or fluoroscopy (smaller irradiation 

than X-ray) is much easier than the use of metal 

detectors. 44,45 

In 6% of our patients, the foreign body was radiolucent, 

with five cases with a fish or chicken bone 

Diagnosis and differential diagnosis 695 

that penetrated the esophageal mucosa and 16 

cases of impaction of a food bolus 6 . Three of these 

children were psychomotor retarded, and the 

other children had been operated upon previously 

because of an esophageal atresia and were known 

to have a residual esophageal stenosis. 6 Non-radioopaque 

foreign bodies represent a much more 

difficult diagnostic challenge than radio-opaque 

bodies. A negative radiographic analysis does not 

rule out the presence of a foreign body in the 

gastrointestinal tract. 42 Indeed, non-radio-opaque 

foreign bodies such as plastic bag clips seem to be 

relatively frequently swallowed, and may cause 

obstruction and perforation. 46 If a non-radioopaque 

foreign body is not observed in the stools 

after a period of 2 weeks, control investigations 

should be performed. We perform contrast X-ray to 

detect a gastric foreign body, because we consider 

this less invasive than endoscopy. 

Chronic unexplained respiratory disease necessitates 

the exclusion of a foreign body in the gastrointestinal 

tract or airways. This object can be radiolucent 

and therefore difficult to diagnose. In such 

a case, the majority of centers recommend diagnostic 

and immediate therapeutic bronchoscopy. 47 


Over 80% of foreign body ingestions that come to 

medical attention are naturally eliminated spontaneously. 

Ten to twenty per cent require endoscopic 

removal, and less than 1% require surgery. 6 

Foreign bodies located in the oropharynx may be 

visible on physical examination, and if this is the 

case, the foreign body can be removed with the 

help of a Magill’s forceps or similar equipment. 48 

In our experience, the foreign body was impacted 

in 28 (9%) of the patients in the oropharynx on 

presentation, and could be extracted with a Magill 

forceps. 6 

Symptomatic patients who are unable to swallow 

their secretions and those with respiratory symptoms 

should undergo emergency endoscopy. 49 The 

first endoscopic extraction dates from 1972. 50 

Different forceps and baskets used for removal are 

shown in Figure 41.2. Sharp objects and batteries 

should be removed whenever possible. 21 Straight 

pins are the exception to the perforation risk,

696 


because the blunt-ended head passes first through 

the gastrointestinal tract. (However, sharp metal 

objects can also be removed safely with a magnet.) 

The incidence of endoscopic removal is as low as 

25% in our series, but is 77% and 85% in other 

series, 8,23 and with a success rate of 99% in our 

experience and that of Kim et al, 6,13 whereas 

Olives reported a failure rate of 36%. 8 The timing 

of the extraction of the body from the esophagus 

depends on the severity of the symptoms and the 

fasting state of the patient. 6 Sedation and anesthesia, 

or esophageal introduction of the endoscope or 

magnet probe, in half of our patients caused relaxation 

of the sphincter, resulting in a spontaneous 

passage of the foreign body into the stomach. If the 

patient was under anesthesia, the foreign body was 

removed. If the patient was only sedated, 

endoscopy was stopped and the management for 

gastric foreign bodies was applied (Figure 41.3). 6 

Intravenous administration of glucagons dilates 

the esophagus and has been successfully used in 

adults, but has not been effective in children. 51 

Figure 41.2 Alligator jaw forceps, tripod or pentapod 

forceps and baskets used for endoscopic removal. 

Figure 41.3 Foreign bodies that have been extracted from the gastrointestinal tract in our unit.

Esophageal extraction with a Foley catheter was 

already reported in 1966 by Bigler. 52 Smooth 

foreign bodies can be removed from the esophagus 

with a Foley catheter. 10 This technique has been 

reported to be 95% successful. 53 Fluoroscopically 

guided Foley catheter extraction of retained coins 

in pediatric patients who lack evidence of significant 

esophageal edema causing tracheal compromise 

is a safe and efficacious technique. 54 

However, the procedure has also been said to be 

potentially dangerous, because a foreign body can 

flip out with catheter removal, and cause immediate 

respiratory complications. 55 

If the foreign body is in the stomach at the moment 

of presentation, the recommended attitude is to 

‘wait and observe’, except for long sharp objects 

such as needles and pins (>3 to 4cm). 6 Gastric 

coins do not have to be extracted, since the majority 

of them will be eliminated spontaneously. 30 

However, extraction is recommended if, after 

several weeks, the object is still in the stomach. 6 

Also, administration of prokinetics has been 

reported in this indication, 7 although this is not 

recommended. Objects greater than 10cm in 

length in the stomach of an adult-size patient 

cannot pass the duodenum. 49 An ovoid object 

greater than 5cm in length or with a thickness 

greater than 2cm is unlikely to pass the pylorus. 56 

Objects of the size of toothbrushes 1 or pencils 

(own experience) should be removed from the 

stomach. Anecdotally, in one of our cases, when a 

child had swallowed a ring worth over $2000 in a 

jeweler’s shop, the ring was removed immediately. 

In our department, magnetic foreign bodies are 

removed with a magnet probe. 6 In the series we 

reported, extraction of batteries was attempted 

with a magnet probe, but failed in four cases out of 

36. 6 The largest series of battery ingestions 

reported was from a national survey registry 

reporting 2382 ingestions in 2320 patients. 57 

Button batteries from hearing aids are frequently 

ingested. Children imitate body piercing by using 

small powerful magnets across parts of their body 

including nose, ears, penis and tongue. 58 Some 

swallowed the magnets while attempting to use 

them, resulting in at least one near fatal complication. 

58 There have been 25 reported cases of batteries 

dislodged in the esophagus, causing develop- 


ment of fistula, strictures and even death. 57 

Batteries impacted in the esophagus should be 

immediately removed. 49,59 Severe complications 

have occurred even with small batteries, and 

esophageal perforation was reported within 6h 

after ingestion. The caustic material in the battery, 

and perhaps discharge of current, may be responsible 

for the rapid development of severe complications. 

60 Batteries contain corrosive substances 

and may cause necrosis of the mucosa in case of 

leakage. 4,21,61 Ingestion of 12 small magnets 

caused perforation; the magnets were attracted to 

each other and caused pressure necrosis. 62 As a 

consequence, according to some authors, batteries 

cause a dilemma between a ‘wait-and-see’ attitude 

and an urgent laparoscopy. 59,63 Therefore, the 

development of a magnet probe is a useful tool, 

since it enables easy extraction in safe conditions. 

9,61,64,65 In our series, all gastric needles and 

pins could be removed with the magnet probe, 

except for two patients who had swallowed open 

safety pins. In these cases, endoscopic extraction 

under anesthesia was performed. 6 

Prevention is preferable to treatment. Modification 

of toy manufacturing practices and labeling 

standards may decrease the relative incidence 

of toy part ingestion. The US Consumer Product 

Safety Commission considers the toys within eggs 

to violate the small parts regulation of this 

Commission with respect to children under 3, and 

therefore these chocolate eggs are not allowed to 

be marketed in the USA, although no injuries 

involving these toys have been reported to date. 66 

Appropriate equipment and personnel for emergency 

resuscitation should be present when 

removing a foreign body without general anesthesia 

and intubation. 6 

Food impaction 

Impaction of food, usually meat, is the most 

common obstruction in adolescents and in 

toddlers after esophageal repair for congenital 

atresia. 67,68 Contrast radiography is not indicated 

because of the risk of aspiration. 49 If the symptoms 

are not too serious, tenderizers can be help. 67 Cola 

drinks in small amounts can also help in digesting 

impacted food (own experience).

698 


Cocaine ingestion 

This phenomenon occurs primarily in adolescents 

and young adults who act as a ‘mule’ and ingest 

cocaine-filled condoms as a method of smuggling. 

49 Absorption of 1–3g of cocaine following 

condom rupture is fatal, but one condom contains 

3–5g. 

Follow-up 

A telephone survey 2 weeks after ingestion of the 

foreign body did not reveal any unexpected 

complication. 6 In our experience, with a gastric 

foreign body that was not extracted, we advise the 

parents to observe the stools for 2 weeks. 6 If the 

foreign body was not observed in the stools, which 

was the case in as much as 62% of our patients, a 

control X-ray was performed. 6 In our series, in 

about two-thirds of the cases, the foreign body 

appeared to be eliminated spontaneously, despite 

being undetected by the parents. 6 This finding is 

in accordance with those of Macgregor and 

Ferguson stating that almost 50% of the foreign 

bodies were not recovered in the stools. 7 In about 

one-third, the foreign body was still present in the 

stomach. In that case, the foreign body was 

actively removed. 6 Kim et al 13 reported a spontaneous 

elimination of the foreign body in only 22% 

of cases, whereas we observed this phenomenon in 

almost half of our patients (46%). Amin et al 

reported a gastric passage of only 19% of ingested 

coins. 22 The transit time is variable and unpre- 

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49. Wahbeh G, Wyllie R, Lay M. Foreign body ingestion in 

infants and children: location, location, location. Clin 

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50. Morrissey JF. Gastrointestinal endoscopy. Gastroenterology 

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51. Mehta D, Attia M, Quintana E, Cronan K. Glucagon use 

for esophageal coin dislodgment in children: a prospective, 

double-blind, placebo-controlled trial. Acad Emerg 

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52. Bigler FC. The use of a Foley catheter for removal of 

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53. Campbell JB, Condon VR. Catheter removal of blunt 

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54. Harned RK 2nd, Strain JD, Hay TC, Douglas MR. 

Esophageal foreign bodies: safety and efficacy of Foley 

catheter extraction of coins. Am J Roentgenol 1997; 169: 

443–446. 

55. Myer CM III. Potential hazards of esophageal foreign 

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56. Koch H. Operative endoscopy. Gastrointest Endosc 1977; 

24: 65–68. 

57. Litovitz T, Schimitz BF. Ingestion of cylindrical and 

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1992; 89: 747–757. 

58. McCormick S, Brennan P, Yassa J, Shawis R. Children 

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59. Chan YL, Chang SS, Kao KL et al. Button battery ingestion: 

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60. McDermott VG, Taylor T, Wyatt JP. Orogastric magnet 

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62. Cauchi JA, Shawis RN. Multiple magnet ingestion and 

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bougienage. J Pediatr Surg 1999; 34: 412–414.

42 

Introduction 

Medical aspects of intestinal 



Intestinal transplantation was first demonstrated 

to be technically feasible in humans in the early 

1960s. 1 The initial excitement, however, rapidly 

decreased when post-transplant rejection and 

severe sepsis resulted in high morbidity and 

mortality rates. 1 After extensive experimental 

reports, and despite very encouraging clinical 

results for heart and liver transplantation, the use 

of cyclosporin A did not enable, except in one 

child, 2 long-term survival after isolated smallbowel 

transplantation for short-bowel syndrome. 3 

In the early 1990s, two advances made intestinal 

transplantation a promising option for the treatment 

of end-stage intestinal failure: the combination 

with liver transplantation 4 and the development 

of FK506 (tacrolimus). 5 Recent advances in 

immunosuppressive treatment and the better 

monitoring and control of acute rejection have 

brought intestinal transplantation into the realm of 

standard treatment for intestinal failure. The 

results from the Intestinal Transplant Registry 

(www.intestinaltransplant.org) indicate that intestinal 

transplantation is currently an acceptable 

clinical modality for selected patients with irreversible 

intestinal failure. 6,7 

Irreversible intestinal failure 

Intestinal failure is a condition in which gastrointestinal 

function is insufficient to satisfy body 

nutrient and fluid requirements. Parenteral nutrition 

(PN) and home PN remain the mainstay of 

therapy for intestinal failure, whether it is partial 

or total, provisional or permanent. Since its introduction, 

PN has improved greatly, especially with 

the development of home PN. 8–12 Data from the 

European Registry indicate that the long-term 

survival of non-malignant patients on home PN is 

currently higher than the 1–3-year survival after 

isolated intestinal transplantation. 9 The North 

American Home Parenteral and Enteral Nutrition 

Registry reported 1- and 4-year survival rates of all 

children receiving PN at home as a result of shortbowel 

syndrome of 94 and 80%, respectively. 12 

The survival rates of patients with chronic intestinal 

pseudo-obstruction are inferior, being 87 and 

70%, respectively. Although long-term PN is associated 

with complications such as liver impairment, 

bone disease, vascular thrombosis and 

sepsis, innovative therapeutic modalities are 

required. Indeed, some patients develop complications 

while receiving standard therapy for intestinal 

failure and are considered for intestinal 

transplantation. Indications for intestinal transplantation 

involve mostly pediatric patients and 

may be divided into three main group: short-bowel 

syndrome, intestinal motility disorders and 

congenital diseases of the epithelial mucosa. 


Short-bowel syndrome (see also Chapter 29) 

caused by extensive resection of the small bowel 

has logically been the first indication for intestinal 

transplantation. After extensive resection of the 

small bowel, most neonates now survive and 

acquire gastrointestinal autonomy after a period 

depending on the extent and site of resection, the 

preservation of the ileocecal valve and the quality 

of the remaining gut. 13,14 Two groups are potential 

candidates for intestinal transplantation. Infants 

left with only a duodenum or at most 10cm of 

jejunum and no ileocecal valve will remain permanently 

dependent on PN. A small number of 

infants, approximately 10–15% in our experience, 

who have undergone massive intestinal resection 

701

702 

Medical aspects of intestinal transplantation 

in the neonatal period are at high risk of permanent 

intestinal failure when a stereotypical combination 

of features are present: small-bowel length 

of less than 30–40cm, absence of ileocecal valve, 

resection of some colon, minimal tolerance of 

enteral feeding within the first months after 

intestinal resection, dilated intestinal loop and 

bacterial overgrowth, and multiple surgical procedures. 

15 Older children or adolescents have a 

lesser degree of growth potential of the bowel 

compared with neonates who have extensive 

intestinal resection. Intestinal adaptation and 

intestinal absorption sufficient to meet growth 

requirements can only be obtained if the length of 

remaining small bowel is more than 50–60cm 

beyond the angle of Treitz. Some children do not 

become autonomous even after more than 10 years 

of home-based PN, and are thus candidates for 

intestinal transplantation. 16 

In patients with short-bowel syndrome on longterm 

PN, intestinal transplantation can only be 

envisaged once it has been formally shown that 

the remnant bowel cannot adapt. Surgical approaches 

such as lengthening of the small bowel, loop 

interposition or assembly of a ‘reverse’ intestinal 

loop should be attempted. 17–21 

Trophic factors such as recombinant human 

growth hormone (rhGH) might be helpful in some 

patients and might contribute to decreasing the 

need for intestinal transplantation in the near 

future. Studies have indicated that pituitary 

hormones modulate small-bowel growth in 

animals. 22–24 Clinical studies have provided 

controversial results. 25–30 Recent data in adults as 

well as in pediatric patients demonstrated that 

rhGH treatment sometimes allows improvement in 

intestinal function. 27–30 Glucagon-like peptide-2 

(GLP2) might, in the near future, be very helpful in 

enhancing gut mucosa trophicity and in reducing 

delay for achieving intestinal autonomy. 31 

Therefore, only a small number of patients with 

short-bowel syndrome are candidates for intestinal 

transplantation in the absence of life-threatening 

complications, especially progressive liver disease 

which raises another problem. The prevalence of 

complicated home PN-related liver disease 

increases with a longer duration of PN. This condition 

is one of the main causes of death in patients 

with permanent non-malignant intestinal failure. 32 

Some pediatric patients were reported to have 

received an isolated liver transplantation for endstage 

liver disease complicating short-bowel 

syndrome. 33–35 Some of them became intestinally 

autonomous after liver transplantation. However, 

it is important to stress that to be obliged to transplant 

the liver to achieve intestinal autonomy is 

clearly not the most logical or the easiest procedure. 

Thus, the primary aim must remain to 

prevent end-stage liver disease in short-bowel 

patients by using appropriate and long-term PN 

especially in the patients at high risk of liver 

disease. 

Intestinal motility disorders 

Motility disorders in childhood include total aganglionosis 

(extensive Hirschsprung’s disease) and 

chronic intestinal pseudo-obstruction syndrome. 

The first causes the same problems as short-bowel 

syndrome, with two main differences. The nonfunctioning 

colon is excluded and the ganglionic 

small bowel has motility disorders. Therefore, 

when normally innervated small bowel is shorter 

than 60cm the probability of long-term PN dependency 

is high. Logically, this situation requires a 

combined colon transplantation. 36,37 Chronic 

intestinal pseudo-obstruction syndrome (see 

Chapter 18) is a very heterogeneous condition with 

regard to clinical presentation, histopathological 

features, severity of motility disorders and 

outcome. 38–40 In our experience, 20–25% of 

patients will become dependent on long-term 

PN. 38 Recent data reported that intestinal transplantation 

or multivisceral transplantation have 

been performed in these patients, including some 

with associated urinary tract involvement. 41,42 

Munchäusen syndrome by proxy causing intestinal 

pseudo-obstruction must be recognized, even 

if difficult, and never justifies intestinal transplantation, 

as previously reported. 43 

Congenital enteropathies 

Two congenital intractable epithelial mucosal 

diseases are responsible for permanent intestinal 

failure and are currently recognized as requiring 

intestinal transplantation: microvillus inclusion 

disease and epithelial dysplasia (see Chapter 1). 

Both are autosomal recessive inherited disorders

with neonatal onset of severe watery diarrhea and 

total malabsorption. Microvillus inclusion disease 

involves the intracellular pathway of brush-border 

development, 44 whereas epithelial dysplasia is associated 

with abnormal enterocytes and basement 

membrane. 45 The primary inherited defect is not 

currently known for either of these diseases. Some 

children with one of these two mucosal diseases 

have undergone successful small-bowel transplantation 

in isolation or in combination with the liver. 46–52 

Clinical results after intestinal 


Immunosuppressive treatment 

The current immunosuppression we use is based on 

tacrolimus (Prograf ® ), steroids and monoclonal antibodies 

directed against interleukin-2 (IL-2) receptors 

(anti R-IL2 mAb). Tacrolimus is started intraoperatively 

to maintain whole blood levels using 

microparticle enzyme immunoassay technology, 

around 15–20ng/ml during the first month, 

10–15ng/ml during the following month and 

5–10ng/ml thereafter. Methylprednisolone is given 

as an initial bolus (20–25mg/kg over 6 hours), then 

2mg/kg per day during the first month and then 

progressively tapered to 0.5mg/kg every other day. 

Rapamycin (sirolimus) is now used in children, but 

follow-up is too short, even if encouraging results 

have been reported. 53 However, no randomized trial 

using this drug for intestinal transplant recipients is 

yet available. Azathioprine (Imuran ® ) is now rarely 

used and has mainly been replaced in some 

programs by mycophenolate mofetil. Caution is 

recommended with the use of mycophenolate 

mofetil because it has been shown to induce diarrhea. 

54 A new monoclonal antibody Campath ® was 

recently reported to improve survival after intestinal 

transplantation. 55 

Other procedures have been proposed for decreasing 

immunogenicity of the graft such as irradiation or 

for enhancing the natural microchimerism by infusing 

recipients with donor bone marrow during the 

perioperative period. 56 Combined bone marrow 

augmentation did not significantly improve graft 

survival 57 and was reported to favor the occurrence 

of graft-versus-host disease (GVHD) in animals. 58 

Clinical results after intestinal transplantation 703 

Survival after intestinal transplantation 

Current clinical results come from the data 

collected through the International Intestinal 

Transplant Registry (www.intestinaltransplant. 

org). To date, approximately 1000 intestinal transplantations 

have been performed throughout the 

world, mostly in the USA, Canada, France and the 

UK. The current available data from the registry 

include 989 transplantations in 923 patients from 

61 intestinal transplantation programs. Among 

recipients, 61% were children or adolescents. The 

transplants involved the isolated small-bowel 

transplantation with or without the colon (37%), 

the liver + small-bowel transplantation (50%) and 

multivisceral grafts (13%), including the stomach, 

pancreas, liver and small-bowel. 

The main indications in 563 children were shortbowel 

syndrome (63%), chronic intestinal pseudoobstruction 

syndrome (10%), severe intractable 

diarrhea (10%), total aganglionosis/Hirschsprung’s 

disease (7%), and in 360 adults: ischemia (23%), 

Crohn’s disease (14%), trauma (16%), desmoid 

tumor (9%) or tumors (8%). The main immunosuppression 

included tacrolimus (97%) and steroids in 

association with a variety of immunosuppressive 

agents including mycophenolate mofetil, 

rapamycin, azathioprine and IL-2 blockers. 

Overall 3-year patient survival is around 50–60% 

depending on several factors related to the type of 

transplanted organ (e.g. isolated intestine or combined 

with liver), the experience of the center, the 

immunosuppressive regimen including rapamycin 

or not, and the period from 1991 to now (Figure 

42.1). Post-transplant death was due mainly to 

infections (46%), multiorgan failure (2.5%) or 

lymphoma (10%). Full nutritional autonomy with 

complete discontinuation of PN has been achieved 

in 81% of survivors and partial recovery was documented 

in another 10% giving a total rehabilitation 

rate of 85% in survivors, 8% of the intestinal grafts 

being removed. 

It is clear from the intestinal transplantation 

registry and from individual programs that prognosis 

has improved during the past 10 years. 

Surgical procedures are well described and 

adapted to each organ combination. 59 Patient 

survival is associated with the type of organ transplanted, 

with better survival after small-bowel

704 


% Survival 

1.0 

0.9 

0.8 

0.7 

0.6 

0.5 

0.4 

0.3 

0.2 

0.1 

0.0 

0 1 2 3 4 5 6 7 8 9 10 

Figure 42.1 Actuarial graft survival according to the era of intestinal transplantation (data available from the International 

Intestinal Transplantation Registry, www.intestinaltransplant.org). 

transplantation. Nevertheless, these results must 

be interpreted with care because they represent 

the first 12 years’ experience of a large number of 

programs in children and adults, using different 

immunosuppressive regimens. The results from 

the largest of these centers reflect the current situation 

more closely. 60–65 In addition, programs that 

have performed at least ten transplants have better 

graft and patient survival rates compared with 

those that have performed less than ten. 7 

At the University Hospital Necker in Paris, 25 

isolated intestinal transplantations and 30 

combined intestine–liver transplantations were 

performed from November 1994 in 51 children 

(17 girls) ranging in age between 2.5 and 15 years 

(median 5 years). Associated right colon transplantation 

was performed 37 times (21 

intestine–liver transplants). All patients were on 

long-term PN for a median duration of 4.5 years 

(range 18 months–13 years) for congenital 

≥ 1998 

Years post-transplantation 

1992–1997 

≤ 1991 

enteropathy (n=18), short-bowel syndrome 

(n=14), extensive Hirschsprung’s disease (n=13) 

and intestinal pseudo-obstruction (n=6). 

Immunosuppression included tacrolimus, methylprednisolone, 

azathioprine and IL-2 blockers. With 

a follow-up ranging between 6 months and 8.5 

years, 36 patients are alive (patient survival 

70.5%; graft survival 65%). The following factors 

are significantly related to poor outcome (death or 

graft loss) age >7 years (p

Liver-induced immune tolerance 

It is currently difficult to analyze the difference in 

intestinal graft survival rates between isolated and 

combined liver–intestine transplant. In general, the 

clinical status of liver–small bowel recipients is 

poor at the time of transplantation and contributes 

to the high post-transplant rate of morbidity and 

mortality. This is suggested by the 1- and 2-year 

survival of patients, who have not undergone 

transplantation, being 30 and 22%, respectively, 

and the number of deaths on the waiting list. 66 On 

the other hand, the isolated small-bowel graft not 

only has the highest incidence of rejection, but also 

requires more intense immunosuppression to 

control it. It appears from our experience that the 

most encouraging results have been with combined 

small bowel–liver transplantation. Intestinal graft 

rejection was less frequent and less severe in small 

bowel–liver transplant recipients. Simultaneous 

liver grafting might reduce the risk of intestinal 

rejection as supported by experimental data 67,68 

and clinical results. 60,69 

The mechanism by which the liver induces tolerance 

is still under debate. The deletion of donor 

alloreactive T cells was initially suggested but 

remains controversial. 70 Other mechanisms such as 

anergy or the generation of regulatory cells might 

contribute to liver-induced tolerance, as suggested 

by the decreased expression of CD25 or CD8 T cells 

infiltrating tolerated intestinal graft and the reversal 

of tolerance by IL-2. 71 Currently, the role of 

liver-derived dendritic cells in inducing tolerance 

is stressed. 72 A better insight into the mechanisms 

involved in liver-induced tolerance is important in 

the design of immunosuppressive regimens for 

small bowel–liver transplant recipients, because 

there is experimental evidence that immunosuppressive 

drugs may inhibit the tolerogenic effect of 

the liver. 73,74 

Complications after intestinal 


The singularities of the gut may impede intestinal 

transplantation for several reasons: 

(1) The gut-associated lymphoid tissue can 

induce GVHD and may enhance allograft 

Complications after intestinal transplantation 705 

rejection and the subsequent risk of Gramnegative 

sepsis; 

(2) The secretion of lymphokines or the production 

of cytotoxic T cells in response to intraluminal 

pathogens may impede the induction of 

tolerance and thereby favor allograft rejection; 

(3) The need for heavy immunosuppressive 

treatment increases the risk of developing 

opportunistic infection and post-transplant 

lymphoproliferative disorders (PTLD). 

Graft-versus-host-disease 

GVHD has been extensively studied in animal 

models of intestinal transplantation. 1 In humans, 

despite the presence of circulating donor-derived 

lymphocytes during the first few weeks after transplantation, 

clinical signs of GVHD have rarely 

been reported. 75 GVHD is not therefore a major 

complication after intestinal transplantation, unlike 

graft rejection. 

Intestinal rejection 

Intestinal allograft rejection remains the major 

complication after intestinal transplantation. As a 

result of increased immunosuppressive treatment, 

graft rejection may further precipitate opportunistic 

infections that become additive factors in 

patient and graft losses. As rejection can occur 

rapidly and can be life-threatening, close monitoring 

is required. This has led to the development of 

numerous diagnostic methods, which have not 

been validated in human intestinal transplantation 

or have limited value. 76–78 Therefore, regular biopsies 

of the proximal and distal ends of the graft for 

histological or immunohistochemical analysis are 

required 79–83 (Figure 42.2). Clinical signs of rejection 

occur later than histological and immunohistochemical 

signs and correspond to a relatively 

advanced rejection process with marked histological 

lesions. Rejection and sepsis can be intimately 

related after small-bowel transplantation when 

rejection compromises normal intestinal barrier 

mechanisms and bacterial translocation results 

with consequent multiorgan failure. Graft rejection 

may be reversed by using methylprednisolone 

pulses. Severe exfoliative rejection leaves the 

intestine totally denuded of its mucosa and does 

not respond to methylprednisolone or to anti-

706 


(a) (b) 

(c) 

lymphoglobulins or anti-CD3 mAb. Recovery may 

sometimes occur after exfoliative rejection but 

with a very high cost related to severe protracted 

protein-losing enteropathy during which albumin 

and hemoglobin replacement is needed and 

malnutrition may occur. In case of unresponsive 

exfoliative graft rejection, subepithelial fibrosis 

may appear, leading to severe hypomotility and 

subsequent intraluminal bacterial overgrowth. 81–83 

In our experience, we do consider that a rejection 

unresponsive to methylprednisolone pulses is a 

matter of discussing intestinal graft removal 

instead of dramatic increase of immunosuppression 

with the risk of infection and PTLD. This 

decision is difficult and is based on the specific 

experience of each program with the mandatory 

input of the pathologist. 


Clinical manifestations of allograft rejection are 

non-specific. It is obviously very important to 

Figure 42.2 (a) Mild intestinal graft rejection showing 

only pictures of apoptosis in the gland (HES x1200); (b) 

severe intestinal graft rejection showing epithelial blunting 

and disappearance of glands (HES x200); (c) severe 

‘exfoliative’ intestinal graft rejection with total villous 

atrophy, epithelium disappearance, absence of glands and 

T-cell infiltration (HES x800). 

differentiate other sources of potential intestinal 

allograft disease that may clinically mimic rejection, 

such as cytomegalovirus (CMV), adenovirus, 

Epstein–Barr virus (EBV) or other bacterial/viral 

enteritis. Viral infections are frequent, such as 

CMV primo-infection or reactivation, which is not 

always prevented by the use of pre-emptive treatment 

(ganciclovir). The diagnosis of CMV infection 

improved with the use of the polymerase 

chain reaction (PCR), which has been shown to be 

a sensitive method for the early detection of CMV 

infection in solid-organ and intestinal graft recipients. 

84 The incidence of CMV infection has been 

reported to be as high as 29% in pediatric recipients 

of intestinal grafts. 84 It is recommended to 

avoid using a seropositive graft in a seronegative 

recipient. Nevertheless, patients who are awaiting 

composite grafts are frequently too sick to await a 

CMV-seronegative donor. CMV prophylaxis is now 

well established with the wide use of ganciclovir. 85 

EBV infection in association with immunosuppressive 

drugs used for solid-organ transplantation 

can produce a spectrum of illnesses. Donor selection 

and the prevention of EBV infection remain 

unsolved problems. Indeed, a high incidence of 

EBV-induced PTLD has been reported. 86 The inci-

dence increases with the degree of immunosuppression. 

Because of the high rates of morbidity 

and mortality associated with EBV disease, a preemptive 

therapy based on serial monitoring of the 

EBV viral load is required. Quantitative EBV–PCR 

in the peripheral blood has recently enabled early 

diagnosis as well as the follow-up of patients with 

EBV infection. 87 This may allow the diagnosis of 

EBV infection before the development of PTLD. 

In the case of established EBV-related PTLD, 

therapeutic changes based on quantitative PCR are 

helpful in preventing the end phases of this 

disease. 84 In addition, in the case of documented 

PTLD, the use of anti-CD20 monoclonal antibodies 

has proved to be efficient in reversing the 

disease. 88 

Other severe life-threatening complications have 

been reported, such as diffuse adenovirus enterocolitis 

or hemophagocytosis. 89–91 The early identification 

of viral infections, based on the repeated 

use of appropriate methods, may help in avoiding 

the misdiagnosis of rejection leading to an unnecessary 

increase of immunosuppressive treatment 

with consequent exacerbation of the underlying 

infectious condition. 

Intestinal graft function 

Provided that the small intestine survives ischemia 

and reperfusion injury, long-term graft function is 

dependent on the effects of denervation, lymphatic 

disruption, immunosuppressive treatment, rejection 

and infection. These factors may explain 

impaired function of the intestinal graft and a 

delay in achieving intestinal autonomy. 

Intestinal motor function after intestinal 


The experimental study of small-bowel allografts 

provides a unique opportunity to develop insights 

into the impact of manipulation, preservation, 

ischemia/reperfusion injury, extrinsic denervation 

and immunological injury on intestinal function. 

However, very few data exist on these injuries to 

transplanted human small intestine. Ischemiareperfusion 

injury or intestinal manipulation 

evokes an inflammatory response within the 

intestinal muscularis that is associated with 

Intestinal graft function 707 

intestinal dysmotility. It was shown from human 

intestinal graft specimens obtained during transplantion 

that manipulation during organ harvesting 

initiates a functionally relevant molecular and 

cellular inflammatory response within the graft 

muscularis that is potentiated during the reperfusion 

period. 92 

The loss of extrinsic innervation of the small 

bowel severely impairs intestinal motor function. 

It has been shown in animal models that extrinsic 

denervation with maintenance of intestinal continuity 

only alters the regularity of the interdigestive 

myoelectric complex. 93 However, autotransplantation 

causes complete disruption of the orderly, 

sequential migration of the interdigestive myoelectric 

complex from the innervated to the denervated 

intestine, and food intake no longer inhibits the 

myoelectric complex. 94 Studies have observed the 

changes of the transplanted intestine itself in order 

to evaluate the effects of intestinal transplantation 

on the intrinsic nervous system. Taguchi et al 

found that the contractile properties of smallbowel 

smooth muscle and its sensitivity to drugs 

were unaltered by transplantation. 95 Although the 

excitatory response was comparable with that of 

normal intestine, the inhibitory response was 

modified by the loss of the extrinsic adrenergic 

inhibitory innervation. They also studied the 

temporary additional loss of intrinsic inhibition 

caused by prolonged graft storage, which recovers 

within 7–8 days after transplantation. 96 An 

increase was also shown of the intestinal contractile 

motility after intestinal transplantation, associated 

with a marked increase of non-adrenergic, 

non-cholinergic (NANC) neural components, with 

the dominant intrinsic neural component changing 

from cholinergic to NANC over 4 weeks. 97 

Autotransplantation as well as isotransplantation 

in dogs or rats has allowed the study of the reinnervation 

process after small-bowel transplantation. 

98,99 Reinnervation of the graft intestinal wall 

does occur but requires a prolonged period. The 

major route of reinnervation is along the arterial 

axis of the intestinal graft, not beyond the enteric 

anastomosis. 100 On the other hand, Taguchi et al 

studied immunohistochemically the distribution 

of neurons in a syngeneic model of transplantation 

in Lewis rats. Both the nitric oxide (NO) and 

peptidergic neurons markedly decreased just after 

transplantation, and the NO neurons recovered 

faster than peptidergic neurons suggesting an

708 


important role in the adaptation process in the 

early period after transplantation. 101 After transplantation 

of the entire jejuno-ileum, isotransplanted 

rat intestine has qualitatively normal 

myoelectrical activity but decreased absorptive 

capacity. 102–104 If rejection is controlled and 

ischemic time is kept to a minimum, allografts of 

small intestine will exhibit a normal propagated 

motor myoelectric complex. In humans, the intrinsic 

motor activity of the small intestine is 

preserved for the most part, although there is some 

discoordination between proximal and distal 

elements in the fed state. 105,106 

Acute allograft rejection provokes intestinal paralysis 

before mucosal destruction is established. 107 

In animals, chronic rejection causes thickening of 

muscularis propria by both hyperplasia and hypertrophy 

accompanied by inflammatory cell infiltrate. 

108 Chronic allograft rejection severely 

impairs the enteric nerve with subsequent alteration 

of myoelectrical activity. 108–110 Functional 

impairment partially regresses after FK506 

rescue. 109 In clinical practice, chronic rejection is 

very rare but its expression is dominated by severe 

intestinal obstruction. 

Very few data regarding intestinal motility are 

available in humans. 106 Most knowledge comes 

from the observations of recovery of intestinal 

transit and contrast examination of the transplanted 

intestine. 111 

Absorptive function after intestinal 


Studies performed in animals have shown that 

intestinal tranates, lipids, glutamine, water and 

electrolytes, but there is no evidence in 

humans. 112–120 Feeding must resume as early as 

possible after transplantation because this ensures 

optimal mucosasplantation disturbs the absorption 

of carbohydrl trophicity and reduces gastrointestinal 

stasis, which causes intraluminal bacterial 

overgrowth. Clinical experience has demonstrated 

that because of water–electrolyte malabsorption, 

abnormal motility and impaired lymphatic 

drainage it may take several weeks to achieve 

normal intestinal transit and reduced stool 

volume. If the recipient has no colon, associated 

colon transplantation has physiological advan- 

tages in terms of water and electrolyte re-absorption, 

slowing intestinal transit and trophic factors, 

through colonic synthesis of short-chain fatty 

acids. Finally, it is currently considered that 

intestinal transplantation restores an enteral axis 

capable of ensuring digestion and absorption. 

Intestinal function sufficient to withdraw PN 

completely may be achieved with adequate nutritional 

management. In our experience, colon grafting 

does not impede survival after intestinal transplantation 

and improves the patient’s condition 

with early PN weaning. The colon water–electrolyte 

absorption capacity reduces the need for compensation 

by the parenteral route. 

Post-transplant practice and 

procedures 

Initial post-transplant period 

Total PN is administered continuously, with modifications 

made to the electrolyte and macronutrient 

content of the solution based upon serum and 

urine laboratory parameters. Hyperglycemia may 

result from initial high steroid doses and steroid 

recycles during early rejection episodes and/or 

from tacrolimus. Post-transplant pancreatitis may 

also affect glucose metabolism. Thus, insulin may 

be required in patients with severe hyperglycemia 

to maintain adequate caloric balance. Impaired 

renal function may require the limitation of nitrogen 

intake required for post-transplant wound 

healing and fluid restrictions may prohibit the 

ability to provide enough total PN volume to 

supply adequate calories. Use of intravenous lipid 

emulsion whenever possible according to metabolic 

tolerance and infectious state is recommended 

to achieve adequate calorie intake and 

essential fatty acid provision. The type of emulsion 

has never been evaluated in such situations 

and might be controversial. In our practice, 

we preferentially use medium-chain/long-chain 

triglyceride (MCT/LCT) emulsion without overpassing 

1.5g/kg per day. 

Initiation of enteral and oral feeding 

Continuous enteral feeding through a gastrostomy 

or, for others, from proximal jejunostomy is started

once intestinal motility occurs, generally within 1 

week. Enteral feeding is initiated and advanced 

slowly unless contraindicated, as in the presence 

of severe diarrhea or vomiting and, of course, in 

the presence of an acute graft rejection. In our 

experience and elsewhere, the patients initially 

receive a low-antigenic and low-fat formula and 

are subsequently transferred over a period of 

weeks and months to a more complex product 

with intact macronutrients. The use of an amino 

acid- versus a peptide-based enteral product 

remains a controversial issue in the non-transplant 

critically ill patient with impaired gastrointestinal 

function. 121 However, in the presence of carbohydrate 

and fat, nitrogen absorption has been 

reported to be greater with a 100% elemental free 

amino acid-protein source. 122 Moreover, the presence 

of free glutamine in powdered amino acidbased 

formulas has been shown to be beneficial in 

protecting gastrointestinal mucosa and reducing 

bacterial translocation. 123 Conversely, peptidebased 

elemental formulas are generally lower in 

osmolality which may make them more suitable 

for use in the presence of increased stool output. 

Finally, it is impossible to identify significant 

differences in outcome as measured by the length 

of time until the patient is completely weaned 

from total PN, length of hospital stay, ileostomy 

output or time until transition to oral intake alone, 

by the type of enteral formula used, peptide or 

hydrolyzed casein-based enteral formula versus an 

amino acid preparation. Post-transplant-impaired 

lymphatic drainage with either chylous ascites or 

intestinal lymphangiectasia, limits lipid intake. 

Low-fat formulas and MCT-rich formulas are 

recommended at initiation of enteral feeding. In 

our experience, children with inferior vena cava 

thrombosis are at high risk of chylous ascites and 

must be fed very slowly with MCT-rich formulas. 

More complex products with intact macronutrients 

are progressively introduced according to 

graft status, digestive tolerance and capacity of 

eating. 

Parenteral nutrition weaning 

PN weaning is a crucial objective, allowing the 

intestinal transplantation to be considered 

successful. Full nutritional autonomy with 

complete discontinuation of PN has been achieved 

in 81% of cases and partial recovery was docu- 

Post-transplant practice and procedures 709 

mented in another 11%, for a total rehabilitation 

rate of 92% in survivors. In the absence of major 

complications, recipients of an isolated intestinal 

allograft are weaned from PN relatively quickly, the 

median time ranging between 4 and 6 weeks 60,65 

Patients are weaned from PN as enteral feeding is 

progressively increased according to the tolerance 

of the child. It can take several weeks or months 

depending on the pre-transplant nutritional status, 

post-transplant complication rate, and intestinal 

graft recovery and function. In our experience, 

among 31 survivors after isolated (n=11) or 

combined intestine–liver transplantation (n=20), 

all patients were weaned from PN after a delay 

ranging from 4 weeks to 3 years. In the absence of 

major complications, recipients of an isolated 

intestinal allograft can be weaned from PN relatively 

quickly within 4–6 weeks. The longer time to 

achieve full enteral nutrition after small bowel–liver 

transplantation reflects a more prolonged recovery 

from the surgical procedure compared with isolated 

small-bowel transplantation. 


Chronically ill infants and children are at risk for 

oral aversion caused by the loss of the sucking or 

swallowing reflex in those maintained on total PN 

or tube feeding for an extended period of time 

without oral intake. Further oral-associated problems, 

including delayed speech and language 

development, may also result from this aversion. 

Pre-transplant management of eating disorders and 

early and adequate post-transplant stimulation of 

oral feeding can reduce food aversion. It is essential 

to insert a digestive access (gastrostomy or 

proximal jejunostomy) at the time of transplant 

surgery, especially in patients felt to have eating 

disorders. Full enteral feeding can be progressively 

achieved by using a polymeric diet. Psychological 

evaluation and assistance are of course required in 

each case. In our experience, all patients achieved 

oral feeding, sometimes up to 2 years after 

transplantation. 

Monitoring of intestinal function 

The D-xylose absorption test provides basic information 

regarding mucosal integrity, but is influenced 

by a number of factors, such as impaired

710 


gastric emptying or accelerated intestinal transit. 

This test is never used in our clinical practice. 

Mucosal enzyme activities, especially disaccharidase 

activity, can be assayed from a biopsy specimen 

obtained from endoscopy. Enzyme levels 

correlate with mucosal injury due to allograft 

rejection or viral infection. 124 Thus, the relevance 

of this assessment for monitoring of intestinal 

function in a stable patient is a matter of debate. 

Recipients with an ileostomy, during the 2–3 

months following transplant procedure, or continent 

older patients, can benefit from stool analysis. 

We used to perform a stool balance as 

measured by a comparison of 72-h fecal output 

with oral or enteral intake. Since multiple variables 

may affect fat absorption, including intestinal 

transit, lymphatic integrity, exocrine pancreas 

function and mucosal injury, assessment of fat 

balance is very relevant. However, as most 

patients receive a mixture of LCTs and MCTs, the 

measurement of fat excretion by using the Van de 

Kamer assay is not relevant. It is thus preferable 

to use the Jeejeebhoy method that extracts and 

detects both LCTs and MCTs. 125 In our practice 

we also used to measure energy balance by 

performing bomb calorimetry analysis. Stool 

balance analysis in 20 PN-weaned transplanted 

children, showed that lipid absorption rate was 

decreased, ranging between 70 and 88%. 

Nutritional outcome after intestinal 


Besides the enteral or oral feeding approach, 

nutritional evaluation following intestinal transplantation 

is mandatory. However, few nutritional 

data are available in children after intestinal 

transplantation. 126–128 We studied 20 children 

(8.8±3.5 years) with at least 12 months followup 

(median 27 months). 128 PN was stopped 

110±84 days after grafting. They were on unrestricted 

oral feeding, with enteral supplementation 

in six patients with varying degrees of eating 

disorders. At 12 months post-transplant, body 

weight-for-age and height-for-age were decreased, 

being 89±13% and 93±5%, respectively. Body 

weight-for-height was increased (105±9%) with 

a fat body mass (FBM) of 20.1±4.3% of body 

weight. Growth velocity was decreased 6 months 

before and after grafting by 67±38% and 

57±46% of the normal for age, respectively, but 

was increased by 142±64% of the normal for age 

during the last 6 months of follow-up. Bone 

mineral density (BMD), measured by using dual 

X-ray absorptiometry (DEXA), was decreased in 

all children according to age. Nutritional parameters 

showed normal albumin and pre-albumin 

plasma levels as well as plasma tocopherol. 

Conversely, both vitamin A and RBP plasma 

levels were decreased, as well as serum iron and 

ferritine. 

Weight gain with excessive FBM and catch-up 

growth is observed after intestinal transplantation 

in most cases, in our experience. However, in 

some cases, there is evidence of severe inhibition 

of linear growth at the time of transplantation 

with no evidence of catch-up after transplantation. 

127,128 Growth velocity is severely altered 

both before and just after transplantation due to 

liver disease and high-dose steroid thereafter. 

Thus catch-up growth is delayed. A follow-up 

period of 6 months is too short to observe positive 

trends in height/length. Despite normal growth, 

BMD is low and some nutritional biological parameters 

are altered, such as vitamin A plasma 

levels. Monitoring should not be restricted to 

growth parameters but include body composition 

and biological parameters recording nutritional 

supplementation if required. Post-intestinal transplantation 

nutritional management should 

include BMD assessment on a longitudinal basis. 

Insufficient BMD may be due to previous longterm 

PN worsened with high-dose steroids. 

Potential candidates for intestinal 


In order to improve the risk–benefit ratio and costeffectiveness 

of intestinal transplantation it is 

mandatory to select appropriate candidates and to 

decide the adequate time for performing the procedure. 

The number of potential candidates for 

intestinal transplantation is very difficult to establish 

according to the heterogeneity of patients 

included in home-PN programs, and in general, to 

the mostly well-tolerated long-term PN. 8–12 The 

number of patients will never be as high as the 

number of kidney or liver transplant recipients.

However, intestinal transplantation is theoretically 

indicated for all patients permanently dependent 

on PN. Functional grafts lead to gastrointestinal 

autonomy (weaning off PN) while maintaining 

satisfactory nutritional status and normal growth 

in children. However, as PN is generally well tolerated, 

even for long periods, each indication for 

transplantation must be carefully weighed in 

terms of survival rate, morbidity and quality of 

life. 129–133 By excluding malignant disease and 

immune deficiency, survival rates of patients with 

chronic intestinal failure on long-term home PN 

remain higher than after intestinal transplantation, 

even with the most optimistic interpretation of 

available data. 8–12 Intestinal transplantation is 

often accompanied by numerous life-threatening 

complications such as those briefly reviewed 

above, leading to recurrent or long-term hospitalization 

and sometimes a poor outcome. An evaluation 

of the quality-of-life after intestinal transplantation 

among home PN was recently 

performed in adult patients using a quality-of-life 

instrument in the form of a self-administered questionnaire. 

131 Intestinal transplant recipients with 

functioning grafts reported a significant improvement 

in the quality of their life and function. This 

information is encouraging and should be used 

towards future advancement in intestinal transplantation. 

Thus, when long-term PN is effective and well 

tolerated, it can thus be used pending further 

progress in intestinal transplantation. In contrast, 

when PN has reached its limits, especially in 

those cases associated with extensive thrombosis, 

recurrent sepsis, severe metabolic disorders or 

advanced liver disease, intestinal transplantation 

must be undertaken. 

Intestinal transplantation: isolated or 

combined with liver 

Patients with irreversible intestinal failure and 

end-stage liver disease (liver cirrhosis and complicated 

portal hypertension) are certainly candidates 

for a life-saving procedure such as 

combined small bowel–liver transplantation. 

Patients with severe hepatic fibrosis are more 

difficult to manage. Repeated liver biopsies within 

6–12 months and careful assessment for portal 

Potential candidates for intestinal transplantation 711 

hypertension are mandatory. It is difficult to 

predict the liver damage related to the persistent 

need for PN or to rejection or infection during the 

first weeks or months after transplantation. In 

addition, it is difficult to assess the amount of 

functioning liver necessary to withstand the insult 

of portal diversion during the transplantation 

procedure. Those patients with severe hepatic 

fibrosis or cirrhosis are thus usually listed for 

small bowel–liver transplantation. 

Patients with irreversible intestinal failure and PN 

dependency without consistent liver disease must 

satisfy rigorous criteria to be considered as candidates 

for isolated small-bowel transplantation. 

They must fulfill at least one of the following 

criteria: extensive thrombosis impeding the 

ability to administer PN, recurrent life-threatening 

sepsis, severe metabolic disorders preventing 

nutritional requirements from being met, with 

consequent failure to thrive in children, underlying 

disease with high water–electrolyte losses 

with the risk of life-threatening dehydration in the 

case of PN disruption. Some patients with severe 

chronic intestinal pseudo-obstruction may be 

disabled because of chronic, massive gastrointestinal 

dilation refractory to stomal decompression 

or partial enterectomy. They might be considered 

for intestinal transplantation, although the 

usual indications, including progressive liver 

disease, the threatened loss of vascular access and 

recurring life-threatening sepsis, have not developed. 

Contraindications to intestinal transplantation 

Contraindications to intestinal transplantation do 

not differ from those pertaining to other solid 

organs. 134 According to the high morbidity and 

mortality rates after intestinal transplantation 

and the donor pool size, the concept that the 

patient must have the potential to derive an 

obvious benefit from the procedure must remain 

paramount. Other contraindications include 

congenital or acquired neurological disabilities, 

life-threatening extradigestive illnesses, congenital 

or acquired immune disorders, non-resectable 

malignancy, and insufficient vascular patency to 

guarantee easy central venous access for up to 6 

months after intestinal transplantation.

712 


Timing for referral and prevention of liver 

disease 

Intestinal failure management 

Unfortunately, few centers manage all the stages of 

intestinal failure from onset to intestinal transplantation, 

including the home-PN program. Beath 

et al135 reported a marked discrepancy in clinical 

status between children referred for intestinal 

transplantation from centers with and without 

nutritional care teams. It was shown that 

the mortality rate, death within 6 months of 

evaluation for transplantation, was 90% in children 

with short guts, 50% in those with mucosal 

disease and 40% in those with chronic intestinal 

pseudo-obstruction syndrome. 136 Factors impacting 

the survival of children with intestinal failure 

referred for intestinal transplantation have been 

studied in a series of 257 patients (mean age 

3.4±0.26 years) evaluated for intestinal transplantation. 

66 Only 82 (32%) underwent intestinal 

transplantation (68 small bowel–liver transplantation) 

with a mean waiting time of 10.1±1.3 

months. Of the 175 patients who were not transplanted, 

120 died. The main factors associated 

with poor prognosis were: age below 1 year, surgical 

disease, bridging fibrosis or cirrhosis, bilirubin 

levels of over 3 mg/dl and thrombocytopenia. 

Combined small bowel–liver transplantation 

It is sometimes difficult to decide on liver transplantation. 

Indeed, some PN-dependent patients 

with advanced liver dysfunction in the setting of 

short-bowel syndrome may experience functional 

and biochemical liver recovery which appears to 

parallel autologous gut salvage. 137 On the other 

hand, we reported consecutive cases of severe 

cholestasis that totally resumed after discontinuation 

of intravenous lipid administration. 138 

Histology is not always predictive of functional 

liver recovery. However, in our experience, in the 

absence of biological change and PN administration, 

the time taken to go from portal fibrosis to 

cirrhosis is approximately 12 months, similar to 

the waiting time. 139 Once cirrhosis has been established, 

survival at 1 year is only 30%. 66,135 

It is well established that patients referred for 

small bowel–liver transplantation are more debilitated, 

have multiple complications, and have 

prolonged stays in the intensive care unit. 140 It 

may explain the lower patient and graft survival 

rate compared with isolated small-bowel 

transplantation reported from several programs. 

60–62,64,65 It was suggested that early isolated 

small-bowel transplantation with such a short 

period of postoperative hospitalization could well 

prove to be cost-effective compared with the 

intensive use of resources that characterizes the 

short-bowel patient with liver failure. 141 

Financial considerations 

Financial issues are now considered in managing 

intestinal failure patients. Provision of basic home 

PN is associated with charges. Actual costs for 

total PN, including the pharmacist’s time for 

compounding, are different according to home-PN 

programs and countries. The costs for transplant 

evaluation, the transplant and postoperative care, 

and post-transplant follow-up are not currently 

available for comparison. 142,143 


Patients with short-bowel syndrome can lead a 

productive, lengthy, happy and useful life if 

educated and managed appropriately. It is possible 

to reduce or even eliminate PN requirements 

over time in many of these patients using the 

evidence-based techniques of dietary and PN 

management (see Chapter 29). Hormonal therapy 

may eventually be available to augment the 

intestinal adaptation process as this becomes 

better understood. For patients with irreversible 

intestinal failure who do require total PN, it is 

essential that the therapy be prescribed appropriately. 

PN is associated with several potentially 

serious complications, many of which can be 

prevented when both the patient and the caring 

professional have the appropriate expertise. 

Early referral for irreversible intestinal failure 

As pediatric patients represent almost two-thirds 

of the indications for small-bowel tranplantation, 

appropriate therapeutic strategies should be 

developed for all phases of intestinal failure. It is 

first necessary to recognize, as early as possible, 

the patient with irreversible intestinal failure, 

such as extreme short-bowel syndrome or congen-

ital disease of the intestinal mucosa. These 

patients should be referred at an early stage to 

multidisciplinary teams involved in small-bowel 

transplantation in optimal nutritional status. For 

other patients, attempts at achieving intestinal 

autonomy (PN weaning) require appropriate 

management as previously emphasized. Intestinal 

transplantation thus requires a strategy based on a 

long-term multidisciplinary approach, aimed at 

demonstrating the irreversibility of intestinal 

failure, to avoid the complications of long-term 

PN and to refer early selected patients requiring 

this procedure. 141–145 

Particular procedures 

Because of the reduced size of the donor pool, 

strategies have been developed to enhance it and 

to perform transplantation without delay to avoid 

death on the waiting list, if the patient is in need 

of a combined liver–intestine transplantation. 

Living related donors 

Intestinal grafts are usually obtained from sizematched 

brain-dead adults or children. The ABO 

identity is necessary to avoid hemolysis related to 

circulating antibodies. It is difficult to obtain HLA 

compatibility, mainly for logistical reasons (the graft 

poorly tolerates ischemia). However, the longest 

survival time before the advent of cyclosporin A 

was observed after intrafamilial transplantation. 

Long-term survival has since been obtained in 

intrafamilial transplantation with cyclosporin A or 

FK506 immunosuppression. 146–149 A unique case of 

a successful isolated intestinal transplantation 

without immunosuppressive treatment between 

identical twins was recently reported. 149 However, 

living-related intestinal transplantation should 

remain very limited. 

Reduced-size composite liver–intestinal 

allograft 

Strict donor selection to prevent factors that may 

adversely affect the intestinal graft and size-match- 

Particular procedures 713 

ing have limited donor availability. 66 These factors 

contribute to the long waiting time for pediatric 

patients. Reduced-sized orthotopic composite 

liver–intestinal allografts are technically feasible 

and may increase the donor pool. 150,151 

Multivisceral transplantation 

Multivisceral or ‘cluster’ transplantation of organs 

from the celiac region (liver, stomach, duodenum–pancreas 

and small bowel) was reported for 

the first time in 1989. From the Registry, it represents 

13% in children and 24% in adults of all 

intestinal grafts. This procedure raises specific 

technical problems, but immunosuppressive treatment 

is no different. The Miami group performed 

multivisceral transplantation in very small children 

as an alternative to en bloc liver–intestine 

transplantation due to its advantage in creating 

more room in the abdominal space. 152 They 

reported improved survival rates with an excellent 

functional outcome of the stomach and the 

pancreas. 

Conclusion 

During the past decade, intestinal transplantation 

has gone from being an experimental procedure to 

one that is being increasingly accepted and 

performed. Further improvements depend on 

several factors, including the early and adapted 

management of patients with intestinal failure, 

refractory or likely to become refractory, by trained 

medico-surgical teams, improvements of immunosuppression 

by using new-generation drugs or 

monoclonal antibodies targeting receptors 

involved in T-cell activation, and the better 

prevention of post-transplant infectious complications 

by using appropriate antiviral therapy. 153–156 

Constant progress in immunosuppression 

provides the hope of continuing to improve 

outcome after intestinal transplantation in selected 

patients. Indeed, when successful, intestinal transplantation 

allows patients surviving with their 

graft a recovery of intestinal function sufficient to 

discontinue a mostly long-term dependency on 

parenteral nutrition.

714 


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716 


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43 

Introduction 



Intussusception is a form of intestinal obstruction, 

due to the telescoping or prolapse of one section of 

the intestine (the intussusceptum) into an adjacent 

section (the intussuscipiens). In most cases, the 

terminal ileum telescopes into the colon. Intussusception 

occurs most frequently before the 

age of 2 years; the incidence is highest in the first 

year, during which it is the most frequent cause of 


This disorder has been known since the time of 

Aristotle, but the first detailed description was that 

of Paul Barbette, who in 1676 proposed surgical 

treatment. 1 Until the mid-19th century, however, 

intussusception remained almost invariably fatal. 

The first successful surgical treatment (of a 2-yearold 

boy) was reported in 1873 by Jonathan 

Hutchinson. 2 In 1876, Hirschsprung described the 

treatment of a series of patients with hydrostatic 

enema, marking the start of a period of progress in 

treatment. 3 In 1905 Hirschsprung published a new 

series of 107 cases, with 35% mortality in patients 

treated by enema and 80% mortality in patients 

treated surgically. 

In 1948 Ravitch and McClure published their 

experience with barium contrast radiography, and 

established indications and contraindications for 

hydrostatic reduction. 4 Subsequent publications 

helped generalize the use of hydrostatic reduction, 

typically with high success rates (94%) and low 

mortality (0.02%). 5–7 In the 1980s, ultrasonography 

was introduced as an innocuous and reliable 

method for diagnosis. 

Current standard treatment practice is based on 

careful early diagnosis, generally by contrast radiography 

and/or ultrasonography. Treatment 

usually involves hydrostatic or pneumatic reduction, 

with surgery reserved for a specific small 

subset of cases. When this approach is followed, 

morbidity is less than 1% and mortality close to 

zero. 

Epidemiology 

Intussusception is the predominant cause of 

intestinal obstruction between 5 months and 5 

years of age, with incidence differing between 

countries and races. In the UK and USA, for 

example, reported mean incidences range from 

1.5–4.3 per 1000 liveborn children, 8–10 versus 

2.7–6.1 per 1000 in Spain. 11,12 

Prevalence is typically about three times higher in 

boys than in girls, and indeed about eight times 

higher in boys from age 4 years onwards. 

It can present at any age, but as already noted it is 

most common in the first 2 years of life, with incidence 

peaking between 3 and 12 months (mean 

7–8 months). Two-thirds of cases present in the 

first year of life. 

Some studies have reported different patterns of 

seasonal variation in incidence, but large-sample 

and long-series studies suggest that there is no 

consistent seasonal pattern. Certainly, however, 

the incidence clearly increases during epidemics 

of gastroenteritis, respiratory infection and adenovirus 

infection, and during periods of vaccination 

against rotavirus. 13–16 

719

720 


Etiopathology 

Primary idiopathic intussusception 

Despite numerous publications, the etiology of 

intussusception remains poorly understood. In 

90% of cases there is no detectable organic lesion 

acting as the lead point. 17 The high incidence 

during the first year of life appears to be related to 

the abundant lymphoid tissue of the terminal 

ileum at this age, with lymphoid tissue hypertrophy 

being detected in most surgical interventions, 

and often apparent on ultrasonography. However, 

some authors have suggested that these 

adenopathies are a consequence, not a cause, of 

the intussusception. 18 

As noted, the most commonly intussuscepted 

section is the terminal ileum, telescoped into the 

colon (i.e. ileocolic intussusception). The intussusception 

extends a variable distance along the 

colon, and may even reach the rectum, where it 

can be detected by rectal palpation. Occasionally, 

ileoileal intussusceptions are observed, extending 

to the ileocecal valve. 

In ileocolic intussusception, the intussusceptum is 

a section of the proximal part of the ileum, which 

telescopes into the adjacent distal colon, causing 

compression of the mesentery and strangulation of 

mesenteric blood vessels, with rapid edema of the 

intestinal wall, leading to impairment of venous 

return, edema of surrounding tissues, hemorrhage, 

blood infiltration and intestinal obstruction. The 

venous engorgement and ischemia lead to mucus 

secretion and bleeding, resulting in the classic 

‘currant jelly’ stool. If the venous obstruction and 

ischemia continue, the patient will develop 

gangrene, intestinal perforation due to necrosis of 

the intussusceptum and peritonitis. 

Secondary/organic intussusception 

With increasing age of the patient, it is increasingly 

likely that the intussusception will have an 

organic origin. About 5–10% of intussusceptions 

are caused by an organic lesion. Above the age of 4 

years, this percentage increases to 50%. 

The most frequent organic cause is Meckel’s diverticulum, 

followed by enteric duplications, intesti- 

nal polyps (whether isolated or forming part of 

Peutz–Jeghers syndrome), hemangiomas, traumatic 

hematomas and, less frequently, 

Henoch–Schönlein purpura, foreign bodies and 

trichobezoars, Crohn’s disease, cystic fibrosis, 

leukemias, lymphomas, and intestinal lymphosarcomas. 

11,12,19 

Postoperative intussusception may appear after 

any type of surgery (thoracic, abdominal, otorhinolaryngological, 

etc.), although it is most frequent 

after surgery to the digestive tract. Such intussusceptions 

make up about 1% of the total, and are 

related to postoperative motility alterations and 

paralytic ileus, or anesthetic medication. They 

typically present in the first 15–20 days after 

surgery and are often difficult to diagnose, since 

they are generally ileoileal or jejunoileal, and not 

revealed by contrast enema. They are rarely diagnosed 

in the immediate postoperative period, 

during which the signs and symptoms of intussusception 

are typically masked by postoperative pain 

and other consequences of the surgery. Treatment 

is surgical: usually surgical reduction is sufficient, 

without any need for intestinal resection. 20,21 


Intussusception typically presents in thriving and 

otherwise healthy nursing infants, and starts with 

a sudden crisis of crying and screaming, with 

knees drawn up to the abdomen. After a few 

minutes these responses generally subside, and 

the child appears normal, but the crises then recur 

at regular intervals of 10–20min, and may often be 

dramatic in that the child cannot be calmed. 

Sometimes the child has suffered a similar crisis 

during the preceding days or months. Vomiting of 

undigested food typically occurs a short time after 

onset of the pain crises; bilious vomiting generally 

occurs only if the disorder is left untreated for a 

long period. Stools of normal appearance may be 

passed (i.e. feces already present distal to the 

intussusception), but at later stages (generally not 

before 8–12h after onset of the pain crises) the 

patient will discharge the characteristic blood-andmucus 

clots known as ‘currant jelly’ stools. 

It should be stressed that the ‘typical’ symptom 

triad of abdominal pain, vomiting and blood in

stools is rarely seen early. In other words, 

Ombredanne’s criterion (i.e. intussusception=ileal 

signs+blood in stools), which was widely used in 

the past, is in fact valid only for the late course. 

Occasionally, other symptoms (such as fever, diarrhea 

and prostration) may appear. Diarrhea may 

suggest gastroenteritis and delay diagnosis, as may 

constipation, which occurs in up to 20% of cases. 22 

Repeated occurrence of the typical crises over a 

period of days or weeks may indicate chronic 

intussusception with spontaneous reduction, 

presenting at intervals as acute crises. 

Patients may show lethargy (i.e. apathy, sleepiness, 

prostration) during the early stages. Lethargy most 

commonly occurs between the pain crises, but in 

some cases may be the first symptom noted, before 

the pain crises, possibly suggesting encephalitis. 

Indeed, intussusception initially presenting as 

lethargy alone is typically problematic for diagnosis, 

since lethargy is normally associated with 

structural, toxic or metabolic disorders of the 

central nervous system; in such cases, central 

nervous system-related diagnostic procedures are 

typically applied before it becomes clear that the 

problem is in fact intussusception, with consequent 

diagnostic delay. 23,24 In this connection, it 

has been suggested that intussusception be 

included in mnemotechnics for diagnosis of 

patients with coma, with the letter ‘i’ being used to 

indicate ‘insulin’ and ‘intussusception’. 25 Various 

hypotheses have been put forward to explain the 

lethargy arising in association with intussusception, 

including secretion of endogenous opioids 

and cytokines during the pain crises, absorption of 

toxins into the bloodstream and association with 

rapid dehydration and shock. In almost all cases in 

which lethargy is observed, some other symptoms 

are present, such as vomiting, abdominal distension, 

or irritability. It may also appear in association 

with other neurological symptoms such as 

convulsions, coma, pinpoint pupils, opisthotonos 

and hypotonia. 

Occasionally, intussusception is not diagnosed 

until rectal bleeding occurs. This occurs most 

commonly in patients aged more than 1 year. 

If untreated, the patient’s condition is likely to 

worsen rapidly, with dehydration and possible 

shock. Early diagnosis is thus essential. 

Physical examination 721 

Some years ago we reviewed the symptoms 

observed in cases of intussusception treated at our 

hospital over the period 1969–84. 11 The most 

common symptoms were cramping abdominal 

pain (87% of patients), rectal bleeding (82%) and 

vomiting (78%) (Table 43.1). 


In the early stages physical examination is in most 

cases normal, with the infant typically appearing 

well-fed and healthy. During pain crises, and if the 

crying permits, hyperperistaltic noise may be 

heard, with the abdomen tense and painful to 

palpation. Between the crises the right lower quadrant 

may appear strangely empty if the intussusception 

is ileocecal, with a mass palpable in practically 

any part of the abdomen; this mass is 

typically sausage-shaped and curved, owing to the 

traction exerted by the mesentery on the intestine. 

In rectal examination, the examining finger may 

appear covered with bloody mucus or blood, but 

direct contact between the examining finger and 

the intussuscepted mass is rare. Rectal hemorrhage, 

together with fever and tachycardia, 

become increasingly likely over time. In the past, 

when intussusceptions were typically diagnosed 

late, the intussusceptum was often detectable on 

rectal examination, and indeed there are 

Table 43.1 Signs and symptoms observed in 

intussusception patients seen at the Santiago de 

Compostela Clinical Hospital over the period 

1969–84 

Signs and symptoms Patients 

n % 

Cramping abdominal pain 61 87 

Rectal bleeding 58 82.8 

Vomiting 55 78.5 

Abdominal distension 30 42.8 

Abdominal mass 27 35.8 

Respiratory illness 16 22.8 

Lethargy 12 17 

Gastroenteritis 10 14.3 

Previous intussusception 2 3

722 


descriptions of prolapse through the anus, with 

consequent ischemic damage (an extremely severe 

sign, generally associated with severe illness). If 

the intussusception has remained untreated for a 

long period, the patient may present with symptoms 

of hypovolemic shock. 

Diagnosis 

All pediatricians are well aware that persistent 

crying and abdominal pain in a nursing infant, 

particularly if associated with vomiting, needs to 

be carefully evaluated to confirm or rule out intussusception. 

Cramping pain with vomiting is sufficient 

grounds for continuous monitoring. 

Complementary examinations should follow a 

systematic order. Initially, simple abdominal radiography 

and ultrasonography should be 

performed, which together will reveal intussusception 

and possible repercussions for intestinal 

transit. In the absence of contraindications, hydrostatic 

enema or pneumoenema should then be 

performed, to confirm the diagnosis and, when 

appropriate, to achieve reduction. 

Simple abdominal radiography 

This will reveal about 50% of intussusceptions, 

allowing evaluation of the degree of intestinal 

obstruction and exclusion of perforation due to 

pneumoperitoneum. The radiographic signs are 

not in themselves fully diagnostic, and a normal 

radiograph does not allow intussusception to be 

ruled out; nevertheless, in my opinion it should be 

performed routinely. 

The most characteristic radiographic findings in 

ileocolic intussusception (Figure 43.1) are as 

follows: 

(1) Reduced or absent intestinal gas in the right 

quadrant; 

(2) Air–fluid levels; 

(3) Diffuse radiolucent image, generally located 

in the right hypochondrium; 

(4) Circle sign: two concentric circles and fat 

density, superimposed over the kidney to the 

right of the vertebral column; 

(5) Convex mass effect with interruption of air at 

the level of the transverse colon; 

Figure 43.1 Simple abdominal radiograph showing 

abnormal distribution of intestinal gas, with subhepatic 

mass. 

(6) Obstruction of the small intestine. 26–28 

Ultrasonography 

Since the first report of the diagnosis of intussusception 

in adult patients by ultrasonography in 

1977, this technique has become the imaging 

method of choice, and nowadays emergency ultrasonography 

will detect most cases of intussusception, 

particularly if the abdomen is not greatly 

distended by gas. 29 

There have been numerous descriptions of the 

ultrasonographic signs of intussusception, which 

habitually show a donut or ‘target’ image, with a 

hypoechoic peripheral ring representing the 

edematous walls of the intussusceptum, and a 

hyperechoic central zone made up of areas of 

compressed mucus. In longitudinal section the 

hypoechoic walls on both sides of the hyperechoic 

center show a tubular ‘pseudokidney’ or ‘sandwich’ 

appearance 30 (Figure 43.2).

Figure 43.2 Ultrasonogram showing typical 

‘pseudokidney’ image in subhepatic location, indicative 

of intussusception. 

Ultrasonograms are not entirely pathognomonic 

for intussusception, but most published series 

indicate sensitivity and negative predictive value 

of close to 100%. 31,32 

Ultrasonography also offers a number of other 

important advantages: it is fast, cheap, noninvasive, 

innocuous (no ionizing radiation) and 

capable of detecting intussusceptions that are 

difficult to detect by conventional clinical examination 

and radiography, notably ileoileal and postsurgical 

intussusceptions. Ultrasonography facilitates 

assessment of reducibility and of the 

feasibility of non-surgical reduction, in view of the 

existing amount of intraperitoneal liquid, the 

thickness of the intestinal wall and the degree of 

distension and peristalsis of the intussusceptum. 

Doppler sonography (Figure 43.3) facilitates 

assessment of the degree of vascularization or 

ischemia of the intussusceptum, which is important 

for treatment selection. 33,34 

Ultrasonography may also detect pathological lead 

points such as Meckel’s diverticulum, lymphomas 

of the small intestine, or cysts. 35 In addition, it 

allows the examiner to rule out other causes of 

abdominal pain, such as appendicitis, ovarian 

pathology or anomalies of the urinary tract. 

Since the introduction and widespread use of 

hydrostatic reduction under ultrasonographic 

Diagnosis 723 

Figure 43.3 Doppler sonogram showing good 

vascularization of the intussusceptum, so that enema 

reduction is not contraindicated. 

guidance, reduction success rates of up to 95.5% 

have been reported, 36 with reduction confirmed by 

disappearance of the characteristic image, saline 

and air reflux through the ileocecal valve and 

distension of the ileum by the saline. The principal 

advantages are lack of exposure to ionizing 

radiation and absence of significant complications. 

Indeed, the only complication reported to date is 

perforation, easily recognized during reduction, 

and with fewer associated risks than escape of 

barium into the abdominal cavity. In short, hydrostatic 

reduction under ultrasound guidance is as 

effective as, or more effective than other reduction 

techniques, and has the obvious advantage of 

avoiding radiation exposure. 37 

Barium enema 

As a purely diagnostic method, barium enema is 

nowadays of little value. It may be useful for 

confirming the diagnosis in doubtful cases, 

showing a concave image at the head of the barium 

column corresponding to the apex of the intussusceptum; 

the image may be delimited by barium 

between the intussusceptum and the intussuscipiens, 

and is clearer when some of the barium is 

evacuated from the colon distal to the intussusception 

(Figure 40.4). However, possible organic 

causes of intussusception are rarely detected by 

this method.

724 


Figure 43.4 Diagnostic barium contrast enema: 

radiograph showing non-passage of barium beyond the 

level of the hepatic angle, and with barium extending 

between intussusceptum and intussuscipiens. 

Treatment 

Medical treatment 

Once intussusception has been diagnosed, a nasogastric 

tube should be inserted, and peripheral 

endovenous fluid therapy should be started. Blood 

tests, including coagulation and electrolytes, 

should be done. Routine antibiotic treatment is not 

recommended, and should be reserved for complicated 

cases. Sedation and analgesia are recommended 

(with drugs including diazepam, midazolam, 

meperidine, thiopental sodium, ketamine, 

phenobarbital sodium and atropine) to avoid pain, 

reduce spasm, shorten the time required for reduction, 

and increase the likelihood of success. 

Glucagon is not currently used, in view of its 

doubtful efficacy. 38,39 

We consider non-surgical reduction to be 

contraindicated if the patient shows poor general 

status, with signs of shock, dehydration or peritoneal 

irritation, or clinical, radiographic or ultrasonographic 

signs of perforation or advanced 

intestinal obstruction, or when the patient is 

attended a long time after the onset of intussusception, 

since the success rate of hydrostatic 

reduction declines with increasing time since 

onset. In such cases, the aim should be to recover 

good general status and then perform emergency 

surgery. 

Once successful reduction has been achieved, the 

patient should be maintained on observation for 

24h with nothing per os, and discharged after reintroduction 

and confirmed tolerance of oral 

feeding. 

Hydrostatic reduction 

The publication of Ravitch’s series in 1948 led to 

the widespread adoption of hydrostatic barium 

enema as a standard treatment method. 4 As noted, 

hydrostatic reduction under ultrasonographic 

guidance offers high diagnostic sensitivity together 

with high treatment success rates. 

Various contrast materials are available, the most 

widely used being barium sulfate, dissolved in 

physiological saline to avoid water intoxication 

and hyponatremia, or alternatively non-barium 

hydrosoluble contrasts (which have fewer negative 

effects) (Figures 43.5 and 43.6). 

It is important to note that the column height of 

the enema should be between 1 and 1.2m never 

exceeding 1.5m. The anus should not be fully 

occluded, permitting reflux of contrast medium if 

excessive pressure develops. The abdomen 

should not be manipulated during reduction. 

Each reduction attempt should not exceed 

10min, and if no progress is made the attempt 

should be abandoned. If progress is detected, 

further attempts may be made, at intervals of 

5–15min. 

Pneumatic reduction 

Intussusception reduction using pressurized air 

under radiographic guidance was described by 

Fiorito and Recalde Cuesta, 5 although apparently 

techniques of this type were traditionally used in 

China. 40 

Within the colon, pressurized air ‘pushes’ the 

intussusceptum, and at the same time enters into

Figure 43.5 Barium contrast radiograph showing an 

ileocecal intussusception in the transverse colon. 

the space between the intussusceptum and the 

intussuscipiens, facilitating reduction (Figure 

43.7). The reduction can be guided either by 

contrast radiography or by ultrasonography. 7,41 

Various devices for the introduction of air have 

been described, all including some sort of pump, 

a manometer and an intracolic pressure regulator. 

Pressure can be controlled with a sphygmomanometer 

to control pressure, and any sort of 

expulsion pump can be used (Richardson’s bulb, 

syringe pump, etc.). It has been shown that CO2 

is more readily absorbed than air in the intestinal 

lumen, but reduction efficacy does not seem to be 

any higher. 42 

With the child in the prone position, an 18–20 Fr 

Foley catheter is inserted into the rectum, with an 

initial pressure of 60mmHg, gradually increased 

to no more than 80–100mmHg in infants and 

120mmHg in older children. Intestinal perforation 

is thought not to be a result of excessive 

pneumatic pressure, but of inappropriate application 

of this technique in cases in which the intestine 

is ischemic or necrotic. 

Treatment 725 

Figure 43.6 Barium contrast radiograph showing an 

ileocecal intussusception in the ileocecal valve. 

Figure 43.7 Air contrast radiography of an ileocecal 

intussusception extending as far as the hepatic angle. The 

intussusception is visible as a radiopaque mass that 

prevents the passage of air.

726 


We currently prefer this technique to hydrostatic 

reduction, since it is easier to perform, and permits 

ready visualization of the intussusceptum, does 

not absorb body heat and facilitates confirmation 

of successful reduction (indicated by passage of air 

into the small intestine). Furthermore, if perforation 

occurs this is less problematic than in hydrostatic 

reduction with barium contrast, and is easier 

to treat, since the pneumoperitoneum can be 

drained immediately after insertion of a largegauge 

needle. 41,43,44 

The success rate with hydrostatic or pneumatic 

reduction is 75–95%, with perforation occurring in 

0.11–2% of cases. 6,7,38,39 


Surgery is indicated only in very specific circumstances: 

(1) Whenever there are signs of shock or peritonitis; 

(2) In patients in whom hydrostatic or pneumatic 

reduction has not been fully successful; 

(3) In patients with poor general status, dehydration 

or peritoneal irritation; 

(4) In patients with intussusceptions of the sigmoid 

or rectum; 

(5) When there are clinical, radiographic or sonographic 

signs of perforation or advanced 

intestinal obstruction; 

(6) When the intussusception is not diagnosed 

until a long time after onset; 

(7) In cases of recurrent intussusception, with 

two or three non-surgical reductions previously 

per-formed. 

Successful reduction does not rule out the existence 

of organic pathology, so that any residual 

defect is an indication for laparotomy. Patients 

older than 2–3 years have been the object of some 

controversy, since the possibility that a lead point 

exists is much higher; in our series, 50% of children 

aged more than 2 years had organic causes, 

and some surgeons argue that in these patients 

exploratory laparotomy should be performed, even 

after successful non-surgical reduction. 

Surgery has certain advantages: any organic 

pathology will invariably be detected, the intussusception 

reduction will be complete and the 

recurrence rate is somewhat lower than with nonsurgical 

reduction. However, it also has a higher 

financial/resources cost, longer hospitalization 

time and a higher rate of complications (up to 17% 

in some series). 45 

Comfortable access can be achieved by a right 

transverse incision. The affected intestine can 

generally be readily exposed, enabling the intussusceptum 

to be gently massaged out of the intussuscipiens, 

using classic ‘milking’ movements, and 

not pulling the intussusceptum. Reduction in fact 

often tends to be difficult in surgically treated 

cases, and resections are required rather often; this 

probably reflects the high success rates obtained 

with pneumatic and hydrostatic reduction, and 

the fact that only problematic cases are treated 

surgically. 

Once complete reduction has been achieved, the 

viability of the intestine should be assessed, to 

identify possible regions of necrosis or doubtful 

viability, and to detect possible organic causes. 

After reduction, the cecal region and terminal 

ileum show a highly characteristic appearance, 

with thickening of the intestinal walls, and in 

some cases presence of a hard edematous plaque at 

the level of the terminal ileum; this should not be 

confused with an organic cause and does not 

require any sort of surgical response, which indeed 

would only cause complications. When intestinal 

resection is necessary, this should be as conservative 

as possible, aiming to maintain the ileocecal 

valve. Appendectomy should be performed 

routinely if the edema of the ileocecal region 

permits, although some authors have questioned 

its utility. Surgical treatment does not exclude the 

possibility of recurrence, which in one study was 

reported in 3.2% of cases. 46 

Intestinal fixation techniques (e.g. fixation of the 

cecum, suture of the terminal ileum to the ascending 

colon, Noble’s plication) were in the past 

widely used to prevent recurrence, but are now 

generally regarded as being ineffective and unnecessary. 

Recurrent intussusception requires a personalized 

treatment program: characteristically, surgery is

not required in patients aged less than 2 years, 

when they show a second or third crisis over a 

short period of time. In older patients, radiographic 

and sonographic findings should be 

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44 

Introduction 



Meckel’s diverticulum is the most common 

congenital anomaly of the gastrointestinal tract 

and the most common cause of serious gastrointestinal 

bleeding in children. Anatomically, it is 

an outpouching on the antimesenteric border of 

the small bowel (Figure 44.1). Although first 

reported by Fabricus Hildanus in 1598, this abnormality 

derives its name from Johann Friedrich 

Meckel, who in 1809 detailed its embryological 

origin and identified it as a potential cause of 

disease. 1,2 Reports estimate that Meckel’s diverticulum 

affects 2% of the general population. 

However, it is usually clinically silent, identified 

only as an incidental finding during laparotomy, 

laparoscopy, or at autopsy. Estimates of the life- 

Figure 44.1 Operative view of a Meckel’s diverticulum. 

The distal tip had heterotopic gastric mucosa. 

time risk of complications occurring range from 4 

to 6%. 3–5 These complications are usually due to 

ectopic tissue within the diverticulum or to 

omphalomesenteric or mesodiverticular bands. 

The clinical presentation of Meckel’s diverticulum 

is diverse. Symptoms often mimic those associated 

with other more common abdominal disorders, 

making preoperative diagnosis quite difficult. This 

chapter focuses on the major complications of this 

anomaly, describing its pathogenesis, diagnosis 

and management. Relevant embryology, histology 

and epidemiology will set the stage for this discussion. 

Pathoembryology 

Meckel’s diverticulum is one of a spectrum of 

congenital anomalies of the midgut that are embryological 

remnants of the vitelline (omphalomesenteric) 

duct. During week 3 of gestation, the yolk sac 

communicates with the gut through this duct. 

Between weeks 5–9 of gestation, the duct is 

normally obliterated, as the functioning placenta 

replaces the yolk sac as the source of fetal nourishment. 

Failure of this normal obliteration 

process can result in a number of developmental 

anomalies, of which Meckel’s diverticulum is the 

most common. The diverticulum may remain 

completely attached to the abdominal wall at the 

umbilicus, may remain attached as a fibrous cord 

as the distal portion of the vitelline duct involutes, 

or may remain unattached and free within the 

peritoneal cavity. The last presentation is the most 

common, occurring in 74% of cases. 6 Other anomalies 

related to the disturbance of vitelline duct 

involution include persistence of a patent 

omphalomesenteric duct (Figure 44.2) or the 

development of an omphalomesenteric sinus or 

cyst. Such a cyst may form when both proximal 

729

730 


Figure 44.2 Patent omphalomesenteric duct in a 

neonate. The mucosa can be visualized in the 

transected umbilical cord. The omphalomesenteric duct 

communicates from the distal ileum to the umbilicus. 

Figure 44.3 Drawing depicting an omphalomesenteric 

cyst attached to the umbilical region as well as to a 

fibrous band to the terminal ileum. 

and distal obliteration occurs while the central 

portion of the duct remains patent (Figure 44.3). 

The blood supply to Meckel’s diverticulum is 

derived from the paired vitelline arteries. The left 

vitelline artery involutes, whereas the right 

persists as the superior mesenteric artery. A 

remnant of the primitive right vitelline artery 

arises directly from the mesentery to supply the 

diverticulum. The blood supply is anatomically 

unique in that the vessels to the diverticulum pass 

over the serosa of the ileum, terminating on the 

antimesenteric rather than the mesenteric side of 

the bowel. Although these vessels usually terminate 

at the tip of the diverticulum, they may 

continue on to the abdominal wall. They may also 

persist as a fibrous cord connecting the ileum to 

the umbilicus after obliteration of the diverticulum. 

The tip of the diverticulum may remain 

attached to the base of the mesentery by a fibrous 

remnant of the vitelline vessels, creating a mesodiverticular 

band through which loops of small 

bowel may pass and become incarcerated. 

Histology 

Meckel’s diverticulum is usually located within 

100cm (3 feet) of the ileocecal junction on the 

antimesenteric border of the ileum. It is a true 

diverticulum, containing all layers of the intestinal 

wall. Heterotopic mucosa is found in up to 

55–60% of Meckel’s diverticula 7–9 and is found 

predominantly in symptomatic patients. 5,10–12 

Gastric and pancreatic tissue predominate, with 

corresponding incidences of 60–90% and 

5–16% 5,10–13 (Figure 44.4); both ectopic tissue 

types may be found together within the diverticulum. 

Although colonic, duodenal, jejunal, hepatic 

and endometrial ectopic tissues have been 

found, 11,14–17 these are rare and are not generally 

associated with complications. 

Epidemiology 

Of symptomatic Meckel’s diverticula, 50–60% 

occur in children younger than 2 years of age. A 

significant increase in the 1–2% incidence in the 

general population is seen in association with a 

number of other congenital anomalies. In a series 

of nearly 6000 pediatric autopsies, authors 

reported significant increases in the incidence of 

Meckel’s diverticulum in children born with a 

cleft palate, bicornuate uterus, annular pancreas, 

esophageal or anorectal atresia, or gross malformation 

of the central nervous or cardiovascular 

systems. 18 Meckel’s diverticulum is also more 

common in patients with Crohn’s disease 19 and in 

patients with omphalocele, approximately 25% of 

whom exhibit some form of omphalomesenteric

Figure 44.4 Histology of a Meckel’s diverticulum 

demonstrating gastric and ileal mucosa. The deep cleft 

is an ulcer separating the two types of mucosa. 

remnant. 20 Although rare, carcinoid tumors have 

been found to arise from the diverticulum. 21–23 

Other tumors have also been reported, but these 

have occurred primarily in adult patients. 7 

Clinical presentations 

Predisposing factors 

While heterotopic tissue within the diverticula is 

the most significant predisposing factor to complications, 

several other factors also appear to be 

associated with an increased likelihood of complications. 

The reported predominance of symptomatic 

Meckel’s diverticulum in males (ratios 

ranging from 2:1 to 5:1) indicates that gender may 

play a role. 11,13 Studies have also shown that diverticular 

length 11 and base diameter 24 are predispos- 

Clinical presentations 731 

ing factors. Long, narrow-based diverticula are 

thought to be more prone to obstruction or inflammation, 

whereas short, large-based diverticula are 

subject to foreign body entrapment. Whether or 

not age can be correlated with the incidence of 

complications is currently controversial. Although 

the risk of complications has historically been 

thought to decline with age, 3,11,24 two relatively 

recent studies have demonstrated an even age 

distribution in patients with complications. 13,26 

Complications 

The most common complications are gastrointestinal 

bleeding, intestinal obstruction and inflammation. 

Clinical presentation is generally associated 

with the presence of ectopic gastric mucosa within 

the diverticulum or fixation of omphalomesenteric 

duct remnants to the abdominal wall. The ectopic 

mucosa may cause ulceration, which can result in 

inflammation, bleeding, or perforation. Fixation of 

omphalomesenteric duct remnants to the abdominal 

wall may result in intestinal obstruction from 

torsion of small-bowel loops around the point of 

fixation (Figure 44.5). The Meckel’s diverticulum 

may be recognized on preoperative studies or at 

operation, or it may be found unexpectedly in a 

resected specimen. The likelihood of the presence 

of heterotopic mucosa in surgically resected 

Meckel’s diverticula depends on the clinical 

presentation. It is found in approximately 50% of 

all symptomatic patients who have gastrointestinal 

bleeding, obstruction or inflammation (diverticulitis). 

Gastrointestinal bleeding 

Gastrointestinal bleeding occurs in 22% of all children 

with Meckel’s diverticula and 40–60% of 

symptomatic children. 12,26 It is the most common 

presenting symptom in children younger than age 

4, and the mean age of presentation is 2.8 years. 12 

Painless rectal bleeding is the usual manifestation. 

Although the bleeding may be significant, it is 

often episodic. The color of blood may vary from 

bright red to dark red or maroon to black and tarry, 

and may even appear as the ‘currant jelly stool’ 

typically associated with intussusception. 26 

Bleeding is sometimes massive, transfusions are 

often required and life-threatening hemorrhage

732 


(a) (b) 

Figure 44.5 (a) Drawing depicting a segmental ileal volvulus around an omphalomesenteric band. 

(b) Intraoperative photograph showing a segmental ileal volvulus around a Meckel’s diverticulum and 

omphalomesenteric band. 

occasionally occurs. This requires rapid resuscitation 

and stabilization and early diagnosis and 

treatment. 

Bleeding is thought to occur as a result of peptic 

ulceration caused by secretion of hydrochloric 

acid from parietal cells within the ectopic gastric 

mucosa located in the diverticulum. In patients 

who show bleeding only, the prevalence of heterotopic 

gastric mucosa approaches 100%. 7 Unlike 

the stomach, the ileum cannot buffer the resulting 

low pH and is thus more prone to ulceration. The 

ulceration may be small, visible only to the pathologist. 

It is generally located at the base of the diverticulum, 

at the junction of ectopic gastric mucosa 

and normal ileal mucosa. It may, however, also be 

found within the ectopic gastric mucosa itself or 

on the mesenteric side of the ileum, opposite the 

diverticulum (Figure 44.6). Ectopic gastric mucosa 

and ulceration are identified in about 95% 

and 98%, respectively, in specimens resected for 

bleeding. 5 

Although Helicobacter pylori plays a major role in 

ulcerogenesis elsewhere, it does not appear to be a 

significant factor in the pathogenesis of bleeding 

and inflammatory complications from the ectopic 

gastric mucosa in Meckel’s diverticula, and has 

only rarely been isolated from specimens. 27–29 

Differential diagnosis includes inflammatory 

bowel disease, intestinal polyps, duplications and 

arteriovenous malformations. Peptic ulcer disease 

and variceal bleeding may also present in a similar 

fashion, but can be distinguished through bloody 

nasogastric aspirates or with upper endoscopy. 

Occult bleeding with anemia is an infrequent 

presentation of Meckel’s diverticulum. 

Intestinal obstruction 

Bowel obstruction in any previously healthy child 

merits a high index of suspicion for Meckel’s 

diverticulum. When this anomaly is present, the 

obstruction is usually due to intussusception 

(46%) or volvulus (24%). 7 In children with intussusception, 

Meckel’s diverticulum often serves as 

the lead point of the intussusception (Figure 44.7). 

The clinical presentation of intussusception 

includes vomiting, intermittent abdominal pain, 

bloody stools, a palpable lower abdominal mass 

and eventual progression to dehydration and

Figure 44.6 Drawing demonstrating two ileal ulcers 

on the mesenteric side of the ileum which may be seen 

in patients with bleeding related to heterotopic gastric 

mucosa in the Meckel’s diverticulum. 

lethargy. 7 Ultrasonography, as well as pneumatic 

or barium enema are useful in establishing the 

diagnosis of intussusception. Rarely, complete 

reduction is obtained with enema and if Meckel’s 

diverticulum is visualized by imaging, an elective 

diverticulectomy can be performed. Most patients, 

however, have incomplete reduction of their 

ileoileal/ileocolonic intussusception, and require 

surgery to reduce the intussusception and resect 

the Meckel’s diverticulum. 

Volvulus can occur through several mechanisms. 

It is usually an acute event, and if allowed to 

progress, may result in strangulation of the 

involved bowel. Vitelline remnants or the 

omphalomesenteric duct may attach to the abdominal 

wall and form an anchor around which the 

bowel twists. The intestine may herniate under 

mesodiverticular bands, kinking or obstructing 

(Figure 44.8). Rarely, a long diverticulum twists on 

itself (axial torsion), causing obstruction. Also 

rare, intestinal obstruction may result from incarceration 

of a Meckel’s diverticulum within a 

hernia sac (Littre’s hernia). In neonates, an 

inverted Meckel’s diverticulum has been associated 

with intestinal obstruction and microcolon. 30 

Clinical presentations 733 

Figure 44.7 Drawing demonstrating an ileo-ileal 

intussusception caused by a Meckel’s diverticulum. 

Resuscitation for bowel obstruction consists of 

intravenous hydration, correction of electrolytic 

abnormalities, administration of broad-spectrum 

antibiotics, intestinal decompression and definitive 

operation. 

Inflammation 

In contrast to bleeding and intestinal obstruction, 

diverticulitis occurs more commonly in adolescents 

and adults. It is generally indistinguishable 

from appendicitis and, as with appendicitis, failure 

to diagnose the diverticulitis promptly may 

lead to perforation, peritonitis and death. The role 

of the ectopic mucosa in this process is suggested 

by its high incidence in resected inflamed mucosa. 

Thus, when appendicitis is suspected but not 

found at operation, it is critical to inspect the distal 

ileum for a symptomatic Meckel’s diverticulum. 

Other clinical presentations 

Inflammation and perforation of a Meckel’s diverticulum 

by a foreign body in the gastrointestinal 

tract has been reported. 12,16 Although rarely seen

734 


Figure 44.8 Herniation and obstruction of small 

intestine through a Meckel’s band adhering to the base 

of the ileal mesentery. 

in pediatric patients, malignancies, 9 stone formation 

within the diverticulum, and even parasitic 

infections have also been documented. 31,32 

Additionally, a recent report described the atypical 

presentation of recurrent urinary tract infections 

caused by an infected Meckel’s diverticulum that 

displaced the urinary bladder. 33 

Diagnostic evaluation 

Abdominal scintigraphy (Meckel’s scan) using 

Tc-99m pertechnetate is a well-established diagnostic 

technique to evaluate children with lower 

gastrointestinal bleeding and is considered the 

diagnostic procedure of choice when there is a 

suspicion of Meckel’s diverticulum (Figure 44.9). 

Reported results of a 10-year pediatric review of 

this type of scan revealed a sensitivity for detection 

of Meckel’s diverticulum of 85%, a specificity 

of 95% and accuracy of 90%. False-negative results 

occurred in 1.7% of cases, and false-positive 

results in only 0.05% of cases. 34 

The high affinity of Tc-99m pertechnetate for 

gastric mucosa is what makes this radiopharmaceutical 

such a valuable tool. Tc-99m pertechnetate 

is taken up and secreted by the tubular glands 

of the gastric mucosa. The remainder of the 

isotope is concentrated within the urinary bladder. 

Sequential 1-min anterior abdominal images are 

obtained for 30–60min. A positive scan shows 

abnormal uptake of isotope outside the stomach 

and urinary bladder. 35 

False-positive results have been reported with 

intestinal duplications, certain genitourinary 

anomalies, Barrett’s esophagus, ulcers, inflammatory 

bowel disease, intussusception, bowel 

obstruction, neoplasms and vascular lesions such 

as hemangiomas and arteriovenous malformations; 

these results are caused by non-specific 

accumulation of the isotope. False-negative Tc- 

99m pertechnetate scintigraphy may result from a 

small diverticulum or hemorrhage washing out the 

isotope. Also, residual contrast in the bowel from 

previous barium studies may hinder its detection, 

or tracer in the urinary bladder may obscure visualization 

of heterotopic gastric mucosa if it is 

located near the bladder. 35 Several pharmacological 

agents, including pentagastrin, histamine-2 

blockers (e.g. cimetidine), and glucagon have been 

used to enhance the diagnostic accuracy of the 

scan. Pentagastrin stimulates gastric mucosal 

uptake, histamine-2 blockers inhibit excretion of 

the isotope once it is taken up and glucagon 

inhibits peristalsis, thereby increasing retention of 

the isotope in the diverticulum. While some 

authors maintain that pharmacological enhancement 

is necessary only when results of a nonpharmacologically 

enhanced study are inconclusive, 

35 I feel that enhancement reduces the need 

for repeated radionuclide studies and therefore use 

it routinely. Fasting, nasogastric suctioning, and 

bladder catheterization may also increase the diagnostic 

yield of the scan. 

Although Tc-99m pertechnetate scintigraphy is the 

diagnostic procedure of choice, there are limitations 

to its use in clinical decision-making. 

According to a recent study, 36 in patients with 

gastrointestinal bleeding and a serum hemoglobin 

level of less than 11g/dl, the Meckel’s scan has a 

relatively low negative predictive value (0.74). 

Authors suggest that replacing the scan with early 

operative evaluation may be cost-effective,

Figure 44.9 Positive Tc-99m pertechnetate radionuclide scan at 60min demonstrating 

abnormal uptake of the radionuclide in the lower abdomen in a child with a Meckel’s 

diverticulum. Note the normal gastric uptake in the upper abdomen. 

especially in patients in whom there is a high 

index of suspicion for a bleeding Meckel’s diverticulum. 

The known advantages of minimally 

invasive laparoscopy have led others to advocate 

this operative approach as a means of identifying 

the presence of a bleeding Meckel’s diverticulum. 

They have suggested that it may replace the 

Meckel’s scan in the diagnostic evaluation of pediatric 

patients with clinically significant gastrointestinal 

bleeding and high suspicion for this 

disease process. 37,38 

Visceral angiography is rarely needed, but is occasionally 

useful as a diagnostic tool in the actively 

bleeding patient (more than 0.5–1ml/min) when 

the Meckel’s radionuclide scan is negative. In this 

instance, the angiogram may show extravasation of 

contrast from the ileocolic branch of the superior 

mesenteric artery. A superselective superior 

mesenteric artery angiogram may show a nonbranching, 

elongated artery originating from the 

ileal artery and a group of dilated tortuous vessels 

at the distal portion of this artery in patients with 

Meckel’s diverticulum. 39 This technique allows 

visualization of Meckel’s diverticulum, even in the 

absence of bleeding. 

Management 


Management of the asymptomatic patient with an 

incidentally discovered Meckel’s diverticulum has 

long been controversial. The debate focuses on the 

probability of the diverticulum becoming symptomatic 

in the future as opposed to the likelihood of 

complications associated with resection. To date, 

there are no definitive intraoperative anatomic or 

biological features that enable the surgeon to 

predict the probability of future complications. 

While predisposing factors for symptomatic 

Meckel’s diverticula have been identified, these 

factors are only of limited value to the surgeon in 

deciding whether or not to resect an asymptomatic 

diverticulum. 

In some clinical situations, there is a degree of 

consensus that helps in making an intraoperative 

judgment. Resection is clearly indicated in 

patients with a long, narrow-based Meckel’s diverticulum 

or in those in whom the diverticulum is 

palpably thickened at its terminal portion; in 

patients who have vitellointestinal remnants or 

abdominal wall attachments; and in patients with 

a history of unexplained abdominal pain. These

736 


Figure 44.10 Drawing demonstrating the concept of segmental ileal resection and anastomosis. 

factors all increase the likelihood of bleeding, 

obstruction, or diverticulitis. Because Meckel’s 

diverticulum can become symptomatic at any age, 

the age of the patient is not the primary factor in the 

decision to resect the asymptomatic diverticulum. 

In general, this decision must be made after careful 

consideration of the risks and benefits for each 

patient. Owing to the risk of suture line disruption, 

an elective diverticulectomy is contraindicated if a 

Meckel’s diverticulum is identified during repair of 

gastroschisis. 7 

Symptomatic Meckel’s diverticulum must be 

resected, and resection should be preceded by 

prompt and aggressive fluid resuscitation and blood 

transfusion when necessary. In patients with intestinal 

obstruction and possible intestinal ischemia, the 

patient’s physiology should be stabilized to the 

degree possible prior to operation. When a laparotomy 

is performed, the diverticulum is generally 

approached through a transverse right lower quadrant 

incision. Visual inspection and palpation to 

identify the location of ectopic gastric mucosa and 

ulceration is critical. If one is confident that the 

ulceration is confined to the diverticulum, simple 

diverticulectomy may be performed with either 

sutures or a stapling device. To prevent luminal 

narrowing, especially with broader-based diverticula, 

the defect may be closed transversely in a 

Heineke–Mikulicz fashion. If the base of the diverticulum 

is too broad, or if ulceration is identified on 

the mesenteric side of the ileum opposite the diverticulum, 

segmental resection of the ileum containing 

the diverticulum with an end-to-end anastomosis 

is preferred (Figure 44.10). Care must be taken 

to separately ligate the blood supply to the Meckel’s 

diverticulum. When a right lower quadrant incision 

is used, an appendectomy should be concomitantly 

performed to prevent future diagnostic dilemmas. 

Laparoscopic resection performed either intracorporeally 

or extracorporeally has increasingly been 

reported. 40–42 With intracorporeal resection, the 

diverticulum is identified and grasped, and a diverticulectomy 

is performed using a stapling device if 

the diverticulum is deemed anatomically suitable 

for such an approach (Figure 44.11). The disadvantage 

of this technique with a bleeding Meckel’s 

diverticulum is the inability to exclude ulceration 

on the mesenteric side of the ileum opposite the 

diverticulum, which could result in continued 

bleeding after resection. Also, it is technically more 

difficult to perform a segmental small-bowel resection 

if indicated. With extracorporeal resection, the

Figure 44.11 Laparoscopic stapling and removal of a Meckel’s diverticulum. 

diverticulum is identified, grasped and brought out 

through the umbilical or other trocar site. Once the 

diverticulectomy or segmental small bowl resection 

is performed, the bowel is returned to the peritoneal 

cavity. The advantage of this technique is that it 

allows the surgeon to inspect and palpate the bowel, 

and to perform an intestinal anastomosis, easily. 

One limitation of laparoscopic resection is that it 

does not allow for the management of a giant 

Meckel’s diverticulum, which may be difficult to 

resect through small laparoscopic incisions. 

Although theoretical advantages of a laparoscopic 

approach include improved cosmesis and less postoperative 

pain, prospective studies that demonstrate 

these advantages are warranted. 

Outcomes 

Since the 1980s, incidental diverticulectomy for 

patients with asymptomatic Meckel’s diverticulum 

has been associated with morbidity and mortality 

rates ranging from 0–9% to 0–1%, respectively. 

13,24,26,43 In a comprehensive Mayo Clinic 

study including both children and adults, the 

overall rate of morbidity of incidental removal of 

Outcomes 737 

Meckel’s diverticulum was 2%, while the postoperative 

mortality rate was 1%. The risk of developing 

long-term complications by 20 years after an incidental 

diverticulectomy was only 2%. In view of the 

4–6% lifetime risk of complications 3–5 from a 

Meckel’s diverticulum, these combined findings 

suggest that incidental Meckel’s diverticulectomy is 

justified in select cases in which the anatomical 

features of the diverticulum put patients at higher 

risk for future complications. 

Reported morbidity and mortality rates for diverticulectomy 

in symptomatic patients vary widely, 

ranging between 0–18% and 0–9%, respectively. 

11,13,24,26,43 The Mayo Clinic study 13 reported a 

12% incidence of early postoperative complications; 

these were mainly wound infection (3%), 

prolonged ileus (3%) and anastomotic leak (2%). 

The mortality rate was 1.5%. The incidence of late 

postoperative complications during a 20-year 

follow-up was 7%. In our own institution, operation 

in symptomatic pediatric patients has yielded excellent 

long-term outcomes. The perioperative complication 

rate has been less than 6%, with the most 

common complications being wound infection and 

prolonged ileus. We have had no reported deaths in 

over a decade.

738 


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Physiol 1809; 9: 421–453. 

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Ann Surg 1976: 183: 30–33. 

11. Mackay WC, Dineen PA. Fifty-year experience with 

Meckel’s diverticulum. Surg Gynecol Obstet 1983; 156: 

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12. Vane DW, West KW, Grosfeld JL. Vitelline duct anomalies. 

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of Meckel’s diverticulum. An epidemiologic, populationbased 

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55 years of clinical and surgical experience. JAMA 

1962; 182: 131–133. 

16. Moses WR. Meckel’s diverticulum. Report of two 

unusual cases. N Engl J Med 1947; 237: 118–122. 

17. Baker AL, Marshall SF. Meckel’s diverticulum: a report 

on ninety three cases. Am Surg 1955; 21: 1173–1181. 

18. Simms M, Corkery J. Meckel’s diverticulum: its association 

with congenital malformation and the significance 

of atypical morphology. Br J Surg 1980; 67: 216–219. 

19. Andreyev HJN, Owen RA, Thompson I et al. Association 

between Meckel’s diverticulum and Crohn’s disease: a 

retrospective review. Gut 1994; 35: 788–790. 

20. Nicol JW, MacKinlay GA. Meckel’s diverticulum in 

exomphalos minor. J R Coll Surg Edinb 1994; 39: 6–7. 

21. Moyana TN. Carcinoid tumors arising from Meckel’s 

diverticulum: a clinical, morphologic, and immunohistochemical 

study. Am J Clin Pathol 1989; 91: 52–56. 

22. Nies C, Zielke A, Hasse C et al. Carcinoid tumors of 

Meckel’s diverticula. Report of two cases and review of 

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23. Silk YN, Douglass HO Jr, Penetrante R. Carcinoid tumor 

in Meckel’s diverticulum. Am Surg 1988; 54: 664–667. 

24. Leijonmarck CE, Bonman-Sandelin K, Frisell J et al. 

Meckel’s diverticulum in the adult. Br J Surg 1986; 73: 

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25. Arnold JF, Pellicane JV. Meckel’s diverticulum: a ten-year 

experience. Am Surg 1997; 63: 354–355. 

26. Rutherford RB, Akers DR. Meckel’s diverticulum: a 

review of 148 pediatric patients, with special reference 

to the pattern of bleeding and to mesodiverticular vascular 

bands. Surgery 1966; 59: 618–626. 

27. Bemelman WA, Bosma A, Wiersma PH et al. Role of 

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of Meckel’s diverticula. Eur J Surg 1993; 159: 171–175. 

28. Kumar S, Small P, Mohammed R. Helicobacter pylori and 

Meckel’s diverticulum. J R Coll Surg Edinb 1991; 36: 

225–226. 

29. Fich A, Talley NJ, Shorter RG et al. Does Helicobacter 

pylori colonize the gastric mucosa of Meckel’s diverticulum? 

Mayo Clin Proc 1990; 65: 187–191. 

30. Donnelly LF, Johnson JF. Case report: inverted Meckel’s 

diverticulum with associated microcolon. Clin Radiol 

1988; 53: 226–227. 

31. Pujari BD, Deodhare SG. Ascarideal penetration of 

Meckel’s diverticulum. Int Surg 1978; 63: 113–114. 

32. Hangloo VK, Koul I, Safaya R et al. Primary ascaridial 

perforations of small intestine and Meckel’s diverticulum. 

Indian J Gastroenterol 1990; 9: 287–288. 

33. Oguzkurt ˘ 

P, Arda S, Kayaselcuk F et al. Cystic Meckel’s 

diverticulum: a rare cause of cystic pelvic mass presenting 

with urinary symptoms. J Pediatr Surg 2001; 36: 

1855–1858. 

34. Sfakianakis GN, Conway JJ. Detection of ectopic gastric 

mucosa in Meckel’s diverticulum and in other aberrations 

by scintigraphy: II. Indications and methods – a 10year 

experience. J Nucl Med 1981; 22: 732–738. 

35. Emamian SA, Shalaby-Rana E, Majd M. The spectrum of 

heterotopic gastric mucosa in children detected by Tc- 

99m pertechnetate scintigraphy. Clin Nucl Med 2001; 26: 

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36. Swaniker F, Soldes O, Hirschl RB. The utility of technetium 

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of patients with Meckel’s diverticulum. J Pediatr Surg 

1999; 34: 760–765. 

37. Stylianos S, Stein J, Flanigan LM et al. Laparoscopy for 

diagnosis and treatment of recurrent abdominal pain in 

children. J Ped Surg 1996; 31: 1158–1160. 

38. Teitelbaum DH, Polley TZ Jr, Obeid F. Laparoscopic diagnosis 

and excision of Meckel’s diverticulum. J Pediatr 

Surg 1994; 29: 495–497. 

39. Okazaki M, Higashihara H, Saida Y et al. Angiographic 

findings of Meckel’s diverticulum: the characteristic 

appearance of the vitelline artery. Abdom Imaging 1993; 

18: 15–19. 

40. Echenique M, Dominguez A, Echenique I et al. 

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Laparoendosc Surg 1993; 3: 145–148. 

41. Sanders LE. Laparoscopic treatment of Meckel’s diverticulum. 

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42. Huang CS, Lin LH. Laparoscopic Meckel’s diverticulectomy 

in infants: report of three cases. J Pediatr Surg 

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45 

Introduction 



Acute appendicitis is a common pediatric surgical 

disease requiring urgent attention. In many cases it 

shows characteristic clinical manifestations, but in 

others it may simulate several other syndromes, 

leading to delays in diagnosis and thus increased 

morbidity and mortality. It is the most frequent 

cause of emergency surgery in infancy, and one of 

the most frequent causes of abdominal pain. 

In 1731, Aymand reported in Philosophical 

Transactions of the Royal Society the first successful 

appendectomy, performed in a child with a 

very large inguinoscrotal hernia, the sac of which 

contained an appendix perforated by a needle and 

giving rise to a stercoral fistula. The intervention 

lasted 30min, and the patient survived. 

The term ‘appendicitis’ was coined in 1886 by the 

American pathological anatomist Reginald Fitz, 

who stressed the need for early diagnosis and 

surgery in cases of acute inflammation of the 

appendix. 1 In 1889, McBurney declared that ‘In 

every case the seat of greatest pain, determined by 

the pressure of one finger, has been very exactly 

between an inch and a half and two inches from 

the anterior spinous process of the ilium on a 

straight line drawn from that process to the 

umbilicus’. 2 Since that time this manifestation has 

been known as the McBurney sign, marking the 

start of a period of greater scientific rigor in the 

diagnosis and treatment of acute appendicitis, 

with early diagnosis and treatment being recognized 

as essential. 

Epidemiology 

The incidence of acute appendicitis in the USA 

has been estimated at about 11 cases per 10000 

people per year, rising to 23 per 10000 per year in 

the 10–19-year-old age group, with slightly higher 

incidence among boys. Incidence among 

preschool children is lower, but in this age group 

delayed diagnosis and complications are more 

frequent. 3,4 About a quarter of operated acute 

appendicitis cases are found to be perforated at 

surgery. 

In fact, only about 0.5–2% of cases of acute 

appendicitis appear in children aged less than 2 

years. Heredity seems to be important: children 

who have appendicitis are twice as likely to have 

a positive family history as children who present 

lower abdominal quadrant pain not due to appendicitis, 

and almost three times as likely to have a 

positive family history as surgical controls without 

abdominal pain. 5 

In recent decades, as a consequence of the development 

of new and more effective antibiotics, and 

of advances in postoperative treatment, a marked 

reduction in morbidity and mortality has been 

achieved, but early diagnosis continues to be the 

most important factor for a good prognosis. 6 To 

reduce the incidence of complications and perforated 

appendicitis, practitioners should err on 

the side of caution: it is considered acceptable for 

up to 10% of laparotomies for suspected acute 

appendicitis to prove unnecessary (i.e. normal 

appendix). 

Anatomy 

The development of the cecum and appendix 

commences in the cecal diverticulum on the 

antimesenteric side of the caudal end of the medial 

intestine, around the 5th week of gestation. During 

its descent, the cecoappendiceal complex may 

locate in a retrocecal or retrocolonic position 

739

740 


(about 75% of cases) or inferomedial to the cecum 

(about 20% of cases). The infant cecum is located 

in the right iliac fossa in about 55% of individuals. 

7 In newborn children it is funnel-shaped with 

the ‘base’ oriented upwards and the vertex continuous 

with the appendix. The proximal end of the 

appendix is narrower, and its muscle layers 

thicker, which explains why perforations occur 

most frequently at the tip. Both cecum and appendix 

are irrigated by the ileocecal trunk, the ileocolic 

artery. The arterial supply is terminal, so that 

thrombosis leads to rapid necrosis. The veins drain 

to the superior mesenteric vein, which is a 

common route for propagation of infections from 

the appendix to the liver. 

The lymphatics of the cecum and appendix drain 

into a group of five or six lymph nodes located in 

the area of the terminal ileum, so that infections of 

the appendix may reach the peritoneum or even 

the thorax. 8 

The cecum and appendix are innervated by the 

solar plexus via the superior mesenteric plexus, 

from thoracic sympathetic nerves IX–XI. The autonomic 

innervation is provided by a small number 

of ganglion cells irregularly distributed in the 

submucosa and muscular layers, without forming 

a plexus. 9 


The function of the appendix is unknown: it 

possibly plays some immunological role in the 

identification of foreign proteins and bacteria, and 

in the manufacture of IgA. It has been demonstrated 

experimentally that mucus secretion 

(1–2ml/day) when drainage is blocked increases 

intraluminal pressure with consequent vascular 

compromise. The appendix shows independent 

irregular peristaltic activity, detectable on 

radiography. 9 

Obstruction is a fundamental factor in the development 

of acute appendicitis. The position of the 

blind sac of the appendix favors obstruction of the 

lumen (by foreign bodies, fecaliths, doubling of the 

lumen upon itself, lymphoid hyperplasia, infection 

or tumor), which increases intraluminal 

pressure leading to ischemia, bacterial invasion, 

necrosis and perforation. 10 In the early phases, 

activation of receptors in the intestinal wall leads 

to perception of pain in the periumbilical region; 

in later phases, pain is perceived in the right iliac 

fossa, as a result of irritation due to purulent 

secretion or contact between the appendix and the 

parietal peritoneum. 

The bacteriological causes of appendiceal infection/inflammation 

are highly varied. For some 

authors, infection almost always occurs via the 

blood, 11 while others consider that intraluminal 

bacteria are generally responsible. 12–14 The characteristic 

bacteria are those present in the human 

colon, predominantly anaerobic, including 

Escherichia coli, Enterococcus, Bacterioides 

fragilis, Pseudomonas, Klebsiella and Clostridium. 

The higher incidence of acute appendicitis at 

certain times of the year suggests that respiratory 

and/or digestive infections showing similar 

seasonal trends may predispose to lymphoid 

hyperplasia and resulting narrowing of the 

appendiceal lumen. 

The apparent etiological relationship with certain 

infections (whether exanthematous or not) probably 

reflects lymphoid hyperplasia and resulting 

inflammation and obstruction, as observed in 

measles, infectious mononucleosis and infections 

with HIV, adenovirus or coxsackievirus B. The 

incidence of acute appendicitis is abnormally high 

in patients with such infections, and with a higher 

incidence of perforation because of the difficulty 

of early diagnosis. 15,16 

Likewise, it has been suggested that intestinal 

parasites may contribute to appendicitis, although 

a study in the USA found that parasites were 

present in less than 10% of 100 extirpated appendices. 

17 

Carcinoid tumors may cause acute appendicitis in 

children, especially when close to the tip; in such 

cases simple appendectomy is generally sufficient 

treatment. 18 

Clinicopathological course 

The course of appendicitis – from the normal state 

to gangrene – follows a series of clinicopathological 

states, classifiable as follows:

Simple appendicitis 

The first clinical manifestation is congestion of the 

subserous blood vessels and inflammatory 

exudate, together with loss of the characteristic 

shininess of the serous layer. Parietal thickening 

and luminal obstruction are typically manifested 

by swelling of the appendix and particularly its 

tip, with appearance of fibrin. Microscopy reveals 

small intraluminal groupings of pyocytes, scaling 

plaques in the mucosa, cryptic abscesses and 

scarce polymorphonuclear lymphocytes in the 

lamina propria. At this stage the patient typically 

begins to feel periumbilical pain, which gradually 

shifts towards the right iliac fossa. 

Phlegmonous appendicitis 

Suppurative areas are seen on the wall of the 

appendix, and venous thromboses in the mesoappendix. 

Microperforations are observed, generally 

in large numbers. The appendix is typically 

covered with omentum. Microscopy reveals an 

inflammatory infiltrate, together with evident 

signs of thrombosis and necrosis. 

Ulceronecrotic appendicitis 

The appendix has become a soft, friable, purplish 

red structure, with very evident signs of necrosis, 

including in some cases macroscopic perforation 

and purulent exudate. 19 

Fibrin increases the adherence of the appendix to 

neighboring structures, above all in older children. 

Initially, the peritoneal cavity is seen to contain a 

clear sterile liquid, due to increased pressure 

within the lumen. Later, the cavity is invaded by 

fibrin, leukocytes and pathogens, forming an 

exudate which, when invaded by bacteria (from 

the intestine, or due to perforation of the appendix) 

leads to abdominal abscess formation, generally 

in the right iliac fossa, close to the cecum and 

usually foul-smelling; this typically occurs in the 

phlegmonous or necrotic stages of acute appendicitis. 

Diagnosis 

The incidence of acute appendicitis gradually 

increases from age 1 year onwards, peaking at 

Diagnosis 741 

around age 12 years, when the number of 

lymphatic follicles in the appendix is maximal, 

favoring its obstruction. 7 Appendicitis is rare 

during the first year of life, although an association 

has been reported between Hirschsprung’s disease 

and appendiceal perforation. 20 

Diagnosis of acute appendicitis may be easy or 

difficult, depending on the patient. All clinicians 

are familiar with the classic course of acute appendicitis, 

but early diagnosis is necessary to minimize 

complications and ensure successful treatment. 

Diagnosis can almost always be achieved on 

the basis of a brief history and physical exploration 

of the abdomen. Difficulties of diagnosis 

may arise with obese patients (particularly preadolescent 

girls), and with girls younger than 2 

years. Except in these two patient categories, 

analytical and imaging studies are not usually 

necessary, since they provide relatively little additional 

information. 


The classic sequence (fever, persistent abdominal 

pain and localized pain on palpation at 

McBurney’s point) starts with periumbilical pain, 

preceded by appetite loss in about 50–60% of children. 

Over a varying period of time, this pain gradually 

shifts to the right iliac fossa, with a corresponding 

increase in pain on palpation. The pain 

may be constant, colic or stabbing, or a dull ache. 

Characteristically the pain is implacable and is 

exacerbated by movements and pressure, making 

deambulation painful and difficult. 21 

The change in location of pain is an important 

diagnostic sign, related to parietal peritoneal irritation, 

which as it intensifies leads to disappearance 

of the periumbilical pain. 

Nausea and vomiting are also important for diagnosis. 

They appear after the onset of pain. Indeed, 

if vomiting appears before the onset of pain, other 

diagnoses (notably enteritis) should be considered. 

During the early stages of appendicitis, diarrhea 

simulating that occurring in the early stages of 

gastroenteritis is not infrequent; furthermore, in 

very advanced stages, diarrhea is characteristic. 

Urological symptoms (dysuria, urine retention) 

may be similarly misleading, even when urine 

analysis reveals high white blood cell (WBC)

742 


counts, given the proximity of the appendix to the 

bladder and the ureter. In other words, the clinician 

should not allow diarrhea or urological symptoms 

to distract from the possibility of acute 

appendicitis. 

A child with acute appendicitis typically walks 

bent over and slowly, taking care not to make 

brusque movements. Often, he or she finds it difficult 

or impossible to get up onto the examination 

table. 

Fever, which appears after pain and vomiting, is 

generally not very high; indeed, patients typically 

have low-grade fever. In many cases there is a 

marked difference (up to about 1°C) between axillary 

and rectal temperature. Early-onset high fever 

argues against acute appendicitis, but late-onset 

high fever with generalized abdominal pain 

suggests peritonitis, which is also accompanied by 

general malaise. 

Children with appendicitis are typically anorexic. 

When a child with abdominal pain shows strong 

appetite, appendicitis can generally be ruled out, 

although there are exceptions. Symptoms may be 

influenced by the anatomic location of the appendix. 

For example, a retrocecal appendix may cause 

flank pain or back pain. If the inflamed tip 

contacts the ureter, pain may be experienced in the 

inguinal region or testes, and may cause urinary 

symptoms. Pelvic appendicitis with the inflamed 

tip contacting the bladder may cause pollakiuria 

and/or dysuria, or ureteral compression with 

hydronephrosis (Figure 45.1). 

Approximately two-thirds of appendices are retrocecal 

or retrocolic. In some cases the appendix 

may cross the abdomen, with the tip extending 

into the other quadrant. In cases of incomplete 

rotation of the intestine, the appendix may be 

found in the right upper quadrant of the abdomen, 

or less frequently on the left side. 22 

In pre-weaning and young weaned infants, the 

diagnosis of acute appendicitis is more difficult, 

and from 24h after onset the risk of perforation 

increases considerably. 23 This is particularly problematic, 

given the still immature immunity of 

young infants. The omentum is also not fully 

developed, so that the effects of the appendicitis 

(e.g. fluid release into the peritoneal cavity) are 

typically less localized. Early diagnosis is thus 

Figure 45.1 Urography showing a mass in the right iliac 

fossa compressing the bladder and obstructing the ureter, 

giving rise to hydronephrosis, with an abscess secondary 

to undiagnosed acute appendicitis. 

imperative, and is complicated by the difficulty of 

clinical examination. Infants with acute appendicitis 

typically show vomiting and irritability, and 

draw up their legs to reduce pain. Other common 

manifestations include abdominal distension, 

diarrhea, lethargy and anorexia, together with 

fever. In 50% of cases an abdominal mass is 

detectable on palpation. 24 

In conclusion, all patients with abdominal pain, 

vomiting and moderate fever should be considered 

as suffering acute appendicitis until otherwise 

demonstrated. 


Physical examination performed with empathy, 

patience and experience is more valuable than a 

well-equipped laboratory. 25 A good start for the

physical examination is to take the patient’s pulse, 

for at least 30s; indeed, the pulse rate may be a 

more useful diagnostic clue than temperature. 

Observations of features such as general condition, 

mucocutaneous wetness or dryness, posture, and 

frequency and type of respiration (in small children 

with diaphragmatic respiration, immobility 

of the diaphragm due to peritoneal irritation may 

lead to respiratory compromise) may all be useful 

for achieving the diagnosis. Excessively hasty and 

brusque examinations may of course lead to incorrect 

diagnosis. Inspection of the throat and rectal 

examination are uncomfortable for the patient, and 

should be left for last. A distended bladder is 

painful and may lead to false diagnosis; the child 

should therefore urinate before the examination. 

Abdominal auscultation should be performed 

routinely, and should precede palpation. The 

examiner should take advantage of the stethoscope 

to auscultate suspected areas. A silent abdomen 

suggests inflammatory pathology, while hyperperistaltism 

is more indicative of gastroenteritis or 


If the patient is asleep, an initial abdominal palpation 

should be performed above the clothing, since 

a sleeping patient is easier to examine. Some 

maneuvers, such as slight bending of the hips, 

improve relaxation. In some patients, abdominal 

palpation may be so difficult that it necessitates 

sedation to suppress voluntary contractions. 17 

Palpation should always be first superficial and 

then deep. Involuntary reflex contractions and 

guarding are very important. To locate pain in 

response to deep palpation, the palpation should 

start in an area without pain, and the patient’s face 

should be watched for signs of discomfort. 

In addition to McBurney’s point, other palpation 

points have been described (Morris’s, Gray’s, 

Loeper’s, Lanz’s, Kelly’s, etc.), together with 

maneuvers aimed at localization of pain (psoas 

maneuver, obturator test, etc.). 10–13,17 In fact, the 

important thing to look for during examination is 

any localized area of abdominal pain. 

Rebound tenderness or Blumberg’s sign (i.e. pain 

felt on sudden release of steady pressure in the 

right iliac fossa region) simply reflects irritation of 

the parietal peritoneum of the inflamed appendix, 

and associated fluid secretion. 

Laboratory tests 743 

Rectal examination invariably causes discomfort 

to children, but is necessary for detection of possible 

pelvic abscess, right-sided pain, or pain on 

movement of the bladder. 


WBC counts are of limited diagnostic value. It is 

increasingly clear that diagnosis of acute appendicitis 

is basically clinical. However, a WBC count 

may be useful to confirm the diagnosis. Acute 

appendicitis leads to an increased WBC count 

(generally between 10000 and 20000 per mm 3 ), 

with increased polymorphonuclear leukocytes, 

neutrophils and immature neutrophils. The WBC 

count will generally be higher in cases of peritonitis 

or perforation. 

Some patients with acute appendicitis may, 

however, show a normal or low WBC count. This 

may reflect retrocecal or occult appendicitis. In 

such cases toxic granulations should be looked for. 

Determination of C-reactive protein level helps 

improve diagnostic certainty, but only when pain 

has been present for over 12–14h. 26,27 

Experience indicates that neutrophilia is more 

decisive for diagnosis than leukocytosis. In doubtful 

cases it is useful to monitor WBCs, as long as 

the patient is not receiving antibiotics. 28,29 

Urine sediment analyses are useful for detecting 

diseases of the urinary tract, ranging from infection 

to lithiasis; such analyses can be considered 

more important than WBC counts. However, it 

should be borne in mind that irritation of the 

ureter or the bladder by a retrocecal or pelvic 

appendix may lead to the appearance of leukocytes 

or blood in the urine, confusing the diagnosis. 30,31 

Diagnostic imaging 

It is currently accepted that simple radiography is 

both inadequately sensitive and inadequately 

specific for diagnosis of acute appendicitis; in 

addition, the cost–benefit relationship is poor. It 

thus seems probably that we will see a decline in 

the use of simple radiography as a primary diagnostic 

approach in patients with acute pain in the 

right iliac fossa; however, it will probably remain

744 


useful for detecting secondary problems associated 

with inflammation. The signs most frequently 

encountered are a dilated cecum with air–fluid 

level, antalgic scoliosis of the right concavity, 

obscuration of the right psoas muscle, free peritoneal 

fluid, minimal pneumoperitoneum and 

appendiceal fecalith. 30 The presence of a fecalith is 

highly suggestive of acute appendicitis if clinical 

characteristics are observed; however, an appendicolith 

(Figure 45.2) is observed in only 10% of 

cases. 

Ultrasonography has constituted a significant 

advance in the diagnosis of acute appendicitis, in 

view of its rapidity, innocuity, sensitivity of 

85–90% and specificity of 92–96%. It is of particular 

value in adolescent and prepubertal girls, since 

it helps to identify other possible causes of abdominal 

pain. It should be the first approach in doubtful 

cases. It is worth mentioning that the examiner 

must be an expert in pediatric ultrasound. The 

Figure 45.2 Simple radiography of the abdomen in a 

patient with acute appendicitis, showing anomalous 

distribution of gas with scoliosis of the right concavity 

and an appendicolith in the right iliac fossa. 

normal appendix is not usually visualized on 

ultrasonography. The most characteristic signs are 

the presence of free liquid and a distended noncompressible 

tubular structure corresponding to 

the inflamed appendix, with a size greater than 

6mm. Other useful signs are pericecal inflammatory 

changes and an appendix located in the retrocecal 

position or in front of the psoas (Figure 

45.3). 32–34 

In recent years, abdominal computed tomography 

(CT) has become the most informative imaging 

technique in the study of patients with atypical 

manifestations, with sensitivity and specificity of 

98% according to Rao et al. 35 In the future, it seems 

likely that continued development of helical CT 

Figure 45.3 Ultrasonography of a patient with acute 

appendicitis, showing a distended non-compressible 

tubular structure, with size greater than 6mm, an 

appendicolith and surrounded by free fluid.

technology will make this the diagnostic method 

of choice. 35 It is accepted that the sensitivity and 

specificity of diagnosis by CT is greater than that 

of ultrasound, with the following criteria: fluidfilled 

tubular structure measuring >6mm in 

maximum diameter, fat stranding, abscess or 

phlegmon in adjacent tissue, appendicolith and 

focal cecal apical thickening. 32,36,37 

Recent studies suggest that imaging should be 

performed even in cases where the diagnosis of 

acute appendicitis is clinically likely, as the procedure 

would enable the detection of a high 

percentage of normal appendices and the detection 

of other diagnoses. 38,39 


The disorders most frequently confused with acute 

appendicitis are urinary diseases (infections, 

hydronephrosis, lithiasis), basal pneumonias, 

constipation and gastroenteritis. 17,22,30,40 It should 

here be stressed that repeated examination is of 

key importance for differential diagnosis, with 

careful monitoring of the patient during the first 

few hours of abdominal symptoms. 

Pollakiuria with dysuria and an increased pyocyte 

count in the urine suggests a urinary tract infection, 

but these signs may also be observed in 

pelvic appendicitis, or in appendicitis with the 

appendix close to the ureter or bladder. It may be 

helpful to note that flank pain is more commonly 

associated with renal infection, in which fever and 

leukocytosis may be observed despite minimal 

abdominal symptoms. Other urological pathologies 

to be borne in mind are obstructive disorders 

such as pyeloureteral or ureterovesical stenosis, as 

well as vesicoureteral reflux, all of which may 

cause acute abdominal pain. 41 

Infectious pathologies of the lower lobe of the right 

lung may cause abdominal pain and generalized 

abdominal muscular spasm, but such cases do not 

show localized hypersensitivity in the right iliac 

fossa; in addition, these children are typically 

drowsy and sleep a great deal, with high fever and 

sometimes cough. In rarer cases, the pneumonia is 

secondary to appendicitis. This occurs when the 

inflamed appendix is in the retrocecal or subhepatic 

location, and develops an abscess that invades 


the subphrenic area with pleural effusion and radiological 

images suggestive of pulmonary pathology. 

Constipation is common in older children, and 

may involve crises with abdominal pain, fever, 

vomiting and leukocytosis. There are not always 

clear antecedents of constipation. In these cases 

there is no migration of pain from the epigastric 

region to McBurney’s point, and in addition there 

are no signs of peritoneal irritation. Hard packed 

feces may be palpated through the abdominal wall. 

Gastroenteritis is probably the most common 

cause of acute abdominal pain, and is frequently 

confused with appendicitis. Early-onset vomiting 

accompanied by abdominal pain is the most reliable 

feature of gastroenteritis, while in appendicitis 

vomiting appears late after the onset of abdominal 

pain. Abundant foul-smelling diarrhea is 

likewise indicative of gastroenteritis, by contrast 

with the scant mucosal secretions appearing in 

pelvic appendicitis. Nevertheless, it should be 

stressed that frequent bowel movements do not 

rule out appendicitis. 42 

In pubertal girls, premenstrual syndrome and 

dysmenorrhea are common causes of unnecessary 

surgery, and their differential diagnosis is not 

always easy. Ovarian cysts can be diagnosed by 

rectal examination or ultrasonography; they cause 

acute pain when ruptured or torsioned, and the 

patient typically shows vomiting. In doubtful 

cases, laparoscopy is of key value. 

In primary peritonitis due to pneumococcus or 

streptococcus, the severe effects on general wellbeing 

call for emergency surgery; in any case, 

acute appendicitis and peritonitis are often not 

distinguishable without surgery. 

Differential diagnosis with respect to mesenteric 

lymphadenitis may be very difficult, because of 

the close clinical similarities with acute appendicitis. 

Criteria indicative of adenitis include 

initial high fever, severe spasmodic abdominal 

pain, absence of anorexia and, in some cases, a 

history of respiratory infection. As noted in the 

classic texts, careful monitoring of the patient is 

extremely important. 12 

Inflammatory bowel diseases, notably Crohn’s 

disease, may sometimes be first detected during

746 


acute appendicitis, but generally the patient will 

present with a prolonged history of abdominal 

pain, diarrhea attacks and growth restriction, in 

some cases with a positive family history. 

Patients with severe leukopenia due to cancer or 

chemotherapy may show invasive infection of the 

entire wall of the cecal region (i.e. typhlitis), with 

pain and guarding of the right iliac fossa. If there is 

no improvement on antibiotic treatment, or if 

symptoms are suggestive of irritation or perforation 

of the bowel, surgery should be performed. 

Other differential diagnoses to be taken into 

account are viral hepatitis (especially in the 

preicteric phase), as a result of lymphoid– 

appediceal involvement by viral infections (hepatitis 

B, Herpes, coxsackievirus, adenovirus); intussusception; 

viral exanthematous diseases; sickle 

cell anemia; cholecystitis; pancreatitis; omentum 

infarction; and duodenal ulcer (Table 45.1). 

Treatment 

The treatment of choice for acute appendicitis is of 

course early appendectomy. Rapid administration 

of intravenous fluid and electrolytes (to restore 

acid–base balance) is fundamental for a good 

course. Depending on the clinical characteristics 

(degree of dehydration, fasting status, presence of 

vomiting), the rehydration fluid may be physiological 

saline with glucose, or lactate Ringer’s solution, 

in either case with supplementary potassium 

if necessary. In cases of peritonitis, losses to the 

third space should be taken into account, since 

this will increase the rehydration requirement. 

Once surgical intervention has been decided upon, 

intravenous antibiotic treatment should be 

started. 43 

In cases of intestinal obstruction or distension, the 

insertion of a nasogastric tube facilitates decompression 

of the abdomen and minimizes the risk of 

aspiration during anesthesia induction. 

If the appendix is gangrenous with peritonitis and 

the patient is seriously ill, intensive reanimation 

will be required before appendectomy, with immediate 

intravenous administration of antibiotics 

together with rehydration. In some cases, a vesical 

drainage will be necessary as well as nasogastric 

Table 45.1 Main differential diagnosis of 

acute appendicitis 

Urological pathology 

Urinary tract infections 

Pneumonia 

Constipation 


Premenstrual syndrome 

Ovarian pathology 

Primary peritonitis 

Mesenteric adenitis 

Meckel’s diverticulitis 


Viral hepatitis 



Typhlitis 

Viral exanthematous diseases 

Sickle cell anemia 

Cholecystisis 

Pancreatitis 

Omentum infarction 

Duodenal ulcer 


Acute porphyria 

Familial Mediterranean fever 

Hemolytic uremic syndrome 

drainage, but generally the patient can undergo 

surgery within 6–8h of the start of reanimation. 

The type of antibiotic therapy used varies among 

different centers. Some authors have recommended 

prophylactic administration of one dose 

of cefotoxin before surgery and three doses after 

surgery. 44 However, cefotoxin may be less effective 

than a combination of aminoglycosides, synthetic 

penicillin and metronidazole in the treatment of a 

perforated appendix. Other authors have 

suggested the use of piperacillin and tazobactam. 30 

Presurgery treatment with ampicillin, gentamycin 

and clindamycin has been successfully used in 

some countries since the 1970s. 45 In the Pediatric 

Surgery Service of our hospital (the Santiago de 

Compostela University Hospital in northwest

Spain), we currently use treatment with 

tobramycin plus metronidazole, with a low incidence 

(

748 


After surgery of any type, late adherences may be 

observed, but a large proportion of adherencerelated 

obstructions are secondary to surgery for 

acute appendicitis, even though they first present 

months or even years later. Adherences and infections 

of this type have also been implicated in the 

sterility observed in some girls after surgery for 

acute appendicitis; 53 however, other studies have 

not been able to detect any raised incidence of 

sterility in patients of this type. 54 

Summary 

The large series to date have suggested that mortality 

in acute appendicitis is about 1%, and rather 

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46 

Introduction 

Vascular lesions of the 

gastrointestinal tract in 

childhood 

Steven R Allen and Richard G Azizkhan 

Over the years, various histopathological systems 

combined with descriptive vernacular have been 

used to describe vascular lesions. Changes in 

nomenclature and inconsistencies in terminology 

have led to confusion and misunderstanding 

among medical specialists, making it difficult to 

compare published literature describing pathology, 

treatment and outcomes. A comprehensive 

biological classification system proposed in 1982 

correlated endothelial and mast cell kinetics of 

vascular lesions with their clinical characteristics 

and natural history. 1 With minor modifications, 

this classification system is now universally 

accepted by those at the forefront of this specialized 

field and is used to classify all vascular 

lesions in infancy and childhood. 

According to the current system, there are two 

main types of vascular lesion: tumors and malformations. 

Within the category of vascular tumors, 

hemangiomas are by far the most common. 

Lesions in the two classifications differ in their 

clinical, radiological, histopathological and hemodynamic 

presentations. 2,3 However, both types of 

lesion can permeate any organ system. Although 

they generally present cutaneously, they can also 

develop in multiple anatomic sites, and often 

involve the extremities, thoracoabdominal walls 

and cavities, solid organs, hollow viscera and 

brain. 4 Clinical symptoms are diverse, ranging 

from minor cervicofacial manifestations to serious 

and potentially life-threatening symptoms that 

may be difficult to identify (e.g. pain, bleeding, 

mass effect and congestive heart failure). Because 

management approaches and prognostic assessment 

for various lesions are different, accurate, 

precise and consistent terminology is essential. 

To clarify long-held misconceptions and to ensure 

that readers share common terminology and a 

common knowledge base, we will first describe the 

key clinical and biological features that distinguish 

hemangiomas from vascular malformations. 

Our discussion will then focus on the clinical 

presentation, diagnosis and management of vascular 

lesions of the gastrointestinal tract. We will 

briefly describe similar cutaneous vascular 

lesions. Since they are often associated with 

gastrointestinal manifestations, familiarity with 

them provides a useful framework for establishing 

a correct diagnosis. 

Clinical differences between vascular 

tumors and malformations 

Hemangiomas are benign tumors. They are characterized 

by endothelial hyperplasia with multilamination 

of the basement membrane and increased 

numbers of mast cells. After a period of rapid postnatal 

proliferation beginning shortly after birth, 

hemangiomas typically undergo slow, spontaneous 

involution. As involution is completed, mast cells 

fall to normal levels. Involution occurs in 50% of 

lesions by the age of 5 and in 70% by the age of 7. 

Other lesions continue to regress until the ages of 

10–12. Because of this clinical course, most 

hemangiomas do not require treatment. 

In contrast to hemangiomas, vascular malformations 

are not neoplastic lesions. Rather, they result 

from errors of vascular morphogenesis, and 

usually exhibit normal endothelial turnover and 

normal numbers of mast cells. Typical microscopic 

findings show progressive ectasia of structurally 

abnormal blood vessels. The blood-filled channels 

751

752 

Vascular lesions of the gastrointestinal tract in childhood 

are lined by a thin, flat endothelium, overlying a 

thin basal lamina. Additionally, there is a paucity 

or absence of smooth muscle within the vessel 

walls of vascular malformations. Although present 

at birth, these lesions may not manifest until childhood, 

adolescence, or even adulthood. Unlike 

hemangiomas, malformations generally grow 

commensurately with the child. They encompass a 

wide spectrum of anomalies, appearing with 

unique presentation and varying pathophysiology. 

Malformations are subcategorized by their 

predominant channel type as capillary, venous, 

arterial, lymphatic, or some combination of these. 

Lesions that have an arterial component are 

termed ‘fast-flow’ malformations, while capillary, 

venous and lymphatic lesions are slow-flow 

malformations. Fast-flow malformations are associated 

with high-output cardiac states, cardiac 

failure and disproportionate growth of involved 

organs and extremities. 

Whereas proliferating hemangiomas rarely cause 

bone distortion or hypertrophy, slow-flow malformations 

are frequently associated with diffuse 

bone hypertrophy, distortion, or elongation. Fastflow 

malformations can cause destructive 

interosseous changes. 

Vascular malformations also show hematological 

dissimilarities with vascular tumors. Hemangioendothelioma 

and tufted angioma, both of which 

are rare types of vascular tumors, can cause 

platelet trapping, shortened platelet half-life and 

profound thrombocytopenia. Vascular malformations, 

particularly the venous type, induce a true 

intravascular coagulation defect with only mild 

thrombocytopenia and slightly decreased platelet 

survival (Table 46.1). 

In most cases, the type of vascular anomaly can be 

correctly diagnosed by correlating physical 

Table 46.1 Clinical differences between vascular tumors and malformations (modified from 

reference 5) 

Vascular tumors Vascular malformations 

Neoplasm Congenital abnormality 

Generally apparent during first few weeks of life May not become apparent until months or even 

years after birth 

Female/male ratio of 3:1 No gender predilection 

Rapid postnatal growth followed by slow involution Slow steady growth; sepsis, trauma, or hormonal 

change may cause rapid expansion; no involution 

Endothelial cell hyperplasia Normal endothelial cell turnover 

Increased mast cells Normal mast cell count 

Multilaminated basement membrane Normal basement membrane 

Infrequent mass effect on adjacent bone; Slow-flow: frequent bone hypertrophy, distortion, 

hypertrophy rare or elongations 

Fast-flow: destructive interosseous changes 

Hemangioendothelioma and tufted angioma Mild thrombocytopenia and only slightly 

associated with platelet trapping and decreased platelet survival 

thrombocytopenia 

Angiographic findings: well circumscribed, Angiographic findings: diffuse, no parenchyma 

intense lobular–parenchymal staining with equatorial Low-flow: phleboliths, ectatic channels 

vessels High-flow: enlarged, tortuous arteries with 

arteriovenous shunting 

Response to corticosteroids and antiangiogenic agents No response to corticosteroids or antiangiogenic 

agents

findings and case history. Nevertheless, deep cutaneous 

and visceral lesions can be difficult to identify 

without radiological evaluation. Also, overlapping 

of clinical characteristics of the two 

classifications does occur, and because distinctive 

histopathological features of hemangiomas diminish 

during their evolution from the proliferative to 

the involutive phase, their differentiation from 

vascular malformations becomes increasingly 

difficult. 5 Doppler ultrasonography is often used to 

distinguish between these two types of lesion and 

to detect arterial flow. Depending on clinical 

circumstances, computerized tomography, 

magnetic resonance imaging, blood cell scintigraphy 

and angiography may also be required to 

determine the type, location and extent of lesions. 

Common errors in nomenclature 

Fishman and Fox 6 describe several important 

errors and inconsistencies in nomenclature that 

are readily apparent in the literature and are 

important for clinicians to be aware of. The term 

‘hemangioma’ is ubiquitously misused to label a 

wide spectrum of vascular lesions with different 

etiologies and natural histories. Moreover, some 

authors add misleading and incorrect descriptors 

such as ‘capillary’ or ‘cavernous’. Lesions with 

large blood-filled spaces, often referred to as 

‘cavernous hemangiomas’ are generally not 

hemangiomas, but are rather venous malformations. 

Also important to note, the suffix ‘oma’ in 

modern medical parlance implies a neoplastic 

process with rapid cellular turnover. Since vascular 

malformations are non-neoplastic lesions with 

quiescent endothelium, terms that are often seen 

in the literature such as ‘lymphangioma’, ‘cystic 

hygroma’, and ‘angioma’ are misnomers that 

should be avoided. Lesions that are commonly 

referred to as ‘lymphangiomas’, should be classified 

as lymphatic malformations. Cystic hygromas 

are more accurately classified as cystic lymphatic 

malformations, usually of the head and neck. 

Hemangiomas 

Hemangiomas are the most common tumor in 

infancy and are more common in girls than in 

boys, with a ratio of 3:1. They range in appearance 

Hemangiomas 753 

from small, hardly noticeable birthmarks to large 

grotesque tumors that can destroy tissue, obstruct 

the airway, or impair vision. Cutaneous hemangiomas 

generally become apparent early in the 

neonatal period, beginning as a faint discoloration. 

During proliferation, they typically turn bright red 

or crimson, and may ulcerate and/or bleed. After 

spontaneous regression, the lesion may become 

unnoticeable or may leave a fibrofatty residuum 

without much color. 6 A hemangioma that has 

ulcerated during proliferation can, however, leave 

wrinkling, telangiectasia, a yellowish inelastic 

patch, or a scar. 5 

Gastrointestinal hemangiomas can occur anywhere 

in the gastrointestinal tract. Although the liver is 

the most common visceral site, specific and 

adequate discussion of hepatic lesions is beyond 

the scope of the present chapter. Unlike cutaneous 

hemangiomas, gastrointestinal hemangiomas are 

rarely seen. They become evident only when 

lesions are symptomatic, and are often associated 

with multifocal cutaneous lesions (Figure 46.1). 

Mild to life-threatening gastrointestinal bleeding 

may occur, the later requiring repeated blood transfusions. 

Since an intestinal hemangioma rarely 

Figure 46.1 A 2-month old infant with multiple 

cutaneous hemangiomas.

754 


bleeds after the proliferative phase has ended, 

such a lesion would not, however, be a likely cause 

of bleeding beyond the first year or two of age. 

Another possible presenting symptom, though 

even less commonly seen, is intestinal obstruction. 

Treatment for hemangiomas is based on the degree 

and severity of symptoms. A small isolated hemangioma 

of the stomach or colon can be banded 

endoscopically, although not without risk of perforation 

or increased hemorrhage. 7 Occasionally, a 

focal lesion may be amenable to treatment with 

other endoscopic techniques such as multipolar 

thermocoagulation or argon plasma coagulation. 

For lesions visible by endoscopy, intralesional 

injection with corticosteroid may also be considered. 

6 Indications for excision include complications 

such as intussusception or obstruction, 

uncontrollable ulceration with hemorrhage or 

perforation, or infection (Figure 46.2). A surgical 

approach is not indicated when there is diffuse 

multifocal involvement of the gastrointestinal 

tract. Such lesions are more appropriately treated 

with corticosteroids, interferon α-2a, or other 

antiangiogenic agents (Table 46.2). 

In summary, if symptoms can be managed with 

persistent and aggressive blood replacement and 

pharmacotherapy, these are often the most prudent 

treatment strategies. Bleeding will diminish and 

cease after lesions enter the involution phase, 

which in many cases can be accelerated with 

angiogenesis inhibitors. Studies have shown that 

oral corticosteroids are effective within 2 weeks in 

one-third of patients; they yield an equivocal stabilizing 

response in one-third; and are ineffective in 

the remainder. 8 Although interferon α-2a induces 

regression in almost all patients, this process is 

less rapid than with corticosteroids. 9 Also, a 

number of studies 10–12 have indicated the development 

of spastic diplegia resulting from neurotoxic- 

Table 46.2 Pharmacotherapy options for problematic hemangiomas 

Figure 46.2 Jejunoileal hemangioma associated with 

significant gastrointestinal hemorrhage in a 5-month-old 

infant. 

ity during the course of interferon therapy; this is 

more commonly seen in infants younger than 1 

year of age. Although the condition generally 

reverses with the termination of therapy, careful 

monitoring of neurodevelopmental status is 

required. In light of the potential side-effects, 

interferon therapy is used only when hemangiomas 

are unresponsive to steroids or are life 

threatening. 

Vascular malformations 

Dosage Duration 

Gastrointestinal vascular malformations parallel 

the four main malformation groups described 

earlier: capillary, venous, lymphatic and arteriovenous 

(and complex combined lesions). Severity 

varies greatly both among malformations within 

each clinical group and among the four general 

group classifications. 

Oral prednisone 3-4mg/kg per day (initial dosage) gradual tapering over several months 

Interferon α-2a 1–3 million units/m 2 per day 12–18 months 

Vincristine 0.05mg/kg weekly 4–12 weeks

Capillary malformations 

Capillary malformations of the skin include port 

wine stain (also known as nevus flammeus) and 

congenital telangiectasias. These are present at 

birth and remain throughout life. With aging, the 

surface of the red vascular stain becomes raised 

and studded with nodular lesions. Lesions can be 

localized or can occur extensively on the face, 

trunk or limbs, and can be isolated or associated 

with other congenital malformations or vascular 

anomalies. Sturge–Weber syndrome consists of 

facial capillary malformation in association with 

ipsilateral leptomeningeal and ocular anomalies. 

Malformations on the trunk or extremities may 

coexist with venous and lymphatic abnormalities 

(Klippel–Trénaunay syndrome) (Figure 46.3). They 

may also overlie a deep arteriovenous malformation 

anywhere in the body. A facial lesion may 

indicate a unilateral arteriovenous malformation 

of the retina and intracranial optic pathway 

(Wyburn–Mason’s syndrome). 

Symptomatic capillary malformations of the 

gastrointestinal tract are extremely rare in childhood. 

Patients with hereditary hemorrhagic telangiectasia 

(Osler–Weber–Rendu syndrome) may 

experience gastrointestinal bleeding, but this 

rarely occurs before adulthood 13 and is generally 

preceded by pulmonary manifestations, which 

include arteriovenous malformations and cerebrovascular 

lesions. Diagnosis is usually established 

by endoscopic evaluation. Treatment for identified 

Figure 46.3 Complex combined capillary venous and 

lymphatic malformation involving the left lower extremity 

and trunk of an infant with Klippel–Trénaunay syndrome. 

Vascular malformations 755 

bleeding sites can readily be accomplished by 

endoscopic laser photocoagulation. 

Two published case reports 14,15 describe an association 

between hereditary hemorrhagic telangiectasia 

and juvenile polyposis. These reports are, 

however, inconclusive as to the actual cause of 

bleeding, since colonic polyps themselves are 

highly vascular and thus a common source of 

bleeding in childhood. 

Venous malformations 

These slow-flow lesions appear as a faint blue 

patch or a soft blue mass. Because of their 

coloration and soft, spongy consistency, they are 

frequently mislabeled as ‘cavernous hemangiomas’. 

Venous malformations are not tumors, do 

not regress spontaneously and do not respond to 

antiangiogenesis inhibitors. Lesions can be localized 

or extensive, and can range from miniscule to 

massive and disfiguring. Phleboliths are pathognomonic 

and, if present, can easily distinguish a 

venous malformation from a hemangioma. While 

cutaneous and soft tissue lesions are often asymptomatic, 

they may cause pain; this is probably due 

to congestion and/or low-grade thrombosis. 

Venous malformations are the most commonly 

symptomatic vascular anomalies of the gastrointestinal 

tract in childhood. 7 They generally 

present with either chronic or acute upper or 

lower gastrointestinal bleeding, which is often not 

identified until the patient is found to be severely 

anemic. Less commonly, malformations of the gut 

may cause pain or obstruction. 

Gastrointestinal lesions appear in the varying 

patterns described below. 5 Diagnostic and management 

approaches are best tailored according to 

these patterns. 

Focal venous malformations 

Focal venous malformations can occur anywhere 

in the gastrointestinal tract. These lesions may 

vary in size and may be mucosal, mural, or transmural. 

Endoscopic ultrasound may be helpful in 

making this determination. A small focal lesion 

that is clearly not transmural may be treated nonoperatively. 

Such a lesion can be managed with 

endoscopic sclerotherapy using sclerosing agents

756 


such as absolute ethanol or 1% sodium tetradecyl 

sulfate, which are generally effective in obliterating 

abnormal venous channels. Because of the 

danger of systemic intravascular migration of the 

sclerosing agent, clinicians should consider 

performing pretreatment angiography or a direct 

intralesional contrast study to identify any anomalous 

or large vessels communicating with the 

lesion. Another treatment option for small 

mucosal venous lesions is endoscopic banding. 7 

However, since perforations can occur after endoscopic 

treatment of small, unsuspected transmural 

lesions, it is best to provide for surgical back-up 

should complications arise. 5 Surgical excision is 

required for large or transmural gastrointestinal 

venous malformations. 

Multifocal venous malformations (blue rubber bleb 

nevus syndrome) 

Blue rubber bleb nevus syndrome is a rare multifocal 

syndrome of cutaneous and gastrointestinal 

venous malformations. Cutaneous lesions can be 

found over the entire body surface and usually 

become apparent by 2 years of age. They typically 

vary in size from 1–2mm to 2cm, and range in 

number from a single lesion to several hundred 

lesions that grow in proportion to the growth of the 

child. Skin lesions are most commonly flat or 

minimally raised and are deep blue or purple. 

They are often most dense on the plantar aspect of 

the feet. 5 Lesions may be tender to palpation and 

may become spontaneously painful. They may be 

partially emptied of blood if firm pressure is 

applied. 16 

Gastrointestinal manifestations can occur 

anywhere from the mouth to the rectum and may 

become symptomatic years after the appearance of 

cutaneous lesions. The number of intestinal 

lesions in a patient generally tends to parallel the 

number of cutaneous lesions, varying from a few 

to several hundred. Large gastrointestinal lesions 

may cause intussusception, resulting in the onset 

of acute abdominal pain and vomiting. Oral and 

esophageal lesions may compress the airway. 

Blood loss tends to be most prominent from small 

bowel lesions. Almost all patients have multiple 

lesions in the liver, but lesions can be present in 

the subcutaneous tissues, muscles, or almost any 

organ. A total body survey can be obtained using 

Tc-99m-labeled red blood cell scintigraphy. 5 

Characteristically, there is pooling of the Tc-99m 

red blood cells within the lesions. Lesions have a 

pathognomonic endoscopic appearance, presenting 

as discrete purple, berry-like protuberances 

from several millimeters to several centimeters in 

size. Most lesions are sessile. A broad rim of 

normal mucosa is often at the base of the lesion 

and encircles its reddish blue apex. 5 

Patients inevitably develop chronic gastrointestinal 

bleeding and anemia, beginning early in 

infancy or in young adulthood. They eventually 

require ongoing transfusions and iron replacement 

supplemented with the administration of erythropoietin. 

Melena is common. Some patients also 

experience intermittent bouts of severe abdominal 

cramping secondary to recurrent small-bowel 

intussusceptions. 5,16 

Treatment varies depending on the degree of 

gastrointestinal tract involvement and the severity 

of symptoms. Patients with mild or moderate 

anemia usually do not require transfusions or 

surgical intervention. Acid reduction therapy with 

proton pump inhibitors is used to reduce bleeding 

from gastric lesions. Patients are advised to eat a 

diet rich in iron and to take iron supplements as 

well as multivitamins. Also, to reduce the chance 

of trauma and bleeding from lesions in the left 

colon, stool softeners are sometimes advised. 

While patients with moderate anemia require 

occasional blood transfusions, they are treated 

similarly. Additionally, endoscopic ablation may 

be used to treat problematic gastric or colonic 

lesions. Patients with persistent or severe anemia 

require multiple interventions over time, including 

frequent blood transfusions, endoscopic ablation 

and surgical excision of small-bowel lesions. 

Octreotide is used as a temporizing treatment 

method to stabilize patients prior to surgery. 16 

Although there have been several published 

reports of treatment with pharmacological therapy, 

there is no sustained efficacy in their use. For 

patients with life-threatening bleeding that necessitates 

repeated transfusions, Fishman and Fox 6 

advocate surgical excision. Through a combined 

endoscopic and open surgical approach, these 

authors inspect the entire gastrointestinal tract. 

Small-intestinal lesions are identified and 

resected. If superficial, lesions of the esophagus, 

stomach, duodenum, colon and rectum are eradicated 

by endoscopic band ligation. If not amenable

to this approach, such lesions are surgically 

excised. The authors have reported that, with up to 

a 7-year follow-up, none of the nine patients who 

had undergone surgery developed anemia or 

required a transfusion after hospital discharge. 6 

Diffuse venous malformations 

Diffuse venous malformations involve large adjacent 

segments of bowel and extraintestinal structures, 

including mesentery, retroperitoneum, 

pelvic space, muscles, subcutaneous tissue and 

skin. Diffuse upper visceral malformations may 

warrant treatment only if there is symptomatic 

portal hypertension. Selective portosystemic 

shunts may be beneficial in that they reduce 

portal–venous pressure in the malformation. 

Malformations of the lower gastrointestinal tract 

typically extend from the anorectum proximally, 

involving the left colon or the entire colon. Most of 

these lesions are transmural and may extend into 

the pelvic structures. Imaging studies often reveal 

thickening of the colonic and rectal wall. 

Colonoscopic examination reveals engorged 

purple mucosa with varix-like projections. These 

lesions often cause chronic hemorrhage that 

requires transfusions throughout life. Endoscopic 

therapy is often futile and may exacerbate hemorrhage 

and cause perforation. Depending on the 

extent of involvement, a variety of surgical options 

are used. These include partial or subtotal colectomy 

with end ileostomy or colostomy, or colectomy 

with anorectal mucosectomy and endorectal 

pull-through. 17 In most cases, full-thickness resection 

of the rectum should be avoided because of 

the risk of uncontrollable hemorrhage from the 

extrarectal pelvic venous malformation. 

Lymphatic malformations 

Lymphatic malformations (often incorrectly 

referred to as ‘lymphangiomas’) include a wide 

spectrum of anomalies that can vary from simple 

cutaneous lymphatic lesions to severe lymphatic 

malformations that involve different organs and 

anatomic regions. These malformations can be 

seen in any anatomic region but are more 

commonly seen in rich lymphatic areas, such as 

the neck, axilla, mediastinum, groin and retroperitoneum. 

They present in many forms, from tiny 

cutaneous or mucosal blebs to large channel or 

Vascular malformations 757 

multilocular lesions. There are two morphological 

types of lymphatic malformation: microcystic and 

macrocystic. The former present as clear, tiny 

cutaneous vesicles that permeate the skin and 

muscles; these vesicles are often firm and may give 

the impression of a brawny edema. Macrocystic 

lesions are large, soft, smooth, translucent masses 

under normal or bluish skin. Capillary or venous 

malformations are frequently seen in association 

with lymphatic malformations. 

Mesenteric cysts 

Mesenteric cysts are rare macrocystic lesions that 

are thought to be lymphatic malformations (Figure 

46.4). They may be malformations of the lacteals 

and major mesenteric lymphatic vessels, including 

the cisterna chyli, or may be more diffuse, involving 

retroperitoneum and mesentery. Lesions are 

occasionally associated with chylous ascites and 

protein-losing enteropathy. Although they can be 

found anywhere from the duodenum to the 

rectum, they most commonly occur in the mesentery 

of the small bowel; the retroperitoneum is the 

second most frequent site. 18 Children tend to 

present acutely, requiring urgent admission and 

surgical intervention. Complaint at presentation is 

commonly abdominal pain due to hemorrhage or 

obstruction. Intestinal obstruction may occur from 

volvulus or acute enlargement from hemorrhage 

into the cyst, or from compression of the adjacent 

bowel. Diagnosis is primarily made with ultrasonography, 

often followed by a computed tomography 

scan to confirm the cystic nature of the 

lesions (Figure 46.5). Ultrasonography also 

Figure 46.4 A mesenteric cyst seen at laparotomy in a 

4-year-old with partial intestinal obstruction.

758 


Figure 46.5 Computed tomography scan demonstrating 

a mesenteric cyst (asterisk). 

provides preoperative measurements and is valuable 

for postoperative monitoring. When lesions 

are localized, small portions of the intestine can be 

resected with a good prognosis. In children in 

whom there is a diffuse process involving most of 

the intestinal mesentery, unroofing of major cysts 

to allow drainage of lymphatic fluid into the 

abdomen provides long-term relief of symptoms. 

In some patients with unremitting chylous ascites, 

oversewing of leaking retroperitoneal lymphatics 

is reportedly effective. 19 When there is respiratory 

compromise from massive chylous ascites or when 

other efforts are unsuccessful, peritoneovenous 

shunting is useful, although it carries significant 

risks. 20 

Arteriovenous malformations 

Arteriovenous malformations are fast-flow lesions 

in which there are usually many abnormal 

communications between abnormal arteries and 

veins that bypass the normal capillary bed. The 

length of channels between the arteries and the 

veins can vary from millimeters to centimeters, 

and convoluted or cavernous abnormal vascular 

structures may be intercalated between the arterial 

and venous ends of the malformations. 6 

Arteriovenous malformations can be present in 

any part of the body, including the upper and 

lower extremities, the head and neck, the gut, the 

liver, the lungs and the central nervous system. 

Cutaneous lesions become evident in infancy or 

childhood and are often initially mistaken for 

hemangioma or port wine stain. Puberty, pregnancy 

and trauma tend to trigger expansion, 

causing lesions to exhibit the cutaneous signs of its 

fast-flow nature. The skin becomes red or 

purplish, a mass appears beneath the vascular 

stain and there is local warmth, thrill and bruit. 4 

This inevitably results in ischemic skin changes, 

ulceration, intractable pain and intermittent bleeding. 

In severe cases, lesions can result in highoutput 

cardiac failure. 

Symptomatic arteriovenous malformations of the 

gastrointestinal tract are extremely rare in childhood. 

Typically, patients develop massive hematochezia 

or chronic melena with iron deficiency 

anemia. A case of intestinal perforation secondary 

to an arteriovenous malformation has also been 

reported. 21 As with cutaneous arteriovenous 

malformations, some patients present with pain 

and, in severe cases, with high-output cardiac 

failure. Endoscopic examination of the bowel may 

reveal a pulsatile vascular lesion. Endoscopic 

ultrasonography demonstrates high flow through 

the lesion. 

Traditional angiography or magnetic resonance 

imaging help in localizing the arteriovenous 

malformation and are essential for diagnosis and 

treatment planning. Angiography frequently shows 

characteristic enlargement and an increased 

number of arteries; on the venous phase, there is 

early venous return and venous dilatation in the 

region of the malformation. 

Embolization alone may lead to intestinal necrosis 

and perforation. Embolization combined with 

surgical excision is, however, the treatment of 

choice. Amenability of lesions to complete excision 

depends upon their extent and location. Specific 

localization in the gastrointestinal tract before 

resection can be enhanced by tattooing during 

selective angiography. 22 When resection is possible, 

it is curative. Proximal vessel ligation alone or 

embolization combined with incomplete surgical 

resection may result in the re-establishment of 

additional feeding vessels, and lead to re-expansion 

of the arteriovenous malformation. 5 

Complex combined vascular malformations 

While various combinations of anomalous vessel 

channel types can occur, the most common gross

vascular abnormalities to affect the gastrointestinal 

tract are evidenced in Klippel–Trénaunay 

syndrome. This condition results from a combination 

of capillary, lymphatic and venous malformations 

and is characterized by purple capillary 

stains, limb hypertrophy, congenitally abnormal 

veins and lymphatic vesicles that often protrude 

through the skin. It is not uncommon for lesions to 

extend into the pelvis, involving both the bowel 

and the bladder. As with lower visceral diffuse 

venous malformations, these lesions typically 

extend from the anus proximally to involve part of 

or the entire colon (Figure 46.6). 5 Colonoscopic 

Figure 46.6 Computed tomography scan in a patient 

with Klippel–Trénaunay syndrome and profuse rectal 

bleeding demonstrating a complex venous malformation 

(V) adjacent to the rectum (R). 

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22. Frémond B, Yazbeck S, Dubois J et al. Intestinal vascular 

anomalies in children. J Pediatr Surg 1997; 32: 873–877. 

23. Telander RL, Ahlquist D, Blaufuss MC. Rectal 

mucosectomy: a definitive approach to extensive 

hemangiomas of the rectum. J Pediatr Surg 1993; 22: 

379–381.

47 

Introduction 

The role of minimally invasive 

surgery in pediatric 

gastrointestinal disease 

Stig Somme and Donald C Liu 

Traditionally, large incisions have been considered 

necessary for adequate surgical exposure. 

However, these wounds frequently result in significant 

perioperative stress and postoperative pain 

and morbidity, not to mention poor cosmesis. The 

concept of avoiding large incisions to perform 

invasive surgery forms the basis for the revolution 

of minimally invasive surgery. In this chapter, we 

focus on and describe minimally invasive procedures 

that are performed in infants and children 

with gastrointestinal disease. 

Background 

With advances in microchip technology and 

micro-instrumentation, as well as the development 

of sophisticated video equipment with supreme 

optics, the stage was set for the rapid development 

of minimally invasive surgery in the form of intracavitary 

endoscopic surgery, better known as 

laparoscopy in adults. The first significant minimally 

invasive surgery performed in adults was 

the laparoscopic cholecystectomy. 1 This sentinel 

event in general surgery, however, had little initial 

impact on the practice of pediatric surgery in children 

with gastrointestinal disease. 

Several factors are thought to be responsible for 

the slow development of the practice of minimally 

invasive surgery in children. Unfortunately, physicians, 

particularly surgeons, typically have underappreciated 

postoperative pain and surgical stress 

in young children, who essentially are unable 

adequately to verbalize their discomfort. 

Furthermore, the advantages of smaller incisions 

were underestimated by pediatric surgeons, 

because they already use ‘small incisions’ in their 

patients. However, in reality, when incision length 

is compared with body size, pediatric incisions for 

open procedures are proportional to adult incisions 

for comparable procedures. 

The need to develop endoscopic techniques 

further deters their use in children. Minimally 

invasive surgery demands that the surgeon acquire 

not only an entirely new set of surgical skills, but 

often requires an entirely different way of thinking 

about common pediatric surgical problems. The 

lack of depth perception and tactile sensation 

required during endoscopic procedures necessitate 

major changes in operative technique. The operative 

choreography for minimally invasive surgery 

often deviates from the routine fixated in the mind 

of the pediatric surgeon from years of traditional 

training. Increasingly, however, reports and the 

literature are documenting the safety, efficacy and 

cost-effectiveness of minimally invasive surgery in 

children and are showing a rapid evolution in 

instrumentation and the performance of such 

procedures. 2,3 

Minimally invasive surgery in children has 

become a highlight and focus of many general 

pediatric surgery practices across the world. At the 

present time, the number of minimally invasive 

procedures being performed for pediatric gastrointestinal 

diseases is growing rapidly. Current 

practice techniques for various pediatric gastrointestinal 

diseases are listed in Table 47.1 and are 

categorized under laparoscopy. 

Technical considerations 

The key concepts behind laparoscopic surgery are 

to obtain safe access to the abdominal cavity and 

create an ‘operating dome’ through establishment 

of pneumoperitoneum. Small trocars ranging 

from 2 to 12mm in size are subsequently placed 

761

762 

The role of minimally invasive surgery in pediatric gastrointestinal disease 

Table 47.1 Pediatric gastrointestinal diseases treatable via minimally 

invasive surgery 

Disease Laparoscopy 

Achalasia Heller myotomy 

Appendicitis appendectomy 

Chronic abdominal pain diagnostic laparoscopy 

Constipation appendicostomy (ACE procedure) 

Crohn’s disease enterectomy 

Gallstone disease cholecystectomy 

Gastroesophageal reflux disease fundoplication 

Hirschsprung’s disease endorectal pull-through 

Imperforate anus anal reconstruction 

Pyloric stenosis pyloromyotomy 

Ulcerative colitis colectomy, ileoanal reconstruction 

strategically to facilitate placement of miniaturized 

endoscopic instruments to perform surgery. 

Initial access to the peritoneum via the umbilicus 

is generally obtained by two different methods: 

direct puncture via the Veress needle or direct 

vision through the Hasson technique. 4 The skin is 

bluntly grasped, a small incision through the 

dermis made and the spring-loaded Veress needle 

advanced into the abdominal cavity. Gas insufflation 

is started using low gas flow and pneumoperitneum 

achieved. The Hasson technique mandates 

direct vision of the fascia and peritoneum before a 

blunt trocar is passed into the abdominal cavity, 

and is the technique preferred for patients with a 

history of previous abdominal surgery. Some 

surgeons advocate the use of the Hasson technique 

on a routine basis because of some support in the 

literature for a lowered risk of major complications 

compared with the Veress needle technique. 5 

The intra-abdominal pressure is adjusted according 

to the size of the patient with intra-abdominal 

pressures ranging from 5 to 15mmHg. 6 For 

example, in infants of

Figure 47.1 Laparoscopic Nissen fundoplication: 360º 

fundic wrap. 

Figure 47.2 Laparoscopic pyloromyotomy. The pylorus is 

incised sharply with a sheathed blade and the pyloric 

muscle is then carefully split and spread along the hypertrophic 

pylorus. 

fundoplication. 8,9 Importantly, strict postoperative 

dietary regimen enforcement and manipulation 

appears to contribute significantly to the avoidance 

of the necessity of esophageal dilatation in a 

population expected to have varying degrees of 

dysphagia secondary to the nature of the operation. 

Results in preventing GERD thus far have 

been excellent with recurrence rate less than 10% 

at 5 years, similar to if not in some cases lower 

than historical controls obtained from the ‘open’ 

operation. 8–10 Longer follow-up, however, would 

be needed to establish the rate of recurrence in 

children undergoing laparoscopic fundoplication 

for GERD. 

Pyloric stenosis 763 

It is likely that new treatment modalities, that are 

even less invasive, will be used to a larger extent in 

the treatment of GERD. One such technique that 

has recently been introduced is Stretta. 11 This 

utilizes an endoscopic device with several perpendicular 

probes that are launched by the operator 

under videoscopic guidance. The probes are 

advanced into the mucosa of the lower esophageal 

sphincter and an electrical current is applied 

through the probes. This creates fibrosis in the 

area that, in cases of mild-to-moderate GERD, is 

enough to obviate gastroesophageal reflux. Data 

from the adult patient population indicates that 

Stretta is safe and that it relieves the symptoms of 

GERD. 12,13 No published follow-up data exists for 

pediatric patients. 

Pyloric stenosis 

In infants with pyloric stenosis, laparoscopic 

pyloromyotomy is performed through three puncture 

wounds (approximately 2mm in length each) 

in the upper abdomen. The pylorus is incised 

sharply with a sheath blade, and the pyloric 

muscle is then carefully split and spread along the 

length of the hypertropic pylorus (Figure 47.2). 

Children typically are discharged the following 

day with complete resolution of symptoms. 

Several studies have demonstrated the safety and 

efficacy of this procedure, although improvements 

in relevant surgical outcome parameters such as 

operating time and length of hospital stay have not 

been demonstrated when compared to the open 

procedure. 14,15 However, cosmesis is excellent and 

can be compared with that of an open pyloromyotomy 

(Figure 47.3). 


Several series reporting the results of laparoscopic 

procedures for the treatment of inflammatory 

bowel disease have clearly demonstrated the feasibility 

of minimally invasive surgery in the pediatric 

population. Laparoscopic colectomy was first 

described in 1991 and, since then, laparoscopic 

colorectal procedures in adults ranging from 

simple ileocolic resection for Crohn’s disease to 

complex total colectomy with ileal/anal reconstruction 

for ulcerative colitis have been well

764 


(a) (b) 

Figure 47.3 Children who have undergone laparoscopic pyloromyotomy (a) and (b) typically are discharged the 

following day with complete resolution of symptoms. Cosmesis is excellent (b) and can be compared with that of an open 

pyloromyotomy (a). 

described. 16–18 However, acceptance of minimally 

invasive surgery as a standard surgical technique 

for Crohn’s disease remains controversial. 

Theoretically, the gross inflammation and phlegmon 

characteristic of Crohn’s disease can simulate 

landmines to the inexperienced laparoscopic 

surgeon. Nevertheless, these complications, plus 

their severe sequelae, can be effectively addressed 

by the careful, experienced laparoscopic surgeon. 

This, and the fact that Crohn’s disease affects a 

predominately younger group of patients who are 

likely to require re-resection, lends support to the 

application of minimally invasive surgery in 

Crohn’s disease. The pan-enteric and recurrent 

nature of Crohn’s disease renders a surgical cure 

impossible and results in re-operation in 70–90% 

of all patients and multiple procedures in more 

than 30%. 19 Ileocolic disease comprises the majority 

of surgical morbidity and predicts a high probability 

for surgical intervention. Furthermore, 

patients with ileocolic disease have the highest 

risk of recurrence, contributing to >40% probability 

for re-operation at 15 years. Laparoscopic ileocecectomy, 

the most common minimally invasive 

surgery procedure in children with Crohn’s 

disease, can be performed without complications 

and with excellent cosmesis (Figures 47.4 and 

47.5). 16 Furthermore, in children with intraabdominal 

abscesses, minimally invasive surgery 

techniques can be used successfully to drain the 

abscess, lyse the adhesions and also ascertain that 

the involved bowel was healthy enough according 

to the surgeon’s judgement to warrant or not 

warrant resection, keeping in mind that bowel 

preservation is the hallmark of surgery for Crohn’s 

disease. 20 Thus, minimally invasive surgery with 

its advantages of decreased postoperative pain 

from small wound sites, low incidence of hernias, 

better cosmesis and decreased rate of adhesive 

small-bowel obstruction compared with traditional 

laparotomy seem ideal in this patient population, 

who more often than not will require reoperation 

in the future. Laparoscopy reduces the 

need for surgical procedures not related to disease 

in this population and preserves the abdominal 

wall should stomas be needed in the future. Also, 

tiny, nearly invisible, strategically placed scars 

improve the perception of cosmesis in this 

younger population with already significant body 

image issues. 

Children with acute ulcerative colitis are generally 

referred for surgery on an emergency basis after 

failing to respond to aggressive medical therapy, 

including high-dose steroids and other immunosuppressants. 

17 In these often acutely ill children, 

we favor a staged surgical approach highlighted by 

initial subtotal colectomy and ileostomy followed 

by completion proctectomy and ileoanal pouch 

reconstruction several months later. From a

(a) (b) 

technical standpoint, a mini-Pfannenstiel incision 

of 2–3cm is a critical addition to our procedure 

because it facilitates safer dissection and subsequent 

transection at the rectosigmoid junction 

and, in addition, facilitates removal of the entire 

specimen. Laparoscopic subtotal colectomy in 

several series has been shown to be a safe procedure 

with acceptable blood loss. 17,21–27 Subsequent 

proctectomy and ileoanal reconstruction can be 

successfully completed with excellent results. 

The most common criticism of laparoscopic 

intestinal surgery in patients with inflammatory 

bowel disease has been increased operative time 

Appendicitis 765 

Figure 47.4 (a) Laparoscopically dissected diseased terminal ileum of Crohn’s disease; (b) exteriorized diseased bowel 

segment after laparoscopic dissection. 

Figure 47.5 Excellent cosmesis following laparascopic 

colectomy for Crohn’s disease. 

with resultant increased morbidity due to length of 

surgery. With increasing operative experience, it is 

fair to assume that operating times will decrease as 

surgeons gain experience and will be comparable 

to traditional open surgery. 

Although larger numbers of patients, longer-term 

follow-up, and a prospective, randomized, 

controlled study are necessary to determine the 

advantages of minimally invasive surgery in children 

with inflammatory bowel disease, preliminary 

results from several studies have demonstrated 

at the very least that minimally invasive 

surgery is a safe and viable surgical option. We are 

of the opinion that, with improving technology, 

increased surgeon expertise and better selection of 

patient populations, minimally invasive surgery 

may well become the standard approach when 

surgery for inflammatory bowel disease becomes 

necessary. 

Appendicitis 

Appendicitis is the most common diagnosis in 

children that requires emergency surgical intervention. 

Several randomized studies have 

compared open versus laparoscopic appendectomy 

and the results show a slight, but significant, 

reduction in postoperative wound infections. 28,29 

However, all other parameters compared, including 

length of stay, need for re-exploration, cost and 

pain showed no significant difference between the

766 


two groups. Some studies have even indicated that 

the laparoscopic/minimally invasive surgery operation 

takes more time. 2,30 It is apparent that, in 

children with appendicitis, the outcome depends 

mainly on the severity of the inflammation and the 

stage of the disease progression at which the 

surgery is performed. It is clearly less important 

whether the procedure is performed via minimally 

invasive or open techniques. There are, however, 

some patients who are clearly better served with a 

minimally invasive approach, in particular when 

the preoperative diagnosis is in question. The 

laparoscope provides the capability of looking at 

other organ systems, e.g. ovaries, Fallopian tubes 

and even the gallbladder, to investigate various 

pathologies. Patients who often fall into this category 

are adolescent females or obese patients. 

In cases where the appendix has perforated, as 

documented via radiological studies, a decision 

can be made regarding the practice of ‘interval’ 

appendectomy. 29 In these cases intravenous antibiotics 

or a combination of intravenous and oral 

antibiotics are initiated in the patient and carried 

out for 4–6 weeks, at which time the appendix is 

subsequently removed (‘interval appendectomy’) 

on an out-patient basis via minimally invasive 

surgery. 

In summary, laparoscopic appendectomy is a good, 

albeit sometimes unnecessary, option in uncomplicated 

appendicitis. In the cases that are difficult 

to diagnose, and where exposure would be difficult, 

minimally invasive surgery is the technique 

of choice, resulting in better cosmesis. 

Chronic abdominal pain of unknown 

origin 

In children with complaints of non-specific 

abdominal pain and where an extensive work-up 

including abdominal ultrasonography, computerized 

tomography, upper gastrointestinal series 

and/or upper and lower endoscopy cannot identify 

any pathology, laparoscopic exploration of the 

abdomen has been shown to be useful. 31 The 

laparoscope provides an optimal tool for visualizing 

the entire abdominal cavity. Particularly in 

females, the adnexa and uterus can be inspected 

and manipulated atraumatically. The bowel can be 

inspected in its entire intraperitoneal length. In 

patients with Mediterranean fever, laparoscopic 

evaluation of the abdomen and elective appendectomy 

have been found useful, to rule out perforated 

appendicitis as a cause for peritonitis. Some 

surgeons believe laparoscopic exploration for illdefined 

abdominal pain or abdominal sepsis 

provides the ability to identify the problem and in 

most cases also the possibility of immediate repair. 

Importantly, unusual causes of abdominal pain 

such as Meckel’s diverticulum and related pathology 

(diverticulitis), obstruction, intussusception 

secondary to various lead points including 

Meckel’s, perforated duodenal ulcer, or inflammatory 

bowel disease, notably Crohn’s disease, can be 

discovered at laparoscopy and addressed from 

both a diagnostic and therapeutic perspective. 

Furthermore, unnecessary large disfiguring incisions 

can be avoided with the same postoperative 

result. 

Laparoscopic exploration of the abdomen, notably 

the right lower quadrant, can be performed in a 

variety of techniques as described in the literature. 

These vary specifically between series and authors 

and can be performed by one-, two- or three-port 

technique. 28,29 In all cases these ports can be 

placed in strategic positions where they are ‘nearly 

invisible’. The positive effect on the development 

of future small-bowel obstruction secondary to 

adhesions cannot be overemphasized, nor can the 

theoretical affect of preserving fertility secondary 

to minimizing adhesions in a female child. 

Cholecystectomy 

Etiologies for gallbladder disease in children are 

many and have been extensively reviewed elsewhere 

in this text. When cholecystectomy 

becomes necessary, laparoscopic cholecystectomy 

can be performed safely and effectively with excellent 

cosmetic results. Laparoscopic cholecystectomy 

has for more than a decade been considered 

a standard of care for removal of the gallbladder in 

uncomplicated cases. 1 Important adjuncts to 

biliary track surgery including performance of 

intraoperative cholangiogram and common bile 

duct exploration for choledocholithiasis can also 

be performed via minimally invasive techniques. 

Laparoscopic cholecystectomy is generally performed 

through four ports (2–5mm) and the gallbladder 

is removed through the umbilicus. Both

automatic and single reloadable stapling devices 

are used to ligate the cystic duct and artery. 

Important considerations in laparoscopic cholecystectomy 

include consideration of potential 

aberrant anatomy of the hepatic arteries specifically 

the right hepatic artery coming off the superior 

mesenteric artery (10% of occasions). 

Sometimes, the superior mesenteric artery can be 

mistaken for the cystic artery, especially in a small 

child. The greatest complication that can occur in 

laparoscopic cholecystectomy is injury to the 

common bile duct, which can be devastating, 

notably in a small child where biliary reconstruction 

can be prohibitive. 1 Thus, it is important to 

identify clearly the common bile duct, cystic duct 

and cystic artery prior to ligation and division of 

any of these structures. If there is any doubt as to 

the anatomy of the biliary tract, an intraoperative 

cholangiogram should be performed and conversion 

to laparotomy considered to prevent a devastating 

common bile duct injury. 

Constipation 

Constipation in children is 90% from functional 

causes versus 10% from mechanical causes. 

Hirschsprung’s disease is the most common surgical 

cause of constipation in children. Endorectal 

pull-through for Hirschsprung’s disease was first 

described by Soave in 1963. 32 In this technique, a 

ganglionic segment of colon is pulled down to the 

muscular cuff in the rectal canal after transabdominal 

mucosectomy of the distal sigmoid colon. The 

technique was modified by Boley, who performed 

a coloanal anastomosis to complete the operation. 

33 Common to these techniques is the fact that 

the rectal mucosectomy was performed via laparotomy. 

Today, advancements in minimally invasive 

techniques and instrumentation permit surgeons 

to mobilize the colon and perform a pull-through 

operation by minimally invasive techniques. 

Furthermore, rectal mucosectomy, aganglionic 

colectomy and normal ganglionic pull-through are 

performed by some surgeons entirely through the 

anus without the aid of laparotomy or laparoscopy, 

a truly minimally invasive approach. 32,33 

A critical step in any minimally invasive surgery 

technique for Hirschsprung’s disease is transanal 

mucosectomy. 34 Transanal mucosectomy provides 

several advantages, as follows. In open cases, it 

Constipation 767 

allows for shorter operating times, because a 

mucosectomy can be performed simultaneously 

and even completed during laparotomy. Transanal 

mucosectomy in conjunction with laparoscopic 

techniques theoretically confers all the advantages 

of laparoscopy versus laparotomy, including 

reduced hospital stay, less postoperative ileus and 

better cosmesis. Favorable postoperative outcomes 

with an acceptable rate of constipation, strictures, 

no reported incontinence of stools and an acceptable 

incidence of enterocolitis, the most significant 

complication of Hirschsprung’s disease, have been 

reported by several authors. 

In cases were children have been deemed to have 

functional constipation and where no surgical 

causes can be found, few surgical options exist. 

One option, however, that has been shown to be 

effective is the appendicostomy enema or so-called 

ACE procedure. 35 In this technique, the appendix 

is used as a conduit for daily enemas to relieve 

symptoms of constipation. This procedure can be 

performed laparoscopically; the appendix is mobilized 

and brought out to the skin and used effectively 

as the entry site for enemas. The minimally 

invasive techniques used to complete the ACE 

procedure allow for easier postoperative recovery, 

less postoperative ileus and, importantly, better 

cosmesis, especially in children who already have 

self-image issues, such as children with spinal 

dysraphism syndromes. 

Ladd’s procedure 

As part of the work-up for recurrent emesis in children, 

an upper gastrointestinal series is performed 

generally to assess for gastroesophageal reflux 

disease. Occasionally during these studies, 

however, malrotation is found to be present and 

thought to be the etiology. In order to address 

emesis surgically in cases of malrotation, and 

importantly lower the future incidence of midgut 

volvulus, an elective Ladd’s procedure is 

performed. Surgeons today have described 

performing this procedure through minimally 

invasive techniques where division of Ladd’s 

bands, appendectomy and placement of the cecum 

in the left side of the abdomen can be performed 

laparoscopically. 36 Clearly, the advantages of 

performing this procedure via minimally invasive 

techniques are less postoperative pain, shorter

768 


time until recovery from the postoperative ileus 

and a much improved cosmetic result. A longer 

follow-up period will be necessary to compare the 

incidence of midgut volvulus in the two groups 

receiving the open versus minimally invasive 

procedure. 

Complications 

In addition to the complications that are specific 

for each procedure, there are complications 

uniquely associated with laparoscopic procedures 

in general. 5 The most feared complications are the 

major vascular injuries. These injuries are not 

common, with an incidence of 0.05% in the adult 

literature, but have a high mortality when they 

occur, ranging from 8 to 17%. The most common 

major complication is perforation of hollow-organ 

viscera during insertion of the Veress needle or 

trocar, the most commonly injured being the small 

bowel. Dissection-related hollow- or solid-organ 

injuries may also occur, though with lower 

frequency. Most safety studies have clearly demonstrated 

a higher incidence of complications early 

in the learning curve of the surgeon, with significant 

decrease coinciding with increasing experi- 

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17. Jacobs M, Verdeja JC, Goldstein HS. Minimally invasive 

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18. Hunter JG. The case for fellowships in gastrointestinal 

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reoperation for Crohn’s disease. A role of disease 

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ileus. Dis Colon Rectum, 2000; 43: 61–65. 

23. Duepree HJ, Senagore AJ, Delaney CP et al. Advantages 

of laparoscopic resection for ileocecal Crohn’s disease. 


24. Milsom JW, Bohm B, Hammerhofer KA et al. A 

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25. Paik PS, Beart RW Jr. Laparoscopic colectomy. Surg Clin 

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48 

Introduction 

Polyps and other tumors of the 


Warren Hyer and John Fell 

Gastrointestinal polyps in children most 

commonly present with rectal bleeding and may 

have potential for malignant change if part of a 

polyposis syndrome. This chapter reviews the 

polyposis syndromes, the genetics of these conditions, 

their malignant potential and their management 

algorithms. Other tumors of the gastrointestinal 

tract are discussed. 

Gastrointestinal polyps 

Histopathological classification 

Gastrointestinal polyps in children fall into two 

major categories: hamartomas and adenomas 

(Table 48.1). Solitary polyps in children are most 

Table 48.1 Polyps and polyposis syndromes 

seen in childhood 

Adenomatous polyposis syndromes 

familial adenomatous polyposis 

Turcot’s syndrome 

Hamartomatous polyps 

solitary juvenile polyp 

juvenile polyposis syndrome 

Peutz–Jeghers syndrome 

Bannayan–Riley–Ruvalcaba syndrome 

Gorlins’s syndrome 

Cowden’s syndrome 

Lymphoid nodular hyperplasia 

Inflammatory polyps 

Mixed polyposis syndrome 

commonly hamartomas, predominantly of the 

juvenile type. Of the familial syndromes, familial 

adenomatous polyposis is more common than 

juvenile polyposis or Peutz–Jeghers polyposis. 

Table 48.2 outlines the different histological 

features. 

Clinical management 

The most common manifestation of a large-bowel 

polyp is painless rectal bleeding. Other symptoms 

attributed to polyps include abdominal pain, 

altered bowel habit, or prolapse of the polyp or 

rectum. Some children are completely asymptomatic 

– their polyps may be found as part of a 

screening program for a familial polyposis 

syndrome. 

Diagnosis is made at full colonoscopy and 

polypectomy. Apart from biopsying for histology, 

polypectomy serves to remove the symptomatic 

polyp, e.g. source of bleeding or intussusception 

(Table 48.3). 

In order to plan management appropriately, the 

pediatrician treating a child with a gastrointestinal 

polyp must know the histopathological type, the 

number and site of polyps, and whether or not 

there is a family history of polyps or colorectal 

cancer. The clinician should direct his history and 

examination towards complications related to 

polyposis syndromes (Table 48.4). 

Juvenile polyp (solitary at diagnosis) 

Clinical presentation and diagnosis 

Children with a solitary juvenile polyp present at 

a mean age of 4 years with painless rectal bleeding 

or peranal polyp protrusion. Up to 40% of children 

771

772 

Polyps and other tumors of the gastrointestinal tract 

Table 48.2 Pathological features of polyps seen in children 

Macroscopic Microscopic 

Polyp type appearance appearance Dysplasia 

Juvenile pedunculated dilated cysts filled rare, approximately 

1–3cm in size, rarely with mucin, abundant

Table 48.4 History and examination in a child 

with possible gastrointestinal (GI) polyps 

History 

Nature of bleeding and frequency 

Painful or painless rectal bleeding 

History of GI obstructive symptoms 

Detailed family history, exploring early deaths or 

diagnosis of GI cancer 

Weight loss, anorexia (tumor) 

Learning difficulties (JPS) 

Examination 

Mucosal pigmentation (PJS) 

Dysmorphic features (JPS) 

Edema (hypoalbuminemia in infantile JPS) 

Extraintestinal manifestations of FAP – see Table 

45.6 – e.g. subcutaneous cysts, exostosis, 

congenital hypertrophy of the retinal pigmented 

epithelium 

Hepatic mass (FAP) 

Thyroid mass (FAP or Cowden’s syndrome) 

JPS, juvenile polyposis syndrome; PJS, 

Peutz–Jeghers syndrome; FAP, familial 

adenomatous polyposis 

with a juvenile polyp have multiple polyps; 60% 

are proximal to the rectosigmoid, confirming the 

need for full colonoscopy even if a polyp is found 

in the rectum. 1 Although the risk of developing 

malignancy in a solitary juvenile polyp is very 

small, such polyps should be removed even when 

discovered incidentally by endoscopic polypectomy. 

If a polyp is found to be solitary after full 

colonoscopy, and there is no relevant family 

history, endoscopic polypectomy is sufficient 

treatment. 

Complications and follow-up 

The risk of malignant change for a solitary juvenile 

polyp is almost negligible, although neoplastic 

change has been documented. 2 In patients 

with a solitary juvenile polyp, there appears to be 

no increased risk of colorectal cancer or of dying 

as a result of the polyp. 3 

If the polyp was solitary and the patient is 

discharged, parents must be aware that juvenile 

polyps may be the first feature of juvenile polyposis. 

If fresh symptoms arise, the child should 

Gastrointestinal polyps 773 

be reinvestigated. When, however, there is a positive 

family history, or when multiple juvenile 

polyps are found, the possibility of juvenile polyposis 

syndrome (JPS) is raised and a different 

management strategy should be employed. 

Juvenile polyposis syndrome 

Clinical signs and diagnosis 

JPS is a rare autosomal dominant condition characterized 

by the occurrence of multiple juvenile 

polyps in the gastrointestinal tract. In children, 

the most common presentation is at a mean age of 

9 years with rectal bleeding, anemia or prolapse 

of either the polyp or the rectum. A significant 

proportion of patients with juvenile polyposis 

have been reported to have other morphological 

abnormalities, including digital clubbing, macrocephaly, 

alopecia, cleft lip or palate, congenital 

heart disease, genitourinary abnormalities or 

mental retardation. 4 

Compared to patients with solitary juvenile 

polyps, patients with JPS have more polyps, and 

are more likely to have right-sided polyps (hence 

the need for full colonoscopy), polyps with 

adenomatous change and anemia. 5 As the condition 

progresses, the number of polyps rises to 

50–200. Polyps are found primarily in the colon, 

but also in the stomach and small intestine. 6 The 

number of polyps needed to make the diagnosis 

remains controversial (between three and five). 2,7 

Less commonly, the condition presents in infancy 

with anemia and hemorrhage, diarrhea, proteinlosing 

enteropathy and rectal bleeding. 8 In this 

scenario the entire gastrointestinal tract is 

usually affected and there may be mild dysmorphic 

features (e.g. macrocephaly, clubbing, nail 

dystrophy); the prognosis appears to be related to 

the severity and extent of gastrointestinal 

involvement. The course in such infants is fulminant 

and death frequently occurs before the age 

of 2 years in severe cases despite colectomy. 9 

Genetics of juvenile polyposis 

A family history is found in 20–50% of patients, 

the inheritance apparently being autosomal dominant. 

There is evidence for genetic heterogeneity 

in JPS. Subsets of families have mutations in the

774 


tumor-suppressor gene PTEN located at 10q23.3, 

but these patients may have features suggestive 

of other polyposis syndromes, e.g. Cowden’s 

syndrome. 10,11 A proportion of JPS patients 

(especially those without stigmata of other polyposis 

syndromes) do not have germline mutations 

in PTEN – instead they have mutations in 

SMAD4/DPC4 located at 18q21. 12 It would appear 

that germline SMAD4 mutations predispose to 

hamartomas and cancer through disruption of 

the transforming growth factor (TGF)-β signaling 

pathway. Multiple genetic alterations (including 

APC mutations and K-ras mutations) appear to 

play a role in the neoplastic transformation of 

juvenile polyps of JPS patients. 

Complications 

There is little doubt that juvenile polyposis is a 

premalignant condition. There is a 15% incidence 

of colorectal carcinoma occurring in 

patients under the age of 35 years, leading to a 

cumulative risk of colorectal cancer of 68% by 

the age of 60 years. 7 Neoplastic changes have 

been documented both in the polyps and in flat 

apparently normal colonic mucosa. Malignancies 

in the stomach, duodenum and pancreas have 

been described in adults. 

Treatment and follow-up 

Patients with features suggestive of JPS should 

have surveillance colonoscopy with random 

biopsies of polyps and flat mucosa every 2 years 

(see Management algorithm, Figure 48.1). When 

the number of polyps is small, endoscopic 

polypectomy and follow-up may suffice, but it is 

not clear whether endoscopic surveillance is 

adequate to prevent malignancy. When there are 

numerous polyps, or symptoms such as bleeding 

and diarrhea persist, prophylactic colectomy 

should be considered after adolescence. As yet, 

there are insufficient data to justify prophylactic 

colectomy solely for the risk of colorectal carcinoma. 

With a risk of polyps in close relatives, firstdegree 

relatives of patients with JPS should be 

screened by colonoscopy starting at age 12 years, 

even when the subject is asymptomatic. 13 

Diagnosis of juvenile polyposis made at 

colonoscopy and histology 

Screen first-degree 

relatives 

Adequate control of 

poyp number and 

size – continue 

screening 


Correct anemia and 

malnutrition if relevant 

Colonoscopy and polypectomy 

at least every 2 years* 

If unable to control symptoms, 

e.g. bleeding or diarrhea, 

or polyps are too numerous and 

difficult to control via endoscopy 

Consider surgery – ileorectal 

anastomosis or proctocolectomy 

*Consider upper gastrointestinal surveillance 

Figure 48.1 Management of juvenile polyposis in 

childhood. 

Clinical features and diagnosis 

Peutz–Jeghers syndrome (PJS) is a rare autosomal 

dominant condition in which gastrointestinal 

polyps occur in association with macular melanin 

pigmentation. A definitive diagnosis of PJS can be 

made if a person fulfills one of the following criteria: 

(1) Two or more PJS polyps in the gastrointestinal 

tract; 

(2) One PJS polyp in the gastrointestinal tract, 

together with either the classical PJS pigmentation, 

or a family history of PJS. 

Presumptive diagnosis can be made in those with 

a positive family history and typical PJS freckling. 

14 

Polyps arise primarily in the small bowel, and to a 

lesser extent in the stomach and colon. 

Pigmentation occurs in most, although not all,

Figure 48.2 Macular pigmentation of the lips in a child 

with Peutz–Jeghers syndrome. 

patients and is seen most frequently on the lips and 

buccal mucosa (Figure 48.2) and occasionally on the 

hands, feet and eyelids. Clinicians should be aware 

that buccal mucosa pigmentation can occur in the 

normal population. The primary concern to the 

pediatrician is the risk of small-bowel intussusception 

causing intestinal obstruction (Figure 48.3), 

vomiting and pain. In addition, intestinal bleeding 

leading to anemia can occur. 

Genetics of Peutz–Jeghers syndrome 

The gene for this condition has recently been identified. 

The mutated gene LBK1/STK11 located on 

chromosome 19p13.3 is associated with PJS and 

encodes a serine/threonine kinase. 15,16 It appears 

that STK11 is a tumor-suppressor gene that might 

act as a gatekeeper regulating the development of 

hamartomas and adenocarcinomas in PJS. 17,18 

Allelic imbalance (allele loss and loss of heterozygosity) 

has previously been reported in a number of 

PJS cases, suggesting the existence of a hamartoma–carcinoma 

sequence in tumorigenesis. 19 

There is marked inter- and intra-family phenotypic 

variability in PJS. Therefore, the availability of 

predictive genetic testing may have some value, but 

cannot determine the likely severity of phenotype. 20 

In addition, not all PJS patients have the demonstrated 

LKB1/STK11 gene, 21 there remain potential 

loci for alternative mutated genes predisposing to 

PJS. If the gene mutation is known for previous 

affected cases in the family, it might have a role in 

presymptomatic testing in those patients with no 

pigmentation (or even potential prenatal diagnosis). 


Figure 48.3 Small-bowel barium study showing a 

massive Peutz–Jeghers syndrome polyp in the second part 

of the duodenum. 

Management and complications 

Controversy exists over the management of the 

young child with mid-gut polyps. There is a high 

re-operation rate after initial laparotomy for smallbowel 

obstruction; this rate might be reduced in 

skilled hands by intraoperative enteroscopy 

(possibly through a surgical enterotomy) to remove 

other polyps. Intraoperative small-bowel 

endoscopy picked up 38% more polyps at laparotomy 

(17 additional polyps) compared with external 

palpation and small-bowel transillumination22 (Figure 48.4). Surgery for small-bowel complications 

in children with PJS is common (65% of 

patients

776 


Figure 48.4 A 2-cm pedunculated polyp in 

Peutz–Jeghers syndrome at resection after intraoperative 

endoscopic surveillance. 

Only small 

(< 5 mm) 

polyps 

present 

Investigate relevant symptoms (e.g. pain or 

anemia by upper and lower endoscopy, and 

barium FT/wireless capsule endoscopy 

Counsel parents, 

regular follow-up. 

Re-image according 

to symptoms 

Polyps 

5–10 mm, 

evaluate 

according to 

number 

Diagnosis made by phenotype 

or family history of PJS plus 

symptoms 

children who are asymptomatic with small polyps 

(less than 1.0cm in size), the parents should be 

counseled about the risk of intussusception. 24,25 

In order to reduce the need for repeat barium 

contrast studies in children, several centers are 

piloting the use of the wireless endoscopy capsule. 

This has identified polyps missed at contrast 

study, and may prove ideal for small-bowel 

surveillance in the future. 

Follow-up 

The risk of neoplasia is well documented in young 

adults and includes development of unusual 

tumors such as Sertoli cell tumor of the ovary and 

testicular tumors in prepubescent boys. 26 A metaanalysis 

of the existing literature to assess the risk 

of cancer in PJS identified a relative risk for all 

cancers in PJS patients (aged 15–64) of 15.2 

compared to the normal population, with tumors 

reported throughout the gastrointestinal tract, and 

extraintestinal tumors of the lung, testis, breast, 

uterus, ovary and cervix. 27 Clinicians caring for 

Large polyp > 1.5 cm, 

counsel and resect by 

polypectomy 

with intraoperative 

small-bowel endoscopy 

Presents with mid-gut 


Depending on symptoms (e.g. 

anemia or pain), carry out 

upper and lower endoscopy 

and barium FT/wireless 

capsule endoscopy at 

intervals (e.g. every 2 years) 

Refer for exploratory 

laparotomy with 

intraoperative 

endoscopy and 

polypectomy 

Figure 48.5 Management of Peutz–Jeghers syndrome (PJS) in childhood. Barium FT, barium follow-through.

adolescents with PJS should be aware of unusual 

symptoms, e.g. those due to a feminizing testicular 

tumor, and have a low threshold for investigating 

potential malignancies. A recommended screening 

program for PJS patients after adolescence is 

shown in Table 48.5, but it is not clear that such a 

program will reduce morbidity or mortality. 

Familial adenomatous polyposis 

In children, gastrointestinal adenomas are almost 

always associated with hereditary adenomatous 

polyposis syndromes. Therefore, whenever a 

colorectal adenoma is found in a child, total 

colonoscopy with dye spray is mandatory. Familial 

adenomatous polyposis (FAP) is the most common 

of the adenomatous polyposis syndromes. 


Patients with FAP typically develop multiple 

adenomas throughout the large bowel, usually 

more than 100 and sometimes more than 1000 

(Figure 48.6). Polyps begin to appear in childhood 

or adolescence and increase in number with age. 

By the fifth decade colorectal cancer is almost 

inevitable if colectomy is not performed. Adult 

patients with FAP are also at increased risk of 

malignancies of the duodenum, ampulla of Vater, 

Table 48.5 Program for screening for 

malignancies in Peutz–Jeghers syndrome after 

adolescence 

Annual investigations 

Hemoglobin 

Pelvic ultrasound, gynecological and breast examinations 

(in females) 

Testicular ultrasound examinations (in males) 

Two-yearly investigations 

Upper and lower endoscopy 

Small bowel contrast X-ray 


thyroid and pancreas. Papillary carcinoma of the 

thyroid has been reported in adolescence. 28 

Children under 5 years of age may develop hepatoblastoma. 

29 It may be advisable to measure 

serum α-fetoprotein levels and/or carry out 

abdominal ultrasound examination in children at 

risk. 

There are three ways in which a patient with FAP 

may present to the pediatrician. 

(1) Most will be called for screening because of a 

positive family history. 

(2) Some will present with colorectal symptoms 

such as bleeding or diarrhea. 

(3) A minority present with extracolonic manifestations 

(Table 48.6). General pediatricians 

treating a child with an unusual lesion such 

as maxillary osteoma or a rare tumor such as 

hepatoblastoma should consider the possibility 

of FAP, particularly if there are multiple 

tumors or another sibling is affected. 30 

Genetics of familial adenomatous polyposis 

The prevalence of FAP is estimated at 1:10000. It 

is inherited as an autosomal dominant trait with 

high penetrance but with a variable age of onset. 

The rate of spontaneous mutations is relatively 

high – reported as 10–30%. 31 

Other investigations 

Cervical smear 3-yearly 

Breast mammography 5-yearly from age 25 years Figure 48.6 Colectomy specimen demonstrating 

carpeting with dense polyposis in an adolescent with 

familial adenomatous polyposis.

778 


Table 48.6 Extracolonic manifestations of familial adenomatous 

polyposis in children and young adults 

Site Examples 

Bone osteomas, mandibular and maxillary 

exostosis 

sclerosis 

Dental abnormalities impacted or supernumerary teeth 

unerupted teeth 

Connective tissue desmoid tumors 

excessive intra-abdominal adhesions 

fibroma 

subcutaneous cysts 

Eyes congenital hypertrophy of the retinal pigmented 

epithelium 

Central nervous system glioblastomas, e.g. Turcot’s syndrome 

Adenomas stomach 

duodenum 

small intestine 

adrenal cortex 

thyroid gland 

Carcinomas thyroid gland 

adrenal gland 

Liver hepatoblastoma 

The gene responsible for FAP, APC (adenomatous 

polyposis coli), is located on chromosome 5q21 

and appears to be a tumor-suppressor gene. 32 Most 

mutations are small deletions or insertions that 

result in the production of a truncated APC 

protein. In FAP a germline mutation inactivates 

one of the two APC alleles that underlie the predisposition 

to adenoma formation. 

Mutations are widely distributed throughout the 5′ 

half of the gene, although two ‘hot spots’ are found 

at codons 1061 and 1309 (Figure 48.7). These 

account for around one-third of all mutations 

detected and are associated with a more severe 

phenotype. Other phenotype–genotype correlations 

have been observed. 33 A variant of FAP has 

been described which is characterized by fewer 

colonic polyps and a generally milder phenotype, 

so-called attenuated FAP. 34,35 These correlations 

are not absolute and there may be considerable 

intrafamilial variation suggesting that there are 

other factors involved in the pathogenesis of the 

disease. Some of the phenotypic variability seen in 

patients cannot be explained by the location of 

their APC mutation. Environmental factors and 

other genes – often termed modifier genes – may 

have critical effects on APC function and disease 

expression. 36 

More than 300 different germline mutations have 

been described; finding the mutation may be a 

formidable task. Families need to be aware that the 

mutation may be detected in only 60–80% of cases. 

It is only in these cases that a predictive test can be 

offered to individuals at risk. 

Diagnosis – interpretation of the genetic test and 

clinical screening in familial adenomatous polyposis 

In order to define which screening protocol is 

appropriate for a given family, the first step is to 

determine, where possible, which mutation is 

present in the FAP-affected index case. At this 

stage, if a mutation cannot be found, the genetic

Attenuated 

APC 

168 1578 

Common mutations: 

0 400 800 

Classical/Servere FAP 

testing is non-informative and it will not be possible 

to offer predictive testing to asymptomatic atrisk 

relatives (Figure 48.8). 

For the 60–80% in whom a mutation is detected, 

at-risk relatives can be tested. A negative test is 

considered accurate in excluding FAP and the 

subject should be considered to hold an average 

population risk for the subsequent development 

of adenomas and cancer. Such genotype-negative 

individuals can be discharged from follow-up. 

Those patients where the deletion has not been 

sequenced, but has been excluded by linkage 

analysis with intragenic markers alone (a less 

reliable method for determining the risk of carrying 

the APC gene mutation) should not be 

discharged and they should undergo endoscopic 

surveillance. 

A positive test confirms the diagnosis of FAP and 

patients should undergo endoscopic assessment. 

The diagnosis is confirmed by finding polyps at 

flexible sigmoidoscopy, histologically confirmed 

as adenomas (Figure 48.9). Affected individuals 

undergo annual flexible sigmoidoscopy from the 

age of 10–14 years until adenomas are found. 37–39 

Most gene-positive children will have had a full 

colonoscopy by the age of 16 years to determine 

polyp density and location, and degree of dysplasia. 

1061 1068 1309 

APC GENE chromosome 5q21 

Exon 15 

Codon number 

Figure 48.7 Structure of the APC gene. FAP, familial adenomatous polyposis. 

Family 

genotype 

known, 

positive gene 

Positive family history – 

genetic counseling and 

detailed family pedigree 

Family 

genotype 

not known 

Start annual sigmoidoscopy 

from age 10–14, until rectal 

adenomas are confirmed 

Once adenomas found, 

counsel regarding timing for 

colectomy; consider 

colonoscopy wtih or 

without dye spray 


1200 1600 2000 

Family genotype 

known, 

negative gene 

test 

Discharge 

No adenomas found – 

continue annual 

sigmoidoscopy, add in 

5-yearly colonoscopy 

Colectomy with IRA Restorative proctocolectomy 

6–monthly 

sigmoidoscopy and 

remove polyps of > 5 mm 

Attenuated 

APC 

Annual pouch 

examination 

Figure 48.8 Management protocol for screening 

children and adolescents at risk of familial adenomatous 

polyposis. IRA, ileorectal anastomosis.

780 


Figure 48.9 Endoscopic appearance of colon showing 

occasional adenomas in a 10-year-old with familial 

adenomatous polyposis. Dye spray emphasizes small 

polyps down to < 0.5 mm. 

In families in which the genotype is not known, 

protocols vary. The approach at St Mark’s Hospital 

is to perform annual sigmoidoscopy in all firstdegree 

relatives until adenomas are found. In 

addition, from the age of 20 years, colonoscopy 

with dye spray is performed at 5-yearly intervals. 

The presence on indirect ophthalmoscopy of more 

than four pigmented ocular fundus lesions – 

congenital hypertrophy of the retinal pigment 

epithelium – carries a 100% positive predictive 

value for FAP in families at risk, particularly if the 

lesions are large. The absence of pigmentation, 

however, is of no predictive value. 

No patient should undergo screening for FAP 

without detailed counseling. It is essential that 

the individual being screened understand the 

nature of the test and its possible outcomes. 40 

Issues such as emotional, family, insurance and 

employment implications of a positive result 

should be discussed prior to testing and there 

should be a clear protocol for post-test management. 

41 

Controversy surrounds the issue of screening in 

childhood for a condition that will cause few 

problems before adolescence. 42 Many authorities 

feel that the child should be involved in the decision-making 

process, and the diagnosis be 

delayed until the child is old enough to contribute 

to the screening program – for example, from the 

age of 11 years onwards. 43,44 Some children 

understand the genetic screening and its consequences 

at a younger age, e.g. 8 years; each family 

situation should be considered individually. 

Severe dysplasia and even malignancy have been 

documented in children with FAP under the age 

of 12 years. Consequently, those children from 

families in which severe dysplasia or carcinomas 

have been found at a young age should undergo 

screening at an earlier age. 45 This is particularly 

so if the family has one of the mutations associated 

with a severe phenotype, e.g. 1309 in exon 

15. Those children with symptoms such as diarrhea 

or rectal bleeding/anaemia should be investigated 

early, as this may signify severe colonic 

disease. 38 

Duodenal and ampullary cancers are currently the 

most common cause of cancer deaths in adults 

who have had a colectomy for FAP. Upper endoscopic 

surveillance of the stomach, duodenum 

and periampullary region with a side-viewing 

endoscope is recommended after the age 20 years, 

unless the patient has symptoms such as upper 

abdominal pain, which warrant earlier investigation. 

46 

Management of familial adenomatous polyposis 

Colectomy is the only effective therapy that eliminates 

the inevitable risk of colorectal cancer. In 

the absence of severe dysplasia, colectomy is 

usually performed in the mid- to late teens or 

early twenties to accommodate work and school 

schedules. Some clinicians advocate colectomy 

before puberty so that the patient can adapt to life 

without a colon before adolescence – each case 

should be considered on its own merits. Almost 

all FAP screen-detected adolescents are asymptomatic 

and may not contemplate interruptions in 

their schooling or effects on relationships. The 

surgical option, therefore, must not only be carefully 

timed but also have low morbidity and an 

excellent functional result.

The timing of primary preventative surgery may 

be influenced by knowledge of the mutation site 

and the likely severity of the polyposis. For 

example, patients with a deletion at exon 15 at 

codon 1309 may be offered earlier surgery since 

this phenotype is characterized by a large number 

of polyps and a higher risk of cancer. 47 Even 

though a low polyp density suggests a lower risk 

of developing malignancy, 48 it is unsafe to delay 

surgery on the grounds of polyp density alone. 49 

Surgical options include subtotal colectomy with 

ileorectal anastomosis, or restorative proctocolectomy 

with ileo-anal anastomosis (pouch procedure). 

The ileorectal anastomosis is a low-risk 

operation with good functional results, but the 

rectum remains at risk of cancer. Six-monthly 

surveillance of the rectum is needed postoperatively; 

despite this, inexperience can result in 

early cancers being missed. 50 A pouch procedure 

removes the colorectal cancer risk almost 

completely, but is more complicated than an ileorectal 

anastomosis, carrying a higher morbidity 

and often requiring a temporary ileostomy. The 

pouch procedure may carry a higher risk of 

complications, reoperations, longer hospital 

stays, night evacuation and influence on later 

sexual function. 51,52 Other authors have differing 

experience and claim acceptable morbidity 

following pouch construction for FAP 53,54 or total 

colectomy with rectal mucosectomy and straight 

endorectal pull-through. 55 Pouch creation is associated 

with an as yet unknown risk of pouch 

neoplasia; the pouch should be examined regularly. 

56 

The advantages of a pouch with a lower risk of 

cancer must be compared against the higher operative 

morbidity; the patients and parents must be 

carefully counseled. Conversion to an ileoanal 

pouch can be carried out when the patient is 

much older. 57 Patients with a large number of 

rectal polyps, or those with high-risk genotypes, 

may be better with a pouch procedure in the first 

instance, owing to the greater risk of malignancy. 

58–60 

Desmoid disease 

Desmoids are locally aggressive but non-metastasizing 

myofibroblastic lesions which occur with 


disproportionate high frequency in patients with 

FAP. Associated etiological factors include 

germline mutation, estrogens and surgical 

trauma. 61 Desmoids occur most commonly in the 

peritoneal cavity (Figure 48.10), and may infiltrate 

locally leading to small-bowel, ureteric or 

vascular obstruction. These lesions may progress 

rapidly or may resolve spontaneously, their 

unpredictable nature making them difficult to 

treat. 62 Attempted surgical resection carries a high 

morbidity and mortality (10–60%) and usually 

stimulates further growth. 63 Medical treatments 

including non-steroidal anti-inflammatory drugs 

(NSAIDs) and antiestrogens have limited success. 

Cytotoxic chemotherapy is used as a last resort. 

Pediatricians treating children with extraintestinal 

desmoid tumors should consider the possibility 

of FAP in the family. 

Other polyposis syndromes 

Infrequently, juvenile polyposis may occur as part 

of the Bannayan–Riley–Ruvalcaba syndrome. 

This is characterized by macrocephaly, intestinal 

juvenile polyposis, pigmentation of the genitalia, 

psychomotor delay in childhood and occasionally 

lipid storage myopathy. 64 Cowden’s disease is the 

Figure 48.10 Abdominal computed tomography scan 

showing a massive intra-abdominal desmoid tumor in a 

14-year-old with familial adenomatous polyposis.

782 


association of multiple hamartomas of the 

stomach, small intestine or colon with macrocephaly, 

fibrocystic disease and cancer of the 

breast and thyroid. Germline mutations in the 

tumor-suppressor gene PTEN have been found in 

Cowden’s and Bannayan–Riley–Ruvalcaba pedigrees. 

65 Gorlin’s syndrome is an autosomal dominant 

condition comprising upper gastrointestinal 

hamartomas and pink or brown macules in 

exposed areas such as the face and hands. In addition, 

patients may have frontal and parietal 

bossing, hypertelorism and variable skeletal 

abnormalities and intracranial calcification and 

are at risk of medulloblastoma. 

Turcot’s syndrome is characterized by concurrence 

of a primary brain tumor and multiple 

colorectal adenomas. Patients with a polyposis 

syndrome and neurological symptoms should 

undergo thorough neurological examination and 

investigation for possible brain tumor. The 

management of the colonic polyps in Turcot’s 

syndrome is the same as for FAP. 

In the vast majority of patients with polyposis, a 

clear-cut diagnosis can be made, e.g. FAP or PJS. 

However, there are some rare cases where distinctions 

cannot be made on histology – the mixed 

polyposis syndromes. 66 

Future chemoprevention 

Studies have suggested that NSAIDs may be 

protective against colon cancer. NSAIDs inhibit 

prostaglandin synthesis via their effects on cyclooxygenase 

(COX). Several trials have shown 

regression of adenomas using the NSAID sulindac, 

67,68 but widespread use of sulindac has been 

limited by concerns regarding gastrointestinal 

side-effects with prolonged administration and 

case reports of rectal cancer despite treatment. 69 

Clinical trials using selective COX-2 inhibitors 

have reported a reduction in the number of 

colorectal polyps. 70 It remains to be seen what 

role this agent, and also the non-cyclo-oxygenase 

metabolite of sulindac, sulfone-sulindac, may 

have in the future management of colorectal and 

duodenal adenomas. They may have a role prior 

to surgery in young patients, but sulindac administered 

before polyps developed in genotype-positive 

adolescents did not prevent the development 

of adenomas. 71 Primary chemoprevention with an 

NSAID may not prevent polyp formation. 

Intestinal neoplasia 

In pediatric practice, colonic carcinoma and 

lymphoma are very rare, yet an awareness of these 

conditions is still important since a delay in diagnosis 

adversely affects outcome. 

Carcinoma of the colon 

Colorectal cancer is a major cause of morbidity 

and mortality in adult practice but its incidence in 

younger individuals is very low, with fewer than 

200 pediatric cases reported in the literature by 

1994. 72 Compared to adults, where sporadic cases 

of cancer predominate, in children there is an 

over-representation of cases with pre-existing 

polyposis or colitis (10%). 73 

Pathogenesis 

Colorectal carcinoma is believed to result from 

several sequential genetic mutations known as the 

adenoma–carcinoma sequence. Although the 

pattern of mutation is not consistent in all colorectal 

cancers, it is proposed that progress to malignant 

transformation occurs following the accumulation 

of a combination of four or five defects 

including mutational activation of oncogenes and 

inactivation of tumor-suppressor genes. 74,75 

Pathology 

The pathology of colonic carcinoma in children 

when compared to adult cases is characterized by 

more right-sided disease, with 50% located in the 

cecum to transverse colon. 76 Colorectal cancers 

grow locally, eventually penetrating the bowel 

wall. They can spread to regional lymphatics and 

subsequently to distant lymph nodes, and also to 

the liver, lungs and vertebrae. Cases are staged 

according to the degree of local spread and the 

presence or absence of transmural penetration, the 

degree of lymph node involvement and presence 

of distant metastases. In a review of younger 

patients with colonic cancer, 82% of these cases

had either distant metastases, lymph node involvement, 

or transmural penetrating disease, significantly 

higher than in adult patients. 77,78 

The usual histological appearance of colorectal 

cancers in adults is of a moderate to well differentiated 

adenocarcinoma. In children the proportion 

of tumors with mucinous (30%) and signet-ring 

(10%) histological appearances, associated with a 

poorer prognosis, is greater, and together with the 

tendency towards a more advanced stage at 

presentation may account for the poorer outcome 

of the disease in children. 


Abdominal pain is the main presenting symptom, 

occurring in over 90% of cases, although other 

symptoms – weight loss, vomiting, rectal bleeding 

and altered bowel habit – may also be present. The 

clinical presentation is influenced by the site of 

the lesion, with constipation, obstruction and 

bleeding more common with left-sided disease, 

whereas right-sided disease may not present with 

obstruction, for example, until the lesion is larger, 

and a mass is palpable. 

Diagnosis is by colonoscopy in most cases, 

although the lesion can also be identified by other 

imaging modalities such as ultrasound or magnetic 

resonance imaging. Although serological markers 

such as carcinoembryonic antigen (CEA) are available, 

their role in establishing this rare diagnosis 

in children has not been fully evaluated. 79 

Treatment and outcome 

Surgery is the main treatment for colonic carcinoma, 

with complete resection of the primary 

lesion and draining lymphatics being the primary 

objective. Complete resection is often not possible 

in children, owing to the advanced stage at presentation. 

Chemotherapy for metastatic disease has in 

general been disappointing, and the role of radiotherapy 

or combination therapies awaits further 

study in the pediatric age group. 

The prognosis for children with colon cancer is 

poor, with 5-year survival rates of 10–20% 

reported. 80 These poor results are due to a combination 

of unfavorable histology and delayed 

presentation. 

Lymphoma 

Intestinal neoplasia 783 

Compared to adults, in younger patients there is a 

significant difference in the preponderance of the 

various histological types of lymphoma and also in 

the frequency of disease at different intestinal 

sites. 

Epidemiology and classification 

In the developed world, lymphoma accounts for 

10% of all cancers in children under 15 years of 

age. 81 In central Africa there is a very high incidence 

of Burkitt’s lymphoma (small non-cleaved 

B-cell lymphoma), accounting for up to 50% of all 

childhood cancers, whilst in North Africa and the 

Middle East there is a high rate of immunoproliferative 

small intestinal disease (IPSID). 

Etiology 

Non-Hodgkin’s lymphoma is associated in some 

cases with immunodeficiency syndromes, both 

inherited (e.g. ataxic-telangiectasia) and acquired 

(e.g. HIV infection), and also with immune 

suppressive therapy (e.g. after organ transplantation). 

An infectious agent (Epstein–Barr virus) may 

play a role in disease pathogenesis in some cases. 

This appears particularly to be the case for 

endemic Burkitt’s lymphoma, although the 

geographical association with malaria infection 

implies that co-infection may be important in 

promoting B-cell activation as part of the process 

leading to malignant change. Other conditions that 

give rise to chronic mucosal inflammation have 

also been linked to lymphoma. T-cell non- 

Hodgkin’s lymphoma is associated with celiac 

disease, whilst both lymphoma and adenocarcinoma 

are associated with both Crohn’s disease, 

where the lesion is typically in the small bowel, 

and ulcerative colitis. 82,83 

Pathology 

Intra-abdominal non-Hodgkin’s lymphoma in children 

typically is of an undifferentiated histological 

type – only around 50% have a primary intestinal 

origin84 – most common intestinal primary sites 

are the distal ileum, cecum and appendix. Bonemarrow 

involvement occurs in up to 40% of undifferentiated 

lymphoma, whilst central nervous

784 


system involvement is uncommon. In endemic 

Burkitt’s lymphoma 60% have abdominal disease, 

60% have characteristic involvement of the 

mandible. 84 


Disease may present with non-specific symptoms 

such as abdominal distension, nausea, vomiting, 

altered bowel habit and abdominal pain. Disease 

primarily in the intestinal tract, typically localized 

to the distal ileum and cecum in children, may 

present with a mass, an ileo-cecal intussusception, 

obstructive symptoms or bleeding. 

The diagnosis of non-Hodgkin’s lymphoma depends 

on histological examination with immunophenotyping 

and cytogenetics. Staging of disease with 

chest and abdominal imaging, lumbar puncture and 

bone-marrow examination are also required, and 

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Index 

abdominal migraine 218, 219 

abdominal pain see acute 

abdomen; chronic abdominal pain; 

functional abdominal pain 

abdominal wall defects 25–27 

exomphalos 26 

gastroschisis 26 

treatment 26–27 

abscess, intra-abdominal 682 

acetylsalicylic acid, gastric injury 

97–98 

achalasia 61–69 

epidemiology 61 

etiology 61–62 

investigations 64–66 

manometry 65, 66 

radiography 64–65 

pathology 62 

pathophysiology 62–63 

signs and symptoms 63–64 


endoscopic botulinum toxin 

injection 67 

esophageal dilatation 67 

esophagomyotomy 67–69 

medical treatment 66 

acid reflux 42, 43 

see also gastroesophageal reflux 

disease 

acid secretion 77 

acute abdomen 677–687 

caused by procedures 684–687 

imaging studies 679–680 

laboratory tests 679 

specific diseases 681–684 

biliary diseases 682–683 

foreign body ingestion 681 

infectious and parasitic 

disease 683–684 


681–682 

pancreatitis 683 

symptoms and signs 677–679 

abdominal pain 677–678 

fever 678 

stool characteristics 678 

vomiting 678 

treatment considerations 

680–681 

acute appendicitis see appendicitis 

acyclovir, esophagitis treatment 

34, 35, 36 

adenocarcinoma 

cardia 47 

esophagus 47 

adenomas 771 

see also gastrointestinal polyps 

adenoviruses 138 

with HIV infection 117 

adsorbents 667–668 

Aichi virus 138–139 

AIDS (acquired immunodeficiency 

syndrome) 114–115 

esophagitis and 29, 30 

see also HIV infection 

alanine aminotransferase (ALT) 

394–395 

albendazole 181–182 

mass community treatment 

184, 185–186 

albumin 451–452 

alcohol, gastric pathology and 98 

Algicon 52 

allergic diseases 532–535 

allergic angiitis and 

granulomatosis 427 

allergic esophagitis 46 

dietary antioxidants and 

533–534 

dietary lipid mediators 533 

elimination diets 532 

modification of allergenic 

proteins 532–533 

probiotics and 534–535 

see also food allergies 

alosetron 51 

α2ß1 integrin 8 

α6ß4 integrin 8 

amebiasis 176–178 

clinical features 177–178 

diagnosis 178 

epidemiology 176–177 

pathophysiology 177 

prevention 178 

treatment 183, 184 

see also Entamoeba histolytica 

amino acid oral rehydration 

solutions 662 

aminosalicylic acid (ASA) drugs 

Crohn’s disease treatment 366, 

367 


management 382 

side-effects 368 

ulcerative colitis treatment 

398–400, 402 

colorectal cancer and 408 

amoxicillin 

H. pylori eradication 86–87 

malnutrition management 515 

amphotericin B, esophagitis 


amylase resistant starch oral 

rehydration solutions 663 

anal sphincter complex 249 

anaphylaxis 320, 322–323 


Ancylostoma duodenale 168 


see also hookworm 

Ancylostoma-secreted proteins 

(ASPs) 169 

anemia 


iron deficiency 354, 440 

H. pylori infection and 81 

malnutrition 500 


pernicious 106, 110 

angiography 645–646 

anisakiasis 97, 684 

annular pancreas 16, 17 

anorectal congenital abnormalities 

23–24 

clinical features 23 

outcome 24 


anorexia 493, 498 

antacids 51–52 

anti-Saccharomyces cerevisiae 

antibody (ASCA) 361, 381, 390 

anti-tumor necrosis factor-α agents 

370–371 

antibiotic treatment 

acute abdomen 680–681 

appendicitis 746–747 


787

788 

Index 

diarrhea 665, 666–667 

Campylobacter 150, 666 

cholera 147, 666 

Clostridium difficile 156, 667 

E. coli 152, 153, 666 

persistent diarrhea 196 

Salmonella 148, 149, 666 

Shigella 150, 666 

Yersinia 150–151, 666 

esophagitis 37 

H. pylori eradication 86–88 


pouchitis 406 

short-bowel syndrome 470 

small-bowel bacterial 

overgrowth 209–210, 468 

ulcerative colitis 403 

see also specific drugs 

anticholinergics, abdominal pain 


antiemetic drugs 665–667 

anti-endomysium antibodies 446 

antifungal drugs, esophageal 

candidiasis 33 


antigliadin antibodies (AGA) 

445–446 

antimotility agents 156, 667 

abdominal pain management 

226 

short-bowel syndrome 

management 468–469 

antineutrophil cytoplasmic 

antibodies (ANCA) 421 

cytoplasmic (c-ANCA) 421 

perinuclear (P-ANCA) 361, 381, 

390, 421 

antioxidants, role in allergic 

diseases 533–534 

antiphospholipid antibody 

syndrome (APS) 431 

antisecretory drugs 668 

apnea 239 

appendectomy 746–747 

inflammatory bowel disease and 

351 

ulcerative colitis risk 387 

laparoscopic 765–766 


clinical manifestations 741–742 

complications 747–748 

diagnosis 741 

differential diagnosis 

745–746 


imaging studies 743–745 


pathological course 740–741 

phlegmonous appendicitis 

741 

simple appendicitis 741 

ulceronecrotic appendicitis 

741 


physical examination 742–743 


laparoscopic procedures 

765–766 

appendix anatomy 739–740 

appetite 

anorexia 493, 498 

handicapped children 284 

in malnutrition 493, 498, 517, 

518 

arginine 626 

arteriography 426–427 

arteriovenous malformations 758 

arthralgia 440 

arthritis 440 

arthropathy 394 

ascariasis 166–168 


diagnosis 168 


immune responses 166–167 


treatment 182, 183, 185–186 

Ascaris lumbricoides 166 

life cycle 166 

see also ascariasis 

aspiration 46, 240, 485 

evaluation 242, 243 

see also dysphagia 

astrovirus 137 

virology 137 


atopic dermatitis, food allergy and 

325–327 

atresia 

biliary 21 

choanal 8 

duodenal 16 

esophageal 13–14 

jejunoileal 17–19 

pyloric 8 

autoimmune disease 

chronic intestinal 

pseudo-obstruction and 

275–276, 280 

see also celiac disease 

azathioprine 

Crohn’s disease treatment 369 

ulcerative colitis management 

402–403 

vasculitis treatment 432 

B-cell lymphoma 89 

baclofen 51 

bacterial infections 145 

appendicitis 740 

diarrhea 145, 656, 657 

evaluation 156 

treatment guidelines 156 

see also specific bacteria 

esophagitis 37 

gastritides 95–97 

gastrointestinal bleeding and 

643 

in malnutrition 514–515 

see also small-bowel bacterial 

overgrowth (SBBO); 

specific infections 

Bannayan–Riley–Ruvalcaba 

syndrome 781 

barium enema 

constipation 254 


Hirschsprung’s disease 261, 262 

intussusception 723–724 


barium swallow 64–65, 361 

Barrett’s esophagus 40, 46, 47 

Becker muscular dystrophy 276 

Behçet’s disease 428 

benzimidazoles 181–182 

Bifidobacterium lactis 210 

bile duct perforation 683 

bile reflux gastropathy 100 

bile salt malabsorption 356 

short-bowel syndrome 462 

biliary atresia 21 

biofeedback training, constipation 


biopsy 

celiac disease 444–445 

rectal suction biopsy 


vasculitides 425–426 

biopsychosocial model 217–218 

bismuth subsalicylate 668 

bisphosphonates 359 

bleeding see gastrointestinal 

bleeding 

blue rubber bleb nevus syndrome 

756 

body mass index (BMI) 495–496 

bone disease 


parenteral nutrition-related 571 

see also osteopenia; osteoporosis 

botulinum toxin, achalasia 

treatment 67 

bradycardia 239 

brain–gut interaction 216 

breast feeding 

as model for optimal growth 

and development 528–529 

diarrhea management 663–664 


gut microbiota and 530 


and 349 

necrotizing enterocolitis and 

579 

breast milk 610–615 

benefits of 610–611 

fortification of 611–613 

limits of 611 

brush-border abnormalities 2

udesonide 

Crohn’s disease treatment 

368–369 

ulcerative colitis treatment 400, 

402 

Burkitt’s lymphoma 783, 784 

Cag-A protein 78, 79 

calcium channel blockers, 

achalasia treatment 66 

calcium requirements, premature 

infants 607–608, 630 

caliciviruses 139–140 

Campylobacter 150, 666 

cancer see specific forms of cancer 

cancrum oris 122 

Candida (candidiasis) 

esophageal infection 29–32 

diagnosis 30–32 

management 30, 31, 32, 33 

predisposing conditions 30 

symptoms 30, 31 

HIV infection and 117, 118–119 

malnutrition and 522 

capillary malformations 755 

carbohydrate intolerance 221–222 

lactose intolerance 195, 198, 

221–222 

carbohydrate malabsorption 

in HIV infection 116 

in small-bowel bacterial 

overgrowth 203 

carbohydrates 

in enteral nutrition 545 

premature infants 606–607 

in parenteral nutrition 559–560, 

568–569 


carcinoma 

colonic 782–783 

gastric, H. pylori infection and 

88–89 

cardia perforation 686 

cardiovascular disease 528 

carnitine 564, 629 

catheter-related sepsis 570, 633 

CCR5 co-receptor 114 

CD4 counts, in HIV infection 

116–117 

CD-10 immunoreactivity 3–4 

cecum 739–740 

celiac disease 334–335, 435–447 

associated diseases 441–442 

Down’s syndrome 442 

type 1 diabetes 442 

atypical/extraintestinal celiac 

disease 439–441 

arthritis/arthralgia 440 

dental enamel hypoplasia 440 

dermatitis herpetiformis 

439–440 

hepatitis/hypertransaminasemia 

440 

infertility 441 

iron-deficiency anemia 440 

neurological problems 441 

osteopenia/osteoporosis 

440–441 

psychiatric disorders 441 

short stature/delayed puberty 

440 

clinical presentations 438–439 


hyposplenism 443 

malignancy 444 

non-responsive disease 443 

refractory sprue 444 


duodenal biopsy 444–445 

serology 445–446 

tissue transglutaminase 

antibodies 446 

differential diagnosis 223 




celiac gastritis 102–103 

central venous catheters (CVCs) 

557–558 

cereal-based oral rehydration 

solutions 662 

cerebral palsy 283, 285–286 

Chagas’ disease 280 

chloramphenicol, typhoid fever 


choanal atresia 8 

cholecystectomy 766–767 

cholecystokinin (CCK) 463–464 

choledochal cyst 21 

cholelithiasis 222, 462, 682 

cholera 145–148 

treatment 147 

vaccine development 147 

cholera toxin (CT) 147 

cholestasis, with parenteral 

nutrition 571–572 


chronic abdominal pain 213 

causes of 221 

laparoscopic procedures 766 

see also functional abdominal 

pain 

chronic granulomatous disease 

104, 110 

chronic intestinal pseudoobstruction 

(CIP) 269–281, 

702 

clinical presentation 269–270 

enteric myositis 275–276 

enteric nervous system 

disorders 276–280 

primary visceral neuropathies 

276–278 

sporadic visceral 

neuropathies 278–280 


Index 789 

familial visceral myopathies 

273, 274–275 

infantile visceral myopathy 

273–274 

megacystis microcolon 

hypoperistalsis syndrome 

274 

primary visceral myopathies 

273 

intestinal smooth muscle 

disorders 275 

investigation 270–272 

manometry 271–272 

radiography 271 

surface electrogastrography 

271 

muscular dystrophy 276 


chronic varioliform gastritis 102 

Churg–Strauss syndrome 427–428 

cidofovir, esophagitis treatment 

35, 36 

cigarette smoking see smoking 

cisapride 

cardiac effects 51 


disease treatment 50–51 

clarithromycin, H. pylori 

eradication 86–88 

cleft lip and palate 13 

cloaca 23 

Clostridium spp 201, 667 

C. difficile 155–156 

cocaine ingestion 698 

colectomy 

laparoscopic 763–764, 765 


405 

colitis 

amebic 183 

indeterminate 379–383, 393 

diagnostic criteria 380–381 


medical therapy 382–383 

natural history 381–382 

serologic markers 381 

surgical treatment 383 

necrotizing 177 

pseudomembranous (PMC) 155 

toxic 681–682 

see also enterocolitis; 


(IBD); ulcerative colitis 

collagenous gastritis 105–106 

colon 

carcinoma 782–783 

strictures 396 

see also colitis 

colonoscopy 

acute abdomen and 685 


gastrointestinal bleeding 

investigation 646

790 

Index 

ulcerative colitis 390–392 

colorectal cancer 782–783 

ulcerative colitis and 408 

computed tomography (CT) 


Crohn’s disease 361, 362 

pancreas evaluation 310, 

311–313 


condyloma accuminata 122 

congenital biliary dilatation 21 

congenital diaphragmatic hernia 

24–25 

classification 24–25 


treatment 25 

connective tissue disorders 275, 

430 


chronic 222 


defecation frequency 

248–249 

differential diagnosis 253, 745 

functional 247, 248 



abdominal X-ray 253–254 

anorectal manometry 254 

barium enema 254 

colonic manometry 254 

defecography 254 

medical history 252 



prognosis 256–257 

slow-transit constipation 

250–252 


biofeedback training 256 

fecal impaction prevention 

256 

fecal impaction removal 255 

fluid intake 255 


pharmacotherapy 255 

continuous enteral nutrition see 

enteral nutrition 

coronaviruses 139 

corticosteroids 


366–369 

gastric injury 98 




400, 401–402 



430 

polyarteritis nodosa 427 

corticotropin releasing factor (CRF) 

216 

role in cyclic vomiting 

syndrome 295 

costochondritis 223 

Cowden’s disease 781–782 

cow’s milk allergy 334 



cow’s milk-sensitive enteropathy 

(CMSE) 195–196, 325 

COX-2 inhibitors 109, 387 

Crohn’s disease (CD) 275, 

347–373, 388 

clinical signs and symptoms 

352–356 


hepatobiliary complications 

356 

local intestinal complications 

359–360 

malnutrition 356, 357–358 

metabolic bone disease 359 

nephrolithiasis 358 

pancreatic complications 358 

thromboembolic events 

358–359 

diagnosis 360–365, 380–381 

clinical suspicion 360–361 

endoscopic studies 363–365, 

390–392 

laboratory studies 361 

radiographic studies 361 

scintigraphy 361–363 

serological markers 361 



environmental factors 

349–351 

genetic factors 348–349 

follow-up management 371–372 

gastric 103–104, 110 


prognosis 373 


5-aminosalicylic acid (5-ASA) 

drugs 366 

antibiotics 371 

corticosteroids 366–369 

enteral nutrition 541–542 

immunoregulatory agents 

369–371 


763–764 

nutritional therapy 365–366 

supportive measures 371 

surgery 371 

see also inflammatory bowel 

disease (IBD) 

cryptosporidiosis 171–174 


diagnosis 173 



prevention 173–174 


Cryptosporidium parvum 

HIV infection and 117–118, 

171, 172 


transmission 171–172 

see also cryptosporidiosis 

cutaneous lymphocyte antigen 

(CLA) 325 

cyclic vomiting syndrome (CVS) 

289–301 

clinical patterns 289–292 

cyclic versus chronic patterns 

291–292 

complications 297 

diagnosis 296–297, 298 


292–293 

natural history 297 


autonomic dysfunction 295 

migraines 294 

mitochondrial dysfunction 

294–295 

neuroendocrine dysfunction 

295 

subtypes 295–296 


cyclophosphamide 432 

Cyclospora cayetanensis 118, 171, 

180–181 

cyclosporin 401 

cyst 

choledochal 21 

duplication 24, 644 

mesenteric 757–758 

cystic fibrosis (CF) 306 

enteral nutrition and 542–543 

inguinal hernia and 592 

cytomegalovirus (CMV) 



following intestinal 

transplantation 706 

gastric infection 97 

HIV infection and 118, 119 

cytoplasmic antineutrophil 

cytoplasmic antibodies (c- 

ANCA) 421 

defecation 

frequency 248–249 

normal anatomy and physiology 

249–250 

dehydration 133, 657–658 

estimation of 659 

prevention in short-bowel 

syndrome 469 

with malnutrition 512 

see also rehydration therapy 

dendritic cells 113 

dental enamel hypoplasia 440 

dermatitis herpetiformis 439–440

desmoid disease 781 

diabetes mellitus, celiac disease 

and 442 

diaphragmatic hernia see 

congenital diaphragmatic hernia 

diarrhea 

bacterial 145, 656, 657 

evaluation 156 



treatment guidelines 156 

see also specific bacterial 

infections 


definitions 655–656 



dehydration estimation 659 


electrolyte measurement 660 

fecal screening tests 660 

microbiological testing 

659–660 

epidemiology 193, 656 

etiology 656 

Hirschsprung’s enterocolitis 23 

HIV infection and 115–117, 194 

HIV enteropathy 117 

host responses and 

susceptibility 116–117 


mucosal structure/function 

and 115–116 

inflammatory 656–657, 660 

intestinal parasites and 

161–163 

see also specific parasites 

malnutrition and 193–194, 195, 

657–658 

management approach 655, 

660–669 

hospital admission 663 

nutritional management 

663–665 

pharmacological therapy 

665–669 

rehydration 660–663 

non-inflammatory 656 

pathogenesis 656–657 

persistent see persistent diarrhea 

phenotypic 9 

short-bowel syndrome 462, 465 

viral 127–141, 656, 657 


132–134 



pathogens and virology 

135–139 

pathophysiology 128–132, 133 

treatment 139 

vaccine development 

139–141 

see also intractable diarrhea of 

infancy (IDI); 

protracted diarrhea of 

infancy (PDI) 

diet see nutrition 

dietary deficiency 492 

see also malnutrition 

dietary intervention 

functional abdominal pain 226 

handicapped children 285–287 

malnutrition 513–514, 517, 

518–519 

persistent diarrhea 197–198 

short-bowel syndrome 467–468 

see also nutritional therapy 

Dieulafoy’s lesion 644 

dimethicone 52 

dioctahedral smectite 667–668 

diverticulitis 733 

see also Meckel’s diverticulum 

domperidone 50 

Down’s syndrome 283 

celiac disease and 442 

drooling 239 

Duchenne muscular dystrophy 

276 

duodenum 

atresia 16 

hematoma 686 

obstruction 16–17 


treatment 17 

stenosis 16–17 

ulceration 

H. pylori and 76 

see also peptic ulcer disease 

(PUD) 

duplication cysts 24, 644 

duplications of the alimentary tract 

24, 223 

dysentery 149–150 

amebic 177 

treatment 183 

Trichuris dysentery syndrome 

171 

see also diarrhea 

dysmotility 215 

allergic 327–328 

see also visceral myopathy; 

visceral neuropathies 

dyspepsia 

functional 218, 219 

H. pylori infection and 80–81, 

218, 220 

dysphagia 238 

achalasia and 63–64 

anatomic considerations 235 


239 



respiratory complications 

239–240 

Index 791 

sialorrea 239 


fiberoptic endoscopy 243 

history 240–241 

pharyngeal manometry 

242–243 

physical evaluation 241 

radiographic assessment 

241–242 

scintigraphy 243 

ultrasonography 242 

differential diagnosis 233, 234 


etiology 233 


prognosis 244 

treatment options 243–244 

enteral nutrition 543 

eating disorders see feeding 

disorders 

eczema, food allergy and 325–327 

edema, in malnutrition 496–497 

see also kwashiorkor 

egg allergy 334 

eicosapentaenoic acid (EPA) 605 

electrogastrography (EGG) 271 

electrolyte measurement 660 

encopresis 248 

endometriosis 223 

endoscopic retrograde cholangiopancreatography 

(ERCP) 

310–314, 683 


endoscopy 

abdominal pain investigation 

224 

achalasia 65 

botulinum toxin injection 67 

acute abdomen causation 

684–686 

Crohn’s disease diagnosis 

363–365, 390–392 

gastroesophageal reflux disease 

54 


investigation 646 

lymphonodular hyperplasia 

479–480 

portal hypertension 


swallowing disorder evaluation 

243 

ulcerative colitis evaluation 

390–392 

vasculitides 425 

endothelin signalling pathway 266 

energy expenditure (EE) 558–559 

enteral nutrition effects 540 

energy requirements 558–559 

premature infants 603, 622 

protein/energy ratio 603–604, 

623

792 

Index 

reduction in malnutrition 

500–501 

Entamoeba dispar 176–177 

Entamoeba histolytica 176, 667 




see also amebiasis 

enteral nutrition (EN) 539–550 


gastrointestinal complications 

548 

infectious complications 549 

mechanical complications 

548 

metabolic complications 549 


transplantation 708–709 

home enteral nutrition 549–550 

indications 549 

organization 549–550 

prevalence/incidence 549 

results 550 

teaching parents 550 

in preterm infants 544, 599–615 

early adaptive period 599–600 

nutrient needs 600–610 

practical aspects 610–615 

indications 540–544 

cholestatic liver disease 543 

cystic fibrosis 542–543 

eating disorders 543 

hypermetabolic states 544 

inborn errors of metabolism 

544 

inflammatory bowel diseases 

541–542 

neonatal abdominal surgery 

542 

premature infants 544 

protracted diarrhea of infancy 

541 


466–467, 540–541 

physiological basis 539–540 

digestive secretion and 

hormonal response 540 

effects on energy expenditure 

540 

effects on mucosal trophism 

540 

gastrointestinal motility 539 

techniques 544–548 

choice of formula 546–547 

intake regulation 547–548 

nasogastric tubes 544–545 

nutrients 545–546 

percutaneous gastrostomy 

545 

enteric fever 148, 149 

enteric myositis 275–276 

enteric nervous system (ENS) 

214–215 

enterobiasis 178–179 

Enterobius vermicularis 178–179 

enterocolitis 

food protein-induced 323–325 

Hirschsprung’s 23, 260 

see also colitis 

enterocyte heparan sulfate 

deficiency 457 

enterotoxins 152 


208–209 


eosinophilic enteropathy 328–329 

eosinophilic esophagitis 46–47 

food allergy and 328–329 


eosinophilic gastritis 105 

eosinophils, in food allergy 338–339 

eotaxin 105, 338–339 

epidermal growth factor (EGF) 

464, 466 

epidermolysis bullosa 8 

episcleritis 394 

epithelial dysplasia see intestinal 


Epstein–Barr virus (EBV) 

esophageal infection 35 



erythema nodosum 394 

erythromycin 

Campylobacter treatment 150 


treatment 50 

Escherichia coli 151–155, 666 

diffusely adhering (DAEC) 154 

enteroaggregative (EAggEC) 

154–155 

enterohemorrhagic (EHEC) 

152–153 

enteroinvasive (EIEC) 152 

enteropathogenic (EPEC) 151 

enterotoxigenic (ETEC) 151–152 

esomeprazole 53 

esophageal dilatation 67 

esophagitis 

allergic 46 

eosinophilic 46–47 

food allergy and 328–329 



643 

reflux 40, 46, 643 

see also infectious esophagitis 

esophagomyotomy 67–69 

esophagus 

adenocarcinoma 47 

atresia 13–14 

Barrett’s 40, 46, 47 

perforation 686 

pH monitoring 47–48, 225, 585 

stenosis 46 

strictures 46 

ulceration 34–35, 37, 46 

variceal bleeding 649–651 


see also achalasia 

exomphalos 26 


famciclovir, esophagitis treatment 

36 


(FAP) 777–781 



genetics 777–778 


familial dysautonomia (FD) 295 

familial Mediterranean fever (FMF) 

223–224 

fasciolopsiasis 180 

Fasciolopsis buski 180 

fat overload syndrome 562–563 

fats see lipids 

fecal continence 249–250 

fecal retention 251 

fecal impaction prevention 256 

fecal impaction removal 

255–256 

fecal screening tests 660 

fecal soiling 247–248 

feeding development 235–238 

critical period 236 

feeding disorders 



physical evaluation 241 




and 43 

prognosis 244 


enteral nutrition 543 

see also dysphagia; sucking 

disorders 

feminization, in malnutrition 499 

fever 678 

fish oils 

in parenteral nutrition 563–564 


404 

fluconazole 32, 33, 119 

fluid balance, premature infants 

600, 621–622, 635 

fluid retention, with parenteral 

nutrition 568 

folate deficiency 490 



folic acid, diarrhea management 

669 

food allergies 319–341 


cow’s milk allergy 334

egg allergy 334 

elimination diets 532 

food allergen avoidance 

recommendations 336 

future challenges 340–341 

immune response mechanisms 

336–340 

antigen presentation by 

epithelium 337 

mast cells and eosinophils 

338–339 

skewing of B cells towards 

IgE 337–338 

T-cell responses in oral 

tolerance 339–340 

lymphonodular hyperplasia and 

482–483, 485 



multiple food allergy 335–336 

patterns of allergic responses 

321–329 

allergic dysmotility 327–328 

eczema/atopic dermatitis 

325–327 

eosinophilic enteropathy 

328–329 

eosinophilic esophagitis 

328–329 

food protein enteropathy 325 

food protein-induced 

enterocolitis 323–325 

quick-onset symptoms 

321–323 

respiratory symptoms 329 

peanut allergy 335 

soy allergy 334 

testing for 329–333 

food challenge testing 

329–331 

in vitro testing 332–333 

skin patch testing 331–332 

skin prick testing 331 

specific IgE testing 332 


wheat allergy 334–335 

see also allergic diseases 

food impaction 697 

food intolerance 319–320 

foreign body ingestion 691–698 



692–695 


location of object 692–694 

cocaine ingestion 698 

diagnosis 695 


food impaction 697 


follow-up 698 

foscarnet, esophagitis treatment 

35, 36 

Fredet–Ramstedt’s pyloromyotomy 

590–591 

functional abdominal pain 

213–229 

diagnostic testing 224–225 

blood studies 224 

endoscopic studies 224 

intraesophageal pH 

monitoring 225 

lactose hydrogen breath test 

225 

stool studies 224 

ultrasound 224–225 

differential diagnosis 220–224 


future trends 229 

natural history 228–229 


biopsychosocial model 

217–218 

brain–gut interaction 216 


genetics 217 

immunity 216 

inflammation 216 

stressors 216–217 

visceral hyperalgesia 215 

physiology of gastrointestinal 

pain response 214–215 


alternative and 

complementary therapy 

228 

anticholinergics 226 

antidiarrheal medications 

226 

diet 226 

laxatives 226 

reassurance 225–226 

selective serotonin re-uptake 

inhibitors 227 

serotonin receptor 

antagonists 227–228 

tricyclic antidepressants 

226–227 

functional bowel disorders 213, 

218–219 

abdominal migraine 218, 219 


dyspepsia 218, 219 

see also irritable bowel 

syndrome (IBS) 

functional constipation see 

constipation 

functional non-retentive fecal 

soiling 247–248, 252 

fundoplication 587–588, 762–763 

fungal infections 

esophagitis 29–32 

gastritides 97 

G-cell hyperfunction 101 

G-cell hyperplasia 101 

Index 793 

galactosyl ceramide (GalCer) 114 

gallstones 222 

ganciclovir 

cytomegalovirus infection 

management with HIV 119 

esophagitis treatment 35, 36 

gastric acid secretion 77 

continuous enteral feeding and 

540 

gut microbiota regulation 202 

hypersecretion 101, 462–463 

gastric asthma 46 

gastric carcinoma, H. pylori 

infection and 88–89 

gastric ulcers 


643, 644 


H. pylori and 76 


(PUD) 

gastrin 77 

hypergastrinemia 101 

gastritis 95, 96 

alkaline 100 

autoimmune disease and 106 

chemical 97 

classification 83 

clinical assessment 107 

collagenous 105–106 

diagnosis 82–84, 107, 108 

eosinophilic 105 

focal enhanced 104 

granulomatous 103–104 

H. pylori-associated 80–81, 

82–84, 103 

prognosis 88 

lymphocytic 101–103 

celiac 102–103 

chronic varioliform 102 

H. pylori 103 

proton pump inhibitor gastritis 

106 


tuberculosis 95–97 

gastroenteritis 127, 135, 745 



(GERD) 39–54 


43–45, 584–585 

complications 46–47, 585 

definitions 39 

differential diagnosis 47–48, 

585–586 

environmental factors 40 

epidemiology 39–40, 584 

etiology 584 

genetic factors 40 


percutaneous endoscopic 

gastrostomy and 287 

neonatal 583–588

794 

Index 

pathophysiology 40–43, 584 

prognosis 588 

respiratory disease and 45–46, 

585 

treatment 48–54, 586–588 

antacids 51–52 

complications of nonintervention 

48–49 

endoscopic procedures 54 

H2-receptor antagonists 

52–53 

laparoscopic techniques 

762–763 

non-pharmacological/ 

non-surgical therapies 49 

prokinetics 49–51 

proton pump inhibitors 53–54 

surgery 54, 586–588 

gastrointestinal bleeding 639–651 

confirmation of 641 

definitions 639–640 

diagnostic investigations 

645–646 

endoscopy 646 

enteroscopy 646 

imaging 645–646 



childhood 643–644 

infancy 643 

neonatal period 642–643 

management and prevention 

646–651 

peptic lesions 647–648 

portal hypertension 649–651 

Meckel’s diverticulum and 

731–732 

ongoing bleeding 640–641 

presentations 639–640 

severity 640 

upper versus lower 


641–642 

with ulcerative colitis 395 

gastrointestinal duplications 24, 

223 

gastrointestinal motility see 

intestinal motility 

gastrointestinal pain response 

214–215 


pain 

gastrointestinal polyps 771–782 

chemoprevention 782 

desmoid disease 781 


777–781 

histopathological classification 

771 


773–774 

juvenile polyps 644, 651, 

771–773 



774–777 

gastropathies 95, 96 

bile reflux 100 


clinical assessment 107 

diagnosis 107, 108 

drug-induced 97–98 

corticosteroids 98 

NSAIDs 97–98, 109 

portal hypertensive 100–101 

stress-related 98–99 



gastroschisis 26 


Gaviscon 52 

genitourinary disorders 223 

giant cell arteritis 429 

Giardia lamblia 163 

gastric infection 97 

life cycle 163–164 

giardiasis 163–165 


diagnosis 165 


impact on growth and 

development 186 



treatment 183, 184, 667 

gliadin peptides 436 

glucagon-like-peptide-2 (GLP-2) 

473 

glucose 

in parenteral nutrition 559–560, 

568–569 

consequences of excessive 

intake 559–560 

optimal glucose/fat ratio 562 

premature infants 622–623, 

635 

in preterm formula 607 

glutamine (Gln) 464, 565, 626–627 

intestinal mucosa protection 

530–531, 565 

gluten sensitivity see celiac disease 

glycosaminoglycans (GAGs) 457, 509 

glycosylation disorders 457 

Gorlin’s syndrome 782 

graft-versus-host-disease (GVHD) 

106–107, 705 

granulomas 


104, 110 

Crohn’s disease 364, 381, 393 

gastritis and 103–104 

mucin granulomas 393 

vasculitides 421 

growth 494 

intestinal parasite impact 

184–186 

nutrition relationships 491–494 

short-bowel syndrome and 471 

growth hormone 472–473 

gut barrier 529 

gut microbiota 201, 202, 529–530 


351 

regulation 

diet type 201–202 

digestive tract motility 

202–203 

gastric acid secretion 202 

ileocecal valve 203 

intestinal mucosal immunity 

203 

see also probiotics; small-bowel 

bacterial overgrowth (SBBO) 

H2-receptor antagonists 647–648 




hair changes in malnutrition 499 

hamartomas 771 

see also gastrointestinal polyps 


appetite 284 


gastroesophageal reflux 286–287 


gastrostomy and 287 

malnutrition and 283, 284 

nutrient deficiencies 

284–285 

nutritional intervention 

285–287 

Hasson technique 762 

heart failure, with malnutrition 

516 


heartburn 40, 45 


disease 

height-for-age 493–495 

Helicobacter heilmannii 95 

Helicobacter pylori infection 

73–90, 220 

associated diseases 80 

clinical aspects 80–81 



dyspepsia and 80–81, 218, 220 


socioeconomic factors 75 


and 42 

immunization 89–90 

lymphocytic gastritis 103 

peptic ulcer disease etiology 

76–77 

mechanisms 78–80 


transmission 75–76


indications for 85–86 

virulence factors 78 

Heller myotomy 67–69 

helminth parasites 

drug treatment 181–184 

mass community 

anthelminthic treatment 184–186 

immune responses 166–167 


development 184–185 


hemangiomas 751, 752, 753–754 

hematemesis 639, 644 

see also gastrointestinal bleeding 

hematochezia 640 


hematocolpos 223 

hematoma, duodenal 686 

hemolytic uremic syndrome (HUS) 

150, 152–154 

hemorrhage see gastrointestinal 

bleeding 


429–430, 457, 645 

hepatitis, celiac disease and 440 

hepatomegaly, in malnutrition 

497–498 

herbal medicines 


228 

diarrhea management 668 

herpes simplex virus (HSV) 



HIV infection and 118 

hiatal hernia, reflux and 43 

high-amplitude propagated 

contractions (HPAPCs) 250 

Hirschsprung’s disease 21–23, 259, 

702 

clinical signs and symptoms 22, 

260 


diagnosis 22, 253, 261–263 


etiology 259 

follow-up 263 

genetic aspects 265–266 

Hirschsprung’s enterocolitis 23, 

260 


prognosis 23, 264 

treatment 22–23, 263 


HIV infection 113–122 

diarrhea 115–117 

HIV enteropathy 117 

host responses and 

susceptibility 116–117 


mucosal structure/function 

and 115–116 


disease progression 114–115 

enteric infections 117–120 

Candida 118–119 

Cryptosporidium parvum 118 

cytomegalovirus 119 

Microsporidia spp 119–120 

rotavirus 119 


esophagitis and 29, 30, 35–37 




in resourced settings 121 

micronutrients 121 

nutrition 121–122 

surgical aspects 122 

terminal care 121 

pancreatitis and 306 

transmission 113–114 

mother-to-child transmission 

114 

homeopathy, diarrhea management 

668 

hookworm 168–170 


diagnosis 169 


life cycle 168–169 



treatment 182, 183, 185 

5-HT (serotonin) 214–215 

5-HT receptors 214–215 

antagonists, abdominal pain 


Hughes syndrome 431 

human astroviruses (HAstVs) 137 

human papillomavirus, esophageal 

infection 35 

hydrocortisone 402 

hydrogen breath test 204–207, 

209, 221, 225 

hydrostatic reduction, 

intussusception 724 

hymenolepiasis 178 

Hymenolepis nana 178 

hyperganglionosis 264, 279 

hypergastrinemia 101 

hyperinsulinemic hypoglycemia 

21 

hypermetabolic states 

enteral nutrition and 544 

hypernatremia 657–658 

hypersensitivity 320 

see also food allergies 

hypertransaminasemia 440 

hypertrophic pyloric stenosis see 

infantile hypertrophic 

pyloric stenosis (IHPS) 

hypnotherapy, abdominal pain 


hypoalbuminemia 451–452 

Index 795 

hypoganglionosis 278–279 

hypoglycemia, in malnutrition 

515, 658 

hypokalemia 658 

hypomotility agents see 

antimotility agents 

hyponatremia 658 

hyposplenism 443 

hypothermia, with malnutrition 

503, 506, 515–516 


hypoxia 283 

IgE responses in food allergy 

337–338 

specific IgE testing 332 

ileal pouch–anal anastomosis 

(IPPA) 383, 405–406 

ileocecal valve 


resection 462 

ileum 



resection 462 

treatment 19 

immune complexes, pathogenetic 

420 

immune response 



351–352 


482–483 

to Cryptosporidium 172–173 

to dietary antigens 336–340 

antigen presentation by 

epithelium 337 

mast cells and eosinophils 

338–339 

skewing of B cells towards 

IgE 337–338 

T-cell responses in oral 

tolerance 339–340 

to helminth parasites 166–167 

to Strongyloides 175 

immunization 

Campylobacter 150 

cholera 147 

enterohemorrhagic E. coli 154 

H. pylori 89–90 

HIV 114 

Norwalk-like viruses 141 

rotavirus 139–141 

typhoid fever 149 

immunoglobulin treatment 

diarrhea management 669 

rotavirus infection 139 

immunosuppressive treatment 703 

immunotherapy 

Crohn’s disease 369–371 

food allergy 340–341 

indeterminate colitis 382

796 

Index 

impedancometry 48 

indeterminate colitis see colitis 

induction therapy 

left-sided colitis/proctitis 

401–402 

mild-to-moderate colitis 

397–400 

moderate-to-severe colitis 

400–401 

infantile hypertrophic pyloric 

stenosis (IHPS) 14, 588–591 


589 







laparoscopic pyloromyotomy 

763, 764 

infectious esophagitis 29–37 

bacterial infections 37 


fungal infections 29–32 

predisposing factors 29 

viral infections 32–37 

infertility, celiac disease and 441 

inflammation 

abdominal pain and 216 


pseudo-obstruction and 276, 

280 

diverticulitis 733 

in malnutrition 500 

pancreatitis 304 

parasitic infection and 167 

Cryptosporidium 172–173 

see also allergic diseases; 

vasculitides 

inflammatory bowel disease (IBD) 

222, 347, 379 

acute abdomen and 681–682, 685 

enteral nutrition and 541–542 




349–351 


extraintestinal manifestations 

394–395 


763–764 


483 


radiological imaging 381 

serologic markers 381 

see also colitis; Crohn’s disease; 

ulcerative colitis 

infliximab 


370–371 

ulcerative colitis treatment 

403–404 

inguinal hernia 591–593 


592 




etiology 592 


treatment 593 

insulin-like growth factor-I (IGF-I) 

472 

interleukin 5 (IL-5) 338–339 

intestinal epithelial dysplasia 6–9, 

702–703 

associated disorders 8 

clinical expression 6 


histological features 6–7 

outcome 9 


transmission 8 

intestinal failure 701, 712–713 


see also intestinal 



452–455 


intestinal malrotation 15, 16, 

19–20, 223 


intestinal microbiota see gut 

microbiota 

intestinal motility 

continuous enteral feeding and 

539–540 

dysmotility 215, 327–328 

gut microbiota regulation 

202–203 


see also visceral myopathy; 

visceral neuropathies 

intestinal neuronal dysplasia (IND) 

264–265, 279 

genetic aspects 266 

intestinal obstruction see 

obstructive lesions 

intestinal parasites 161–163 

abdominal pain and 222 


drug treatment 181–186 

mass community 

anthelminthic treatment 184–186 



development 184–186 


intestinal perforation see 

perforation 

intestinal polyps see 

gastrointestinal polyps 

intestinal pseudo-obstruction see 


pseudo-obstruction (CIP) 

intestinal resection 464 

consequences of 461–463 

associated disorders 462–463 

ileal resection 462 

ileocecal valve resection 462 

jejunal resection 461–462 

small-bowel adaptation 

463–464 

intestinal smooth muscle disorders 

275 

intestinal transplantation 701–713 

clinical results 703–705 

immunosuppressive 

treatment 703 

liver-induced immune 

tolerance 705 

survival 703–704 

combined intestinal and liver 

transplantation 711, 712 

reduced-size composite 

allograft 713 


graft-versus-host-disease 705 

infectious complications 

706–707 

intestinal rejection 705–706 


congenital enteropathies 

702–703 

intestinal motility disorders 

702 


701–702, 712 

intestinal graft function 

707–708 

absorptive function 708 

monitoring 709–710 

motor function 707–708 

living related donors 713 

microvillus inclusion disease 

5–6 

multivisceral transplantation 

713 

nutritional outcome 710 

post-transplant procedures 

708–710 

eating disorders 709 

initial post-transplant period 

708 

initiation of enteral and oral 

feeding 708–709 

monitoring of intestinal 

function 709–710 

parenteral nutrition weaning 

709 

potential candidates 710–713 

contraindications 711 

timing for referral 712–713 

intractable diarrhea of infancy (IDI) 

1

causes 2 


outcomes 2 

see also intestinal epithelial 

dysplasia; microvillus 

inclusion disease 

intractable ulcerating enterocolitis 

1 

intravenous fat emulsions (IVFEs) 

560–564 

fat overload syndromes 

562–563 

fish oil-based emulsions 

563–564 

intravascular metabolism 

561–562 

medium-chain triglycerides 563 

olive oil-based emulsions 564 


structured triglyceride emulsion 

563 


clinical manifestations 

720–721 


barium enema 723–724 


ultrasonography 722–723 


etiopathology 720 


primary idiopathic 720 

secondary/organic 720 


hydrostatic reduction 724 

medical treatment 724 

pneumatic reduction 

724–726 

surgery 726–727 

iron deficiency anemia 

celiac disease 440 


H. pylori infection and 81 

iron requirements, premature 

infants 608–609 

irritable bowel syndrome (IBS) 

213–214, 218, 219 

celiac disease and 443 

pathophysiology 

biopsychosocial model 

217–218 


genetics 217 


visceral hyperalgesia 215 


pain 

isosorbide dinitrate, achalasia 

treatment 66 

Isospora belli 171 

itraconazole, esophagitis treatment 

32, 33 

ivermectin 181, 183 

jejunum 



treatment 19 

resection 461–462 

juvenile dermatomyositis 431 

juvenile polymyositis 431 


773–774 

clinical signs and diagnosis 773 


genetics 773–774 

treatment and follow-up 774 

juvenile polyps 644, 771–773 

polypectomy 651, 773 

Kaposi’s sarcoma 122 

Katayama syndrome 179 

Kawasaki’s disease 429 

ketoconazole, esophagitis treatment 

32, 33 

Klippel–Trénaunay syndrome 755, 

759 

kwashiorkor 496, 508–509 

changes during treatment 

510–511 

specific dermatosis of 522 


D-lactic acidosis 471 

Lactobacillus spp 201, 210, 668 

see also probiotics 

lactose 606 

lactose intolerance 195, 198, 

221–222 

diarrhea and 664–665 

in malnutrition 518 

Ladd’s bands 19 

Ladd’s procedure 767–768 

lamina propria 113–114 

Langerhan’s histiocytosis 455, 456 

lansoprazole 53 

laparoscopy see minimally invasive 

surgery 

laxatives 


226 

constipation management 255, 

256 

leukocytoclastic vasculitis 430 

levamisole 181, 183 

linoleic acid 605 

α-linolenic acid 605 

lipids 

in enteral nutrition 545–546 



clearance of lipid emulsions 

561 

fish oil-based emulsions 

563–564 

lipoprotein interactions 

561–562 

Index 797 

medium-chain triglycerides 

563 

olive oil-based emulsions 

564 

optimal glucose/fat ratio 562 


636 

structured triglyceride 

emulsion 563 

lipoproteins 561 


liver disease 

congenital abnormalities 21 


hepatitis, celiac disease and 420 


parenteral nutrition-related 

571–572, 632–633 

related to short-bowel syndrome 

469–470 


long-chain triglycerides (LCTs) 

605, 629 

lower esophageal sphincter (LES) 

41, 62–63, 65, 584 

transient relaxations (TLESRs) 

41, 42–43 

lymphatic malformations 757–758 

lymphocytic gastritis 101–103 

celiac 102–103 

chronic varioliform 102 

H. pylori 103 

lymphoma 89, 783–784 

lymphonodular hyperplasia (LNH) 

479–486 

assessment 479–480 


differential diagnosis 483–485 

food allergy and 482–483, 485 

histology 480–481 


481–482 


prognosis 486 

symptoms 485–486 

treatment 486 

M cells 113, 114 

magnesium requirement, 


magnetic resonance 

cholangiopancreatography 

(MRCP) 310–314 

magnetic resonance imaging (MRI), 


381 

malabsorption 

bile salts 356 

carbohydrates 116, 203 

in small-bowel bacterial 

overgrowth 203–204, 

208–209 

Mallory–Weiss tear 643

798 

Index 

malnutrition 489–523 


adults 495–496 

children 493–495 


abdominal swelling 500 

anemia 500 

anorexia 498 

bone 499–500 

cheeks 499 

circulation 497 

edema 496–497 

feminization 499 

hair 499 

hepatomegaly 497–498 


mood/behavior 498–499 

skin 499 

splenomegaly 498 


micronutrient deficiencies 

357–358 

diarrhea and 193–194, 195, 

657–658 

drug metabolism and 522–523 

handicapped children 283, 284 

nutrient deficiencies 

284–285 

nutritional intervention 

285–287 

investigations 511 

kwashiorkor (edematous) 496, 

508–509 

changes during treatment 

510–511 

specific dermatosis of 522 


acute phase 512–517 

emotional/psychological 

stimulation 519–520 

preparation for discharge 

520–521 

problems with 521–523, 

567–568 

progress assessment 519 

rehabilitation phase 518–519 

transition phase 517–518 

marasmus 496 

nutritional dwarfism 496 


body composition 503–507 

energy requirement reduction 

500–501 

loss of homeostasis 507–508 

loss of reserve 507 

physiological and metabolic 

changes 501–502, 

504–506 

reduced mass 500–501 

vicious cycles 507 

swallowing disorder and 238 

type I deficiency 490–491 

type II deficiency 491–493 

malrotation see intestinal 

malrotation 

maltodextrin-based oral 


MALToma 89 

manometry 

anorectal 

constipation 254, 262 

Hirschsprung’s disease 261, 

262 

colonic 


272 


esophageal 

achalasia 65, 66 


271 


disease 48, 585–586 

pharyngeal 242–243 

small intestine, chronic 

intestinal pseudo-obstruction 

272–273 

marasmus 496 


mast cells, in food allergy 338–339 

measles 

Crohn’s disease and 350–351 


mebendazole 181–182 

mass community treatment 185 

Meckel’s diverticulum 20–21, 644, 

729–737 




731–732 


intestinal obstruction 

732–733 



histology 730 

management 21, 735–737 

outcomes 737 

pathoembryology 729–730 

predisposing factors 731 

Meckel’s scan 645, 734–735 

meconium ileus 20 

medium-chain triglycerides (MCTs) 

545–546, 563, 605, 629 

megacolon 261 

toxic 395–396, 401, 681, 684 

megacystis microcolon 

hypoperistalsis syndrome 274 

melena 640 


Ménétrier’s disease 99–100 

protein-losing enteropathy and 

456 

treatment 109 

6-mercaptopurine 



402–403 

mesalamine 401, 402 

mesenteric cysts 757–758 

metabolic bone disease 

with Crohn’s disease 359 

methotrexate 



403 


metoclopramide 665–667 


treatment 50 

metronidazole 

amebiasis treatment 183 

Clostridium difficile management 

156 

giardiasis treatment 183 

H. pylori eradication 87 


overgrowth treatment 210 

microbiota see gut microbiota 

Microsporidia spp, HIV infection 

and 118, 119–120, 171 


(MVID) 2–6, 702–703 

clinical expression 2–3 

definitive treatment 5–6 

histological examination 3–4 

outcome 5 



mid-upper-arm circumference 495, 

496 

migraine 

abdominal 218, 219 

cyclic vomiting syndrome and 

294, 295–296, 297 


milk allergy 334 



see also lactose intolerance 

milk protein enteropathy 195–196, 

325 

mineral requirements, premature 

infants 607–609, 630–631 

minimally invasive surgery 

761–768 


background 761 

cholecystectomy 766–767 

chronic abdominal pain 766 




762–763 


763–765 

Ladd’s procedure 767–768 

pyloric stenosis 763

technical considerations 

761–762 

mitochondrial dysfunction 

294–295 

mouth, congenital abnormalities 

13 

mucormycosis 684 

multiple endocrine neoplasia 

277–278 

multiple food allergy 335–336 

multivisceral transplantation 713 

muscular dystrophy 276 

musculoskeletal pain 223 

Mycobacterium, HIV infection and 

118 

mycophenolate mofetil 703 

myenteric (Auerbach’s) plexus 214 

nasogastric tubes 544–545 

in rehydration therapy 661 

Necator americanus 168 


see also hookworm 

necrotizing enterocolitis (NEC) 

177, 579–583, 599 


580–581 






prognosis 583 

risk factors 580 


neonatal esophagogastritis 642 

nephrolithiasis, Crohn’s disease 

and 358 

nifedipine, achalasia treatment 66 

Nissen’s fundoplication 54, 

586–587, 762–763 

nitazoxanide 184 

nitrates, achalasia treatment 66 

nitric oxide (NO) 63, 173, 589 

nitrogen intake 

enteral nutrition 545, 601 

parenteral nutrition 564–565, 

569, 625 

premature infants 601, 625 

nizatidine, gastroesophageal reflux 

disease treatment 52–53 

non-Hodgkin’s lymphoma 783–784 

non-organic failure to thrive 

(NOFTT) 43 

non-steroidal anti-inflammatory 

drugs (NSAIDs) 

gastric injury 97–98, 109 

treatment 109 


350 


role in chemoprevention 782 

Norwalk agent 137 

Norwalk-like viruses (NLV) 

137–138 

vaccine development 141 

NSP4 protein 130–132 

nutrition 489, 525 

diet role in chronic diseases 

527–528 

dietary deficiency 492 


dietary recommendations and 

guidelines 526 

dietary requirements 492 

specific dietary requirements 

of disease 526–527 

early nutrition and later 

consequences 526 

nutritional deficiency see 

malnutrition 

nutritional dwarfism 496 


nutritional therapy 527 



breast feeding 663–664 

diluted or full-strength milk 

or formula 665 

early versus late feeding 663 

lactose-containing versus 

lactose-free feeds 664–665 


see also dietary intervention 

obstructive lesions 15–19, 682 

Ascaris infection 168 


duodenum 16–17 

ileum 17–19 


jejunum 17–19 

Meckel’s diverticulum 732–733 

see also chronic intestinal 

pseudo-obstruction (CIP); 


octreotide 


treatment 54 



variceal bleeding management 

649–650 

olive oil, in parenteral nutrition 564 

omeprazole 648 

gastritis and 106 



oncotic pressure restoration 568 

ondansetron 667 


treatment 51 

oral cavity 235 


oral contraceptives, inflammatory 

bowel disease and 350 

Index 799 

oral rehydration solutions (ORS) 

147, 156, 196, 469, 660–663 

amino acid ORS 662 

amylase resistant starch ORS 

663 

cereal-based ORS 662 

in malnutrition 512, 513 

maltodextrin-based ORS 662 

reduced-osmolarity ORS 662 

scientific background 661–662 

versus intravenous rehydration 

660–661 

ornithine α-keto glutarate (OKG) 

464, 565 

Osler–Weber–Rendu syndrome 

755 

osteopenia 

with celiac disease 440–441 


with ulcerative colitis 395 

osteoporosis 

with celiac disease 440–441 


oxamniquine 181 

pain see functional abdominal pain 

pancreas, congenital abnormalities 

21 

pancreatitis 303–317 

acute 303, 683 

associated conditions 305 


chronic 303 


308 


diagnosis 220, 308–315 

laboratory tests 308–310 

radiographic studies 310–315 


etiology/pathophysiology 

304–308 

anatomic abnormalities 304 

hereditary, metabolic and 

systemic diseases 306–307 

infection 304–306 

medications 307–308 

traumatic causes 304 

hemorrhagic 303 

hereditary 303, 306–307 

necrotic 303 

prognosis 316 

treatment 315 

pangastritis 82 

pantoprazole 53 

parasites see intestinal parasites; 

specific parasites 

Parastrongylus costaricensis 180 

parenteral nutrition (PN) 1, 196, 

555–572, 701 

complications 469, 567–572, 

632–634 

adaptation of intake 570

800 

Index 

body temperature 569 

bone disease 571 

catheter-related sepsis 570, 

633 

glucose homeostasis 568–569 

infection 569, 633 

liver disease 571–572, 

632–633 

micronutrients 569–570 

oncotic pressure restoration 

568 

potassium depletion 569 

protein and energy intake 

569 

refeeding syndrome 567–568 

water and sodium overload 

568 



in clinical practice 557–567 

all-in-one mixture 566–567 

energy requirements 

558–559 

energy sources 559–560 

fat overload syndrome 

562–563 

intravenous fat emulsions 

561–564 

nitrogen sources 564–565 

supplies 558 

vascular access 557–558 

in premature infants 619–636 


nutritional requirements 

619–621 



intestinal epithelial dysplasia 

9 


5 

short-bowel syndrome 461, 

465, 466, 468, 471 

long-term parenteral nutrition 

556–557 

cyclic parenteral nutrition 

556–557 

home parenteral nutrition 

557 

weaning 470, 709 

paromomycin 184 

peanut allergy 335 

pediatric Crohn’s disease activity 

index (PCDAI) 370–372 

peppermint oil (Mentha piperita) 

228 

pepsinogens 77–78 

pepsins 77 

peptic disease (PD) 73, 220 

peptic ulcer disease (PUD) 

clinical aspects 80–81 


corticosteroids and 98 

diagnosis 82, 220 




643, 644 


H. pylori and 73, 78–80 


acid and pepsinogen role 

77–78 

H. pylori-related mechanisms 

78–80 

prognosis 88 


gastrostomy (PEG) 545 

acute abdomen and 685–686 


perforation 15, 682 

bile duct 683 

endoscopic procedures and 

684–686, 768 

following foreign body ingestion 

694–695 

typhoid perforation 683 

perianal lesions, Crohn’s disease 

355–356 

perinuclear antineutrophil 

cytoplasmic antibodies 

(P-ANCA) 361, 381, 390, 421 

periodic acid Schiff (PAS) staining 

3 

peritonitis, HIV infection and 122 

see also acute abdomen 

pernicious anemia 106, 110 

persistent diarrhea 193–211, 658 

HIV relationship 194 


antibiotic therapy 196 

enteral feeding and diet 

selection 197–198 

follow-up and nutritional 

rehabilitation 198 

micronutrient 

supplementation 198 

oral rehydration therapy 196 


risk factors 194–196 

dietary risk factors 195–196 

inappropriate management 

196 


specific pathogens 194–195 




Peutz–Jeghers syndrome 774–777 

clinical features and diagnosis 

774–775 

follow-up 776–777 

genetics 775 

management and complications 

775–776 

Peyer’s patches 529 

pH monitoring, esophageal 47–48, 

225, 585 

pharynx 235 

phosphorus requirement, 


picobirnaviruses 139 

picornaviruses 138–139 

pinworm 178–179 

pirenzipine 53 

pneumatic reduction, 


polyarteritis nodosa (PAN) 427 

polyhydramnios, obstructive 

lesions and 15 

polymyalgia rheumatica 429 

polymyxin, small-bowel bacterial 

overgrowth treatment 210 

polypectomy 651, 771 


polyps see gastrointestinal polyps 

polyunsaturated fatty acids (PUFA) 

533, 605–606, 628–629 

portal hypertension 649–651 

gastropathy 100–101 


endoscopic treatment 

650–651 

prevention of bleeding 650 

potassium requirement, premature 

infants 630 

pouchitis 405, 406–407 

praziquantel 181 

mass community treatment 

184, 185–186 

prebiotics 531 

prednisolone 


366–368 


402 

prednisone, Crohn’s disease 



early adaptive period 599–600, 

620 

enteral nutrition 544, 599–615 

breast milk 610–613 

post-discharge nutrition 

614–615 

preterm formulas 613–614 

intermediate and stable growth 

period 600–610, 620–621 

necrotizing enterocolitis 579, 

599 

nutritional requirements 

600–610, 619–621 

carbohydrates 606–607, 

622–623 

energy requirements 603, 

622 

fluids 600, 621–622, 635 

iron 608–609 

lipids 604–606, 627–629, 636

minerals 607–609, 630–631 

protein 600–603, 623–624, 

635–636 


623 

vitamins 609–610, 631–632 

parenteral nutrition 619–636 



primary sclerosing cholangitis 

(PSC) 395 

probiotics 530, 531 

allergic disease management 

327, 340, 534–535 

diarrhea management 156, 210, 

531, 668 

inflammatory bowel syndrome 


pouchitis management 406–407 


overgrowth management 210 


404 

processus vaginalis 591 

proctitis treatment 401–402 

prokinetics 49–51 


prostaglandin E2 (PGE2) 533 

protein deficiency 490, 509, 565 


protein requirements 492–493 


623–627 

amino acid composition of 


solutions 624–626, 

635–636 

amino acids for special 

purposes 626–627 


623 

protein-losing enteropathy (PLE) 

451–457 

causes 452–457 

defective cellular synthesis 

457 

increased lymphatic pressure 

455 


452–455 

Ménétrier’s disease 456 

mucosal lesions 455 


investigations 452 

proton pump inhibitors (PPIs) 

gastric ulcer treatment 108, 

109, 647–648 

gastritis and 106 




protozoan infections 97 

see also specific protozoans 

protracted diarrhea of infancy 

(PDI) 1 

causes 2 


outcomes 2 

prucalopride 51 

prune belly syndrome 274 

pseudo-obstruction see chronic 

intestinal pseudo-obstruction 

(CIP) 

pseudo-Zollinger–Ellison syndrome 

(PZES) 101 


pseudomembranous colitis (PMC) 

155 

psychotherapy, abdominal pain 


pulmonary aspiration 46, 240 

punctiform keratitis 8 

pyelonephritis 223 

pyloric atresia 8 

pyloric stenosis see infantile 

hypertrophic pyloric stenosis 

(IHPS) 

pyloromyotomy 590–591 

laparoscopic 763, 764 

pyoderma gangrenosum 394 

pyrantel 181, 182 

rabeprazole 53 

racecadotril 668 

radiography 

achalasia 64–65 

acute abdomen 679 



pseudo-obstruction 271 

constipation 253–254 


foreign body ingestion 695 



intussusception 722 

necrotizing enterocolitis 582 

pancreatitis 310–315 

swallowing disorders 241–242 


ranitidine 647–648 



rapamycin 703 

rectovaginal fistula, with HIV 

infection 122 

recurrent abdominal pain (RAP) 

80–81, 213 

see also functional abdomina 

pain 

reduced osmolarity oral 


refeeding syndrome 567–568 

reflux esophagitis 40, 46, 643 


disease 

Index 801 

refractory sprue 444 

regurgitation 39, 44–45 

achalasia and 63–64 



disease 

rehydration therapy 660–663 

oral versus intravenous 

rehydration 660–661 

see also oral rehydration 

solutions (ORS) 

renal solute load (RSL) 600 

respiratory disease 

food allergy and 329 


and 45–46, 585 

swallowing disorder 


RET signalling pathway 265–266 

rhesus rotavirus-tetravalent 

vaccine (RRV-TV) 140 

rheumatoid vasculitis 431–432 

rotavirus 135 

diarrhea and 127, 135–137 

pathophysiology 128–132, 

133 



immunoglobulin treatment 139 


vaccine development 139–141 

virology 136–137 

Salmonella 148–149, 666 


enteric fever 149 


Sapporo-like viruses (SLV) 

137–138 

Sarcocystis hominis 171 

Schistosoma mansoni 179 

schistosomiasis 179–180 


scintigraphy 




Meckel’s diverticulum 734–735 

swallowing evaluation 243 

sclerotherapy 649, 650–651 

secretory leukocyte protease 

inhibitor (SLPI) 114 

selective serotonin re-uptake 

inhibitors (SSRIs) 227 

sepsis 

catheter-related 570, 633 

necrotizing enterocolitis and 

580 

serotonin see 5-HT 

serum amylase evaluation 308, 309 

serum lipase evaluation 308–309 

severe diarrhea requiring 

parenteral nutrition 1

802 

Index 

Shiga-like toxins (SLT) 152–153 

Shigella 149–150, 666 

HIV infection and 118 

shock, in malnutrition 512–513 

short stature, celiac disease and 

440 

short-bowel syndrome 461–474, 

712 

clinical management 464–471 

bacterial overgrowth 468 

dehydration prevention 469 

diet type 467–468 

feeding mode 466–467, 

540–541 

fluid loss adaptation 468 

fluid loss reduction 468–469 

initial surgery 464 

medical therapy 465–466 

parenteral nutrition cycling 

468 

unadapted short small bowel 

472–473 


D-lactic acidosis 471 

liver disease 469–470 

long-term complications 470 

consequences of intestinal 


associated disorders 462–463 

ileal resection 462 

ileocecal valve resection 462 

jejunal resection 461–462 

etiology 465 

follow-up 471 

growth monitoring 471 


small-bowel adaptation after 


pharmacological 

enhancement 472–473 

surgical treatment 473, 701–702 

short-chain fatty acids (SCFA) 464 


404 

sialadenitis 122 

sialorrea 239 

skin changes in malnutrition 499 

skin patch testing 331–332 

skin prick testing 331 

small-bowel adaptation 463–464 

small-bowel bacterial overgrowth 

(SBBO) 201–211, 468 


acute and persistent diarrhea 

208 


208–209 



effects of 204 


in malnutrition 507, 514–515 


treatment 209–211, 468 

see also gut microbiota 

smectite 667–668 

Smith–Lemli–Opitz syndrome 588 

smoking, inflammatory bowel 

disease and 349–350 


sodium, in parenteral nutrition 

568 


somatostatin 649–650 

SOX10 gene 266 

soy allergy 334 

splenomegaly, in malnutrition 498 

stenosis 

esophageal 46 

small bowel 15 

duodenal 16–17 

jejunoileal 17–19 

see also infantile hypertrophic 

pyloric stenosis (IHPS) 

stomach 

bacterial infection 95–97 

see also Helicobacter pylori 

infection 


104, 110 



fungal infection 97 

protozoan infection 97 

viral infection 97 

see also gastritis; gastropathies; 

peptic ulcer disease (PUD) 

stress ulcers 80, 98–99 


stressors 

abdominal pain 216–217 

cyclic vomiting syndrome 291 

stricture 

colonic 396 

esophageal 46 

Strongyloides stercoralis 174 


strongyloidiasis 174–176 



disseminated (hyperinfection) 

175 




treatment 183 

structured triglyceride emulsion 

563 

stunting 494–495 

Sturge–Weber syndrome 755 

submucosal (Meissner’s) plexus 

214 

sucking 236 

sucking disorders 


239 


etiology 233 


sucralfate 54 

sudden infant death syndrome 

(SIDS), H. pylori infection and 

81–82 

sulfasalazine 366, 398–400, 402 

swallowing 236–238 

anatomic considerations 235 

development and 235–238 

swallowing disorders see 

dysphagia 

systemic lupus erythematosus 

(SLE) 430–431 


456–457 

T-cell responses 

in food allergy 337, 339–340 

in vasculitides 421 

tacrolimus 5, 401, 703 

Takayasu’s arteritis 428–429 

tapeworm 178 

tegaserod 51 

Thal procedure 587 

threadworm 178–179 

thromboangiitis obliterans 432 

thromboembolism, inflammatory 

bowel disease and 358–359, 395 

tinidazole 183–184 

tobacco smoking see smoking 

toilet training 250, 255 

toroviruses 138 

total colonic aganglionosis (TCA) 

259 

toxic colitis 681–682 

toxic megacolon 395–396, 401, 

681, 684 

toxic shock 512–513 

tracheoesophageal fistula 13–14 



outcome 14 

treatment 14 

transanal mucosectomy 767 

transdermal nicotine therapy, 


transglutaminase 436 

antibody test 446 

transient lower esophageal 

sphincter relaxations (TLESRs) 

41, 42–43 

trauma, pancreatitis and 304 

Trichostrongylus 180 

trichuriasis 170–171 


diagnosis 171 





treatment 182, 185–186

Trichuris trichiuria 170 

see also trichuriasis 

tricorrhexis nodosa 9 

tricyclic antidepressants (TCA) 

226–227 

Trypanosoma cruzi 280 

tuberculosis 

gastritis 95–97 

intestinal 684 

tufting enteropathy see intestinal 


tumor necrosis factor-α (TNF-α) 

370 

anti-TNF-α agents 370–371 

Turcot’s syndrome 782 

typhoid fever 148, 149 

vaccine 149 

typhoid perforation 683 



388–389 




389–390 

endoscopy 390–392 



epidemiology 385, 386 

etiology/pathogenesis 385–388 


386–387 


extraintestinal manifestations 

394–395 

follow-up 408–409 

pathology 393 


severity 397 


induction therapy 397–402 


764–765 

maintenance therapy 

402–403 

nutritional therapy 404–405 

psychosocial support 407 

surgical therapy 405–407 

see also colitis; inflammatory 

bowel disease (IBD) 

ulcers 

Behçet’s disease 428 

colonic 

amebiasis 177 

Crohn’s disease 363, 364, 

391 

see also ulcerative colitis 

duodenal 76 

esophageal 34–35, 37, 46 

gastric 76 

drug-induced 98 

stress ulcers 80, 98–99 



(PUD) 

ultrasound 

abdominal pain investigation 

224–225 

acute abdomen investigation 

679–680 

appendicitis 744 




pancreas evaluation 310–311 

swallowing disorders 242 

upper esophageal sphincter (UES) 

237–238 

manometric evaluation 242 

uveitis 394 

Vac-A cytotoxin 78 

vaccination see immunization 

variceal bleeding 649–651 


varicella zoster virus (VZV), 

esophageal infection 35 

vascular lesions 751–759 

hemangiomas 753–754 

nomenclature errors 753 

tumors versus malformations 

751–753 

vascular malformations 

754–759 

arteriovenous malformations 

758 

capillary malformations 755 

complex combined 

malformations 758–759 

lymphatic malformations 

757–758 

venous malformations 755–757 



clinical manifestations 421–422 


arteriography 426–427 

endoscopy 425 


imaging studies 425 

laboratory tests 424–425 

physical examination 

423–424 

tissue biopsy 425–426 


follow-up 433 

frequency of intestinal 

involvement 425 

in connective tissue diseases 

430 


antineutrophil cytoplasmic 

antibodies 421 

pathogenetic immunecomplex 

formation 420 

Index 803 

pathogenic T-cell responses 

and granuloma formation 

421 

primary 427–429 


456–457 

secondary 429–432 


see also specific disorders 

vasoactive intestinal polypeptide 

(VIP) 63 

vasopressin 649 

venous malformations 755–757 

diffuse venous malformations 

757 

focal malformations 755–756 

multifocal malformations 

756–757 

Veress needle 762 

very-low-birth-weight (VLBW) 

infants see premature infants 

Vibrio spp 147 

V. cholerae 145–148, 666 

videofluoroscopy 241, 243 

villous atrophy 

diarrhea and 1, 194 

HIV infection 115 

intestinal epithelial dysplasia 6 

microvillus inclusion disease 3 

viral infections 


esophagitis 32–37 



gastritides 97 

see also diarrhea; specific viruses 

visceral hyperalgesia hypothesis 

215 

visceral myopathy 

familial 274–275 

with diffuse abnormal muscle 

layering 273 

infantile 273–274 

primary 273 

visceral neuropathies 276–280 

familial 276–278 

with multiple endocrine 

neoplasia 277–278 

with neurological 

involvement 277 

with neuronal intranuclear 

inclusions 277 

with pyloric stenosis, short 

intestine and malrotation 

277 

without extraintestinal 

manifestations 276–277 

sporadic 278–280 

acquired visceral 

neuropathies 279–280 

chronic inflammation/ 

autoimmune disease 280 

hyperganglionosis 279

804 

Index 

hypoganglionosis 278–279 

infectious agents 280 

intestinal neuronal dysplasia 

279 

vitamin A 

deficiency in malnutrition 515 

diarrhea management 198, 531 

with HIV 121 

intestinal mucosa protection 

531 

vitamin B12 

deficiency in Crohn’s disease 

354 

supplementation following ileal 

resection 470 

vitamin requirements, premature 

infants 609–610, 631–632 

volvulus 15, 16, 19, 223 


vomiting 678–679 

antiemetic treatment 665–667 

obstructive lesions and 15 

infantile hypertrophic pyloric 

stenosis 589 

with diarrhea 133 

see also cyclic vomiting 

syndrome (CVS) 

Waardenburg syndrome 265 

wasting 494–495 

water balance, premature infants 

600, 621–622 

Wegener’s granulomatosis 428 

weight-for height 493–495 

wheat allergy 334–335 

whipworm 170 

see also trichuriasis 

Winiwarter–Buerger’s disease 432 

wireless capsule video-endoscopy 

646 

wireworms 180 

Wyburn–Mason’s syndrome 755 

X-ray see radiography 

Yersinia 150–151, 666 

Z-score 494 

zinc supplementation, diarrhea 

and 195, 198, 669 

Zollinger–Ellison syndrome (ZES) 

101 


zonula occludens toxin (Zot) 147, 

148 

zonulin 436

Helicobacter pylori - Portal Neonatal

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