9. Treatment of Amatoxin Poisoning-20 year retrospective analysis
9. Treatment of Amatoxin Poisoning-20 year retrospective analysis
9. Treatment of Amatoxin Poisoning-20 year retrospective analysis
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ARTICLE<br />
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©<strong>20</strong>02 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission <strong>of</strong> Marcel Dekker, Inc.<br />
Journal <strong>of</strong> Toxicology<br />
CLINICAL TOXICOLOGY<br />
Vol. 40, No. 6, pp. 715–757, <strong>20</strong>02<br />
<strong>Treatment</strong> <strong>of</strong> <strong>Amatoxin</strong> <strong>Poisoning</strong>:<br />
<strong>20</strong>-Year Retrospective Analysis<br />
Françoise Enjalbert,* Sylvie Rapior,<br />
Janine Nouguier-Soulé, Sophie Guillon,<br />
Noël Amouroux, and Claudine Cabot<br />
Laboratoire de Botanique, Phytochimie et Mycologie, Faculté de<br />
Pharmacie, Université Montpellier 1, Montpellier Cedex 5, France;<br />
Laboratoire de Physique Moléculaire et Structurale, UMR-CNRS 5094,<br />
Faculté de Pharmacie, 15 avenue Charles Flahault, BP 14 491, 34093<br />
Montpellier Cedex 5, France; and Centre Anti-Poisons, Hôpital Purpan,<br />
Place du Docteur Baylac, 31059 Toulouse Cedex, France<br />
ABSTRACT<br />
Background: <strong>Amatoxin</strong> poisoning is a medical emergency characterized by a long<br />
incubation time lag, gastrointestinal and hepatotoxic phases, coma, and death. This<br />
mushroom intoxication is ascribed to 35 amatoxin-containing species belonging to<br />
three genera: Amanita, Galerina, and Lepiota. The major amatoxins, the a-, b-, and<br />
g-amanitins, are bicyclic octapeptide derivatives that damage the liver and kidney<br />
via irreversible binding to RNA polymerase II. Methods: The mycology and clinical<br />
syndrome <strong>of</strong> amatoxin poisoning are reviewed. Clinical data from 2108 hospitalized<br />
amatoxin poisoning exposures as reported in the medical literature from North<br />
America and Europe over the last <strong>20</strong> <strong>year</strong>s were compiled. Preliminary medical<br />
care, supportive measures, specific treatments used singly or in combination, and<br />
liver transplantation were characterized. Specific treatments consisted <strong>of</strong><br />
detoxication procedures (e.g., toxin removal from bile and urine, and extracorporeal<br />
purification) and administration <strong>of</strong> drugs. Chemotherapy included<br />
benzylpenicillin or other b-lactam antibiotics, silymarin complex, thioctic acid,<br />
*Corresponding author. Dr. Françoise Enjalbert, Laboratoire de Botanique, Phytochimie et Mycologie, Faculté de Pharmacie,<br />
Université Montpellier 1, 15 avenue Charles Flahault, UM 1/CNRS-UPR A 9056, BP 14 491, 34093 Montpellier Cedex 5, France.<br />
Fax: þ33-467-411-940; E-mail: fenjalbert@ww3.pharma.univ-montp1.fr<br />
715<br />
DOI: 10.1081/CLT-1<strong>20</strong>014646 0731-3810 (Print); 1097-9875 (Online)<br />
Copyright q <strong>20</strong>02 by Marcel Dekker, Inc. www.dekker.com
716<br />
antioxidant drugs, hormones and steroids administered singly, or more usually, in<br />
combination. Supportive measures alone and 10 specific treatment regimens were<br />
analyzed relative to mortality. Results: Benzylpenicillin (Penicillin G) alone and in<br />
association was the most frequently utilized chemotherapy but showed little efficacy.<br />
No benefit was found for the use <strong>of</strong> thioctic acid or steroids. Chi-square statistical<br />
comparison <strong>of</strong> survivors and dead vs. treated individuals supported silybin,<br />
administered either as mono-chemotherapy or in drug combination and Nacetylcysteine<br />
as mono-chemotherapy as the most effective therapeutic modes.<br />
Future clinical research should focus on confirming the efficacy <strong>of</strong> silybin, Nacetylcysteine,<br />
and detoxication procedures.<br />
Key Words: Amanita; <strong>Amatoxin</strong>s; Galerina; Lepiota; <strong>Poisoning</strong>; <strong>Treatment</strong><br />
INTRODUCTION<br />
The hunting and eating <strong>of</strong> wild higher fungi is a<br />
traditional activity in many European countries and has<br />
become an increasingly popular pastime in the United<br />
States. Despite warnings on the risks <strong>of</strong> eating wild<br />
mushrooms, collectors continue to confuse edible and<br />
toxic species. There are few data defining the number <strong>of</strong><br />
worldwide mushroom exposures; [1 – 11] but poisonings are<br />
a relatively common medical emergency. Among severe<br />
mushroom intoxications, the amatoxin syndrome is <strong>of</strong><br />
primary importance because it accounts for about 90% <strong>of</strong><br />
fatality. [12]<br />
<strong>Amatoxin</strong> poisoning is characterized by a long<br />
asymptomatic incubation delay (from 6 to 12 hours)<br />
and three clinical phases. The first phase, or gastrointestinal<br />
phase (12–24 hours), consists <strong>of</strong> cholera-like<br />
diarrhea, vomiting, abdominal pain, and dehydration.<br />
During the second phase, or hepatotoxic phase (24–<br />
48 hours), clinical signs and biochemical evidence <strong>of</strong><br />
hepatic damage leading to a progressive and irreversible<br />
coagulopathy appear. With the development <strong>of</strong> hepatorenal<br />
syndrome (third phase), hemorrhages, convulsions,<br />
and fulminant hepatic failure (FHF) occur resulting in<br />
coma and death (4–7 days). Symptoms and clinical<br />
course <strong>of</strong> amatoxin-containing mushroom poisoning<br />
have been thoroughly reported. [13 – 23] Damage to the<br />
liver is characterized by massive centrilobular necrosis,<br />
vacuolar degeneration, and a positive acid–phosphatase<br />
reaction. The kidney shows signs <strong>of</strong> acute tubular<br />
necrosis and hyaline casts in the tubules. [24]<br />
<strong>Amatoxin</strong> poisoning is caused by mushroom species<br />
belonging to three genera, Amanita, Galerina, and<br />
Lepiota [12,25,26] with the majority <strong>of</strong> lethal mushroom<br />
exposures attributable to Amanita species. Some<br />
Amanitas contain two major groups <strong>of</strong> toxins, amatoxins,<br />
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and phallotoxins. Both are bicyclic peptides composed <strong>of</strong><br />
an amino acid ring bridged by a sulfur atom. The<br />
chemical structures <strong>of</strong> nine amatoxins have been<br />
elucidated as bicyclic octapeptide derivatives; the major<br />
ones are the a-, b-, and g-amanitins (a-Ama, b-Ama, g-<br />
Ama). The three amanitins are also present in some<br />
Galerina and Lepiota species responsible for deceased<br />
persons. Phallotoxins, detected only in Amanita species,<br />
have only slight absorption after oral administration and<br />
should not contribute to amatoxin poisoning.<br />
Enjalbert et al.<br />
[27 – 31]<br />
The molecular mechanism <strong>of</strong> toxicity has been<br />
studied in detail. <strong>Amatoxin</strong>s bind with eukaryotic<br />
DNA-dependent RNA polymerase II, and inhibit the<br />
elongation essential to transcription. Pharmacokinetic<br />
studies have shown that amatoxins use the physiological<br />
transport system for biliary acids to reach the liver, the<br />
site <strong>of</strong> irreversible binding to RNA polymerase II.<br />
Enterohepatic circulation perpetuates high toxin concentration<br />
in the hepatocytes. [32,33]<br />
Our survey based on the literature over the last two<br />
decades lists 2108 detailed cases <strong>of</strong> amatoxin poisoning<br />
from North America and Europe. <strong>Treatment</strong> strategies<br />
were characterized as preliminary medical care, supportive<br />
measures, and specific therapies. Specific therapies<br />
included toxin removal from the digestive, biliary, and<br />
urinary systems, and blood as well as the administration<br />
<strong>of</strong> drugs. Experimental investigations and hypotheses<br />
concerning the hepatoprotective properties <strong>of</strong> each<br />
therapeutic modality justifying its use in human<br />
amatoxin intoxication were also described. The use <strong>of</strong><br />
liver transplantation (LT) in amatoxin-induced FHF was<br />
also characterized as a specific therapy among this<br />
<strong>retrospective</strong> patient group.<br />
The aim <strong>of</strong> this review is a critical <strong>analysis</strong> <strong>of</strong> the<br />
different treatments that were applied to amatoxin<br />
poisoned patients by determining for each therapeutic
mode its use and its efficacy. Two complementary<br />
statistical analyses were carried to compare the number<br />
<strong>of</strong> survivors and dead for each group <strong>of</strong> patients, which<br />
received a particular mode <strong>of</strong> therapy, liver transplant<br />
cases being either included as fatalities or excluded from<br />
each analyzed series. These data enabled a classification<br />
<strong>of</strong> therapeutic modalities based on relatively effective,<br />
ineffective, or unproven asset.<br />
AMATOXIN-CONTAINING MUSHROOM<br />
SPECIES<br />
According to the currently available literature,<br />
[12,25,26,34] 35 species belonging to the genera<br />
Amanita, Galerina, and Lepiota contain amatoxins.<br />
There is agreement on amatoxin-containing Amanita and<br />
Galerina species but the occurrence <strong>of</strong> amatoxins in<br />
some species <strong>of</strong> Lepiota genus is uncertain.<br />
In the genus Amanita, the nine amatoxin-containing<br />
mushrooms are (1) Amanita phalloides (Fr.) Secr. [26] and<br />
the related species, the so-called “deadly white Amanita<br />
species,” (2) A. bisporigera Atk., (3) A. decipiens<br />
(Trimbach) Jacquetant, (4) A. hygroscopica Coker, (5) A.<br />
ocreata Peck, (6) A. suballiacea Murr., (7) A. tenuifolia<br />
Murr., (8) A. verna (Bull.:Fr.) Lamarck, and (9) A. virosa<br />
(Lamarck) Bertillon. [12,25,26,34] A. magnivelaris Peck was<br />
suspected <strong>of</strong> containing amatoxins since intoxications<br />
with a 24-hour latency, liver failure, and hepatic necrosis<br />
were reported for patients from Guatemala and Rhode<br />
Island. [35,36] However, amatoxins have never been<br />
detected in the mushroom tissue. [25,37]<br />
In the genus Galerina, nine amatoxin-containing<br />
species are reported: (1) G. autumnalis (Pk.) Sm. and<br />
Sing., (2) G. badipes (Fr.) Kühn., (3) G. beinrothii Brsky,<br />
(4) G. fasciculata Hongo, (5) G. helvoliceps (Berk. and<br />
Curt.) Sing., (6) G. marginata (Batsch) Kühner, (7) G.<br />
sulciceps (Berk.) Boedjin, [38] (8) G. unicolor (Fr.) Sing.,<br />
[12,26,34,39 – 41]<br />
and (9) G. venenata A. H. Smith.<br />
In the mycological literature on Lepiotas,<br />
[12,25,26,42 – 45]<br />
24 species are presumed to be amatoxin-producing mushrooms<br />
and listed alphabetically as follows. The asterisk<br />
indicates those 16 Lepiota species in which amatoxins<br />
[46 – 49]<br />
were detected by thin layer chromatography.<br />
L. brunneoincarnata Chodat and Martin*<br />
L. brunneolilacea Bon and Boiffard*<br />
L. castanea Quélet*<br />
L. citrophylla (Berk. and Br.) Sacc.<br />
L. clypeolaria (Bull.:Fr.) Kummer [42]<br />
L. clypeolarioides Rea*<br />
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<strong>Amatoxin</strong> <strong>Treatment</strong> 717<br />
L. felina (Pers.:Fr.) Karsten*<br />
L. fulvella Rea* [43] (by semiquantitative Meixner<br />
test [50,51] )<br />
L. fuscovinacea Moeller and Lange<br />
L. griseovirens Maire*<br />
L. heimii Locq.*<br />
L. helveola Bres.*<br />
L. helveoloides Bon ex Bon and Andary<br />
L. josserandii Bon and Boiffard*<br />
L. kuehneri Huijsm. ex Hora*<br />
L. langei Locq.*<br />
L. lilacea Bres. [44]<br />
L. locanensis Espinosa<br />
L. ochrace<strong>of</strong>ulva Orton*<br />
L. pseudohelveola Kühner ex Hora*<br />
L. pseudolilacea Huijsm. [45]<br />
L. rufescens Lge. [44]<br />
[47 – 49]<br />
L. subincarnata Lge.*<br />
L. xanthophylla Orton* [46]<br />
Although a-Ama was detected in North American<br />
Pholiotina (Conocybe) filaris Fr., [52] investigations <strong>of</strong><br />
German collections <strong>of</strong> this species and other Pholiotinas<br />
reported the amatoxins neither in the mushrooms nor in<br />
cases <strong>of</strong> hepatotoxic poisoning. [12] The available<br />
information thus identifies 35 species containing<br />
amatoxins (10 Amanitas, 9 Galerinas, and 16 Lepio-<br />
[46 – 49,51]<br />
tas.<br />
OCCURRENCE OF AMATOXIN<br />
POISONING<br />
<strong>Amatoxin</strong>-containing species and, consequently,<br />
[53 – 56]<br />
amatoxin poisonings occur worldwide: Africa,<br />
America, [25,26,35,57,58] Asia, [46,59 – 66] Europe, [12,67,68] and<br />
Oceania. [63,69 – 71] Given the few reports <strong>of</strong> the amatoxin<br />
syndrome from the African, Asian, and Oceanian<br />
continents, [55,60,61,69,70,72] our review focused on human<br />
cases (Tables 1–6) from North American and European<br />
countries. [73 – <strong>20</strong>4] The sites include the Canadian<br />
province Ontario, [97] Mexico, [35,78,84,85] and 21 different<br />
U.S. states namely Alabama, [89] Arkansas, [93] California,<br />
[42,74,79,90,93,102,109,119,1<strong>20</strong>,151,193,<strong>20</strong>5 – <strong>20</strong>7] Florida, [112]<br />
Georgia, [91,118] Indiana, [132] Kansas, [<strong>20</strong>8] Kentucky, [<strong>20</strong>9]<br />
Michigan, [108,199,<strong>20</strong>9] Minnesota, [122] Mississippi, [118]<br />
Missouri, [118,141] New Jersey, [73,139,<strong>20</strong>5,<strong>20</strong>9] New<br />
York, [93,140,<strong>20</strong>0,<strong>20</strong>6,<strong>20</strong>8] Ohio, [36,<strong>20</strong>7] Oregon, [<strong>20</strong>6,<strong>20</strong>9] Pennsylvania,<br />
[124] Rhode Island, [36,104,<strong>20</strong>6] Virginia, [<strong>20</strong>8]<br />
Washington, [<strong>20</strong>7] and Wisconsin [178] as well as 22<br />
European countries namely Austria, [127,128] Belgium,<br />
[168,190] Bulgaria, [179,210,211] Croatia, [117] Czech
718<br />
Republic, [105,157] Denmark, [154,165,<strong>20</strong>2] Finland, [95,106,<br />
152] France, [75,80,86,103,121,136 – 138,146,148,169,191,192,194 –<br />
198,212] Germany, [87,88,130,133,155,156,163,164,166,167,<strong>20</strong>1]<br />
Hungary, [<strong>20</strong>3,<strong>20</strong>4,213]<br />
Italy, [76,83,92,94,96,100,111,116,125,126,<br />
131,143 – 145,147,161,176,177,181,185,186]<br />
the Netherlands, [159]<br />
Norway, [153] Poland, [99,170 – 173,175,214] Portugal, [162] Slovak<br />
Republic, [113,114,129,160,180,215] Slovenia, [110,174]<br />
Spain, [43,50,77,98,115,182 – 184,187 – 189] Sweden, [101,149]<br />
Switzerland, [158,216,217] Turkey, [81,82,107,134,135,142] and<br />
United Kingdom. [123]<br />
The amatoxin poisoning cases found in the literature<br />
were divided into three groups. The first group comprised<br />
2108 amatoxin poisoning cases that were adequately<br />
documented by hospital reports with detailed therapeutic<br />
information including 32 LTs (Tables 1–6). A second<br />
[11,36,89,93,97,108,118,199,<strong>20</strong>5 –<br />
group from North American<br />
<strong>20</strong>9,218,219] [24,103,111,136,142,160,181,<br />
and European sources<br />
212 – 217,2<strong>20</strong>]<br />
consisted <strong>of</strong> 169 amatoxin poisonings that<br />
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Table 1<br />
<strong>Amatoxin</strong> <strong>Poisoning</strong> Cases Treated with Supportive Measures Alone with/without Liver Transplant<br />
Enjalbert et al.<br />
Date/Country T/E Cases Mushroom LT Survivors References<br />
1981 New York 1/3 a.sp 0 1 [73]<br />
1981 California 1/10 A.ph 0 0 [74]<br />
1981 California 4/10 a.sp 0 3 [74]<br />
1982 France 1/1; child G.mar 0 0 [75]<br />
1982 Italy 2/2 L.bi 0 1 [76]<br />
1983–1986 Spain 7/85 a.sp 0 7 [43,50]<br />
1986 Spain 1/3 L.bi 0 1 [77]<br />
1987 Guatemala 19/19; (children) A.mag 0 11 [35]<br />
1987 Mexico 8/8; 2 children A.vi 0 6 [78]<br />
1988 California 4/4 A.ph 0 0 [79]<br />
1988 France 1/1; child A.ph 1 1 [80]<br />
1988 Turkey 11/11; 8 children L.hel 0 0 [81]<br />
1988 Turkey 3/27 L.cas, L.hel 0 2 [82]<br />
1990 Italy 1/2 L.bi 0 1 [83]<br />
1990 Mexico 7/7 A.vi 0 2 [84,85]<br />
1992 France 1/3 L.bi 0 1 [86]<br />
1992 France 2/3; 1 child L.bi 2 2 [86]<br />
1992 Germany 2/3 A.ph 0 1 [87]<br />
1992 Germany 1/3; child A.ph, amat 1 1 [87]<br />
1994 Germany 9/12 A.ph 0 9 [88]<br />
1996 Alabama 1/4; child A.ve 0 0 [89]<br />
1997 California 1/4 a.sp 0 1 [90]<br />
1997 Georgia 1/1 A.ph 1 1 [91]<br />
1998 Italy 1/1 A.ph 1 1 [92]<br />
1999 Arkansas 1/1 A.bis 0 1 [93]<br />
T/E Cases ¼ treated/exposed individuals; LT ¼ liver transplant; amat ¼ amatoxins in biological fluids; a.sp ¼ amatoxin-containing species;<br />
A.bis ¼ Amanita bisporigera; A.mag ¼ A. magnivelaris; A.ph ¼ A. phalloides; A.ve ¼ A. verna; A.vi ¼ A. virosa; G.mar ¼ Galerina marginata;<br />
L.bi ¼ Lepiota brunneoincarnata; L.cas ¼ L. castanea; L.hel ¼ L. helveola; undefined cases are reported in brackets.<br />
were cited in clinical reports but had no treatment<br />
information. A third group contained cases <strong>of</strong> mushroom<br />
exposures reported only as “cyclopeptide intoxication<br />
with hepatotoxic effects” and with incomplete clinical<br />
data. [3 – 9,11,210,211,221] The majority <strong>of</strong> the cases in the<br />
second and third groups were either mildly intoxicated or<br />
asymptomatic individuals who shared the poisoned meal<br />
and did not necessarily require hospital admission. Only<br />
the cases in the first group were included in the data<br />
<strong>analysis</strong>.<br />
Of the 35 amatoxin-containing species, 14 were<br />
responsible for most <strong>of</strong> the intoxications listed in Tables<br />
1–6: A. bisporigera, A. magnivelaris, A. ocreata,<br />
A. phalloides, A. verna, A. virosa, G. autumnalis, [<strong>20</strong>8]<br />
G. marginata, L. brunneoincarnata, L. brunneolilacea,<br />
L. castanea, L. fulvella, L. helveola, and L. josserandii.<br />
The small number <strong>of</strong> species identified may be an artifact<br />
<strong>of</strong> incomplete information; in less than 5% <strong>of</strong> the
Table 2<br />
<strong>Amatoxin</strong> <strong>Poisoning</strong> Cases Treated with Detoxication Procedures with/without Liver Transplant<br />
<strong>Treatment</strong>s<br />
Detoxication<br />
Date/Country T/E Cases Mushroom Oral C/GA Urin. FD ECP HD–HP/ PL LT Surv. References<br />
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<strong>Amatoxin</strong> <strong>Treatment</strong> 719<br />
1975–1990 Italy 93/93; children a.sp 0/0 93 0–0/0 0 86 [94]<br />
1978 Finland 2/2 G.mar 0/0 2 0–0/0 0 2 [95]<br />
1981 California 3/10 a.sp 3/0 0 0–0/0 0 3 [74]<br />
1981 Italy 1/1; pregnant A.ph, amat 0/0 1 0–0/1 0 1 [96]<br />
1982 Canada 1/2 A.bis, A.vi 0/0 0 1–1/1 0 1 [97]<br />
1982 Canada 1/2 A.vi 0/0 0 1–0/0 0 0 [97]<br />
1982 Spain 2/8 A.ph 0/0 0 0–0/2 0 2 [98]<br />
1982–1983 California 11/21 a.sp 11/0 0 0–0/0 0 11 [42]<br />
1982–1983 California 4/21 A.o, amat 4/0 0 0–0/0 0 4 [42]<br />
1982–1983 California 1/21; child A.ph, amat 1/0 0 0–0/0 0 1 [42]<br />
1982–1986 Poland 7/7 A.ph 0/0 0 0–0/7 0 4 [99]<br />
1982–1991 Italy 2/8; 1 child A.ph 0/0 0 0–0/2 0 1 [100]<br />
1983–1986 Sweden 93/93 A.ph, A.vi, a.sp, amat 0/0 93 93–93/0 0 93 [101]<br />
1988 Turkey 3/27; 1 child L.cas, L.hel 3/0 0 0–0/0 0 3 [82]<br />
1988 Turkey 6/27; children L.cas, L.hel 0/0 0 6–0/0 0 0 [82]<br />
1989 California 2/2 A.ph 2/2 0 2–0/0 2 2 [102]<br />
1990 France 1/1 A.ph 0/0 0 1–0/0 1 1 [103]<br />
1990 Rhode Island 1/1 A.vi 1/0 0 0–0/0 0 0 [104]<br />
1990–1991 Czech 35/35 A.ph 0/0 0 0–35/0 0 28 [105]<br />
1990–1991 Czech 38/38 a.sp 0/0 0 0–38/0 0 38 [105]<br />
1991–1999 Italy 6/8 A.ph 0/0 0 0–0/6 1 6 [100]<br />
1994 Finland 1/1 A.vi 0/0 0 1–0/0 1 1 [106]<br />
1994–1995 Turkey 52/60 A.ph 0/0 0 0–52/0 0 52 [107]<br />
1994–1995 Turkey 8/60 A.ph 0/0 0 8–0/0 0 4 [107]<br />
1995 Michigan 1/1 A.vi 1/0 0 0–0/0 0 1 [108]<br />
1996 Alabama 3/4 A.ve 3/0 0 0–0/0 0 3 [89]<br />
1996–1997 California 2/10 A.ph, a.sp 1/0 0 2–0/0 0 0 [109]<br />
1997 California 1/4 a.sp 0/0 0 1–0/0 0 0 [90]<br />
1997 Slovenia 1/1; child a.sp 0/0 1 0–0/1 0 0 [110]<br />
1998 Italy 2/2 a.sp 0/0 0 2*–2/0 0 2 [111]<br />
<strong>20</strong>00 Florida 1/1 a.sp 1/0 0 0–0/0 1 1 [112]<br />
T/E Cases ¼ treated/exposed individuals; Oral ¼ oral detoxication using C ¼ activated charcoal and GA ¼ gastroduodenal aspiration; Urin. ¼ urinary detoxication by FD ¼ forced diuresis;<br />
ECP ¼ extra-corporeal detoxication including * ¼ continuous venovenous hem<strong>of</strong>iltration, HD ¼ hemodialysis, HP ¼ hemoperfusion, and PL ¼ plasmapheresis; LT ¼ liver transplant;<br />
Surv. ¼ survivors; amat ¼ amatoxins in biological fluids; a.sp ¼ amatoxin-containing species; A.bis ¼ Amanita bisporigera; A.o ¼ A. ocreata; A.ph ¼ A. phalloides; A.ve ¼ A. verna;<br />
A.vi ¼ A. virosa; G.mar ¼ Galerina marginata; L.cas ¼ Lepiota castanea; L.hel ¼ L. helveola.
7<strong>20</strong><br />
Table 3<br />
<strong>Amatoxin</strong> <strong>Poisoning</strong> Cases Treated with Mono-chemotherapy, with/without Detoxication Procedures and with/without Liver Transplant<br />
<strong>Treatment</strong>s<br />
Detoxication<br />
Date/Country T/E Cases Mushroom Drugs Oral C/GA Urin. FD ECP HD–HP/PL LT Surv. References<br />
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1988 Turkey 1/27; child L.cas, L.hel 1ATB 0/0 0 1–0/0 0 0 [82]<br />
1971–1995 Slovak Republic 103/103; 14 children A.ph, a.sp B.pen 0/0 (FD) (HD–HP)/0 0 95 [113,114]<br />
1981 Spain 2/2 A.ph B.pen 0/2 0 2–0/0 0 2 [115]<br />
1982 Spain 6/8 A.ph B.pen 0/0 0 0–0/6 0 5 [98]<br />
1982–1986 Spain 13/85; 1 child 5 A.ph, 2 A.ve, 3 L.bi, B.pen 2/2 9 0–1/2 0 12 [43,50]<br />
3 a.sp; amat<br />
1986 Spain 2/3 L.bi B.pen 0/0 0 0–0/0 0 2 [77]<br />
1986–1989 Italy 12/12 A.ph B.pen 12/0 0 12–0/0 0 9 [116]<br />
1988 Croatia 18/18; (children) A.ph B.pen 18/18 18 2–0/16 0 14 [117]<br />
1991 Ohio 1/1 G.sp B.pen 1/0 0 0–0/0 0 1 [36]<br />
1994 Missouri 2/2 A.bis B.pen 0/0 0 0–0/0 0 1 [118]<br />
1996 California 3/3 A.ph B.pen 0/0 0 0–0/0 1 a<br />
3 [119,1<strong>20</strong>]<br />
1998 France 1/1 A.ph B.pen 1/0 0 0–0/0 0 1 [121]<br />
1998 Minnesota 1/1; child A.vi B.pen 1/0 0 0–0/0 0 1 [122]<br />
1982 U.K. 2/2 A.ph Cimetid 0/0 0 0–2/0 0 0 [123]<br />
1999 Pennsylvania 1/6 a.sp Cimetid 1/0 0 0–0/0 0 1 [124]<br />
1987–1993 Italy 86/86 A.ph NAC 86/0 86 0–0/0 0 80 [125]<br />
1994 Italy 1/1; pregnant A.ph, amat NAC 1/0 1 0–0/1 0 1 [126]<br />
1996–1997 California 1/10 A.ph NAC 1/0 0 0–0/0 0 1 [109]<br />
1997 California 1/4 a.sp NAC 1/0 0 0–0/0 0 1 [90]<br />
1980–1986 Europe 25/252 A.ph, a.sp Silybin 0/0 (FD) (HD–HP)/0 0 24 [127,128]<br />
1991–1999 Slovak Republic <strong>20</strong>/<strong>20</strong>; (children) A.ph, a.sp Silybin <strong>20</strong>/0 <strong>20</strong> 0–0/0 0 <strong>20</strong> [129]<br />
1993 Germany 26/154 a.sp Silybin 0/0 0 0–0/0 0 26 [130]<br />
1994 Germany 3/12 A.ph Silybin 0/0 0 0–0/0 3 2 [88]<br />
1981 California 1/10 A.ph Steroid 0/0 0 0–0/0 0 1 [74]<br />
1982–1983 California 2/21 a.sp, amat Steroid 2/0 0 0–2/0 0 0 [42]<br />
1982–1983 California 3/21 a.sp Steroid 3/0 0 0–0/0 0 3 [42]<br />
1988 Turkey 1/27 L.cas, L.hel Steroid 0/0 0 0–0/0 0 1 [82]<br />
1997 Italy 1/1 A.ph Steroid 0/0 0 0–0/1 0 1 [131]<br />
1981 New York 2/3 a.sp Thioc.a 0/0 0 1–0/0 0 2 [73]<br />
1981 California 1/10 a.sp Thioc.a 0/0 0 0–0/0 0 0 [74]<br />
1982 Indiana 1/1 A.vi Thioc.a 0/0 0 0–0/0 0 1 [132]<br />
1982–1986 Spain 4/85; 1 child A.ph, amat Thioc.a 2/3 3 0–2/0 0 4 [43,50]<br />
Enjalbert et al.<br />
T/E Cases ¼ treated/exposed individuals; Oral ¼ oral detoxication using C ¼ activated charcoal and GA ¼ gastroduodenal aspiration; Urin. ¼ urinary detoxication by FD ¼ forced diuresis;<br />
ECP ¼ extra-corporeal detoxication including HD ¼ hemodialysis, HP ¼ hemoperfusion, and PL ¼ plasmapheresis; LT ¼ liver transplant; Surv. ¼ survivors; amat ¼ amatoxins in<br />
biological fluids; undefined cases are reported in brackets.<br />
Drugs: ATB ¼ antibiotic agent; B.pen ¼ benzylpenicillin; Cimetid ¼ cimetidine; NAC ¼ N-acetylcysteine; Thioc.a ¼ thioctic acid.<br />
a.sp ¼ amatoxin-containing species; A.bis ¼ Amanita bisporigera; A.ph ¼ A. phalloides; A.ve¼A. verna; A.vi ¼ A. virosa; G.sp ¼ Galerina species; L.bi ¼ Lepiota brunneoincarnata;<br />
L.cas ¼ L. castanea; L.hel ¼ L. helveola.<br />
a<br />
Auxiliary liver transplant.
poisoning cases is the mushroom species actually<br />
identified. [222] When the species attribution is uncertain<br />
the onset <strong>of</strong> clinical symptoms may be a useful indicator<br />
<strong>of</strong> potential amatoxin ingestion.<br />
<strong>Amatoxin</strong> exposures were more frequently caused by<br />
A. phalloides in Central and Southern Europe, A. virosa<br />
in Northern Europe, and A. phalloides and related deadly<br />
white Amanitas in North America. Unidentified amatoxin-containing<br />
species caused 21% <strong>of</strong> poisonings and<br />
are listed as a.sp. in Tables 1–6.<br />
STATISTICAL ANALYSIS<br />
An overall table (189 rows, 12 columns) was<br />
constituted from Tables 1–6 with the actual or coded<br />
values <strong>of</strong> the following parameters: date; country; modes<br />
<strong>of</strong> care, number <strong>of</strong> exposed individuals and treated<br />
patients; number and percentage <strong>of</strong> survivors and<br />
nonsurvivors; mushroom or mixture <strong>of</strong> mushrooms;<br />
single drug or drug combination; and LTs. A general<br />
frequency table was constructed <strong>of</strong> the observed<br />
frequencies for each mode <strong>of</strong> care. Eleven modes <strong>of</strong><br />
care had a sufficient representation for <strong>analysis</strong>: one<br />
treatment mode (supportive measures alone, Table 1) and<br />
10 specific treatments: detoxication procedures (Table 2)<br />
and nine chemotherapies from Tables 3–6 (monochemotherapies:<br />
benzylpenicillin, N-acetylcysteine<br />
(NAC), silybin; bi-chemotherapies: benzylpenicillin/<br />
antioxidant drug, b-lactam antibiotic (benzylpenicillin<br />
or ceftazidime)/silybin, benzylpenicillin/steroid, benzylpenicillin/thioctic<br />
acid; and tri- and poly-chemotherapies:<br />
benzylpenicillin combinations with any before<br />
mentioned drug, with or without silybin).<br />
Due to small numbers <strong>of</strong> treated victims, 13 other<br />
specific chemotherapies were not analyzed: monochemotherapy<br />
with cimetidine, vitamin C, thioctic acid,<br />
steroid or antibiotic agent (<strong>20</strong> cases from Table 3); and<br />
bi-, tri-, and poly-chemotherapies with silybin/thioctic<br />
acid, antibiotic/antiseptic/vitamin C, steroid/thioctic<br />
acid/vitamin C, antibiotic/thioctic acid/vitamin C, two<br />
antibiotics/steroid, two antibiotics/NAC, antiseptic/silybin/steroid/vitamin<br />
C and three antibiotics/steroid (26<br />
cases from Tables 5 and 6).<br />
Outcome without surgery for the 32 cases who received<br />
liver transplant (LT . 0) combined with one or more from<br />
the 11 analyzed therapeutic modes cannot be known.<br />
Therefore, in order to assess the effectiveness <strong>of</strong> the<br />
nontransplant therapies in preventing the fatal stage <strong>of</strong> the<br />
disease, statistical analyses were performed both with and<br />
without the transplanted cases. The suffixes LTi and LTe<br />
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<strong>Amatoxin</strong> <strong>Treatment</strong> 721<br />
were added to all numbers, percentages, and probabilities<br />
listed or calculated including or excluding the LT cases,<br />
respectively. For each observation (line <strong>of</strong> the general<br />
table) with LT . 0, the number <strong>of</strong> treated patients,<br />
survivors, and deceased persons were corrected as follows:<br />
(i) for mortality rate excluding the transplant cases<br />
(MRLTe), the LT cases were removed from the data set,<br />
i.e., both treated patient and survivor numbers were<br />
decreased by the number <strong>of</strong> transplants, (ii) for mortality<br />
rate including the transplant cases (MRLTi), each LT<br />
patient was considered as a deceased person; only survivor<br />
numbers were decreased by the number <strong>of</strong> transplants.<br />
Complementary statistical analyses were carried out<br />
for <strong>20</strong>62 LTi patients (2108 victims minus 46<br />
nonanalyzed-treatment cases) and <strong>20</strong>31 LTe cases<br />
(<strong>20</strong>62 victims minus 31 LT cases); one LT case was in<br />
an unanalyzed mode <strong>of</strong> care.<br />
The global performance evaluation <strong>of</strong> each therapeutic<br />
mode was achieved by a statistical comparison <strong>of</strong><br />
the number <strong>of</strong> survivors and nonsurvivors using a Chisquare<br />
calculation from the two rows (survivors,<br />
fatalities) and six columns (six tables) contingency<br />
table. The effect <strong>of</strong> each mode <strong>of</strong> care was studied by<br />
comparison <strong>of</strong> survivor and dead numbers in the 2 £ 2<br />
tables constituted from the general table.<br />
The Chi-square test applied to the general frequency<br />
tables rejected the hypothesis that outcome and treatment<br />
were independent; the distribution <strong>of</strong> survivors and<br />
deceased persons was statistically different for Tables<br />
1–6, both including and excluding the LT patients. When<br />
the p-value was #0.05, the null hypothesis was rejected<br />
at the 95% confidence level. The Yates’ correction was<br />
applied when the number <strong>of</strong> survivors or deceased<br />
patients was #5, and the Fischer’s exact test was<br />
calculated in the case <strong>of</strong> contingency table 2 £ 2 with<br />
less than 100 observations. The statistical <strong>analysis</strong> was<br />
carried out using STATGRAPHICS w PLUS s<strong>of</strong>tware<br />
version 3.3 (Manugistics, Inc., Rockville, MD, USA).<br />
DESCRIPTION OF TREATMENTS<br />
The management <strong>of</strong> amatoxin poisoning involves four<br />
main categories <strong>of</strong> therapy: preliminary medical care,<br />
supportive measures, specific treatments, and LT. Since<br />
there is a relative consensus <strong>of</strong> opinion about<br />
the preliminary medical care and supportive<br />
measures, [14,18 – <strong>20</strong>,23,223 – 228] only their major features<br />
are described. The specific treatments consisting <strong>of</strong><br />
detoxication procedures, chemotherapies, and LT are<br />
described below in detail.
722<br />
Table 4<br />
<strong>Amatoxin</strong> <strong>Poisoning</strong> Cases Treated as Bi- and Tri-chemotherapy with Benzylpenicillin, with/without Detoxication Procedures and with/without Liver Transplant<br />
<strong>Treatment</strong>s<br />
Detoxication<br />
ECP HD–HP/PL LT Surv. References<br />
Urin.<br />
FD<br />
Date/Country T/E Cases Mushroom Drugs Oral<br />
C/GA<br />
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1977–1994 Germany 9/12 A.ph, a.sp ATB, silybin 0/9 9 9–9/0 0 8 [133]<br />
1977–1994 Germany 3/12 A.ph ATB, silybin 0/3 3 3–3/0 3 3 [133]<br />
1988 Turkey 2/27; 1 child L.cas, L.hel ATB, steroid 2/0 0 1–0/0 0 0 [82]<br />
1988 Turkey 1/3; child A.ph ATB, steroid 1/0 0 1–0/0 0 1 [134]<br />
1995 Turkey 3/3; 1 child A.ph, amat ATB, steroid 3/0 3 2–3/0 0 3 [135]<br />
1988 France 1/1 A.ph ATS, steroid 1/0 0 0–0/0 1 1 [136]<br />
1980 France 1/1 A.ph ATS, Vit.C 0/0 0 0–0/0 0 1 [137]<br />
1984 France 1/29 A.ph ATS, Vit.C 1/0 0 0–0/0 0 1 [138]<br />
1992 New Jersey 3/3 A.ph Cimetid 3/0 0 1–2/0 0 3 [139]<br />
1992–1993 New York 2/2 a.sp, amat Cimetid 2/0 0 0–0/0 0 1 [140]<br />
Enjalbert et al.<br />
1999 Pennsylvania 5/6 A.ph, a.sp Cimetid 5/0 0 0–0/0 0 5 [124]<br />
1996–1997 California 1/10 a.sp Cimetid, 1/0 0 0–0/0 0 1 [109]<br />
NAC<br />
<strong>20</strong>00 Missouri 2/2 A.ph, amat Cimetid, 2/0 0 2–2/0 0 2 [141]<br />
NAC<br />
<strong>20</strong>00 Turkey 1/1; child a.sp Cimetid, 1/0 0 0–0/1 0 1 [142]<br />
Vit.C<br />
1986–1992 Italy 73/73; (child.) A.ph, amat NAC a<br />
73/0 73 0–0/0 0 67 [143–145]<br />
1996 France 1/1 L.bi, amat NAC 0/0 0 0–0/0 0 1 [146]<br />
1996–1997 California 6/10 1A.ph, 5 a.sp NAC 6/0 0 0–0/0 0 6 [109]<br />
1996–1998 Italy 11/11 A.ph, amat NAC 11/0 0 11–0/0 1 11 [116]<br />
1997 California 1/4 A.ph NAC 1/0 0 0–0/0 0 0 [90]<br />
1990 Italy 1/1; child a.sp, amat NAC, steroid 0/0 1 0–0/0 0 1 [147]<br />
1994 France 5/29 A.ph NAC, Vit.C 5/0 0 0–0/0 0 5 [138]<br />
1979–1988 France 29/29; (child.) A.ph, amat Silybin 0/0 0 (HD)–0/0 0 26 [148]<br />
1980–1986 Europe 159/252 A.ph, a.sp Silybin 0/0 (FD) (HD–HP)/0 0 156 [127,128]<br />
1985–1994 Sweden 22/41 A.ph, A.vi, a.sp, Silybin 22/0 0 22–22/0 0 22 [149]<br />
amat<br />
1988 California/Oregon 5/5 A.ph Silybin 0/0 5 0–0/0 4 5 [150,151]<br />
1988 Finland 4/4 A.vi Silybin 0/0 1 0–3/0 0 4 [152]<br />
1988 Norway 2/2 A.vi, amat Silybin 2/0 2 0–0/0 0 2 [153]<br />
1988–1994 Denmark 8/8 A.ph, A.vi Silybin 5/8 0 0–3/1 1 6 [154]<br />
1989 Italy 1/2 a.sp, amat Silybin 1/0 1 0–0/0 0 1 [83]<br />
1992 Germany 1/1 A.ph Silybin 1/1 0 0–0/1 0 1 [155]
1992 Germany 4/4; 1 child A.ph, amat Silybin 4/0 0 0–4/0 1 4 [156]<br />
1993 Czech 1/1; child A.ph Silybin 0/0 0 0–0/0 0 1 [157]<br />
1993 Germany 128/154 a.sp Silybin 0/0 0 0–0/0 0 113 [130]<br />
1993 Switzerland 5/5 A.ph, amat Silybin 5/0 0 0–0/0 0 5 [158]<br />
1994 The Netherlands 2/2 A.ph Silybin 2/0 0 0–0/0 0 2 [159]<br />
1994 Slovak Republic 1/1; pregnant A.ph Silybin 0/0 0 1–1/0 0 1 [160]<br />
1996 Italy 3/4 A.ph Silybin 3/0 0 0–0/0 0 3 [161]<br />
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<strong>Amatoxin</strong> <strong>Treatment</strong> 723<br />
<strong>20</strong>01 Portugal 4/4; 1 child A.ph, a.sp Silybin 3/2 0 0–0/2 2 4 [162]<br />
1981–1983 Germany 6/13 A.ph, amat Silybin,<br />
0/0 0 0–6/0 0 6 [163]<br />
steroid<br />
1983 Germany 3/3 A.ph Silybin,<br />
0/0 0 0–0/0 0 3 [164]<br />
steroid<br />
1986 Denmark 11/11 A.ph, amat Silybin, 0/11 11 0–0/0 0 10 [165]<br />
steroid<br />
1994 Germany 2/2 A.ph Silybin,<br />
2/0 2 0–0/0 0 2 [166]<br />
steroid<br />
1980–1986 Europe 62/252 A.ph, a.sp Silybin,<br />
0/0 (FD) (HD–HP)/0 0 62 [127,128]<br />
Thioc.a<br />
1982–1986 Spain 2/85 a.sp, amat Silybin,<br />
2/2 2 0–2/0 0 2 [43,50]<br />
Thioc.a<br />
1986 Germany 1/1 A.ph, amat Silybin,<br />
1/0 1 0–1/0 0 1 [167]<br />
Thioc.a<br />
1991 Belgium 1/1 A.ph, amat Silybin, Vit.C 0/0 0 1–0/0 0 1 [168]<br />
1992 France 1/4; 1 child L.hel Silybin, Vit.C 1/0 0 0–0/0 0 1 [169]<br />
1993 France 1/29 a.sp Silybin, Vit.C 1/0 0 0–0/0 0 1 [138]<br />
1983–1987 Poland 5/90 A.ph, a.sp, amat Steroid 5/0 5 (HD)–0/0 0 4 [170–172]<br />
1984–1985 Poland 8/30 A.ph, a.sp Steroid 0/8 0 0–8/0 0 7 [173]<br />
1984–1985 Poland 22/30 A.ph, a.sp Steroid 0/22 0 0–0/0 0 16 [173]<br />
1988 Slovenia 10/10; 1 child A.ph, amat Steroid 10/0 0 0–0/10 0 9 [174]<br />
1988 Turkey 2/3; child. A.ph Steroid 1/0 0 1–0/0 0 2 [134]<br />
1988 Turkey 1/27 L.cas, L.hel Steroid 1/0 0 0–0/0 0 1 [82]<br />
1988–1989 Poland 47/90 A.ph, a.sp Steroid 47/47 47 0–0/27 0 42 [170,175]<br />
1979–1981 Italy 64/64 a.sp Steroid, 64/0 0 0–0/0 0 58 [176]<br />
Thioc.a<br />
1981 Italy 44/44; 4 child. A.ph, amat Steroid, 44/0 0 0–0/0 0 40 [177]<br />
Thioc.a<br />
1981–1983 Germany 1/13 A.ph, amat Steroid,<br />
0/0 0 0–0/0 0 1 [163]<br />
Thioc.a<br />
1990 Wisconsin 2/2 A.vi Steroid,<br />
1/1 2 0–2/0 0 2 [178]<br />
Thioc.a<br />
1984 France 2/29 A.ph Steroid, Vit.C 0/0 0 0–0/0 0 2 [138]<br />
(continued)
724<br />
Table 4. Continued<br />
<strong>Treatment</strong>s<br />
Detoxication<br />
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Urin.<br />
FD ECP HD–HP/PL LT Surv. References<br />
Oral<br />
C/GA<br />
Date/Country T/E Cases Mushroom Drugs<br />
1991–1998 Bulgaria 25/25 A.ph, a.sp Steroid, Vit.E 25/0 25 (HD–HP)/(PL) 0 15 [179]<br />
1977–1992 Slovak 58/58 A.ph Thioc.a 0/0 44 17–58/12 0 38 [180]<br />
Republic<br />
1979–1985 Sweden 19/41 A.ph, A.vi, a.sp Thioc.a 19/0 0 19–19/0 0 19 [149]<br />
1982–1984 Italy 2/6; child. A.ph, a.sp, amat Thioc.a 2/0 0 2–0/2 0 0 [181]<br />
1982–1986 Spain 59/85; (child.) 27 A.ph, 24 a.sp, 7 Thioc.a 18/15 28 0–4/2PL 3 EXE 0 56 [43,50,182–<br />
L.bi, 1 L.f<br />
184]<br />
1985 Italy 53/53; 6 child. A.ph, amat Thioc.a 53/53 (FD) (HD)–0/(PL) 0 47 [185]<br />
1986–1988 Spain 2/4 A.ph, amat Thioc.a 2/0 2 0–0/0 0 0 [182,183]<br />
1987 Italy 2/2 A.ph, amat Thioc.a 0/0 0 0–0/2 0 2 [186]<br />
1988 Spain 1/1 A.ph Thioc.a 0/0 0 0–1/0 0 1 [187]<br />
1989 Spain 10/10 3 L.bi, 7 L.hel, Thioc.a 10/0 0 0–10/0 0 8 [188]<br />
amat<br />
1990 Spain 1/1 A.ph Thioc.a 0/0 0 1–0/0 0 1 [189]<br />
b<br />
1982 Belgium 4/4; 1 child A.ph, amat Thioc.a,<br />
0/0<br />
0–0/0 0 3 [190]<br />
Vit.C<br />
1990–1994 France 11/29 5 A.ph, 6 a.sp Vit.C 4/0 0 1–0/0 0 10 [138]<br />
1992 France 3/4 L.hel Vit.C 1/0 0 0–0/0 0 3 [169]<br />
T/E Cases ¼ treated/exposed individuals; Oral ¼ oral detoxication using C ¼ activated charcoal and GA ¼ gastroduodenal aspiration; Urin. ¼ urinary detoxication by FD ¼ forced diuresis;<br />
ECP ¼ extra-corporeal detoxication including HD ¼ hemodialysis, HP ¼ hemoperfusion, and PL ¼ plasmapheresis (or EXE ¼ exsanguino transfusion); LT ¼ liver transplant;<br />
Surv. ¼ survivors; amat ¼ amatoxins in biological fluids; undefined cases are reported in brackets; ATB ¼ antibiotic agent; ATS ¼ antiseptic agent (nifuroxazide); Cimetid ¼ cimetidine;<br />
NAC ¼ N-acetylcysteine; Thioc.a ¼ thioctic acid; Vit.C ¼ vitamin C; Vit.E ¼ vitamin E; a.sp ¼ amatoxin-containing species; A.ph ¼ Amanita phalloides; A.vi ¼ A. virosa; L.bi ¼ Lepiota<br />
brunneoincarnata; L.cas ¼ L. castanea; L.f. ¼ L. fulvella; L. hel ¼ L. helveola.<br />
a<br />
Neomycin instead <strong>of</strong> benzylpenicillin.<br />
b Spironolactone.<br />
Enjalbert et al.
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<strong>Amatoxin</strong> <strong>Treatment</strong> 725<br />
Table 5<br />
<strong>Amatoxin</strong> <strong>Poisoning</strong> Cases Treated as Bi- and Tri-chemotherapy without Benzylpenicillin, with/without Detoxication Procedures and with/without Liver Transplant<br />
<strong>Treatment</strong>s<br />
Detoxication<br />
Date/Country T/E Cases Mushroom Drugs Oral C/GA Urin. FD ECP HD–HP/PL LT Surv. References<br />
1996 France 1/1; pregnant A.ph 2 ATB, NAC 1/0 0 0–0/0 0 1 [191,192]<br />
1983 California 1/1; child A.o 2 ATB, steroid 1/0 0 0–0/1 1 1 [193]<br />
1981 France 3/3 A.ph ATB, ATS, Vit.C a<br />
0/0 0 0–0/0 0 3 [194]<br />
1986 France 5/5; (child.) L.blil ATB, ATS, Vit.C a<br />
0/0 0 0–0/0 0 4 [195]<br />
1988 Turkey 3/27 L.cas, L.hel ATB, Thioc.a, Vit.C 3/0 0 3–0/0 0 1 [82]<br />
1989 France 6/6 A.ph, amat Ceftazid, silybin 6/0 0 0–0/0 0 6 [196]<br />
1990 France 5/5 A.ph, amat Ceftazid, silybin 5/0 0 0–0/0 0 5 [197]<br />
1994 France 1/1 L.blil Ceftazid, silybin 0/0 0 0–0/0 1 1 [198]<br />
1980–1986 Europe 6/252 A.ph, a.sp Silybin, Thioc.a 0/0 (FD) (HD–HP)/0 0 5 [127,128]<br />
1982–1984 Italy 4/6; child. A.ph, a.sp, amat Steroid, Thioc.a, Vit.C 4/4 0 0–0/4 0 4 [181]<br />
T/E Cases ¼ treated/exposed individuals; Oral ¼ oral detoxication using C ¼ activated charcoal and GA ¼ gastroduodenal aspiration; Urin. ¼ urinary detoxication by FD ¼ forced diuresis;<br />
ECP ¼ extra-corporeal detoxication including HD ¼ hemodialysis, HP ¼ hemoperfusion, and PL ¼ plasmapheresis; LT ¼ liver transplant; Surv. ¼ survivors; amat ¼ amatoxins in<br />
biological fluids; undefined cases are reported in brackets; ATB ¼ antibiotic agent; ATS ¼ antiseptic agent (nifuroxazide); Ceftazid ¼ ceftazidime; NAC ¼ N-acetylcysteine;<br />
Thioc.a ¼ thioctic acid; Vit.C ¼ vitamin C; a.sp ¼ amatoxin-containing species; A.o ¼ Amanita ocreata; A.ph ¼ A. phalloides; L.blil ¼ Lepiota brunneolilacea; L.cas ¼ L. castanea;<br />
L.hel ¼ L. helveola.<br />
a<br />
Bastien protocol.
726<br />
Table 6<br />
<strong>Amatoxin</strong> <strong>Poisoning</strong> Cases Treated as Poly-chemotherapy with/without Benzylpenicillin, with/without Detoxication Procedures and with/without Liver Transplant<br />
<strong>Treatment</strong>s<br />
Detoxication<br />
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Date/Country T/E Cases Mushroom Drugs Oral C/GA Urin. FD ECP HD–HP/PL LT Surv. References<br />
1992 Michigan 1/1 a.sp 3 ATB, B.pen 0/0 0 0–0/0 1 1 [199]<br />
1996 Italy 1/4 A.ph 2 ATB, B.pen, Silyb 1/0 0 0–0/0 0 1 [161]<br />
1983 New York 1/1 L.jos, amat 3 ATB, Ster 0/0 0 0–1/0 0 0 [<strong>20</strong>0]<br />
1984–1993 Germany 21/21; (child.) A.ph, amat ATB, B.pen, Silyb, Ster, 10/0 0 0–0/21 0 <strong>20</strong> [<strong>20</strong>1]<br />
TA<br />
1988 Turkey 2/27 L.cas, L.hel ATB, B.pen, Ster, TA 2/0 0 0–0/0 0 2 [82]<br />
1988 Turkey 1/27 L.cas, L.hel ATB, B.pen, Ster, TA, 1/0 0 0–0/0 0 1 [82]<br />
Vit.C<br />
1988 Turkey 4/27 L.cas, L.hel ATB, B.pen, Ster, Vit.C 4/0 0 0–0/0 0 2 [82]<br />
1984 France 4/29 A.ph ATS, B.pen, Silyb, Vit.C 0/0 0 0–0/0 0 4 [138]<br />
1988 France 2/29 A.ph ATS, B.pen, Ster, Vit.C 0/0 0 0–0/0 0 2 [138]<br />
1990 France 2/29 A.ph ATS, Silyb, Ster, Vit.C 0/0 0 0–0/0 0 1 [138]<br />
1988 Denmark 4/4 1 A.ph, 1 A.vi, B.pen, Cimet, Silyb, Ster 4/0 4 0–4/0 0 3 [<strong>20</strong>2]<br />
2 a.sp<br />
1993 France 1/29 A.ph B.pen, NAC, Silyb, Vit.C 0/0 0 0–0/0 0 0 [138]<br />
1981–1983 Germany 6/13 A.ph, amat B.pen, Silyb, Ster, TA 0/0 0 0–5/0 0 5 [163]<br />
1991 Hungary 4/4; 1 pregnant A.ph, A.ve B.pen, Silyb, Ster, TA 4/0 4 0–0/0 0 3 [<strong>20</strong>3]<br />
1993 Hungary 8/8; (child.) A.ph B.pen, Silyb, Ster, TA 0/0 0 0–6/1 0 7 [<strong>20</strong>4]<br />
1983–1987 Poland 57/90 A.ph, a.sp, amat B.pen, Ster, Insul, Gluc 57/0 57 (HD)–0/0 0 47 [170–172]<br />
1988–1989 Poland 2/90 A.ph, a.sp, B.pen, Ster, Insul, Gluc 2/2 2 0–0/1 0 2 [170,175]<br />
1983–1987 Poland 28/90 A.ph, a.sp, amat B.pen, Ster, Insul, hGH 28/28 28 0–0/11 0 25 [170–172]<br />
1988–1989 Poland 41/90 A.ph, a.sp B.pen, Ster, Insul, hGH 41/41 41 0–0/29 0 33 [170,175]<br />
T/E Cases ¼ treated/exposed individuals; Oral ¼ oral detoxication using C ¼ activated charcoal and GA ¼ gastroduodenal aspiration; Urin. ¼ urinary detoxication by FD ¼ forced diuresis;<br />
ECP ¼ extra-corporeal detoxication including HD ¼ hemodialysis, HP ¼ hemoperfusion, and PL ¼ plasmapheresis; LT ¼ liver transplant; Surv. ¼ survivors; amat ¼ amatoxins in<br />
biological fluids; ATB ¼ antibiotic agent; ATS ¼ antiseptic agent (nifuroxazide); B.pen ¼ benzylpenicillin; Cimet ¼ cimetidine; Insul, Gluc ¼ insulin and glucagon; Insul, hGH ¼ insulin<br />
and human growth hormone; NAC ¼ N-acetylcysteine; Silyb ¼ silybin; Ster ¼ steroid; TA ¼ thioctic acid; Vit.C ¼ vitamin C; a.sp ¼ amatoxin-containing species; A.ph ¼ Amanita<br />
phalloides; A.ve ¼ A. verna; A.vi ¼ A. virosa; L.cas ¼ Lepiota castanea; L. hel ¼ L. helveola; L. jos ¼ L. josserandii; undefined cases are reported in brackets.<br />
Enjalbert et al.
Preliminary Medical Care<br />
Preliminary medical care consists <strong>of</strong> gastrointestinal<br />
decontamination procedures if appropriate, to make an<br />
attempt at obtaining baseline values <strong>of</strong> key biological<br />
parameters for diagnostic monitoring. When a patient<br />
develops a gastroenteritis 6–24 hours after mushroom<br />
ingestion, all asymptomatic and symptomatic persons<br />
who consumed the same meal should be immediately<br />
evaluated and treated as appropriate to prevent toxin<br />
absorption. Because <strong>of</strong> the long asymptomatic latency,<br />
the clinical utility <strong>of</strong> most gastrointestinal decontamination<br />
procedures seems limited. Although effective in<br />
inducing emesis, there is no evidence from clinical<br />
studies that ipecac syrup improves the outcome <strong>of</strong><br />
poisoned individuals; data to support or exclude its<br />
administration are insufficient. [229] Gastric lavage should<br />
be considered only when it could be performed within<br />
60 minutes after ingestion <strong>of</strong> a life-threatening amount <strong>of</strong><br />
toxin. [230] It is contraindicated if the patient has loss<br />
<strong>of</strong> airway protective reflexes or a decreased level <strong>of</strong><br />
consciousness without endotracheal intubation. [230,231]<br />
There is no conclusive evidence for the use <strong>of</strong> whole<br />
bowel irrigation (WBI), which appears to decrease the<br />
binding capacity <strong>of</strong> the activated charcoal. [232] Some<br />
authors [13,14,22,23,233] advocate the administration <strong>of</strong><br />
activated charcoal alone or with cathartics whereas<br />
others find no data supporting a cathartic in combination<br />
with activated charcoal. [234]<br />
The regional poison center can provide appropriate<br />
decontamination information and also suggest and track<br />
mycological, clinical, and biological data for each<br />
amatoxin victim. [223,231] The identification by a mycologist<br />
<strong>of</strong> any remaining mushrooms can be a key to<br />
diagnosis. The time lag between mushroom ingestion<br />
and hospital admission is an essential information.<br />
Biological parameters including blood sugar, serum<br />
transaminases (aspartate aminotransferase, ASAT; alanine<br />
aminotransferase, ALAT), lactate dehydrogenase<br />
(LDH), serum bilirubin, urea, and coagulation studies<br />
[prothrombin time (PT)] are proposed as indicators <strong>of</strong><br />
hepatotoxicity. [18,19] Ryzko et al. [235] and Parra et al. [236]<br />
noted that hypocalcemia and alkaline phosphatase<br />
isoenzyme (ALP) are also indicators <strong>of</strong> amatoxin<br />
poisoning. Horn et al. [124] recommended concurrent<br />
measurement <strong>of</strong> serum markers <strong>of</strong> hepatocellular<br />
necrosis combined with markers <strong>of</strong> hepatocellular<br />
regeneration (g-glutamyl transferase and a-fetoprotein).<br />
Analysis <strong>of</strong> diarrhea fluids has been recommended<br />
since high levels <strong>of</strong> amatoxins are eliminated in feces.<br />
<strong>Amatoxin</strong>s may also be assayed in urine and serum by<br />
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<strong>Amatoxin</strong> <strong>Treatment</strong> 727<br />
radio-immunoassay, [237,238] high-performance liquid<br />
chromatography with UV detection method as reviewed<br />
by Dorizzi et al., [239] electrochemical detection, [240] and<br />
capillary electrophoresis. [241] Thin layer chromatography<br />
using a color index <strong>of</strong> amatoxins by Schiff’s test is<br />
reported by Russian authors. [242] Unfortunately, the<br />
amatoxin concentrations in biological samples do not<br />
correlate with the severity <strong>of</strong> poisoning and do not<br />
indicate intra-hepatic toxin accumulation. High individual<br />
differences in urinary amatoxin concentrations may<br />
only be <strong>of</strong> qualitative value. [243]<br />
Supportive Measures<br />
Supportive measures for the management <strong>of</strong> gastroenteritis<br />
and hepatotoxicity are so frequently used that an<br />
<strong>analysis</strong> <strong>of</strong> their utility was not attempted with this data.<br />
In the gastrointestinal phase, diarrhea and emesis can<br />
produce hypovolemic shock requiring intensive intravenous<br />
fluid resuscitation. Electrolyte abnormalities,<br />
metabolic acidosis, hypoglycemia, impaired coagulation<br />
due to decreased hepatic synthesis <strong>of</strong> Factors II, V, VII,<br />
and X are corrected. A normal or slightly high urine<br />
output is maintained during the first 48 hours to avoid<br />
acute renal failure. Parenteral nutrition with protein<br />
intake restriction is instituted.<br />
Specific recommendations for supportive treatment <strong>of</strong><br />
hepatoxicity include: (i) correction <strong>of</strong> coagulation<br />
disorders by parenteral vitamin K (10 mg daily for<br />
three consecutive days), fresh frozen plasma and<br />
antithrombin III, (ii) oral lactulose and neomycin to<br />
prevent encephalopathy, [244] and (iii) mannitol to lower<br />
intracranial pressure and avoid cerebral edema. [245]<br />
Ninety-one <strong>of</strong> the 2108 patients reported since 1980,<br />
including six LT victims, were given supportive<br />
measures alone (Table 1). A total <strong>of</strong> <strong>20</strong>17 <strong>of</strong> 2108<br />
victims were treated with supportive measures combined<br />
with specific treatments as detoxication procedures alone<br />
(Table 2) and various protocols <strong>of</strong> chemotherapy with or<br />
without detoxication procedures (Tables 3–6).<br />
Detoxication Procedures<br />
Detoxication involves two different approaches: the<br />
reduction <strong>of</strong> absorption and enhancement <strong>of</strong><br />
excretion. [246]<br />
Oral Detoxication<br />
Theoretically activated charcoal should bind amatoxins<br />
excreted via the bile into the duodenum and upper<br />
jejunum, although there is no evidence that its use
728<br />
improves clinical outcome if it is used more than 1 hour<br />
after ingestion. [247] Toxicokinetic studies in the dog<br />
suggested amatoxin absorption or reabsorption from the<br />
intestine. [248] Given the enterohepatic circulation <strong>of</strong><br />
amatoxins, administration <strong>of</strong> activated charcoal as<br />
multiple doses could reduce amatoxin absorption if in<br />
contact with toxin present in the gastrointestinal tract.<br />
Serial charcoal dosing either as a continuous nasogastric<br />
drip or pulse dosing with <strong>20</strong>–40 g every 3–4 hours (for<br />
24 hours or more) has been advocated by most authors as<br />
a relatively noninvasive enterohepatic and enteric<br />
dialysis technique. [42,74,233,249 – 251] However, clinical<br />
data are insufficient to support or exclude this oral<br />
detoxication method. [247]<br />
Gastroduodenal aspiration (GA) from the upper<br />
portion <strong>of</strong> the small intestine through a nasogastric tube<br />
has been recommended as a sole technique or combined<br />
with activated charcoal to remove bile fluids and<br />
interrupt enterohepatic circulation [252] but the actual<br />
benefit <strong>of</strong> these procedures is not documented.<br />
<strong>Amatoxin</strong>s are present in the gastroduodenal fluids<br />
until 60 hour after mushroom ingestion. [253] Long term<br />
intubation may lead to side effects <strong>of</strong> bleeding and<br />
pancreatitis and is not always recommended. [14]<br />
Urinary Detoxication<br />
Toxicokinetic reports <strong>of</strong> human mushroom poisoning<br />
have shown that diuresis substantially enhances the<br />
amatoxin elimination rate. Large amounts <strong>of</strong> amatoxins<br />
(60–80%) are filtered through the glomeruli. [254] Urinary<br />
elimination <strong>of</strong> amatoxins has been detected within the<br />
first 8 hours and for 3–4 days after mushroom<br />
ingestion. [167] <strong>Amatoxin</strong> concentrations in the urine are<br />
from 100 to 150 times higher than those <strong>of</strong> serum and can<br />
be quantified even when no serum circulating amatoxins<br />
are detectable. [50,51,255 – 257] Maintenance <strong>of</strong> early and<br />
adequate urine output is theoretically important even<br />
though there is no re-absorption in the proximal tubules<br />
or tubular secretion; “forced diuresis (FD)” with fluids<br />
plus a loop diuretic cannot increase amatoxin elimination.<br />
[14,248] According to Jaeger et al., [257] there is no<br />
pro<strong>of</strong> that FD decreases the amount <strong>of</strong> amatoxins bound<br />
to the hepatocytes or is more efficient than the<br />
maintenance <strong>of</strong> an adequate diuresis (from 100 to<br />
<strong>20</strong>0 mL/h). Furthermore, FD is difficult to maintain in a<br />
patient with a severe dehydration.<br />
Extra-corporeal Purification Procedures<br />
<strong>Amatoxin</strong>s are detected in the serum from 24 to<br />
48 hours after mushroom ingestion but at very low<br />
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Enjalbert et al.<br />
[253,256 – 258]<br />
concentrations when compared to the urine.<br />
Extra-corporeal elimination includes hemodialysis (HD),<br />
hemoperfusion (HP), plasmapheresis (PL), and related<br />
methods. HP and HD are theoretically helpful since the<br />
amatoxins are easily dialyzable due to their free<br />
circulation in the serum and their small molecular<br />
weight (about 900 Da); amatoxins also possess a high<br />
affinity for charcoal and polymers used for HP cartridges<br />
and dialyzer membranes. [249] HD initiated as sole<br />
treatment has been reported to be ineffective in the<br />
management <strong>of</strong> amatoxin syndrome [82,97] but should be<br />
instituted if renal failure occurs. [231] Given the low serum<br />
amatoxin concentration, the utility <strong>of</strong> toxin removal by<br />
extra-corporeal purification procedures is questionable.<br />
Extra-corporeal purification procedures such as HD, HP,<br />
and PL, and related methods such as continuous<br />
venovenous hem<strong>of</strong>iltration and exsanguino-transfusion,<br />
are <strong>of</strong>ten used in a combined mode; it is difficult to assess<br />
the efficacy <strong>of</strong> any single treatment.<br />
HP has been applied to amatoxin-intoxicated patients<br />
since 1978 with a possibly favorable effect. [259 – 261] It<br />
has been carried out within the first 36 or 48 hours after<br />
ingestion [246,260,262] but is proposed as most effective if<br />
applied prior to 24 hours. [231] The survival rate <strong>of</strong><br />
poisoned patients is claimed to depend on the time <strong>of</strong><br />
beginning HP. [14,140,180] Polish and Turkish <strong>retrospective</strong><br />
studies have reported increased survival for amatoxinpoisoned<br />
patients treated with HP. [107,173]<br />
Thrombocytopenia, a major side effect <strong>of</strong> HP that<br />
increases the risk <strong>of</strong> bleeding, [123,149] diminishes when a<br />
platelet protective agent such as prostacyclin is<br />
administered. [123] Other complications <strong>of</strong> HP such as<br />
hypotension due to volume loss, hypoglycemia, and<br />
hypocalcemia must be monitored and corrected. [262]<br />
Controversy centers on whether the blood level <strong>of</strong><br />
amatoxins is high enough to justify this procedure.<br />
[249,258] HP performed within 12–14 hours after<br />
ingestion <strong>of</strong> amatoxin-containing mushrooms eliminated<br />
less than 4% <strong>of</strong> the ingested toxin dose. [225] Although the<br />
benefit <strong>of</strong> HP to remove amatoxins in the early stages <strong>of</strong><br />
intoxication was debatable, [263] it may help support the<br />
patient during hepatic failure. [155] HP eliminates<br />
neurotropic and neurotoxic amino acids and mercaptans;<br />
it has been reported to ameliorate the hepatic<br />
encephalopathy in 75% <strong>of</strong> amatoxin poisoned<br />
patients. [264,265]<br />
The HP sorbent most frequently used is activated<br />
charcoal. In the United States, the only available HP<br />
sorbent is activated charcoal-coated polymer membranes.<br />
[262] The efficacy <strong>of</strong> ion-exchange resin (Amberlite<br />
XAD-4) has been experimentally demonstrated. [266]
Czechoslovakian investigations <strong>of</strong> the in vitro absorption<br />
<strong>of</strong> a- and b-Ama standards, using charcoal as well as<br />
XAD-2 and XAD-4 resin types, found Amberlite XAD-2<br />
synthetic resin the most effective and activated charcoal<br />
the least. [267,268] Positive results from in vitro experiments<br />
with Amberlite XAD-2 resin are said to justify<br />
further trials <strong>of</strong> this material in the detoxication<br />
procedures <strong>of</strong> clinical amatoxin poisonings. [269]<br />
HP is <strong>of</strong>ten combined with HD; some reports claim it<br />
is helpful. [14,159,249] American reports on the clearance <strong>of</strong><br />
amatoxins in a series <strong>of</strong> blood samples taken from<br />
poisoned patients before and after treatment as well as in<br />
the HD/HP circuits demonstrate no utility. [141] Italian<br />
authors have recently reported the combination <strong>of</strong><br />
charcoal plasmaperfusion and continuous venovenous<br />
hem<strong>of</strong>iltration (Table 2) to eliminate both low and high<br />
molecular weight toxins. This new method <strong>of</strong> toxin<br />
removal might improve the liver function <strong>of</strong> amatoxin<br />
intoxicated patients. [111]<br />
The first uses <strong>of</strong> PL in mushroom poisoning in<br />
general [270] and Amanita poisoning in particular, [271]<br />
were reported in the late 1970s. Several authors [98,272]<br />
and most recently Jander et al. [273] reviewed advantages<br />
and problems relevant to PL for amatoxin-intoxicated<br />
patients.<br />
PL performed as a single detoxication procedure [98]<br />
or in combination with other extra-corporeal purification<br />
methods such as HD/charcoal HP [97] or Amberlite XAD-<br />
2HP [215] has been reported to decrease mortality. PL<br />
plus chemotherapy are also said to improve survival<br />
as well as the general condition <strong>of</strong> poisoned patients<br />
by stabilizing biliary acid and bilirubin levels. [131,174] In a<br />
large study, mortality was 7.4% when PL plus chemotherapy<br />
was used for 68 <strong>of</strong> 180 patients and<br />
1<strong>9.</strong>6% when the PL was not used. [175] German authors<br />
also reported that early combined treatment<br />
with PL plus chemotherapy was beneficial. [273] According<br />
to 18-<strong>year</strong> Italian experience, plasma-exchange<br />
therapy associated with general intensive care<br />
may improve the health <strong>of</strong> amatoxin poisoned<br />
patients who retain sufficient capacity for liver<br />
regeneration. [100]<br />
Patterns and Frequency <strong>of</strong> Detoxication<br />
Procedures<br />
Of the <strong>20</strong>17 amatoxin-poisoned individuals administered<br />
specific treatments, 385 (1<strong>9.</strong>1%, Table 2) underwent<br />
only detoxication procedures (Detox-group) while<br />
1632 (80.9%, Tables 3–6) received chemotherapy<br />
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<strong>Amatoxin</strong> <strong>Treatment</strong> 729<br />
(Chem-group) either alone or combined with detoxication<br />
procedures.<br />
Activated charcoal (C) was given to 7.5% (29/385)<br />
Detox-group patients and to 35.7% (583/1632)<br />
Chem-group patients. GA was performed in<br />
3.6% (59/1632) Chem-group patients. Combined<br />
C þ GA was reported for 2 <strong>of</strong> 385 Detox-group patients<br />
and 223 <strong>of</strong> 1632 (13.7%) Chem-group patients.<br />
FD was undertaken in 4<strong>9.</strong>4% (190/385) Detox-group<br />
patients and at least 33% <strong>of</strong> Chem-group patients.<br />
HD was reported for 30.6% (118/385) Detox-group<br />
and at least 7.1% <strong>of</strong> the 1632 Chem-group patients. HP<br />
was reported for 57.4% (221/385) Detox-group and at<br />
least 11.4% <strong>of</strong> the Chem-group patients. PL was cited for<br />
5.2% (<strong>20</strong>/385) Detox-group and at least <strong>9.</strong>6% <strong>of</strong> the<br />
Chem-group patients.<br />
The inadequate reporting <strong>of</strong> HD and extra-corporeal<br />
procedures in the sources comprised in Tables 3–6<br />
among the patients who also received chemotherapy<br />
necessitated the pooling <strong>of</strong> patients receiving the same<br />
chemotherapy with and without detoxication procedures.<br />
Chemotherapy with Specific Agents<br />
No specific amatoxin antidote is available, but<br />
therapeutic agents such as b-lactam antibiotics, silymarin<br />
complex, thioctic acid, antioxidant drugs and other<br />
drugs are used in the clinical management <strong>of</strong> amatoxin<br />
poisoning. In vitro experiments and animal model<br />
investigations have been summarized along with the<br />
purported advantages and disadvantages <strong>of</strong> their clinical<br />
use. In this survey, the 1632 patients in the Chem-group<br />
received drugs as mono-chemotherapy (Table 3), bichemotherapy<br />
with or without benzylpenicillin (part <strong>of</strong><br />
Table 4 and part <strong>of</strong> Table 5, respectively), trichemotherapy<br />
with or without benzylpenicillin (part <strong>of</strong><br />
Table 4 and part <strong>of</strong> Table 5, respectively) or polychemotherapy<br />
(.3 drugs) with or without benzylpenicillin<br />
(Table 6). Patients in the Chem-group may have<br />
also received detoxication procedures.<br />
b-Lactam Antibiotics<br />
Benzylpenicillin (Penicillin G) and ceftazidime are blactam<br />
antibiotics thought to be hepatoprotective in<br />
amatoxin poisoning. Benzylpenicillin was first used to<br />
protect mice and rats against lethal doses <strong>of</strong> either A.<br />
phalloides extracts or a-Ama. [274,275] In dogs orally<br />
poisoned with a sub-lethal dose <strong>of</strong> A. phalloides<br />
preparation, intravenous benzylpenicillin injection
730<br />
prevented both the rise <strong>of</strong> the liver enzymes and the fall<br />
<strong>of</strong> clotting factors in the blood. [276]<br />
Benzylpenicillin perfusions <strong>of</strong> isolated rat liver<br />
showed a strong inhibition <strong>of</strong> a-Ama toxicity. [277]<br />
Although most b-lactam antibiotics utilize a common<br />
carrier system for uptake into isolated hepatocytes, [278]<br />
kinetic studies <strong>of</strong> a-Ama absorption in hepatocytes<br />
proved that benzylpenicillin does not inhibit the<br />
membrane transport systems used by the toxin. An<br />
intracellular mechanism rather than interference with<br />
amanitin uptake appears responsible for the purported<br />
hepatoprotective effect. [279]<br />
Several theories have been advanced to explain the<br />
antitoxic action <strong>of</strong> benzylpenicillin. Floersheim’s<br />
hypothesis [280]<br />
that the drug could displace a-Ama<br />
from its binding site on serum protein is challenged by<br />
evidence that the toxic cyclopeptide does not bind to<br />
serum albumin. [266,281] Another hypothesis suggested<br />
that benzylpenicillin reduced or eliminated the GABAproducing<br />
intestinal flora involved in hepatic encephalopathy.<br />
[250,280] Although GABA appeared to be involved<br />
in experimental hepatic encephalopathy, the inhibitory<br />
neurotransmitter does not seem to play a role in human<br />
encephalopathy. [282]<br />
Other reports presented evidence <strong>of</strong> an anti-proliferative<br />
effect <strong>of</strong> b-lactam antibiotics on cultured<br />
eukaryotic cells including human sources and in vitro<br />
DNA replication systems. The intracellular target <strong>of</strong> blactams<br />
appears to be the replicative enzyme polymerase<br />
I. [283,284] Since the amatoxins, particularly a-Ama, are<br />
selective blockers <strong>of</strong> DNA-dependent RNA polymerase<br />
II, it is possible that the b-lactam antibiotics protect via<br />
their effects on eukaryotic DNA replication. [285]<br />
Although there is no formal pro<strong>of</strong>, in vitro experiments<br />
on chicken embryo hepatocytes and in vivo studies on<br />
mouse liver have shown that b-lactam antibiotics inhibit<br />
the toxic effect induced by a-Ama. [286]<br />
Unfortunately, benzylpenicillin commonly causes<br />
allergic drug reactions with an incidence <strong>of</strong><br />
1–10%. [126,287 – 289] The large amount <strong>of</strong> sodium ions<br />
administered with this antibiotic agent to amatoxinpoisoned<br />
patients may disrupt electrolyte balance. [290,291]<br />
Severe granulocytopenia has also been observed with<br />
high doses <strong>of</strong> benzylpenicillin. [292 – 294] Degradation<br />
products formed in vitro are <strong>of</strong>ten the causative agents<br />
<strong>of</strong> such adverse reactions rather than parent antibiotic.<br />
Use <strong>of</strong> freshly prepared single doses <strong>of</strong> benzylpenicillin<br />
prevents the majority <strong>of</strong> side effects. [295] However, given<br />
the bone narrow toxicity <strong>of</strong> b-lactams, these antibiotics<br />
[189,285] could affect all the hematopoietic cell<br />
lines. Lastly, massive benzylpenicillin therapy may<br />
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evoke neurotoxic symptoms in patients with nervous<br />
system disease and renal insufficiency as well as induce<br />
convulsions when cerebral edema is imminent. [14,296]<br />
Although the biological mechanism <strong>of</strong> b-lactam<br />
antibiotics in the treatment <strong>of</strong> amatoxin poisoning is still<br />
unclear and high-dose benzylpenicillin can induce<br />
adverse reactions, the literature seems to support clinical<br />
benefits. Moroni et al. [297] reported 100% recovery for 33<br />
patients treated 1 or 2 days after ingestion <strong>of</strong> Amanita<br />
mushrooms with high doses <strong>of</strong> IV benzylpenicillin plus<br />
thioctic acid and steroids. Statistical <strong>analysis</strong> <strong>of</strong> a clinical<br />
study <strong>of</strong> <strong>20</strong>5 patients from Austria, France, Italy,<br />
Switzerland, and The Netherlands from 1971 to 1980<br />
found benzylpenicillin at 300,000–1,000,000 U/kg/day<br />
IV to be significantly associated with survival. [250,298]<br />
The suggested doses for benzylpenicillin are 40,000,000<br />
and 1,000,000 U/day in adults and children, respectively.<br />
[265] Benzylpenicillin is not approved by the US<br />
Food and Drug Administration (FDA) for treatment <strong>of</strong><br />
Amanita poisonings.<br />
In this <strong>20</strong>-<strong>year</strong> survey, benzylpenicillin was the most<br />
frequently used drug in the management <strong>of</strong> amatoxin<br />
poisoning, either as mono-chemotherapy in 164<br />
cases (10.1%, Table 3) or combined with other drugs<br />
as bi-chemotherapy (797 cases, 48.8%, Table 4), trichemotherapy<br />
(263 cases, 16.1%, Table 4), and polychemotherapy<br />
(187 cases, 11.5%, Table 6). In total,<br />
86.5% <strong>of</strong> Chem-group patients (1411/1632) receiving<br />
chemotherapy were treated with benzylpenicillin.<br />
Ceftazidime, a third generation cephalosporin, is<br />
several times more effective than benzylpenicillin by<br />
DNA replication systems testing in vitro. [284,286]<br />
According to the Neftel protocol, [196] ceftazidime is<br />
administered as 4.5 g IV every 2 hours. Despite the high<br />
drug concentrations in plasma, no renal and neurological<br />
side effects were reported. [197] Ceftazidime was the<br />
second most used b-lactam but was always combined<br />
with silybin (12 cases, Table 5).<br />
Silymarin Complex<br />
Enjalbert et al.<br />
Silymarin is a hepatoprotectant complex <strong>of</strong> natural<br />
substances isolated from seeds <strong>of</strong> Mediterranean milk<br />
thistle, Silybum marianum (L.) Gaertn. (Asteraceae ). [299]<br />
This flavonolignan group includes the three isomers<br />
silydianin, silychristin, and the major compound,<br />
silybin. [300,301] The beneficial effects <strong>of</strong> silymarin on<br />
death rate and survival time in intraperitoneal (IP)<br />
administered mice with a-Ama were reported by Hahn<br />
et al. [302] Silymarin efficacy depended on both the delay<br />
between intoxication and therapy, and the degree <strong>of</strong> liver
damage. [303] Silymarin markedly increased the survival<br />
<strong>of</strong> mice poisoned with IP A. phalloides extracts. [304] In<br />
dogs, which display poisoning resembling human<br />
intoxication, silymarin suppressed both the rise <strong>of</strong> liver<br />
enzymes and the fall <strong>of</strong> clotting factors, and silybin<br />
noticeably reduced the degree <strong>of</strong> bloody necrosis in<br />
animal livers after oral A. phalloides extract. [276,305]<br />
Histochemical studies on isolated rat hepatocytes<br />
have elucidated the mechanism <strong>of</strong> silymarin hepatoprotection.<br />
The flavonolignan complex bound tightly to liver<br />
plasma membrane acts as a membrane stabilizer [306,307]<br />
whereas flavonoid substances such as taxifolin, morin,<br />
and quercetin have no effect. [308]<br />
Silymarin hindered a-Ama penetration <strong>of</strong> the cell<br />
wall. [277,303,308] Silybin competed with a-Ama for the<br />
multi-specific bile salt transport systems <strong>of</strong> the<br />
hepatocyte membrane. [279] Histoenzyme analyses <strong>of</strong><br />
liver from a-Ama poisoned mice revealed that factors<br />
disturbed by the toxin, including glucose-6-phosphatase,<br />
aminopeptidase, ATPase, glycogen, lipid, and nucleic<br />
acid, were restored by silybin. [309]<br />
Silymarin and silybin are also radical scavengers<br />
acting as chain-breaking antioxidants. [310 – 315] Silymarin<br />
complex, by preserving alkaline phosphatase activity,<br />
prevented changes in membrane phospholipid composition<br />
and inhibited the lipid peroxidation in both rat liver<br />
microsomes and isolated hepatocytes.<br />
[310 – 312,316 – 318]<br />
The action site <strong>of</strong> silymarin is the hepatocyte outer<br />
membrane where the drug maintains lipid composition<br />
and aids functional integrity. [316]<br />
Silybin in isolated rat Kupffer cells showed inhibition<br />
<strong>of</strong> the cyclooxygenase and 5-lipooxygenase pathway <strong>of</strong><br />
arachidonic acid metabolism and the subsequent<br />
synthesis <strong>of</strong> the inflammation mediator leukotriene<br />
B4. [319] Silymarin also produced a high anti-inflammatory<br />
effect in vivo by inhibition <strong>of</strong> leukocyte migration<br />
into the inflamed site. [3<strong>20</strong>] Silymarin exerted an<br />
antifibrotic activity and retarded collagen accumulation<br />
in early and advanced biliary fibrosis secondary to<br />
complete bile duct obliteration in rats.<br />
[321 – 323]<br />
Silybin favored the regenerative process <strong>of</strong> both liver<br />
and Kupffer cells <strong>of</strong> partially hepatectomized rats. [324]<br />
These results agree with the observation that silybin<br />
stimulates liver cell metabolism. [325] It increased the<br />
synthetic rate <strong>of</strong> ribosomal RNA not only in rat hepatocyte<br />
but also in the isolated hepatocyte nucleus, via<br />
activation <strong>of</strong> DNA-dependent RNA polymerase I. As a<br />
consequence <strong>of</strong> this stimulation, ribosome formation was<br />
accelerated and protein synthesis increased. Although<br />
protein and RNA syntheses are prerequisites for DNA<br />
synthesis, silybin had no effect on DNA formation in cell<br />
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<strong>Amatoxin</strong> <strong>Treatment</strong> 731<br />
cultures and liver <strong>of</strong> normal rats whereas an effect could<br />
[326 –<br />
be observed in liver <strong>of</strong> partially hepatectomized rats,<br />
329]<br />
suggesting that silybin stimulates protein biosynthesis<br />
and regenerates damaged liver tissue.<br />
Levels <strong>of</strong> silymarin components are found to be low in<br />
plasma and urine after oral and IV silybin administered to<br />
rats and after oral silymarin to cholecystectomized<br />
patients. [330] The three isomers, silybin, silydianin, and<br />
silychristin (silymarin complex) were excreted mainly by<br />
the biliary route either free or as sulfate and glucuronide<br />
conjugates. [330,331] 75–90% <strong>of</strong> the administered dose <strong>of</strong><br />
silybin is metabolized to glucuronide and sulfate<br />
conjugates, which are partly hydrolyzed and cycled<br />
enterohepatically. [315] Silybin elimination is estimated as<br />
<strong>20</strong>–40% over a 24-hour period with a maximum between<br />
2 and 9-hour post-administration. [332] Thus, silybin in the<br />
bile theoretically inhibits enteric absorption and interrupt<br />
enterohepatic circulation <strong>of</strong> the amatoxins. [249,333]<br />
Silybin administration within 60 hours after a toxic<br />
mushroom meal blocked the increased alanine amino<br />
transferase (ALAT) and restored other parameters <strong>of</strong><br />
liver dysfunction. [315,334]<br />
After oral silymarin, collected bile contained high<br />
amounts <strong>of</strong> isosilybin (a silybin isomer) and very low<br />
levels <strong>of</strong> silydianin and silychristin. The low concentrations<br />
in plasma and bile <strong>of</strong> both silydianin and<br />
silychristin indicate a minor contribution <strong>of</strong> these<br />
compounds to the hepatoprotective effect <strong>of</strong> silymarin<br />
complex. [335]<br />
In order to increase silybin concentration in the bile,<br />
recent studies have combined silybin with phosphatidylcholine;<br />
this lipophilic complex is called silipide (IdB<br />
1016). Silybin concentrations in patient bile after silipide<br />
administration were several-fold higher than after oral<br />
silymarin. This suggests that such complexation<br />
increased the oral bio-availability <strong>of</strong> silybin. It is likely<br />
that drug passage through membranes <strong>of</strong> the gastrointestinal<br />
tract was facilitated, favoring hepatic delivery.<br />
[335,336]<br />
Advances in the knowledge <strong>of</strong> the hepatoprotective<br />
properties <strong>of</strong> silymarin complex have yielded convincing<br />
experimental evidence for the efficacy <strong>of</strong> silybin and<br />
justified its use in human amatoxin poisoning. However,<br />
according to Wellington and Jarvis, [315] the value <strong>of</strong><br />
silymarin relates to the toxin dose and time lag before<br />
drug administration. In a clinical series <strong>of</strong> <strong>20</strong>5 cases, all<br />
patients who received silybin survived. [298] Reviewing<br />
the recovery <strong>of</strong> 18 cases <strong>of</strong> Amanita poisoning treated<br />
with silybin, Hruby et al. [290,291] concluded that the drug<br />
administered even up to 48 hour after toxic mushroom<br />
ingestion was effective in preventing severe liver
732<br />
damage. In a <strong>retrospective</strong> study <strong>of</strong> 175 cases with a<br />
mortality rate <strong>of</strong> 8.6%, [315] 131 patients were treated with<br />
silybin/benzylpenicillin combination (14 deaths) and 44<br />
patients received silybin alone (one death). However, the<br />
mean interval between mushroom ingestion and institution<br />
<strong>of</strong> silybin therapy as well as the severity <strong>of</strong> poisoning<br />
were not identical for the two therapeutic modes.<br />
Table 3 lists 74 amatoxin-poisoning cases (4.5% <strong>of</strong><br />
1632) treated with silybin as mono-chemotherapy and<br />
Tables 4–6 list 550 cases (33.7% <strong>of</strong> 1632) treated with<br />
silybin in combination with other drugs. Some authors<br />
suggested the combination <strong>of</strong> silybin plus benzylpenicillin<br />
to be more beneficial than other combinations.<br />
[18,69,224,337] Faulstich and Zilker thought that<br />
both drugs act as competitive inhibitors <strong>of</strong> the amatoxintransporting<br />
system and should not be used in<br />
combination [14] but did not consider the disparate effects<br />
<strong>of</strong> benzylpenicillin and silybin on a-Ama uptake<br />
reported by Kröncke et al. [279] In our survey, 379, 102,<br />
and 49 <strong>of</strong> 1632 amatoxin intoxicated patients received<br />
silybin/benzylpenicillin as bi-chemotherapy (23.2%,<br />
Table 4), tri-chemotherapy (6.3%, Table 4), and polychemotherapy<br />
(3%, Table 6), respectively.<br />
The initial dose <strong>of</strong> silybin dihemisuccinate is 5 mg/kg<br />
by IV infusion over 1 hour followed by <strong>20</strong> mg/kg/day by<br />
continuous infusion for six days until transaminase levels<br />
have normalized. [315] In the United States, silymarin is<br />
available only as a food supplement; at this time there is<br />
no active Investigational New Drug (IND) application<br />
for any component <strong>of</strong> the silymarin complex in the U.S.<br />
FDA. [231,315,338]<br />
No serious side effects have been observed with<br />
silybin [225] but nausea, epigastric discomfort, arthralgia,<br />
headaches, pruritus, and urticaria have been reported.<br />
Due to a lack <strong>of</strong> adequate clinical investigations, silybin<br />
is not administered to children under 12 <strong>year</strong>s <strong>of</strong> age,<br />
unless the benefits outweigh the risks. [315] Oral<br />
silymarin, Legalon w and b-cyclodextrin silybin have<br />
been recommended as an alternative to parenteral<br />
silybin. [133,339]<br />
Hepatoprotective activity <strong>of</strong> the Extractum Silybi<br />
fluidum (fluid extract) and “Silybochol” against rat liver<br />
damage caused by CCl 4 was recently shown. This<br />
preliminary finding suggests potential utility in clinical<br />
trials <strong>of</strong> the bio-active substances from S. marianum fruit<br />
powder, fluid extract, and fatty oil. [340]<br />
Thioctic Acid<br />
Mechanistic studies on thioctic acid (a-lipoic acid;<br />
1,2-dithiolane-3-pentanoic acid) suggest a rationale for<br />
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Enjalbert et al.<br />
potential benefit in amatoxin hepatotoxicity. Acting as a<br />
free radical scavenger, it might prevent lipid peroxidation<br />
<strong>of</strong> the cell membrane by dissociating the hydrogen<br />
ion on the sulfhydryl groups <strong>of</strong> dihydrothioctic acid, its<br />
main metabolite. [354] Due to the antioxidant activity <strong>of</strong><br />
both oxidized and reduced forms, affecting in vitro<br />
cellular metabolic processes, thioctic acid is capable <strong>of</strong><br />
regenerating directly vitamin C and indirectly vitamin E,<br />
as well as influencing the increase <strong>of</strong> intracellular<br />
glutathione content. [355,356] Thioctic acid has a therapeutic<br />
potential in the treatment <strong>of</strong> hepatic diseases<br />
induced by chemical agents in animal models as<br />
reviewed by Bustamante et al. [356]<br />
It was introduced for the treatment <strong>of</strong> amatoxin<br />
poisoning in the Czech Republic by Kubicka in 196<strong>9.</strong> [341]<br />
The successful use <strong>of</strong> a-lipoic acid was also reported<br />
from Italy [342,343] and then reviewed in the Eastern<br />
European literature. [344,345] In the United States, the first<br />
use <strong>of</strong> thioctic acid was described in 1972 in New Jersey<br />
for A. verna intoxication with apparently beneficial<br />
result. [346] The cause–effect relationship between<br />
thioctic acid administration and clinical improvement<br />
in amatoxin poisoning is not clearly established and<br />
opinion concerning efficacy is divergent. [347 – 351] Early<br />
enthusiasm in the United States waned as investigations<br />
<strong>of</strong> thioctic acid carried out in Amanita poisoned mice and<br />
dogs reported either a severe glucose imbalance [352] or<br />
ineffectiveness <strong>of</strong> the drug. [353] A controlled clinical trial<br />
was never conducted and there were too few patients<br />
enrolled in the IND study to support a claim <strong>of</strong> efficacy.<br />
This drug is unavailable for human use in the United<br />
States. Multiple authors discourage its clinical<br />
use. [74,352,357 – 359] According to Floersheim et al. [298]<br />
and Floersheim [360] the administration <strong>of</strong> thioctic acid is<br />
<strong>of</strong>ten associated with a fatal outcome and it should be<br />
removed from the therapeutic protocol. [231] Other<br />
authors support thioctic acid trials in amatoxin poisoning<br />
until its efficacy can be confirmed or refuted. [23,361,362]<br />
Given the experimental findings <strong>of</strong> hypoglycemia as a<br />
major side effect <strong>of</strong> thioctic acid, [348,352] the drug should<br />
beadministeredwithasustainedIVdrip<strong>of</strong>glucose. [349,363]<br />
In clinical use, thioctic acid was combined with glucose<br />
in IV infusions at doses <strong>of</strong> (i) 300 mg/kg/day in four<br />
divided doses and then 600 mg/kg/day [73,361] and (ii)<br />
50–150 mg/kg/day. [364] Allergic skin reactions have<br />
been reported. [355] Because it is sensitive to light and<br />
heat, bottles and infusion lines containing the solution<br />
must be wrapped in aluminum foil. [231,347,349]<br />
In this <strong>20</strong>-<strong>year</strong> case survey beginning in the 1980s,<br />
thioctic acid was used in 8 <strong>of</strong> 1632 amatoxin poisonings<br />
(0.5%, Table 3) as single chemotherapy and in 442 <strong>of</strong>
1632 (27.1%, Tables 4–6) in combined chemotherapy.<br />
Thioctic acid/benzylpenicillin was given as bi-chemotherapy<br />
(<strong>20</strong>7 <strong>of</strong> 1632, 12.7%, Table 4), tri-chemotherapy<br />
(180 <strong>of</strong> 1632, 11%, Table 4), and poly-chemotherapy (42<br />
<strong>of</strong> 1632, 2.6%, Table 6).<br />
Antioxidant Drugs<br />
In recent <strong>year</strong>s, authors have postulated that the<br />
oxidant effects <strong>of</strong> amatoxins could be counteracted by<br />
the use <strong>of</strong> antioxidants such as ascorbic acid, cimetidine,<br />
and NAC. [116]<br />
L-ascorbic acid (vitamin C) is widely distributed in the<br />
plant and animal kingdoms. Biochemistry, physiological<br />
properties, and clinical uses <strong>of</strong> this chemical agent have<br />
been extensively reviewed. [301,365] Vitamin C inhibits<br />
lipid peroxidation and is used as hepatocyte protector in<br />
damage due to acetaminophen and CCl4. [366] It was<br />
introduced in the emergency treatment <strong>of</strong> A. phalloides<br />
intoxication <strong>20</strong> <strong>year</strong>s ago as part <strong>of</strong> a multi-drug regimen<br />
(plus nifuroxazide and dihydrostreptomycin) devised by<br />
Bastien. [194,367,368] The regimen was reviewed by<br />
Chabré [369] and is still used in French poison centers. [231]<br />
Our survey found use <strong>of</strong> vitamin C, usually in<br />
combination with benzylpenicillin, in 60 cases (3.7%,<br />
Tables 4–6).<br />
Cimetidine, a cytochrome P450 inhibitor, is an<br />
antioxidant agent with cytoprotective and antifibrinolytic<br />
effects. [301,370] Therapeutic use in the management <strong>of</strong><br />
amatoxin poisoning is based on the clinical similarity <strong>of</strong><br />
this intoxication to liver damage due to other toxins<br />
affecting cytochrome P450. Histological examination <strong>of</strong><br />
livers from a-Ama poisoned mice revealed major<br />
mitochondrial changes while the hepatic mitochondria<br />
were preserved in a-Ama poisoned mice treated with<br />
cimetidine either prophylactically or within 6 hours. [371]<br />
A three-drug combination <strong>of</strong> cimetidine, benzylpenicillin,<br />
and ascorbic acid significantly improved enzymatic<br />
and histopathological changes and survival rate <strong>of</strong> a-<br />
Ama intoxicated mice. [372] Clinical cimetidine treatment<br />
was reported for only 21 amatoxin poisoned patients<br />
(1.3%, Tables 3, 4, and 6) at a dose <strong>of</strong> 300 mg IV<br />
administered every 8 hours and usually in association<br />
with benzylpenicillin.<br />
NAC acts as a glutathione precursor when natural<br />
stores are depleted and is also a scavenger <strong>of</strong> free radicals<br />
formed in paracetamol poisoning. [373,374] The similarity<br />
between the clinical toxicities <strong>of</strong> a-Ama and paracetamol<br />
suggested NAC inclusion in the management <strong>of</strong><br />
amatoxin poisoning. [125,143 – 145] Japanese authors investigating<br />
mushroom toxicity in isolated rat hepatocytes<br />
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<strong>Amatoxin</strong> <strong>Treatment</strong> 733<br />
showed that Amanita extracts (in particular A. virosa )<br />
markedly decreased intracellular glutathione content.<br />
[375] However, the negative results observed with<br />
NAC treatment for amatoxin poisoned mice indicate that<br />
amatoxin metabolism is probably not identical to that <strong>of</strong><br />
paracetamol and that glutathione may play little or no<br />
role in amatoxin hepatotoxicity. [376] Over the <strong>20</strong>-<strong>year</strong><br />
period, 89 <strong>of</strong> 1632 amatoxin cases (5.5%, Table 3)<br />
received chemotherapy with NAC alone and 103 <strong>of</strong> 1632<br />
(6.3%, Tables 4–6) received NAC combined with other<br />
drugs, usually benzylpenicillin.<br />
Miscellaneous Drugs and Prospective<br />
<strong>Treatment</strong>s<br />
Other drugs such as antibiotics, antiseptic agents,<br />
hormones and steroids used in the management <strong>of</strong><br />
amatoxin intoxicated patients are listed in Tables 3–6.<br />
To our knowledge, no experimental evidence is reported<br />
<strong>of</strong> any hepatoprotective effect <strong>of</strong> antibiotics such as<br />
aminoglycoside derivatives (gentamycin, neomycin,<br />
streptomycin), cyclopeptide derivatives (vancomycin),<br />
and macrolide derivatives (clindamycin). These agents<br />
are not considered in our <strong>retrospective</strong> <strong>analysis</strong>. The<br />
antiseptic agent nifuroxazide plus dihydrostreptomycin<br />
and vitamin C is part <strong>of</strong> Bastien’s regimen. [194,367,368]<br />
The role <strong>of</strong> hormones and steroids in the management <strong>of</strong><br />
amatoxin syndrome is questionable. Other agents<br />
proposed for therapy include iridoid glycosides and<br />
immunotherapy and are discussed below.<br />
Insulin and human growth hormone (hGH) were<br />
reported to be effective in rat liver regeneration after<br />
Amanita poisoning. [377] Intravenous infusion <strong>of</strong> either<br />
insulin/glucagon or insulin/hGH, in combination with<br />
glucose, was administered to amatoxin poisoned children<br />
by clinicians in Poland in an attempt to stimulate liver<br />
cell metabolism. [172,175] A randomized clinical series <strong>of</strong><br />
FHF cases showed no effect <strong>of</strong> insulin/glucagon on liver<br />
regeneration. [378]<br />
Experiments on a-Ama uptake into hepatocytes<br />
suggested that prednisolone might exert a protective<br />
effect by competition between the steroid and toxin for<br />
the transport systems and not by nonspecific effects upon<br />
the cell membrane. [279] Investigations <strong>of</strong> steroids in mice<br />
and dogs poisoned with either A. phalloides extract or a-<br />
Ama revealed a positive effect on recovery <strong>of</strong> mice but<br />
not on survival <strong>of</strong> dogs. [276,304] Since steroids have no<br />
efficacy in acute hepatic failure, the American and<br />
European Associations for the Study <strong>of</strong> the Liver<br />
excluded these drugs for this indication 25 <strong>year</strong>s ago. [264]<br />
A 1979 double-blind randomized trial with acute hepatic
734<br />
failure cases treated by hydrocortisone confirmed that<br />
steroids improved neither hepatic function nor survival<br />
rate. [379]<br />
Although steroids were included as therapeutic agents<br />
for Amanita poisoning by Floersheim et al. in 1982, [298]<br />
he suggested removal <strong>of</strong> steroids from treatment<br />
protocols in 1985 because <strong>of</strong> lack <strong>of</strong> correlation with<br />
the outcome. [360] Despite this, in the cases published<br />
since 1980 steroids were reported in the treatment as<br />
mono-chemotherapy (8 <strong>of</strong> 1632, 0.5%, Table 3) and as<br />
bi-, tri-, and poly-chemotherapies with benzylpenicillin<br />
(443 <strong>of</strong> 1632, 27.1%, Tables 4 and 6), and without<br />
benzylpenicillin (0.5%, 8 <strong>of</strong> 1632, Tables 5 and 6).<br />
Iridoid glycosides such as aucubin and kutkin<br />
represent a group <strong>of</strong> monoterpene glycosides with a<br />
cyclopentane-(c)-pyran ring structure widely distributed<br />
in the plant kingdom. [380] Aucubin is a common iridoid<br />
glycoside isolated from Eucommia ulmoides Oliver<br />
(Magnoliaceae ), [381] Plantago asiatica L. (Plantaginaceae<br />
), [382] and Aucuba japonica Thunb. (Corna-<br />
ceae ). [383]<br />
Iridoid compounds have recently been<br />
successful in experimental amatoxin poisoning, and on<br />
the basis <strong>of</strong> the promising results, these drugs may merit<br />
clinical evaluation. Protective activities <strong>of</strong> aucubin<br />
against a-Ama have been reported in beagle dogs orally<br />
poisoned by A. virosa extract, and in mice I.P. administered<br />
with the toxin, even when the treatment was begun<br />
12 hours later. [380,382] According to these authors, the<br />
mechanism <strong>of</strong> hepatoprotection might be attenuation <strong>of</strong><br />
the continuous depression <strong>of</strong> liver m-RNA biosynthesis<br />
caused by a-Ama. [382,384] This mechanism was not<br />
confirmed in rat studies, however, aucubin enhanced<br />
excretion <strong>of</strong> a-Ama suggesting that it or one <strong>of</strong> its<br />
hydrolyzed products may displace the toxin from binding<br />
sites. [385] Oral administration is ineffective; [380,384] and<br />
the influence <strong>of</strong> the route <strong>of</strong> administration on efficacy<br />
may merit elucidation. [386] As far as we know, no<br />
investigation <strong>of</strong> aucubin in humans has been conducted.<br />
Picrosides I–III and kutkoside, known collectively as<br />
kutkin, were isolated from the roots and rhizome <strong>of</strong><br />
Picrorhiza kurroa Rogle ex Benth. (Scrophulariaceae ),<br />
an Indian plant used for the treatment <strong>of</strong> liver<br />
diseases. [387] Protective activity <strong>of</strong> kutkin was demonstrated<br />
against the hepatic damage <strong>of</strong> A. phalloides in<br />
rodent models. [388,389] Floersheim found the protective<br />
effect <strong>of</strong> kutkin comparable to that <strong>of</strong> silybin. [390]<br />
Constituents from P. kurroa have demonstrated antioxidant<br />
and anti-lipid peroxidation activity as well as<br />
effects on liver regeneration in research cited by<br />
Luper. [313] Further investigations should be carried out<br />
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to assess the place <strong>of</strong> kutkin in clinical amatoxin<br />
poisoning treatment.<br />
In vitro production and cytoprotective properties <strong>of</strong><br />
polyclonal amanitin-specific antibodies were reported in<br />
1993. [391] However, Faulstich et al. [392] reported in 1998<br />
that amatoxin-specific Fab fragments or monoclonal<br />
antibodies enhanced the activity <strong>of</strong> amatoxins and that<br />
this new therapeutic strategy should not be considered.<br />
Retrospective Data on Use <strong>of</strong> Chemotherapy<br />
Enjalbert et al.<br />
Our review <strong>of</strong> chemotherapy administered to 1632<br />
amatoxin poisoned patients underscores its typical use in<br />
combination, and makes it difficult to assess the efficacy<br />
<strong>of</strong> each therapeutic agent individually. The mechanism<br />
by which b-lactam antibiotics (benzylpenicillin, ceftazidime)<br />
afford their therapeutic effect is still scientifically<br />
uncharacterized. Considerable data support the relevance<br />
<strong>of</strong> silymarin complex in amatoxin poisoning; the<br />
mechanisms <strong>of</strong> action include an antioxidant effect,<br />
anti-lipid oxidation, enhancement <strong>of</strong> detoxication, and<br />
stimulation <strong>of</strong> the hepatic regeneration. Biochemical data<br />
suggesting hepatoprotection by antioxidants support the<br />
continued consideration <strong>of</strong> free radical scavengers such<br />
as ascorbic acid, cimetidine, and NAC in the management<br />
<strong>of</strong> amatoxin intoxication. Hepatoprotective effects<br />
<strong>of</strong> iridoid glycosides (aucubin, kutkin) have also been<br />
demonstrated with in vivo animal models; these<br />
promising findings merit further investigations.<br />
In our compilation, 80.9% (1632 <strong>of</strong> <strong>20</strong>17) amatoxin<br />
poisoned patients received chemotherapy (Chem-group)<br />
with or without detoxication procedures (Tables 3–6).<br />
Drugs were given as mono-chemotherapy in 347 cases<br />
(21.3%, Table 3) and in combination in 1285 cases<br />
(78.7%, Tables 4–6) either as bi-chemotherapy (815 <strong>of</strong><br />
1632, 4<strong>9.</strong>9%) or tri-chemotherapy (280 <strong>of</strong> 1632, 17.2%)<br />
or poly-chemotherapy (190 <strong>of</strong> 1632, 11.6%). The<br />
therapeutic agents can be classified into four groups<br />
according to the frequency <strong>of</strong> their administration as<br />
single agent or chemotherapy combinations. Frequency<br />
<strong>of</strong> use ranged from 0.7 to 86.5%. The lowest frequency<strong>of</strong>-use<br />
group among the 1632 amatoxin poisoning cases<br />
is constituted by ceftazidime (0.7%), cimetidine (1.1%),<br />
and antiseptic agent (1.2%). The second group is<br />
represented by vitamin C (3.7%), antibiotics (3.8%),<br />
and NAC (11.8%). The third group consists <strong>of</strong> thioctic<br />
acid (27.1%), steroids (27.6%), and silybin (33.7%). The<br />
highest frequency-<strong>of</strong>-use group is comprised <strong>of</strong> cases<br />
treated with benzylpenicillin (1411 <strong>of</strong> 1632 patients,<br />
86.5%). Benzylpenicillin was the most frequently<br />
administered drug used alone (164 cases, 10.1%,
Table 3) when compared to antibiotic (one case),<br />
cimetidine (three cases), NAC (89 cases), silybin (74<br />
cases), and steroids or thioctic acid (eight cases for each).<br />
It is also the agent most frequently represented in therapy<br />
combinations (1247 cases <strong>of</strong> 1632, 76.4%, Tables 4 and<br />
6). The most common combinations were benzylpenicillin<br />
plus silybin (379 <strong>of</strong> 1632, 23.2%) and benzylpenicillin<br />
plus thioctic acid (<strong>20</strong>7 <strong>of</strong> 1632, 12.0%), in<br />
contrast to the low representation <strong>of</strong> benzylpenicillin plus<br />
steroid (95 <strong>of</strong> 1632, 5.8%).<br />
Retrospective Data on Use <strong>of</strong> Specific<br />
<strong>Treatment</strong>s<br />
Specific treatments consist <strong>of</strong> detoxication procedures<br />
and chemotherapy. In our review, <strong>20</strong>17 <strong>of</strong> 2108<br />
amatoxin-poisoned patients (95.7%) were treated with<br />
either one or both <strong>of</strong> these specific therapeutic modes.<br />
Detoxication procedures alone were applied to 385 <strong>of</strong><br />
<strong>20</strong>17 cases (1<strong>9.</strong>1%, Table 2) whereas chemotherapy with<br />
or without detoxication procedures was administered to<br />
the majority <strong>of</strong> cases (1632 <strong>of</strong> <strong>20</strong>17, 80.9%, Tables 3–6).<br />
Overall survivors (1810 <strong>of</strong> <strong>20</strong>17 patients, 8<strong>9.</strong>7%) as<br />
listed in Tables 2–6 are subsequently analyzed for the<br />
relation to specific therapy and to LT.<br />
Liver Transplantation<br />
Liver transplantation has emerged as the most<br />
important advance in the therapy <strong>of</strong> FHF and is an<br />
intervention formally validated for this disease with<br />
survival rates from 60 to 80%. [282,393] Kinetic studies<br />
have shown no risk <strong>of</strong> toxicity for the transplanted<br />
liver [257] beginning day 4 after mushroom ingestion.<br />
Total Orthotopic Liver Transplantation and<br />
Auxiliary Partial Liver Transplantation<br />
Two surgical options, orthotopic liver transplantation<br />
(OLT) and auxiliary LT have been developed. Total OLT<br />
is a well-established procedure for FHF but requires long<br />
immunosuppression to maintain the graft. Because some<br />
patients with partial hepatectomy and temporary support<br />
may have complete morphological and functional<br />
recovery <strong>of</strong> their own liver, auxiliary partial liver<br />
transplantation (APOLT) represents an alternative. In<br />
APOLT only a portion <strong>of</strong> the native liver is removed and<br />
the remainder is left in situ; the transplant provides<br />
temporary assistance until the native liver recovers and<br />
the immunosuppression can be withdrawn.<br />
[394 – 397]<br />
Within the <strong>20</strong>-<strong>year</strong> period <strong>of</strong> this review, 31 amatoxin<br />
poisoned patients underwent OLT: Six received suppor-<br />
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<strong>Amatoxin</strong> <strong>Treatment</strong> 735<br />
tive measures alone (Table 1), six were treated with<br />
detoxication procedures without chemotherapy (Table 2),<br />
and 19 received chemotherapy with or without<br />
detoxication procedures (Tables 3–6). The success <strong>of</strong><br />
APOLT in one young girl was also reported, [119,1<strong>20</strong>]<br />
(Table 3). These 32 LT patients represent only 1.5% <strong>of</strong><br />
2108 intoxicated cases reviewed in our survey. Twelve<br />
additional LT cases performed since 1985 were cited<br />
but due to lack <strong>of</strong> adequate data were not analyzed.<br />
[87,92,93,100,111,116,<strong>20</strong>6,<strong>20</strong>7,216,218,398,399]<br />
The early use <strong>of</strong> specific treatments (detoxication<br />
procedures and chemotherapy) and <strong>of</strong> biological<br />
parameters predicting recovery may avoid unnecessary<br />
LT. [146,159,187 – 189] Many patients who originally were<br />
candidates for LT showed improvement in hepatic<br />
function and were taken <strong>of</strong>f the transplant waiting<br />
list. [83,156,158,159]<br />
The major dilemma in emergency liver failure is the<br />
right moment to transplant. The time between “too early”<br />
and “too late” may be very short. LT is considered too<br />
late when complications such as multi-organ failure with<br />
cerebral edema or renal insufficiency become contraindications<br />
to transplant because they compromise the<br />
success <strong>of</strong> surgery. The mean delay (about 2 days)<br />
between the decision for LT and finding <strong>of</strong> a liver donor<br />
must be taken into account. The shortage <strong>of</strong> available<br />
livers limits transplantation. Recently, a living, related<br />
donor <strong>of</strong> a 1-<strong>year</strong>-old boy poisoned with amatoxin<br />
provided a partial liver transplant specimen. [57] Fulminant<br />
hepatitis is rapidly fatal; only 50–85% <strong>of</strong> patients<br />
identified as candidates for LT survive long enough to<br />
receive a transplant. [400,401] An explosive course was also<br />
reported for amatoxin poisoned patients included in the<br />
emergency list for LT who died before obtaining a<br />
donor. [89,118,138,188,<strong>20</strong>3]<br />
It is essential to establish early, reliable criteria<br />
identifying the immediate prognosis. [402,403] The number<br />
<strong>of</strong> amatoxin poisoning victims considered for LT is small<br />
and the prognostic indicators for LT are not clearly<br />
defined. [1<strong>20</strong>] Candidacy guidelines for OLT and APOLT<br />
have therefore been extrapolated from experience with<br />
FHF from other etiologies and include repeated clinical<br />
examination and biological investigations. [404]<br />
Prognostic Factors<br />
Most liver units have accepted for emergency liver<br />
transplant the King’s College criteria proposed by<br />
O’Grady et al. [405] from a <strong>retrospective</strong> <strong>analysis</strong> <strong>of</strong> 278<br />
patients with FHF not induced by acetaminophen<br />
overdose. These criteria are based on PT, age, etiology,
736<br />
time between appearance <strong>of</strong> jaundice and onset <strong>of</strong><br />
encephalopathy, and bilirubin concentration. The criteria<br />
have been recently evaluated by the University <strong>of</strong><br />
Pittsburgh for 177 patients over a 13-<strong>year</strong> period and<br />
were found to be relatively effective in predicting death<br />
and the need for transplantation. [406] French emergency<br />
liver units rely on the combination <strong>of</strong> encephalopathy<br />
stages (III and IV) with factor V concentration and<br />
age. [407 – 409] Other prognostic models reviewed by Mas<br />
and Rodés [244] based on hemodynamic disturbances and<br />
clinical course <strong>of</strong> FHF have also been developed.<br />
Furthermore, other variables such as a factor VIII/V<br />
ratio [410] as well as serial a-fetoprotein levels [245] might<br />
be useful tests for predicting survival in FHF. Lastly, a<br />
Gc level ,34 mg/mL 48 hours after admission strongly<br />
suggests a stage <strong>of</strong> liver failure beyond which recovery<br />
will not occur. [411]<br />
Despite the lack <strong>of</strong> absolute predictors, prognostic<br />
factors such as stage <strong>of</strong> encephalopathy, coagulation<br />
tests, metabolic abnormalities, and age are useful in the<br />
rational planning <strong>of</strong> LT. Of 31 transplanted patients<br />
having undertaken OLT (including 4 children below 10<br />
<strong>year</strong>s <strong>of</strong> age), the prognostic factors used for 27 cases are<br />
listed in Table 7.<br />
Encephalopathy Stages<br />
The association between encephalopathy stages<br />
(I–IV) [412] and vital prognosis is controversial. According<br />
to Bernuau et al. [413] and Frohburg et al., [399]<br />
encephalopathy does not always reflect liver function<br />
deterioration. Since advanced encephalopathy typically<br />
occurs late in the course <strong>of</strong> the FHF, the stage <strong>of</strong><br />
encephalopathy may be <strong>of</strong> limited use. [403] Other authors<br />
promote encephalopathy stage as the most powerful<br />
clinical indicator <strong>of</strong> the severity <strong>of</strong> liver disease.<br />
[244,409,414,415] According to Gill and Sterling, [245]<br />
patients with a stage II encephalopathy have a mortality<br />
<strong>of</strong> 30% while those who progress to stage IV have a<br />
mortality rate greater than 80%. In the early use <strong>of</strong> OLT<br />
for amatoxin poisoning, encephalopathy stages (III and<br />
IV) were the major decision factors for this surgery.<br />
[80,103,106,136,154,193,199]<br />
However, Klein’s experience [102] indicated a clinical<br />
course <strong>of</strong> amatoxin poisoning characterized by slow<br />
deterioration over a week that then worsens quickly. This<br />
pattern may lead to an early underestimation <strong>of</strong> liver<br />
damage. Consequently, several authors think that LT<br />
should be considered with the onset <strong>of</strong> mild encephalopathy<br />
(stages I and II) before the onset <strong>of</strong> progressive and<br />
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pr<strong>of</strong>ound neurological signs resulting from severe<br />
amatoxin intoxication [86,156,198,199] (Table 7).<br />
Coagulation Factors<br />
No definitive conclusion can be drawn about the<br />
usefulness <strong>of</strong> the degree <strong>of</strong> coagulopathy as an indication<br />
for LT because too few patients are included in clinical<br />
data, and prophylactic administration <strong>of</strong> fresh frozen<br />
plasma modifies or prevents interpretation <strong>of</strong> coagulation<br />
factors. [401] The PT is considered the most satisfactory<br />
test <strong>of</strong> hepatocellular necrosis and prognosis. [405,414,415]<br />
Some authors suggest that factor V level is more sensitive<br />
and reliable than PT and a better indicator <strong>of</strong> recovery<br />
than other biological factors. [158,407,416,417] According to<br />
Izumi et al., [418] the predictive accuracy <strong>of</strong> plasma factor<br />
V is less than that <strong>of</strong> international normalized result<br />
(INR) as advocated by Harrison et al. [419] A factor VIII/V<br />
ratio <strong>of</strong> more than 30% can be associated with a poor<br />
prognosis. [410] The dynamics <strong>of</strong> a biological marker<br />
could be <strong>of</strong> greater predictive value than the minimum or<br />
maximum level <strong>of</strong> the variable itself. The progressive<br />
prolongation <strong>of</strong> PT was noted as an outcome predictor <strong>of</strong><br />
the patients with FHF and its evolution over 4 days after<br />
the poisonous mushroom meal was suggested as a<br />
reliable indicator <strong>of</strong> recovery or death. [14]<br />
Metabolic Abnormalities<br />
Enjalbert et al.<br />
Metabolic abnormalities such as lactic acidosis,<br />
hypoglycemia, hyperbilirubinemia, and increased aminotransferases<br />
seen in FHF may also provide foundation<br />
for LT decisions. [244] Lactic acidosis and hypoglycemia<br />
are cited as prognostic factors associated with encephalopathy<br />
stage II and prolonged PT that determine urgent<br />
LT. [99,151,156,199] Several studies have shown that a high<br />
level <strong>of</strong> bilirubin (.300 mmol/L) is a sign <strong>of</strong> fatal<br />
prognosis. [399,405,4<strong>20</strong>] On the basis <strong>of</strong> their own<br />
experience, Faulstich and Zilker [14] suggested that LT<br />
be performed when an amatoxin poisoned patient<br />
exhibits a PT below <strong>20</strong>% associated with both high<br />
bilirubin and creatinine (.5 and .2 mg/dL, respectively),<br />
on day 3. Patients with progressive failure have<br />
continued rise in the bilirubin and prolongation <strong>of</strong> PT<br />
despite declining aminotransferases. [245] Recent results<br />
support the hypothesis that a sustained elevation in<br />
markers <strong>of</strong> regeneration (a-fetoprotein, g-glutamyl<br />
transferase) for more than 10–12 hours combined with<br />
a similarly maintained decline in markers <strong>of</strong> necrosis<br />
(ASAT, ALAT, alkaline phosphatase, LDH) levels could<br />
aid in prediction <strong>of</strong> recovery. [124]
Table 7<br />
Prognosis Factors for Liver Transplant<br />
Coagulation Factors<br />
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<strong>Amatoxin</strong> <strong>Treatment</strong> 737<br />
Date/References No. <strong>of</strong> cases Encephalopathy Stage P.T. Factor V(%) Lactic Acidosis Hypoglycemia (mg/dL) Hyperbilirubinemia a (mmol/L)<br />
1985 [193] 1/1; child III coma 34.2 sec NI NI 161 3<strong>9.</strong>3<br />
1988 [136] 1/1 Coma ,<strong>20</strong>% ,<strong>20</strong> NI NI 180<br />
1989 [80] 1/1; child III–IV ,10% ,<strong>20</strong> NI NI NI<br />
1989 [102] 1/2 III 50 sec NI NI NI 427.3<br />
1/2 III 30 sec NI NI NI 341.9<br />
1990 [151] 2/4 I 81 sec NI þ þ <strong>20</strong>8.9<br />
2/4 II 81 sec NI þ þ NI<br />
1991 [103] 1/1 IV coma ,10% ,10 þ þ NI<br />
1992 [199] 1/1 III–IV .100 sec NI NI þ 556.5<br />
1994 [156] 1/1 I–II ,9% 6 NI NI 136.8<br />
1994 [106] 1/1 IV 28% b<br />
32 NI NI 364<br />
1994 [198] 1/1 I ,10% ,8 NI NI NI<br />
1995 [86] 2/2; 1 child II–III ,10% ,10 NI NI NI<br />
1995 [154] 1/1 III–IV ,10% b<br />
NI NI NI 144<br />
1996 [133] 2/2 II ,10% ,10 No prognosis values<br />
1997 [88] 3/3 III–IV ,<strong>20</strong>% NI NI NI 78.6<br />
1997 [91] 1/1 II–III 47.3 sec NI NI NI 124.8<br />
<strong>20</strong>00 [112] 1/1 III–IV 106 sec NI NI 19 158.9<br />
<strong>20</strong>01 [162] 2/2; 1 child NI 49 sec 7 NI NI 4<strong>9.</strong>7<br />
2<strong>9.</strong>1 sec 15 NI NI NI<br />
P.T. ¼ prothrombin test (sec) or (%); NI ¼ not indicated; þ¼presence.<br />
a<br />
Normal bilirubinemia level ranges from 2 to 17 mmol/L.<br />
b Thrombotest (factors II, VII, and X).
738<br />
Age <strong>of</strong> Patient<br />
The age <strong>of</strong> the amatoxin mushroom victim is another<br />
prognostic factor. Fatal outcomes are usually associated<br />
with age less than 10 <strong>year</strong>s. [112,244] In the series <strong>of</strong> <strong>20</strong>5<br />
and 83 patients reported by Floersheim et al., [298] and<br />
Lambert and Larcan, [19] the death rates were 51 and 22%<br />
for children below 10 <strong>year</strong>s and 16.5 and 8.8% for adults,<br />
respectively. The high mortality rate in children is likely<br />
related to the larger dose <strong>of</strong> the toxins per unit <strong>of</strong> body<br />
weight.<br />
Retrospective Liver Transplantation Data<br />
In the absence <strong>of</strong> definitive medical treatment for<br />
amatoxin poisoning, LT has changed the outlook for<br />
severe poisoning and can be the single best option<br />
for selected patients. Since 1985, 32 LTs (31 OLT and 1<br />
APOLT) have been performed for amatoxin mushroom<br />
victims representing 1.5% <strong>of</strong> 2108 intoxicated individuals.<br />
Liver transplant increases the survival rate <strong>of</strong><br />
amatoxin poisoning considering the LT patient was<br />
presumed as a fatal case. Easily applicable criteria are<br />
needed to identify patients for whom transplantation is<br />
indicated. Prognostic indicators such as encephalopathy<br />
stages, coagulation factors, metabolic abnormalities, and<br />
age have to be taken into account in the decision to<br />
perform liver transplant (OLT and APOLT) but do not<br />
replace intensive medical experience. Serious amatoxin<br />
intoxication must no longer be considered only as an<br />
acute disease with massive necrosis whose prognosis<br />
depends only on the early course <strong>of</strong> the poisoning. The<br />
progression <strong>of</strong> severely poisoned cases towards either<br />
massive necrosis or chronic active hepatitis from <strong>20</strong> to<br />
70% [176,177] should be considered factors determining<br />
LT.<br />
Statistical Analysis <strong>of</strong> Retrospective Data<br />
Two general frequency tables were established<br />
including and excluding the LT cases, and composed<br />
for a systematic <strong>analysis</strong>. Statistical comparison <strong>of</strong> the<br />
2 £ 2 tables determined significant differences in the<br />
mortality rates <strong>of</strong> the 11 modes <strong>of</strong> care; the applied<br />
treatments were sorted by increasing efficacy, i.e.,<br />
decreasing mortality rates (MR) combining MRLTi and<br />
MRLTe. Table 8 shows the 11 modes <strong>of</strong> care in order <strong>of</strong><br />
increasing efficacy/decreasing mortality rates from #1 to<br />
#11 and the number <strong>of</strong> cases in each group including and<br />
excluding the liver transplanted patients with the related<br />
mortality rates. Then to further evaluate significant<br />
comparison between the 11 analyzed therapeutic<br />
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Enjalbert et al.<br />
modalities (#1 to #11), five pooled therapies from #12<br />
to #16 have made up.<br />
The mortality rates <strong>of</strong> the 10 analyzed specific<br />
therapeutic modes varied from 5.4 to 16.9% (MRLTi)<br />
and from 1.4 to 16.9% (MRLTe) for the <strong>20</strong>62 LTi and<br />
<strong>20</strong>31 LTe amatoxin victims, respectively. Mortality rates<br />
were 47.3% ðNo: ¼ 91 LTiÞ and 43.5% ðNo: ¼ 85 LTeÞ<br />
for amatoxin poisoned patients receiving supportive<br />
measures alone (Fig. 1).<br />
First, the mortality rates <strong>of</strong> supportive measures alone<br />
(#11) were significantly higher than those found for the<br />
group <strong>of</strong> combined 10 specific therapies (#14, detoxication<br />
procedures plus nine chemotherapies) as reported in<br />
Tables 8 and <strong>9.</strong> Then, the MR <strong>of</strong> detoxication procedures<br />
(#5) compared with #13, the nine combined chemotherapies,<br />
were not statistically different, but were significantly<br />
lower than those <strong>of</strong> two chemotherapies:<br />
BpThioca (#1) and BpwSilybTriPoly (#2). More<br />
importantly, the MRLTe <strong>of</strong> detoxication-proceduresalone<br />
(#5) was significantly higher than those <strong>of</strong> silybin<br />
plus benzylpenicillin (#8) and silybin (#10) as monochemotherapy<br />
(<strong>9.</strong>0 vs. 6.0 and 1.4%, respectively).<br />
Finally, the differences between the 9 individual applied<br />
chemotherapies were evaluated. The chemotherapies<br />
exhibiting the highest mortality rates were the combination<br />
<strong>of</strong> benzylpenicillin and thioctic acid (#1.<br />
BpThioca) followed by benzylpenicillin in drug<br />
combinations without silybin as tri- and poly-chemotherapies<br />
(#2. BpwSilybTriPoly), and by the combination<br />
<strong>of</strong> benzylpenicillin and steroids (#3. BpSter).<br />
The chemotherapies with the lowest mortality rates<br />
were silybin as mono-chemotherapy (#10. Silyb) and<br />
silybin plus benzylpenicillin without and with other<br />
drugs (#8. BpSilyb, #<strong>9.</strong> BpSilybTriPoly) and NAC as<br />
mono-chemotherapy (#7. NAC). Both MRLTi and<br />
MRLTe <strong>of</strong> BpThioca (#1), BpwSilybTriPoly (#2), and<br />
BpSter (#3) were not statistically different between them<br />
(Table 9), and were significantly higher than those <strong>of</strong><br />
BpSilyb (#8), BpSilybTriPoly (#9), and Silyb (#10).<br />
Moreover no significant difference was observed<br />
between the MR <strong>of</strong> the four best therapies with the lowest<br />
mortality rates: NAC (#7), BpSilyb (#8), BpSilybTriPoly<br />
(#9), and Silyb (#10). The MR <strong>of</strong> #6, benzylpenicillin<br />
plus one or more antioxidant drug (cimetidine, NAC, or<br />
vitamin C), were significantly lower only than those <strong>of</strong><br />
BpThioca (#1). The MR <strong>of</strong> NAC (#7) were significantly<br />
lower than those <strong>of</strong> both BpThioca (#1) and BpwSilyb-<br />
TriPoly (#2).<br />
On the other hand, the statistical data were not<br />
significant for certain treatment groups whose mortality<br />
rates appear to be different in part due to the disparity <strong>of</strong>
the group size and the small number <strong>of</strong> analyzed cases:<br />
(i) the MRLTs <strong>of</strong> benzylpenicillin as mono-chemotherapy<br />
(#4) were not statistically different from those <strong>of</strong><br />
NAC (#7) and (ii) the MRLT <strong>of</strong> mono-chemotherapies,<br />
benzylpenicillin (#4), and silybin (#10) was comparable,<br />
11.6 vs. 5.4%, whereas the MRLTe <strong>of</strong> benzylpenicillin<br />
was significantly higher than that <strong>of</strong> silybin, 11.0 vs.<br />
1.4% (Table 9). Furthermore, benzylpenicillin plus<br />
antioxidant (#6. BpantiOx, No: ¼ 111 LTi treated;<br />
MRLTi <strong>9.</strong>1%; No: ¼ 110 LTe treated; MRLTe 8.2%)<br />
was not statistically different from benzylpenicillin plus<br />
other drugs without silybin as tri- and poly-chemotherapies<br />
(#2. BpwSilybTriPoly, No: ¼ 299 LTi treated;<br />
MRLTi 15.4%; No: ¼ 297 LTe treated; MRLTe<br />
14.8%): the Chi-square values were 0.08 and 0.06,<br />
respectively; more data are needed to prove whether any<br />
statistical differences in the fatality rate between these<br />
groups were truly.<br />
To further assess the role <strong>of</strong> silybin in affecting<br />
mortality, the three chemotherapies with the worst<br />
mortality rates (#16. BpThioca, BpwSilybTriPoly and<br />
BpSter) were pooled and compared with the pooled<br />
therapies including silybin (#12. BpSilyb and BpSilybTriPoly);<br />
the MR <strong>of</strong> #12 were significantly lower<br />
than those <strong>of</strong> #16 (MRLTi 7.9 vs. 15.8% and MRLTe<br />
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<strong>Amatoxin</strong> <strong>Treatment</strong> 739<br />
Table 8<br />
Statistical Analysis <strong>of</strong> <strong>Amatoxin</strong>-<strong>Poisoning</strong> Therapies<br />
5.8 vs. 15.5%). This finding supports silybin benefit in<br />
amatoxin poisoning treatment.<br />
Regarding benzylpenicillin, the most frequently<br />
therapeutic agent used among the reported cases, the<br />
bi-chemotherapies with this drug and without silybin<br />
were pooled (#15. BpThioca, BpSter, and BpantiOx),<br />
the MR found for this group were significantly higher<br />
than those <strong>of</strong> BpSilyb (#8) as reported in Table <strong>9.</strong> In<br />
addition, the MR <strong>of</strong> BpwSilybTriPoly (#2) were<br />
significantly higher than those <strong>of</strong> BpSilybTriPoly (#9)<br />
(MRLTi 15.4 vs. 7.3%; MRLTe 14.8 vs. 5.4%). All<br />
these results suggest that benzylpenicillin administered<br />
with any drug except silybin as bi-, tri-, and polychemotherapies<br />
was not beneficial in treatment <strong>of</strong><br />
amatoxin poisoning when mortality and/or liver<br />
transplant was used as the endpoint.<br />
Our statistical <strong>analysis</strong> underscores that the hepatoprotective<br />
effect <strong>of</strong> the flavonolignan complex, silymarin,<br />
and the antioxidant property <strong>of</strong> NAC play a<br />
crucial role in the recovery <strong>of</strong> amatoxin-poisoned<br />
patients. The limitations <strong>of</strong> this data include its<br />
<strong>retrospective</strong> nature and the lack <strong>of</strong> standardized severity<br />
scoring by which to judge the patient mix in each<br />
treatment group. However, these analyses and literature<br />
review point out the most fruitful avenues for future<br />
# No. LTi No. LTe MRLTi (%) MRLTe (%)<br />
Applied therapies<br />
1 BpThioca <strong>20</strong>7 <strong>20</strong>7 16.9 16.9<br />
2 BpwSilybTriPoly 299 297 15.4 14.8<br />
3 BpSter 95 95 14.7 14.7<br />
4 Bp 164 163 11.6 11.0<br />
5 Detox alone 385 379 10.4 <strong>9.</strong>0<br />
6 BpantiOx 111 110 <strong>9.</strong>1 8.2<br />
7 NAC 89 89 6.7 6.7<br />
8 BpSilyb 391 382 8.2 6.0<br />
9 BpSilybTriPoly 151 148 7.3 5.4<br />
10 Silyb 74 71 5.4 1.4<br />
11 Supportive measures alone 91 85 47.3 43.5<br />
Pooled therapies<br />
12 Bp/Silybin combinations (8, 9) 542 530 7.9 5.8<br />
13 Combined nine chemotherapies (1–4, 6–10 above) 1586 1,567 11.2 10.1<br />
14 Combined 10 specific therapies (1–10 above) <strong>20</strong>62 2,031 12.6 11.3<br />
15 Bp bi-chemotherapies without Silybin (1, 3, 6) 413 412 14.3 14.1<br />
16 Combined three worst chemotherapies (1–3) 601 599 15.8 15.5<br />
No. LTi ¼ number <strong>of</strong> patients including liver transplants; No. LTe ¼ number <strong>of</strong> patients excluding liver transplants; MRLTi ¼ mortality rate including<br />
liver transplants; MRLTe ¼ mortality rate excluding liver transplants.
740<br />
Figure 1. Effect <strong>of</strong> the modes <strong>of</strong> care (supportive measures<br />
alone and 10 specific treatments) on the distribution <strong>of</strong> treated<br />
patients in terms <strong>of</strong> survivors and deceased (histograms<br />
including liver transplants), and percentages <strong>of</strong> deceased<br />
patients vs. treated with and without liver transplants (curves).<br />
survLT: survivors including liver transplants; decLT: deceased<br />
including liver transplants; MRLTi: mortality rate including<br />
liver transplants; MRLTe: mortality rate excluding liver<br />
transplants. Supportive M. ¼ supportive measures alone<br />
(Table 1); BpThioca ¼ benzylpenicillin/thioctic acid; Bpw-<br />
SilybTriPoly ¼ benzylpenicillin/drugs without silybin as triand<br />
poly-chemotherapies; BpSter ¼ benzylpenicillin/steroid;<br />
Bp ¼ benzylpenicillin; Detox ¼ detoxication procedures alone<br />
(Table 2); BpantiOx ¼ benzylpenicillin/antioxidant drug<br />
(cimetidine, N-acetylcysteine or vitamin C); Nac ¼<br />
N-Acetylcysteine; BpSilyb ¼ benzylpenicillin/silybin;<br />
BpSilybTriPoly ¼ benzylpenicillin/drugs with silybin as triand<br />
poly-chemotherapies; Silyb ¼ silybin.<br />
clinical research to pursue, and provide a basis for the<br />
discontinuation <strong>of</strong> the clearly less effective therapies.<br />
Investigations for amatoxin treatment should focus on<br />
detoxication procedures, silybin, and NAC. Assessment<br />
<strong>of</strong> more cases would be useful to confirm their benefit.<br />
Clinical data from this <strong>20</strong>-<strong>year</strong> period do not show<br />
benzylpenicillin to be an effective drug; this antibiotic<br />
agent did not enhance the efficacy <strong>of</strong> either silybin or<br />
NAC in the treatment <strong>of</strong> amatoxin syndrome. Perhaps<br />
benzylpenicllin, thioctic acid, and steroids should be<br />
abandoned as therapeutic modalities.<br />
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SUMMARY<br />
Enjalbert et al.<br />
Although the treatment <strong>of</strong> patients exposed to<br />
amatoxin-containing mushrooms has become more<br />
sophisticated, the optimal management <strong>of</strong> the poisoning<br />
is still not determined. Options include various detoxication<br />
procedures, chemotherapies, and liver transplant in<br />
case the hepatic disease reaches a potentially fatal stage.<br />
The clinical efficacy <strong>of</strong> any modality <strong>of</strong> treatment for<br />
amatoxin poisoning is difficult to demonstrate since<br />
randomized, controlled clinical trials verified within the<br />
frame <strong>of</strong> multicenter studies have not been reported. The<br />
use <strong>of</strong> drug combinations also limits the evaluation <strong>of</strong><br />
individual efficacy <strong>of</strong> the therapeutic modalities. The<br />
theoretical and experimental bases for antitoxic action <strong>of</strong><br />
most <strong>of</strong> these agents are not clearly established. Silymarin<br />
complex and free radical scavengers (cimetidine, NAC,<br />
vitamin C) have respective hepatoprotective and antioxidant<br />
properties that yield convincing support for their use.<br />
LT is accepted as a life-saving procedure in amatoxin<br />
poisoning cases leading to acute massive hepatic<br />
necrosis. Early identification <strong>of</strong> liver dysfunction, rapid<br />
evaluation <strong>of</strong> suitability for transplant, immediate listing,<br />
and an available donor research are crucial. It is<br />
important to verify that the prognostic indications for LT<br />
are defined and met.<br />
Our <strong>retrospective</strong> data determined the use and the<br />
mortality rate for each treatment in this overall<br />
compilation <strong>of</strong> heterogeneous subjects. For statistical<br />
<strong>analysis</strong> relative to MR, the 32 amatoxin victims<br />
receiving LT were considered as special cases and<br />
were either excluded from the group <strong>of</strong> treated patients<br />
(MRLTe), or since their outcome was considered<br />
virtually fatal without transplantation, were included as<br />
deadly cases (MRLTi).<br />
Benzylpenicillin, despite mechanism <strong>of</strong> its action<br />
poorly argued, was the most frequently administered<br />
agent (86.5%). Silybin was given to 38.2% <strong>of</strong> patients.<br />
Among the antioxidant drugs, NAC was the most<br />
frequently prescribed agent, utilized in 11.8% <strong>of</strong> cases.<br />
Comparison <strong>of</strong> the mortality rates <strong>of</strong> 11 modes <strong>of</strong> care<br />
representing sufficient numbers <strong>of</strong> patients for statistical<br />
<strong>analysis</strong> showed that supportive measures alone resulted<br />
in high mortality comparable to historical data (.40%).<br />
The mortality rates <strong>of</strong> detoxication procedures alone<br />
were comparable to those <strong>of</strong> the nine combined<br />
chemotherapies suggesting a benefit due to amatoxin<br />
removal after initial absorption. Case data and numbers<br />
were insufficient to allow a comparison <strong>of</strong> the MR <strong>of</strong> the<br />
nine chemotherapies used with and without detoxication
Table 9<br />
Comparison <strong>of</strong> Mortality Rates Relative to the Different Therapies <strong>of</strong> the <strong>Amatoxin</strong>-<strong>Poisoning</strong>: (a) Including Liver Transplants (MRLTi) and (b) Excluding Liver<br />
Transplants MRLTe<br />
# Therapies 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16<br />
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<strong>Amatoxin</strong> <strong>Treatment</strong> 741<br />
(a) Including liver transplants (MRLTi)<br />
1. BpThioca 16.9 * * * ** * * **<br />
2. BpwSilybTriPoly 15.4 * * ** ** * **<br />
3. BpSter 14.7 * ** * **<br />
4. Bp 11.6 **<br />
5. Detox alone * * 10.4 **<br />
6. BpantiOx * <strong>9.</strong>1 **<br />
7. NAC * * 6.7 **<br />
8. BpSilyb ** ** * 8.2 ** **<br />
<strong>9.</strong> BpSilybTriPoly * ** ** 7.3 **<br />
10. Silyb * * * 5.4 **<br />
11. Supportive measures alone ** ** ** ** ** ** ** ** ** ** 47.3 ** ** ** ** **<br />
12. Bp combinations with Silybin (8, 9) ** 7.9 **<br />
13. Combined nine chemotherapies (1–4, 6–10 above) ** 11.2<br />
14. Combined 10 specific therapies (1–10 above) ** 12.6<br />
15. Bp bi-chemotherapies without Silybin (1, 3, 6) ** ** 14.3<br />
16. Combined three worst chemotherapies (1–3) ** ** 15.8<br />
(b) Excluding liver transplants (MRLTe)<br />
1. BpThioca 16.9 ** * * ** * ** **<br />
2. BpwSilybTriPoly 14.8 * * ** ** ** **<br />
3. BpSter 14.7 ** ** ** **<br />
4. Bp 11.0 * **<br />
5. Detox alone ** * <strong>9.</strong>0 * * **<br />
6. BpantiOx * 8.2 **<br />
7. NAC * * 6.7 **<br />
8. BpSilyb ** ** ** * 6.0 ** **<br />
<strong>9.</strong> BpSilybTriPoly * ** ** 5.4 **<br />
10. Silyb ** ** ** * * 1.4 **<br />
11. Supportive measures alone ** ** ** ** ** ** ** ** ** ** 43.5 ** ** ** ** **<br />
12. Bp combinations with Silybin (8, 9) ** 5.8 **<br />
13. Combined nine chemotherapies (1–4, 6–10 above) ** 10.1<br />
14. Combined 10 specific therapies (1–10 above) ** 11.3<br />
15. Bp bi-chemotherapies without Silybin (1, 3, 6) ** ** 14.1<br />
16. Combined three worst chemotherapies (1–3) ** ** 15.5<br />
Significant comparisons <strong>of</strong> mortality rates (*: p # 0:05; **: p # 0:01Þ;1. 5 (MRLTi*, MRLTe**); 1 . 6 and 1 . 7 (MRLTi*, MRLTe*); 1 . 8 (MRLTi**, MRLTe**); 1 . 9 (MRLTi*,<br />
MRLTe*); 1 . 10 (MRLTi*, MRLTe**); 2 . 5 (MRLTi*, MRLTe*); 2 . 7 (MRLTi*, MRLTe*); 2 . 8 (MRLTi**, MRLTe**), 2 . 9 (MRLTi**, MRLTe**); 2 . 10 (MRLTi*,<br />
MRLTe**); 3 . 8 (MRLTi*, MRLTe**); 3 . 9 (MRLTi**, MRLTe**); 3 . 10 (MRLTi*, MRLTe**); 4 . 10 (MRLTe*); 5 . 8 and 5 . 10 (MRLTe*); 11 . 1 to 10 (MRLTi**,<br />
MRLTe**); 12 . 16 (MRLTi**, MRLTe**); 15 . 8 (MRLTi**, MRLTe**); 16 . 8 (MRLTi**, MRLTe**).
742<br />
procedures in order to assess a beneficial toxin<br />
elimination for each applied chemotherapy.<br />
A ranking <strong>of</strong> therapies was based on significant<br />
differences in effectiveness as measured by decreasing<br />
mortality rates (Fig. 1, Tables 8 and 9). The highest<br />
mortality/lowest efficacy was observed with combinations<br />
<strong>of</strong> benzylpenicillin with thioctic acid, steroid,<br />
and other drugs except silybin as bi-, tri-, and polychemotherapies.<br />
The lowest mortality rates were<br />
observed with silybin and NAC both administered as<br />
mono-chemotherapy, and silybin associations with<br />
benzylpenicillin as bi, tri-, and poly-chemotherapies.<br />
Since no significant difference between silybin singly<br />
and silybin/benzylpenicillin combinations was found,<br />
it appears that the flavonolignan complex is effective<br />
in reducing mortality and/or avoid LT whereas<br />
benzylpenicillin singly is ineffective. Similarly, NAC<br />
statistically appears to be a potentially more effective<br />
chemotherapy than the other drug options.<br />
Review <strong>of</strong> the modes <strong>of</strong> care reported for amatoxinintoxicated<br />
patients over the last <strong>20</strong> <strong>year</strong>s demonstrates<br />
wide variability in treatment and response to treatment.<br />
Of particular interest in the environment <strong>of</strong> evidencebased<br />
medicine is the prevalent use <strong>of</strong> a therapy,<br />
benzylpenicillin, which has little theoretical foundation<br />
and little evidence <strong>of</strong> efficacy when compared to<br />
treatment alternatives. It exemplifies the fallacy <strong>of</strong><br />
consensus judgments and recommendations based solely<br />
on widespread use <strong>of</strong> a treatment. These case analyses<br />
and literature review have a number <strong>of</strong> limitations due to<br />
the disparity in severity grades. However, our work<br />
suggests the most successful orientation for prospective<br />
clinical research and provides a basis for the discontinuation<br />
<strong>of</strong> the clearly less effective chemotherapies.<br />
Efficacy <strong>of</strong> several drugs is not supported in this review:<br />
the most widely used agent, benzylpenicllin, as well as<br />
thioctic acid and steroids; perhaps their use should be<br />
discontinued. <strong>Amatoxin</strong> poisoning cases whose treatment<br />
focuses on detoxication procedures, silybin, and<br />
NAC would be useful to confirm their relevance revealed<br />
by our statistical <strong>analysis</strong>. Future research should be<br />
directed towards the iridoid glycosides being potential<br />
agents to inhibit amatoxins and stimulate hepatocyte<br />
regeneration.<br />
ACKNOWLEDGMENTS<br />
The authors are grateful to J. ApSimon (Canada),<br />
S. Badalian (Armenia), R. Courtecuisse (France),<br />
J. Elguero (Spain), G. Eyssartier (France), E. Florac<br />
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(France), F. Fons (France), A. Fraiture (Belgium),<br />
J. Guillot (France), D. Guez (Japan), J. Guinberteau<br />
(France), G. Guzman (Mexico), M. Heil (Germany),<br />
G. Konska (Poland), M. J. Mauruc (France), J. Melot<br />
(Iceland), P. A. Moreau (France), and G. Redeuilh<br />
(France) for providing literature data.<br />
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