Amatoxins
| 1. NAME |
| 1.1 Scientific name |
| 1.2 Family |
| 1.3 Common name(s) |
| 2. SUMMARY |
| 2.1 Main risks and target organs |
| 2.2 Summary of clinical effects |
| 2.3 Diagnosis |
| 2.4 First-aid measures and management principles |
| 2.5 Poisonous parts |
| 2.6 Main toxins |
| 3. CHARACTERISTICS |
| 3.1 Description of the plant |
| 3.1.1 Special identification features |
| 3.1.2 Habitat |
| 3.1.3 Distribution |
| 3.2 Poisonous parts of the plant |
| 3.3 The toxin(s) |
| 3.3.1 Name(s) |
| 3.3.2 Description, chemical structure, stability |
| 3.3.3 Other chemical constents |
| 4. USES/CIRCUMSTANCES OF POISONING |
| 4.1 Uses |
| 4.2 High risk circumstances |
| 4.3 High risk geographical areas |
| 5. ROUTES OF ENTRY |
| 5.1 Oral |
| 5.2 Inhalation |
| 5.3 Dermal |
| 5.4 Eye |
| 5.5 Parenteral |
| 5.6 Others |
| 6. KINETICS |
| 6.1 Absorption by route of exposure |
| 6.2 Distribution by route of exposure |
| 6.3 Biological half-life by route of exposure |
| 6.4 Metabolism |
| 6.5 Elimination by route of exposure |
| 7. TOXICOLOGY/TOXINOLOGY/PHARMACOLOGY |
| 7.1 Mode of action |
| 7.2 Toxicity |
| 7.2.1 Human data |
| 7.2.1.1 Adults |
| 7.2.1.2 Children |
| 7.2.2 Animal data |
| 7.2.3 Relevant in vitro data |
| 7.3 Carcinogenicity |
| 7.4 Teratogenicity |
| 7.5 Mutagenicity |
| 7.6 Interactions |
| 8. TOXICOLOGICAL/TOXINOLOGICAL AND BIOMEDICAL INVESTIGATIONS |
| 8.1 Material sampling plan |
| 8.1.1 Sampling and specimen collection |
| 8.1.1.1 Toxicological analysis |
| 8.2 Toxicological analyses and their interpretation |
| 8.2.3 Interpretation of toxicological analyses |
| 9. CLINICAL EFFECTS |
| 9.1 Acute poisoning: |
| 9.1.1 Ingestion |
| 9.1.2 Inhalation |
| 9.1.3 Skin exposure |
| 9.1.4 Eye contact |
| 9.1.5 Parenteral exposure |
| 9.1.6 Other |
| 9.2 Chronic poisoning by: |
| 9.2.1 Ingestion |
| 9.2.2 Inhalation |
| 9.2.3 Skin exposure |
| 9.2.4 Eye contact |
| 9.2.5 Parenteral exposure |
| 9.2.6 Other |
| 9.3 Course, prognosis, cause of death |
| 9.4 Systematic description of clinical effects |
| 9.4.1 Cardiovascular |
| 9.4.2 Respiratory |
| 9.4.3 Neurological |
| 9.4.3.1 CNS |
| 9.4.3.2 Peripheral nervous system. |
| 9.4.3.3 Autonomic nervous system |
| 9.4.3.4 Skeletal and smooth muscle |
| 9.4.4 Gastrointestinal |
| 9.4.5 Hepatic |
| 9.4.6 Urinary |
| 9.4.6.1 Renal |
| 9.4.6.2 Others |
| 9.4.7 Endocrine and reproductive systems |
| 9.4.8 Dermatologic |
| 9.4.9 Eyes, ear, nose, throat: local effects |
| 9.4.10 Haematological |
| 9.4.11 Immunologic |
| 9.4.12 Metabolic |
| 9.4.12.1 Acid based disturbances |
| 9.4.12.2 Fluid and electrolyte disturbances |
| 9.4.12.3 Others |
| 9.4.13 Allergic reactions |
| 9.4.14 Other clinical effects |
| 9.4.15 Special risks: pregnancy, breast feeding, enzyme |
| 9.5 Others |
| 10. MANAGEMENT |
| 10.1 General principles |
| 10.2 Relevant laboratory analyses and other investigations |
| 10.2.1 Sample collection |
| 10.2.2 Biomedical analysis |
| 10.2.3 Toxicological/Toxinological analysis |
| 10.3 Life supportive procedures and symptomatic treatment |
| 10.4 Decontamination |
| 10.5 Elimination |
| 10.6 Antidote treatment |
| 10.7 Management discussion: alternatives and controversies, research |
| 11. ILLUSTRATIVE CASES |
| 11.1 Case report from the literature |
| 11.2 Internally extracted data on cases |
| 11.3 Internal cases |
| 12. ADDITIONAL INFORMATION |
| 12.1 Availability of antidotes and antisera |
| 12.2 Specific preventive measures |
| 12.3 Other |
| 13. REFERENCES |
| 13.1 Clinical and toxicological |
| 13.2 Botanical |
| 14. AUTHOR(S), REVIEWERS(S) DATES (INCLUDING EACH UPDATING), COMPLETE ADDRESSES |
1. NAME
1.1 Scientific name
Amatoxins
1.2 Family
Agaricacae galerina lepiota
Genera: Amanita, Galerina
Other mushrooms
Other mushrooms also contain amatoxins and/or may induce the same
toxicity:
Amanita: verna, virosa, ocreata, bisporigera, suballiacae,
tenuifolia, hygroscopica.
Galerina: autumnalis, marginata, venenata, fasciculata.
Lepiota: brunneo incarnata, bruneolillacae, castanea, felina,
fuscovinacae, helveola bres. huissman, helveola
josseranda, locanensis, pseudohelveola, rufescens.
1.3 Common name(s)
Amanita phalloides: English Death cap, Deadly Agaric
French Amanite phalloide
German Knollenblätterpilz
Italian Tignosa verdognala
Amanita verna: French Amanite printaniere
German Fruhlings Wulstling
Italian Tignosa primavera
English Destroying angel
Amanita virosa: French Amanite vireuse
German Spitzhutiger
Knollenblätterpilz
Kegeliger wustling
Lepiota helveola: French Lepiote brune
German Fleischröter
Schirmling
2. SUMMARY
2.1 Main risks and target organs
Amatoxins are liver toxins. The main risk is liver necrosis with
acute hepatic failure and subsequent complications, including
hepatic coma, coagulation disorders and renal failure.
2.2 Summary of clinical effects
There are three phases:
A latent phase of approximately 6 - 24 hours (mean 12.3 hours),
rarely extending to 48 hours.
A gastrointestinal phase with abdominal pain, vomiting and
diarrhoea, leading to dehydration, hypovolaemia, electrolytes and
acid-base disorders. This phase usually lasts 2-3 days.
An hepatic phase which begins 36 - 48 hours after ingestion. The
pre-icteric phase can only be detected by an increase in serum
transaminases. Hepatitis becomes clinically evident with the
onset of jaundice on the 3rd -4th day after ingestion. In severe
poisoning, patients develop fulminant hepatitis with hepatic
coma, bleeding and anuria. When liver damage is reversible,
patients usually make a slow and steady recovery. Death occurs
within 6 to 16 days (mean 8 days).
2.3 Diagnosis
Amatoxin analysis is not clinically useful for management.
a) Dehydration, and electrolyte disturbances may occur during
the gastrointestinal phase.
b) Elevated transaminases and serum bilirubin are the first and
best indicators of liver damage and should be monitored.
2.4 First-aid measures and management principles
All patients with suspected poisoning by amatoxin-containing
mushrooms should immediately be admitted to an intensive care
unit.
The following treatment is recommended when patients present
within 48 hours after ingestion: immediate rehydration and
correction of hypovolaemia, gastric lavage (or emesis),
administration of cathartics and oral activated charcoal, forced
diuresis, high IV doses of penicillin and IV silibinin (if
available)
Emesis may be indicated in recent ingestion. Gastric lavage is
indicated if the patient presents before onset of repeated
vomiting.
Activated charcoal is indicated and should be started during
rehydration.
Vigourous and immediate correction of dehydration and
hypovolaemia is indicated. Monitor blood pressure, central
venous pressure and urinary output.
If silibinin is available, administer 20 - 50 mg/kg/day IV.
Administer Penicillin G: 300,000 to 1,000,000 U/kg/day as an IV
infusion.
If hepatic failure occurs, supportive procedures including oral
mannitol or lactulose, low protein diet, vitamin K and fresh
frozen plasma should be instituted. Artificial ventilation may
be necessary.
Haemodialysis is indicated only if the patient develops acute
renal failure.
Consider liver transplantation if the patient develops severe
hepatic failure with encephalopathy, marked jaundice, prothrombin
level below 10 per cent.
2.5 Poisonous parts
All parts of amatoxin-containing mushrooms are poisonous.
2.6 Main toxins
Amatoxins
Alpha, beta and gamma amanitins are the main toxins.
Phallotoxins
Amanita phalloides also contains phallotoxins but these toxins do
not seem to play a major role in human toxicity.
3. CHARACTERISTICS
3.1 Description of the plant
3.1.1 Special identification features
Identification
Complete and precise identification of the mushroom (if
available) should be accomplished by a mycologist. If no
mycologist is available, colour photographs may be helpful
for a first identification. Identification is difficult when
the mushrooms have been altered by cooking, eating or
storage.
Description
Amanita Phalloides:
Cap: 5 - 15 cm diameter, conical when young, then flat-
topped. Surface colour olive green or yellow-green,
sometimes yellowish or white.
Gills: White
Stem: White, height 8 - 15 cm, diameter: 1 - 2.5 cm, filled
with a cottony material when young, hollow at maturity.
Bulbous base.
Annulus: At a short distance beneath the cap, the stem bears
a downward-hanging membranous ring.
Volva: The upper extremity of the bulbous base of the stem
is prolonged upward in a free edge or membrane (volva)
encircling the stem (death's cup)
3.1.2 Habitat
Phalloides:
During summer and autumn under beach or oak trees (rarely
pine).
3.1.3 Distribution
Phalloides:
Frequently encountered throughout Europe
Verna:
Encountered throughout Europe; frequently encountered
throughout the United States and Canada.
3.2 Poisonous parts of the plant
Amatoxins are found in all parts of the mushrooms.
3.3 The toxin(s)
3.3.1 Name(s)
Eight amatoxins have been isolated: alpha, beta, gamma,
epsilon amanitins, amanullin, amanullinic acid, proamanullin
and amanin.
Seven compounds have been isolated: phalloidin, phalloid,
prophalloin, phallisin, phallacin, phallacidin, phallisacin.
3.3.2 Description, chemical structure, stability
Amatoxins
Amatoxins are bicyclic octapeptides. The bicyclic structure
and a gamma hydroxyl group at the dihydroxy isoleucine
portion are necessary for toxicity. Amanitins are the most
toxic compounds.
Phallotoxins
Phallotoxins are bicyclic heptapeptides. The bicyclic
structure and an allo-positioned hydroxyl functional group
at the pyrrolidine ring are necessary for toxicity.
(Wieland and Faulstich, 1978).
Formula
Naturally occurring amatoxins:
Structure and toxicity (LD50 mg/kg for the white mouse, i.p)
(Wieland & Faulstich, 1978).
a) Amatoxins
b) Phallotoxins
Molecular weights
Amatoxins contain 3 or 4 mol of water of crystallization.
Molecular weights are 990 for alpha, 373 for beta, and 974
for gamma amanitin.
Phallotoxins crystallize with 5 mol of water of
crystallization. Molecular weights are 879, 863 and 895 for
phalloidin, phalloid and philistine respectively (Wieland
and Faulstich, 1978).
Stability
Amatoxins and phallotoxins are thermostable and are not
removed by boiling and discarding the water or by any form
of cooking. Nor are they destroyed by drying and they have
been found to remain potent in mushrooms stored for over 10
years.
3.3.3 Other chemical constents
Other chemical substances have been isolated. Antamanide is
a decapeptide isolated from A. phalloides. Experimentally
it prevents death in white mice from the lethal dose of
phalloidin.
Phallolysin has been isolated from A. Phalloides and other
Amanita species and has haemolytic activity in vitro.
4. USES/CIRCUMSTANCES OF POISONING
4.1 Uses
Not relevant.
4.2 High risk circumstances
Amatoxin poisoning occurs mainly in the Summer and Autumn (the
growing period of the mushrooms). However, cases of poisoning
may also be seen in Spring following ingestion of mushrooms such
as Amanita verna.
4.3 High risk geographical areas
Beech and oak woods in Europe and North America.
5. ROUTES OF ENTRY
5.1 Oral
Amatoxin poisonings are always due to ingestion.
5.2 Inhalation
No data available.
5.3 Dermal
No data available.
5.4 Eye
No data available.
5.5 Parenteral
No data available.
5.6 Others
No data available.
6. KINETICS
6.1 Absorption by route of exposure
Oral
Human: Amatoxins are absorbed rapidly in humans; they can be
detected radioimmunologically in the urine as early as 90 - 120
minutes post-ingestion (Homann et al, 1986).
Animal: Animal species differ in their ability to absorb
amatoxins from the gastrointestinal tract. In the mouse and rat,
the poison is absorbed extremely slowly or not at all. In the
guinea pig, cat and dog, doses of a few mg/kg cause death.
Phallotoxins are not absorbed from the gastrointestinal tract.
Parenteral
The kinetics of amatoxins have been studied in the dog after IV
administration, and in the mouse after intraperitoneal
administration (Faulstich et al, 1985; Fiume et al, 1975).
6.2 Distribution by route of exposure
Protein binding
Amatoxins are not bound to albumin (Faulstich et al, 1985; Fiume
et al, 1977)
Volume of distribution
Human: No data available.
Animal: Toxicokinetic study with labelled amatoxins in the dog
showed that the equilibrium distribution volume after intravenous
administration was identical with the extracellular space (160 -
290 ml/kg) (Faulstich et al, 1985).
6.3 Biological half-life by route of exposure
Oral
Human: In a group of patients studied by Vesconi et al (1985),
serial determinations showed a rapid decrease of toxin levels in
all but one patient, with complete disappearance of detectable
concentrations by 48 hours after ingestion in all.
In a group of 32 patients studied by Jaeger et al (1988),
amatoxins disappeared rapidly from serum. Amatoxins could be
detected in serum after 36 hours in only 2 patients.
Animal: No data available.
Parenteral
Human: No data available.
Animal: Amatoxins are eliminated very rapidly from serum. After
intraperitoneal administration of amanitin in mice no toxin could
be detected in serum 4 hours after injection. After intravenous
injection in dogs the plasma half lives ranged from 26.7 - 49.6
minutes and total body clearance were between 2.7 and 6.2
ml/min/kg (Faulstich et al, 1985).
6.4 Metabolism
Human: No data available.
Animal: In experimental studies, no metabolites could be
detected after administration of radioactive amanitin (Jahn et
al, 1980; Faulstich et al, 1985).
6.5 Elimination by route of exposure
Oral
Amatoxins can be detected in urine as early as 90 - 120 minutes
after ingestion of an amatoxin-containing mushroom (Homann et al,
1986). In a group studied by Vesconi et al (1985) amatoxins were
detected in urine up to 24 - 66 hour after ingestion. In 15 cases
studied by Jaeger et al (1988), alpha and beta amanitin
concentrations in urine were 20 - 40 times higher than those
found in serum. The highest concentrations were observed during
the first 24 - 48 hours but in some cases amatoxins were detected
up to 72 - 96 hours after ingestion. Concentrations as high as
4,800 mg/l alpha amanitin and 4,300 mg/l beta amanitin were
observed. Total mean amounts of 950 mg alpha amanitin and 1,700
mg beta amanitin were excreted in the urine of these patients.
In 5 patients reported by Busi et al (1979), amanitin was
detected by radioimmunoassay in gastroduodenal fluids at 12 - 72
hours after ingestion. In 4 cases, Jaeger et al (1988) found high
concentrations of alpha and beta amanitin (HPLC analysis) in
gastroduodenal fluids up to 120 hours after ingestion. The
amatoxins eliminated in bile may be reabsorbed via the
enterohepatic circulation (Vesconi et al, 1985; Faulstich et al,
1985).
Jaeger et al (1988) studied alpha and beta amanitin elimination
in 4 patients. In all cases high concentrations of alpha (mean
1.05 mg/L) and beta amanitin (3.56 mg/L) were detected in
diarrhoea fluids between the 24 and 96 hours post ingestion. In
one case 6.3 mg alpha amanitin was eliminated over a period of 24
hours. The high rate of excretion of amatoxin in the presence of
diarrhoea seems due to non absorption of ingested amatoxins
rather than to excretion of amatoxins by the gastrointestinal
tract.
Animal: No data available.
Parenteral
Human: No data available.
Animal: After administration of labelled amatoxins in dogs, 83 -
89% is eliminated in urine and less than 10% is excreted in the
bile.
7. TOXICOLOGY/TOXINOLOGY/PHARMACOLOGY
7.1 Mode of action
Amatoxins
The amatoxins, particularly the amanitins, have been shown
to impair transcription of both DNA and RNA by interfering
with RNA polymerase II. Cells with the highest rate of
multiplication, such as the intestinal mucosa, are injured first,
followed by the liver and kidney. Amanitins cause necrosis of
hepatocytes and of the cells in the proximal tubules of the
kidney (Fiume and al., 1965). However, direct toxicity on the
kidney has not been confirmed in human poisoning
(Constantino et al, 1978).
Phallotoxins
It is probable that the phallotoxins play no role in human
poisoning. Phallotoxins are not absorbed from the
gastrointestinal tract in the experimental animals investigated,
and probably not in man. When given parenterally to laboratory
animals, phallotoxins destroy the endoplasmic reticulum and
mitochondria of the liver cells and induce necrosis of
hepatocytes. Phalloidin binds to the actin G of the plasma
membranes, polymerizes all actin G irreversibly and hence
increases the permeability of the plasma membranes of
hepatocytes.
7.2 Toxicity
7.2.1 Human data
7.2.1.1 Adults
Amatoxins are among the most lethal poisons known. As
little as 0.1 mg/kg may be a lethal dose for an adult
(Vesconi et al, 1985). Concentrations of 5 - 15 mg
amatoxin per 40 gram fresh mushroom have been found.
This means that one amanita cap or 15 - 20 Galerina
caps could kill a healthy adult.
In a collaborative study of 205 cases of intoxications
recorded throughout Europe from 1971 to 1980, the
overall mortality was 22.4% (Floersheim et al, 1982).
A significant difference between adults and children
was observed. Mortality was 51.3% in children under 10
years of age, and 16.5% in the patients older than 10
years. Prognosis seems to be determined by the
quantity of mushroom eaten (dose of toxins per kg body
weight).
Mortality is 50% if untreated and less than 5% with
intensive care (Lampe, 1978). This group of mushrooms
accounts for over 95% of all cases of fatal mushroom
poisoning in the U.S.
A literature review suggests that the incidence of
mortality has gradually decreased during the last
decades probably due to hospitalisation and intensive
care, with early rehydration (Constantino et al, 1978;
Vesconi et al, 1985).
No data are available on the maximum tolerated dose in
man.
7.2.1.2 Children
In the study of Floersheim et al (1982), the mortality
in children under 10 years of age was 51.3%
7.2.2 Animal data
There is significant variation betwen animal species
(Wieland et Faulstich, 1978).
Dogs
The symptoms of amanitin intoxication have been studied in
beagle dogs. Early symptoms are hyperglycaemia followed by
hypoglycaemia which caused death in most dogs after 1 - 2
days. If given glucose, the dogs developed acute liver
damage with death after 2 - 3 days. Severe haemorrhage in
various organs were the main cause of death in several
cases. A late symptom was kidney failure from which a few
dogs died after 7 days (Wieland and Faulstich, 1978).
Toxic dose
Amatoxins:
In the white mouse, the LD50 after intraperitoneal
administration is 300 mg/kg and death occurs in 2 - 5 days.
The rat is more resistant: the LD50 is about 4 mg/kg after
intraperitoneal administration. The LD50 in dogs is 0.1
mg/kg after intravenous injection (Wieland and Faulstich,
1978).
Phallotoxins:
Phallotoxins are less toxic than amatoxins. In the white
mouse the LD50 is 2.5 mg/kg after intraperitoneal
administration. Rats are more susceptible to phallotoxins
than mice (Wieland and Faulstich, 1978).
7.2.3 Relevant in vitro data
7.3 Carcinogenicity
No data available.
7.4 Teratogenicity
No data available.
7.5 Mutagenicity
No data available.
7.6 Interactions
No data available.
8. TOXICOLOGICAL/TOXINOLOGICAL AND BIOMEDICAL INVESTIGATIONS
To be completed.
8.1 Material sampling plan
8.1.1 Sampling and specimen collection
8.1.1.1 Toxicological analysis
a) Radioimmunoassay
Radioimmunoassay methods for detecting amatoxins in biological
fluids have been developed by Faultisch et al (1987), Fiume et al
(1975), Andres et al (1987). Antibodies against amanitin were
obtained in rabbits (Faultisch, Andres) or in rats (Fiume). The
test used either 3H tracer (Faulstich, Fiume) or 125 I tracer
(Andres). The sensitivity of radioimmunoassay is 0.1 ng/mL for
serum and 0.25 ng/mL for urine (Vesconi et al, 1985; Fiume,
1980); 0.1 ng/mL for serum and 1 mg/mL for urine (Andres et al,
1987).
b) High Performance Liquid Chromatography
HPLC assays have been developed for detection of alpha and beta
amanitins in human serum, urine or gastrointestinal fluids
(Pastorello et al, 1982, Jehl et al, 1985, Caccialanza et al,
1985). Sensitivity is 6 - 10 ng/mL (Jehl et al, 1985;
Caccialanza et al, 1985).
8.2 Toxicological analyses and their interpretation
8.2.3 Interpretation of toxicological analyses
Serum/blood
a) In a group of 29 patients studied by Vesconi et al
(1985), serum amatoxin levels were detectable in 65% of
patients (Vesconi et al 1985) even as late as 30 hours post
ingestion. Concentrations were 0.5 - 24 mg/L. Only 4 of 19
had levels greater than 3 mg/l.
b) Pastorello et al (1982) found serum levels of alpha
amanitin between 70 and 90 mg/l in patients with Amanita
phalloides intoxication.
c) Jaeger et al 1988 (unpublished data) found alpha and
beta amanitin in serum only in one third of patients. Mean
concentrations were 73 +/- 69 mg/l for alpha amanitin (range
8 - 190 mg/l). Amanitin was found in serum in only one case
after 48 hours.
d) Busi et al (1977) found amatoxin in the serum of
intoxicated patients up to 36 hours post-ingestion.
e) Velvaert et al (1982) detected amatoxin in the serum of
poisoned patients in 70% of cases before the 12th hour and
in 50% of cases by 24 hours.
Urine
Urine amatoxin levels in a group of patients studied by
Vesconi et al (1985) ranged from 0.5 to 56 mg/l. Initial
catheterization to obtain concentrated urine found levels as
high as 180 mg/l. In serial determinations, urinary levels
were found 24 - 66 hours post ingestion. Total urinary
output of amatoxins in this period ranged from 12 - 23 mg.
In a group of patients studied by Jaeger et al (1988),
amatoxins were detected in urine in 15 of 24 patients.
Alpha amanitin was present in 14 and beta amanitin in 10
patients. In some cases serial determinations showed that
amanitins were excreted for up to 72 - 96 hours post-
ingestion. Concentrations as high as 4,800 mg/l alpha
amanitin and 4,300 mg/l beta amanitin were observed. Mean
total amounts of 950 mg alpha amanitin and mean 1,700 mg
beta amanitin were excreted in urine in these patients.
Velvaert et al (1982) detected amatoxins in urine (by
radioimmunoassay) in all cases before 24 hours and in 80% of
cases by 48 hours post-ingestion.
Bile
In 4 cases, Jaeger et al (1988) found amanitin
concentrations in gastroduodenal fluid ranging between 44
and 4,950 mg/l between the 44th and 108th hour post-
ingestion.
Faeces
In 4 patients, Jaeger et al (1988) found concentrations of
alpha amanitin (mean 1.05 mg/l) and beta amanitin (mean 3.5
mg/l) in diarrhoeal faeces.
9. CLINICAL EFFECTS
9.1 Acute poisoning:
9.1.1 Ingestion
Amanitin intoxication has 3 chronological phases:
a symptomless latent phase, 6 - 24 hours post-ingestion
a gastrointestinal phase, starting 6 - 24 hours post-
ingestion and lasting for 2 - 3 days, with abdominal pain,
nausea, vomiting and diarrhoea
an hepatic phase, which begins 36 - 48 hours post-ingestion,
with jaundice, hepatitis and coma; death occurs within 6 -
15 days of ingestion.
9.1.2 Inhalation
No data available.
9.1.3 Skin exposure
No data available.
9.1.4 Eye contact
No data available.
9.1.5 Parenteral exposure
No data available.
9.1.6 Other
No data available.
9.2 Chronic poisoning by:
9.2.1 Ingestion
No data available.
9.2.2 Inhalation
No data available.
9.2.3 Skin exposure
No data available.
9.2.4 Eye contact
No data available.
9.2.5 Parenteral exposure
No data available.
9.2.6 Other
No data available.
9.3 Course, prognosis, cause of death
The course of amanitin intoxication has 3 chronological 3 phases:
a) A latent phase of approximately 6 - 24 hours (mean 12.3
hours), rarely extending to 48 hours.
b) A gastrointestinal phase with abdominal pain, vomiting and
diarrhoea causing dehydration, hypovolaemia, electrolyte and
acid-base disorders. This phase usually lasts 2-3 days.
c) An hepatic phase which begins 36 - 48 hours after ingestion.
The pre-icteric phase can only be detected by an increase in
serum transaminases. Hepatitis becomes clinically evident with
the onset of jaundice on the 3rd -4th day after ingestion. In
severe intoxications, patients develop fulminant hepatitis with
hepatic coma, bleeding and anuria. When liver damage is
reversible, patients usually make a slow and steady recovery. In
fatal cases death occurs within 6 - 16 days (mean 8 days).
Prognosis: An analysis of the literature shows that the factors
most likely to indicate a poor prognosis in Amanita hepatitis are
peak prothrombin time > 100 sec; factor V < 10%; lactic
acidosis; gastrointestinal bleeding; and age < 12 years. Other
criteria, such as the duration of the latency period; the peak
serum concentration of aminotransferases; and amanitin analysis
are not useful for prognosis. Orthotopic liver transplantation
should be considered in patients with poor prognosis criteria.
In a study of 205 amanita intoxications, the gastrointestinal
syndrome was present in 199 patients and hepatitis in 198; 52
patients developed hepatic coma and the overall mortality was
22.4% (Floersheim et al, 1982)
9.4 Systematic description of clinical effects
9.4.1 Cardiovascular
In the gastrointestinal phase, vomiting and diarrhoea can
produce severe fluid losses resulting in hypovolaemic shock
with tachycardia and a fall in central venous pressure.
Functional reversible renal failure often accompanies
hypovolaemic shock secondary to gastrointestinal fluid loss.
When shock occurs in the hepatitic phase, it is mainly due
to haemorrhage secondary to severe coagulation disorders.
Cardiovascular collapse also accompanies severe hepatic
failure in the terminal phase.
9.4.2 Respiratory
Respiration is usually normal but hyperventilation
accompanies fulminant hepatitis. Respiratory failure with
hyperventilation or apnoea may occur in patients presenting
with hepatic coma and has a poor prognosis.
9.4.3 Neurological
9.4.3.1 CNS
Neurologic symptoms are related to hepatic
encephalopathy which usually occurs 5 - 6 days after
ingestion. Somnolence and confusion are the first
signs, and coma usually follows. Convulsions may be
observed in hepatic coma.
In severe hepatic failure, coma may also be due to
hypoglycaemia secondary to disordered glucose
metabolism.
9.4.3.2 Peripheral nervous system.
No data available.
9.4.3.3 Autonomic nervous system
No data available.
9.4.3.4 Skeletal and smooth muscle
No data available.
9.4.4 Gastrointestinal
Gastrointestinal symptoms appear after a latent period of 6
- 24 hours (mean 12.3 hours). In a study of 205 Amanita
intoxications, gastrointestinal symptoms were present in 199
patients (Floersheim et al, 1982).
a) Nausea, vomiting, colic.
There is a sudden onset of colicky abdominal pain rapidly
followed by nausea, frequent vomiting and diarrhoea.
b) Diarrhoea
In most cases, diarrhoea is severe, watery and cholera-like.
In the absence of fluid replacement, diarrhoea rapidly
induces dehydration, haemoconcentration and hypovolaemic
shock. Diarrhoea may persist for 2 - 4 days.
9.4.5 Hepatic
Clinical signs of hepatocellular damage usually develop on
the 3rd to 4th day after ingestion. Clinical presentation
may only include a mild jaundice and a mild hepatomegaly.
In severe cases, hepatitis follows a fulminant course with
marked jaundice and hepatic coma and may be accompanied by
renal failure and cardiovascular collapse. In fatal cases,
death occurs within 6 - 16 days (mean 8 days).
9.4.6 Urinary
9.4.6.1 Renal
Two types of renal failure may be observed. During the
gastrointestinal phase a functional renal failure is
frequent. It is associated with hypovolaemia and is
secondary to fluid loss and to hypoperfusion of the
kidneys. It may improve if dehydration and
hypovolaemia are corrected aggressively.
Anuria and renal failure may occur during the third
phase of poisoning together with severe hepatitis,
hepatic coma and haemorrhage.
Serious kidney complications may be avoided by
administration of fluids (Constantino et al, 1978,
Vesconi et al, 1985). A direct nephrotoxic effect of
amatoxins has not been proven in human intoxication.
9.4.6.2 Others
No data available.
9.4.7 Endocrine and reproductive systems
No data available.
9.4.8 Dermatologic
Mild jaundice with icteric sclerae is present in the hepatic
phase.
9.4.9 Eyes, ear, nose, throat: local effects
Eyes:Scleral icterus occurs.
Nose:Nasal haemorrhage may occur in patients with
coagulation disorders secondary to severe
hepatocellular damage. If intubation is necessary, the
nasal route should be avoided because it may induce
severe local haemorrhage.
9.4.10 Haematological
Severe hepatocellular damage may result in severe
haemorrhage.
Usually the earliest indication of coagulopathy is
persistent bleeding from IV puncture sites (Bivins et al,
1985). Other bleeding, epistaxis and gastrointestinal
haemorrhage may occur.
These are due to marked coagulation defects secondary to
impaired synthesis of clotting factors. This indicates a
poor prognosis. (Floersheim, 1987).
9.4.11 Immunologic
No data available.
9.4.12 Metabolic
9.4.12.1 Acid based disturbances
In the gastrointestinal phase, metabolic acidosis may
occur as the result of bicarbonate loss in diarrhoea;
in later stages, acidosis may be due to hepatic
failure.
9.4.12.2 Fluid and electrolyte disturbances
Dehydration and hypovolaemia
The gastrointestinal syndrome often results in marked
dehydration and hypovolaemia with haemoconcentration
and functional renal failure.
Electrolyte disturbances
Hypokalaemia is particularly common in the
gastrointestinal phase.
9.4.12.3 Others
Glucose
Glucose metabolism is often disturbed in severe hepatic
failure. Spontaneous hypoglycaemia results from
impaired glycogenolysis and gluconeogenesis (Bivins et
al, 1985).
Hepatic enzymes
Elevated serum transaminase, LDH and serum bilirubin
are the first and best indicators of liver damage and
should be monitored throughout the course of the
illness. Hepatic enzymes usually reach a peak after 60
- 72 hours and then decrease. Enzyme levels may be
relatively low in massive liver necrosis (Bivins et al,
1985).
Coagulation parameters
Coagulation disorders indicate hepatic insufficiency.
Levels of clotting factors synthesized by the liver,
such as fibrinogen and prothrombin, may be decreased.
A prothrombin level below 10 per cent indicates a poor
prognosis (Floersheim 1987)
9.4.13 Allergic reactions
No data available.
9.4.14 Other clinical effects
Amatoxin does not affect temperature regulation directly but
temperature disorder may occur in severe hepatic failure
with encephalopathy.
9.4.15 Special risks: pregnancy, breast feeding, enzyme
deficiency
Pregnancy: Kauffmann et al, (1978) reported a Amanita
phalloides poisoning in a 25 year old woman at 9 weeks
gestation. The patient developed a toxic hepatitis
(transaminase 1800 U/l). After life threatening maternal
illness was overcome, a therapeutic abortion was carried out
at 12 weeks gestation. Histologic examination of the foetal
liver showed cellular damage related to amanitin toxicity.
Amatoxins therefore cross the placenta barrier in
concentrations sufficient to affect the foetus.
Breast-feeding: Because amatoxins are excreted in breast
milk, nursing mothers who have ingested Amanita, whether
they are symptomatic or not, should be told to stop nursing
until it is determined whether or not they have been
poisoned (Bivins et al, 1985).
9.5 Others
No data available.
10. MANAGEMENT
10.1 General principles
Management depends on the length of time since ingestion and on
symptoms.
Supportive treatment includes:
Gastrointestinal phase: maintenance of fluid and electrolyte
balance.
Hepatic phase: correction of coagulation disorders, serum glucose
disorders, treatment of respiratory and renal failure.
Prevention of absorption:
By emesis or gastric lavage in cases of recent ingestion; by
repeated oral activated charcoal.
Several antidotes have been proposed for the management of
amatoxin poisoning, including thioctic acid, high-dose
penicillin, silibinin, steroids, cytochrome C and hyperbaric
oxygen (Parisch and Doehring 1986, Floersheim 1987). None of
these has been clearly proven to be of clinical efficacy (Bivins
et al, 1985). However, penicillin and silibinin apparently have
some antitoxic effects in vitro and therefore should be included
tentatively in the management.
Enhanced elimination
According to recent toxicokinetic studies (Vesconi et al, 1985,
Jaeger et al, 1988) only forced diuresis appears substantially to
enhance the elimination of amatoxins. This should be instituted
as early as possible.
10.2 Relevant laboratory analyses and other investigations
10.2.1 Sample collection
Collect samples of mushroom material, vomitus, lavage fluid
and diarrhoea for toxicological identification.
10.2.2 Biomedical analysis
Monitor hepatic enzymes: LDH and serum transaminases
bilirubin. they are the first and the best indicators of
liver damage and should be monitored throughout the course
of the illness.
Monitor serum electrolytes, blood gases, BUN, serum
creatinine in order to detect hypokalaemia, metabolic
acidosis and renal failure.
Monitor coagulation parameters especially the clotting
factors fibrinogen and prothrombin synthesized by the liver.
A prothrombin level below 10% indicates a poor prognosis
(Floersheim, 1987).
Monitor serum glucose levels hourly at the bedside in order
to detect and correct hypoglycaemia (Bivins et al, 1985).
10.2.3 Toxicological/Toxinological analysis
Analysis of amatoxins in biological fluids is not clinically
useful in the early management of poisoning. However,
amatoxin determination may be useful to confirm the
diagnosis before the onset of hepatic failure.
10.3 Life supportive procedures and symptomatic treatment
On admission insert a central venous catheter and an urinary
catheter. Frequently monitor blood pressure, central venous
pressure, urinary output and vital signs.
Give supportive treatment for dehydration and electrolyte
disorders.
Vigorous and immediate correction of dehydration and hypovolaemia
is essential to prevent renal failure. Start forced diuresis
(Vesconi et al, 1985, Bivins et al, 1985). Administration of
plasma expanders and fluids should be guided by monitoring of
blood pressure, central venous pressure and urinary output.
Correct hypokalaemia (by KCl diluted in solutions of dextrose 5
%, or NaCl 0.9 %) and metabolic acidosis (by sodium bicarbonate
solution 1.4%) according to the results of repeated laboratory
analyses.
Supportive treatment of hepatic failure
1. Hypoglycaemia
Serum glucose levels should be measured hourly at the
bedside (Bivins et al, 1985). Give IV solution of 10 %
dextrose by continuous infusion and additional boluses of
glucose as indicated by laboratory tests.
2. Coagulation Disorders
Monitor coagulation (prothrombin and fibrinogen). If
hypoprothrombinaemia and hypofibrinogenaemia or clinical
haemorrhage are present give vitamin K (10 - 30 mg/day IV)
and fresh frozen plasma.
3. Hepatic encephalopathy and renal failure require standard
management, including protein restriction, bowel cleansing,
artificial ventilation, haemodialysis.
4. Liver transplantation
Liver transplantation should be considered in poisoning with
severe hepatic failure. Criteria for severe hepatic failure
and a poor prognosis are: hepatic encephalopathy, marked
jaundice, oliguria or anuria, bleeding, hypoglycaemia, and a
prothrombin level < 10%.
10.4 Decontamination
Indications: Treatment depends on the length of time since
ingestion and on the symptoms.
1. Prior to development of symptoms, emptying the stomach by
gastric lavage or emesis and inducing diarrhoea with cathartics.
Then administer oral activated charcoal and perform intermittent
gastroduodenal aspiration.
2. After the onset of the gastrointestinal phase, administer
repeated oral activated charcoal and perform intermittent
gastroduodenal aspiration. Diarrhoea should not be treated except
by fluid replacement.
The advantage of gastric lavage is that charcoal which may be
administered through the lavage tube immediately after gastric
emptying (Bivins et al, 1985).
10.5 Elimination
Cathartics: indicated if the patient is seen before the
gastrointestinal phase or if diarrhoea is not severe.
Gastroduodenal aspiration: Intermittent gastroduodenal
aspiration (between charcoal administrations) is indicated in
order to remove toxins eliminated in the bile (Busi et al, 1979;
Jaeger et al, 1988).
Forced diuresis: Toxicokinetic studies (Vesconi et al, 1985,
Jaeger et al, 1988) indicate that significant amounts of
amatoxins are eliminated in urine especially during the 48 hours
following ingestion. Early forced diuresis is therefore indicated
and should be instituted immediately after admission of the
patient to hospital during correction of dehydration.
Other techniques: Toxicokinetic studies (Vesconi et al, 1985,
Jaeger et al, 1988) showed that amatoxins were present in serum
only during the first 24 - 48 hours and at very low
concentrations compared with concentrations found in urine.
Extracorporeal elimination (plasmapheresis, peritoneal dialysis,
haemodialysis and haemoperfusion) is not indicated. Haemodialysis
or haemoperfusion in order to remove amatoxins would only be
indicated if a patient with previous renal failure develops
Amanita intoxication.
10.6 Antidote treatment
Currently no specific antidote for amatoxins is available.
However it has been suggested that some drugs may have some
"antidotal" effect.
Penicillin G
Experimental studies have shown that penicillin G reduced or
inhibited hepatic uptake of amatoxins and protected mice and rats
against lethal doses of amatoxins (Floersheim, 1987). Moreover,
in a retrospective study administration of penicillin was
significantly more often associated with survival (Floersheim et
al, 1982). Early treatment with high doses of penicillin G is
recommended using 300,000 - 1,000,000 U/kg/day as an IV infusion
(Floersheim, 1987)
Silibinin
The antidotal effects of silibinin against amatoxins has been
confirmed in experimental models. Silibinin is thought to
inhibit the penetration of the amatoxins into liver cells (Jahn
et al, 1980, Floersheim, 1987). Administration of silibinin is
recommended if the patient is seen within 48 hours of ingestion.
The doses are 20 - 50 mg/kg/day IV and treatment should be
continued for 48 - 96 hours.
Silimaryn (Legalon R 70) capsules, 1.4 - 4.2 g/day for 4 days,
may also be given but this treatment may be useless if the
patient presents with vomiting or is treated by oral charcoal.
Thioctic Acid
The clinical efficacy of this agent has not been proved and
experimentally thioctic acid was ineffective as an antidote
against amatoxins in mice and dogs (Floersheim, 1987). There is
no reason to continue its use.
Cimetidine
Cimetidine has been investigated as a possible antidote. In an
experimental study, Schneider et al (1987) noted decreased liver
fatty changes in mice treated by high doses of cimetidine.
However, much work needs to be done before cimetidine can be
recommended as a standard therapy.
Cytochrome C
The clinical efficacy of cytochrome C has not been proven
(Floersheim et al, 1982).
10.7 Management discussion: alternatives and controversies, research
needs
Hospitalisation Criteria
If a patient develops gastroenteritis 6 - 24 hours after
ingestion of mushrooms, poisoning by amatoxin-containing
mushrooms shouldbe considered. The patient should be admitted
immediately to an intensive care unit and appropriate treatment
should be started.
If a group of people ate the same type of mushroom and one
presents with symptoms, consider the possibility that the others
who are not yet symptomatic also may have been poisoned and will
require treatment (Bivins et al, 1985).
Mixed intoxication
If patients who have eaten several kinds of unidentified
mushrooms develop early gastrointestinal symptoms, additional
amatoxin intoxication should be considered if gastrointestinal
symptoms last for more than 24 hours.
11. ILLUSTRATIVE CASES
11.1 Case report from the literature
a) Floersheim et al (1982) studied 205 cases of Amanita
phalloides poisoning. The mortality was 22.4%. Death rate was
51.3% in children below 10 years of age but only 16.5% in
patients older than 10 years.
84% of patients with thromboplastin time below 10% died while all
patients with minimum values greater than 40% survived.
Treatment with a combination of penicillin and silibinin was
associated with an increased survival.
b) Vesconi et al (1985) reported 53 cases of Amanita phalloides
poisoning inpatients aged from 4 - 72 years; the mortality was
11.3%. All deaths were due to acute liver failure and occurred 6
- 12 days after admission. In 19 of 29 patients, amatoxins were
detected in serum (0.5 -24 mg/l). Amatoxins were detected in
urine in all 19 patients studied (0.5 -56 mg/l). The authors
recommend the following treatment:
Immediate and vigorous rehydration, gastroduodenal lavage,
laxatives and adsorbent agents, forced diuresis, high doses of
penicillin and silimaryn.
c) Woodle et al (1985) reported a 3 year-old girl who had
ingested Amanita phalloides. She developed abdominal pain,
vomiting, diarrhoea and then hepatitis. Laboratory data showed
marked cytolysis (SGOT 16,648 U/l; SGPT 9,844 U/l) and
coagulation disorders (prothrombin time 34.2. sec). Serum
bilirubin was 23 mg/L and ammonia was 122 mg/dL. Despite
supportive treatment the patient deteriorated rapidly and
developed Grade III encephalopathy. An orthotopic liver
transplant was performed on the 5th day. After transplantation
the patient improved rapidly but showed neurological sequelae.
d) Genser et Marcus (1987) reported a group of 10 patients who
ingested Amanita virosa mushrooms. All were treated with gastric
lavage, insertion of a tube into the second portion of the
duodenum for suction, charcoal hemoperfusion, and high dose
intravenous penicillin G. Despite these treatment, 3 of the 10
developed moderate to severe hepatotoxicity and renal injury.
One of these three developed hepatic coma and a severe
coagulopathy. The remaining 7 patients had gastrointestinal
toxicity and mild to moderate organ toxicity. All 10 patients
recovered fully.
11.2 Internally extracted data on cases
Jaeger et al (1988) studied amatoxin kinetics in 32 cases.
Amatoxins were found in serum in only 10 patients. Mean
concentrations were 73 mg/l for alpha amanitin and 55.6 mg/l for
beta amanitin. Amatoxins were present in urine in all 15 cases
studied at concentrations as high as 4,800 mg/l for apha amanitin
and 4,300 mg/l beta amanitin. Mean total amounts of 0.95 mg
alpha amanitin and mean 1.7 mg beta amanitin were excreted in
urine over 32 hours. High amatoxin concentrations were also
found in gastroduodenal fluids and in faeces. The authors
recommend early and vigorous rehydration and early forced
diuresis.
A 26 month-old child was admitted with acute hepatitis following
amanita phalloides ingestion. Transaminase levels reached a peak
of 17,400 IU/l for GOT and 14,300 IU/l for GPT. On the 3rd day
she developed severe coma with hepatocellular insufficiency
(prothrombin level lower than 10%). On the 4th day an orthotopic
liver transplant was performed. Clinical and biological status
improved rapidly. Immunosuppressive treatment included
cyclosporin, azathioprine and methylprednisolone (case to be
published by Butscher et al).
11.3 Internal cases
To be added by PCC.
12. ADDITIONAL INFORMATION
12.1 Availability of antidotes and antisera
12.2 Specific preventive measures
12.3 Other
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14. AUTHOR(S), REVIEWERS(S) DATES (INCLUDING EACH UPDATING),
COMPLETE ADDRESSES
Authors: A Jaeger , F Flesch, Ph Sauder, J Kopferschmitt
Centre Anti-Poisons
Hospices Civils de Strasbourg
67091 Strasbourg Cédex
France
Tel: 33-88161114 (direct)
Fax: 33-88161930
Date: 25 April 1989
Peer Review: London, March 1990