Arnold del Mundo
December 9, 1996

Cyclopeptide-Containing Mushroom Toxicity

Amanita pantherina

Amanita pachycolea

Significance

• Accidental exposures to mushrooms represents small percentage of exposures cared for at American Association of Poison Control Centers regional centers.
• Only about 14 mushroom-related fatalities out of 85,556 documented mushroom exposures have been reported over last 11 yrs.
• In 1991, of 9482 exposures, 7576 (78.9%) occurred in children <6yrs old
• 5511 (58.1%) asymptomatic
• 2484 (26.1%) treated in a healthcare facility
• 3 died
• 15 (0.2%) major toxicity
• 225 (2.7%) moderate toxicity
• 8572 (90.4%) species ingested unknown
• 47 (0.5%) cyclopeptide
• 131 (1.3%) monomethylhydrazine
• 3 muscarine
• 13 coprine
• 16 ibotenic acid
• 242 (2.5%) hallucinogenic
• 225 (2.4%) gastrointestinal irritant
• 2 orellanine

Presumptive diagnosis of Amanita poisoning was made. Pt. treated with IV fluids, charcoal slurry per NG. Deterioration of her condition during the next 24 hours prompted transfer to the University Medical Center, where she arrived 48 hours after ingestion.

General Approach to Mushrooms

• Initially, basic regimen of emesis, adsorption, and catharsis should be followed.
• Induce vomiting at home with syrup of ipecac if recognized early.
• Activated charcoal - suitable alternative in pt. seen in ED.
• Save sample of mushroom placed in paper bag and in refrigerator for possible future identification in the event that the pt. becomes symptomatic.
• General Rule: If symptoms develop within 2-3hrs. of ingestion, it is unlikely that the mushroom is one of the potentially fatal hepatotoxic varieties.
• only with single type mushroom ingestions
• with mixed ingestions you may get early and late symptoms from different mushrooms
• Identification of mushroom important in symptomatic patients
• Generally best to rely on symptomatology, not mushroom appearance, to confirm diagnosis
• Sources of identification:
• Poison information center- may have consultants available
• Botanical garden
• Local mycology club

Mushroom Classification

Table 68-2 from Goldfrank

Group I Mushrooms - Cyclopeptide-containing mushrooms

• 95% of all mushroom fatalities in North America are associated with cyclopeptide- containing mushrooms.
• Synonyms: "Death Angel," "Destroying Angel," "Death Cap"
• Amanita species responsible for most fatalities
• Galerina species generally smaller and contain less amatoxin per gram of mushroom
• 0.1 mg/kg is the minimal lethal dose of amatoxin for adults
• Conc. of 5 to 15mg of amatoxin per dried mushroom 1 Amanita cap
• 15 to 20 Galerina caps may kill a healthy adult

Clinical Presentation

• 4 phases:
• Latent phase - 6-12 hrs after ingestion
• Gastrointestinal phase - severe gastroenteritis with profuse watery diarrhea
• Quiescent phase - Symptomatic improvement for 1-2 days during which h
• initial hepatotoxicity begins
• Hepatic phase - 1-6 days after ingestion, also get renal and occasionally pancreatic toxicity
• Hepatic necrosis evidenced by increasing Alk Phos, AST, ALT, and Bili
• Blood coagulation deficiency closely linked to prognosis

Mortality

• Overall mortality estimated from 5% to 40%
• Gradual decrease over past decades due to intensive care hospitalization and early rehydration
• Higher lethality observed in children possibly due to the fact that they often eat similar quantities of mushrooms as adults but, by virtue of their lower body wt., absorb a larger dose of toxins per kg bodyweight.
• Acute, but not long term pretreatment of mice with ethanol diminshed the toxicity of subsequent doses of a lyophilisate from Amanita phalloides .
  

Case #2

• At University Medical Center, 48 hrs. post ingestion
• PE: Vitals : Temp 38.8 C, P 164, R 52 , BP 96/64 mm Hg.
• Skin turgor good, abd. exam showed moderate hepatomegaly with mild RUQ tenderness.
  Labs: H/H 12.9/35.9 Plts 245k
• PT 34.2 sec PTT 41.9
• BUN 6 Creat 0.9
• Glu 161 Bili 2.3
• AST 9844 ALT 16648
• Art. ammonia 122 mcg/dL

Biologically active components

• Amanita toxin composed of two groups of toxic peptides:
• Amatoxins - sole cause of fatal human mushroom intoxications
• inhibit RNA polymerase B and hence protein synthesis
• several analogous cyclic peptides of which a-amantin is predominant
• Phallotoxins - most likely play no role in lethal poisonings in humans
• all sx described for fatal human cases are those observed with experimental intox. of a-amantin alone
• amatoxins are 8-fold more toxic than phallotoxins
• not resorbed by the gastrointestinal tract
• bind to polymeric or oligomeric actin only thus stabilizing the filament
• change the affinity of filaments for other cell components
• low conc. of actin monomers in a poisoned cell delay the intracellular translocation of actin

Kinetics

• Jaeger et al, 1993, analyzed amantin levels in 45 pts. with acute accidental intox.
• Amatoxins disappear rapidly from plasma and there is no correlation between amantin plasma conc. and clinical severity or outcome.
• Amatoxins are excreted in urine in large quantities during first days following ingestion.
• large amounts may be eliminated in feces, mostly ingested amatoxins which have not been absorbed by the GI tract

Treatment

• Gastric lavage - if early, may limit toxicity
• usually useless because pt. presents after 6-12 hrs. and after vomiting has occurred.
• Gastroduodenal aspiration - may be indicated to remove the toxins eliminated in bile and interrupt the enterohepatic cycle
• Cathartics - Whole bowel irrigation - because large amounts are eliminated in the feces, may prevent further gastrointestinal absorption of amatoxins if pt. treated before GI phase or if diarrhea is not severe
• Activated charcoal - if GI sx., such as vomiting, do not prevent administration
  may interrupt the enterohepatic circulation of toxins
• Forced diuresis - maintenance of an adequate diuresis (100 to 200 ml/h) is an urgent and essential objective requiring correction of hypovolemia and dehydration
• No evidence that it is any more efficient than maintaining a normal or slightly enhanced urine volume
• Enhanced elimination - methods such as hemodialysis, hemoperfusion, or plasma exchange cannot remove a large amount of toxins because of the low plasma conc.
• Liver transplant - should be considered in poisonings with severe hepatic failure

Antidotes

Several drugs and antidotes have been proposed but none have clearly proven to be of clinical efficacy.

Benzylpenicillin (Penicillin G)

Based on experimental findings that various antibacterial agents protected mice and rats from lethal doses.

Floersheim et al, 1978, showed penicillin given at 5 hrs. to dogs treated with toxin prevented or reduced the increase in Alk phos, AST, and ALT

Moreover, reduced the incidence and severity of clinical signs

Hypothesis: In liver failure due to Amanita, GABA derived from enteric bacteria may be insufficiently metabolized. Orally administered and bile- excreted penicillin from high dose IV penicillin sterilize and reduce the GABA-producing intestinal flora and may prevent the severe encephalopathy likely to be the final cause of death.

Silibinin

Water soluble preparation available in Europe of the chief constituent of Silymarin, the active principle of the milk thistle Silibin marianum

Thought to inhibit the penetration of amatoxins into liver cells.

Early (within 48 hrs.) administration was an effective prophylactic measure against severe liver damage both in animal studies and in clinical series.

Thioctic acid (a-lipoic acid)

initially reported beneficial in animal studies

clinical efficacy not been proven

some studies show ineffective or more often associated with fatal outcome than when no thioctic acid administered

Cimetidine

based on fact that it is a cytochrome P450 inhibitor

High doses of cimetidine, penicillin, and ascorbic acid in combination have been shown to increase survival in mice exposed to toxic doses

N-Acetylcysteine

Schneider et al, 1991, studied effects of NAC administered at 4 hours in mice

No statistically significant difference in the survival or hepatic enzyme elevation

Suggests glutathione may play little or no role in this particular toxicity

Hospital Course:

• Admitted to PICU
• Treated with IV fluids and lactulose
• 12 hrs post admission became moderately hypotensive despite fluids, dopamine and dobutamine.
• Treated with Amp/Gent and methylprednisolone with subsequent improvement of cardiovascular status.
• During next 24 hrs, developed renal toxicity (evidenced by oliguria, hematuria, and rising serum creat.) and GI toxicity (evidenced by GI hemorrhage and falling hct)
• With progressive liver dysfunction, her encephalopathy progressed to stage III coma, and she was intubated.
• Charcoal hemoperfusion was attempted but resulted in serious hypotension and was discontinued.
• 5 days post ingestion, orthotopic liver transplant was performed.
• 4 days post op abd. distention, hypotension, and severe mental obtundation developed. Blood cultures positive for Bacteroides.
• Liver imaging with technetium showed complete lack of uptake by left lobe.
• Exploratory lap showed a necrotic, infected left lobe and hepatic lobectomy performed.
• Liver function returned to normal, but neurological deficits persisted.

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