Amatoxin Mushroom Toxicity

Etiology

There are thousands of species of mushroom, but only about 50 to 100 of these are toxic to humans. The Amanita species are responsible for the majority of mushroom toxicity cases in humans. The Amanita mushrooms contain both amatoxins and phallotoxins. The amatoxins interfere with protein synthesis and cause liver failure.

Other Amanita species such as Amanita smithiana contain a renal toxin, and Amanita muscaria and Amanita pantherina have isoxazole toxins, causing alterations in mental status but no liver or renal injury.

Epidemiology

Amanita poisoning occurs because most people are not able to tell which mushrooms species are safe for consumption when foraging. Also, certain people seek psychotropic mushrooms to get a “high” but mistakenly ingest amanita mushrooms. Amanita mushrooms have no distinct taste or odor but are large (5 cm to 15 cm) and often indistinguishable in color or appearance from edible species.[3]

Pathophysiology

The amanitin toxin is heat stable, remaining toxic whether eaten raw or cooked. The mechanism of action of amatoxin is by inhibiting RNA polymerase, causing disruption of transcription of mRNA. As a result, hepatocytes cannot synthesize key protein coding genes, leading to the disintegration of nucleoli and pathologically centrilobular hepatic necrosis. This leads to the insidious onset of liver failure over 48 hours. Late onset (more than six hours after ingestion) of vomiting and watery diarrhea occur due to the second component in some of these mushrooms which are phallotoxin. Lepiota species lack phallotoxins so may not have the onset of vomiting and diarrhea until after 12 hours post-ingestion, or may just present with symptoms of liver failure at 24 hours post ingestion.[4]

Toxicokinetics

Amatoxins are rapidly absorbed from the intestine and transported into the liver by OATP transporters. Once in the hepatocyte they start to inhibit RNA polymerase. It takes about 24 hours before any signs or laboratory indicators of liver injury begin to appear.

History and Physical

The course of Amanita toxicity has three phases:

1. The first stage does not begin until six to 12 hours after ingestion; often foragers comment on how good the food made from Amanita species tastes, and there are no signs of a problem for at least 6 hours. After this silent phase, it is followed by the onset of nausea, abdominal cramps, profuse watery diarrhea, and signs of dehydration. A physical exam may reveal dry mucosal membranes and tachycardia, and given sufficient dehydration, hypotension.
2. After the GI phase, the second stage appears where the patient appears to recover transiently, and GI symptoms resolve, but ongoing liver damage continues. This stage may last two to three days and is characterized by rising liver function transaminase, bilirubin, the development of coagulopathy, and eventually hepatic encephalopathy.
3. In the third stage, both liver and renal function become compromised. Hepato-renal syndrome and hepatic encephalopathy may occur rapidly after laboratory signs of liver injury, and death can occur in three to seven days.

Evaluation

All ingestions of suspected liver-toxic mushrooms should have a complete chemistry panel to include liver function tests and a baseline INR.[5]

Treatment / Management

The treatment of Amatoxin mushroom toxicity is predominately supportive care. There is no specific antidote. The patient must have two large bore IVs and fluid loss, electrolyte deficiency, and glucose should be normalized. If the patient presents early (within two to four hours,) decontamination with oral activated charcoal may be performed. Once the stomach is empty, nausea should be treated if needed.[1][2]

Several agents have been used and have anecdotal support in the literature:

1. N-acetyl-cysteine: Used intravenously (IV) as per acetaminophen poisoning to treat potential liver injury, and provide glutathione.
2. Penicillin: High dose IV  (four million units every four hours) is thought to compete with the liver uptake of the amatoxin.
3. Silymarin: Both the pharmaceutical form available in Europe as an intravenous formulation and the over the counter raw milk thistle extract used in North America have been used in a majority of cases in the literature. Its mechanism of action is felt to be an OAT-P transporter inhibitor that slows the entry of amatoxin into the liver. Doses are 1 gm orally four times daily, or its purified alkaloid silibinin intravenously  5 mg/kg IV over one hour, followed by 20 mg/kg/day as a constant infusion.
4. Activated charcoal: May reduce absorption of amatoxins if given early after ingestion and may also prevent toxin readsorption hours later as amatoxins undergo enterohepatic recirculation. A dose of 1 g/kg may be given every 2 to 4 hours.
5. Cyclosporine: Inhibitor of OAT-P transporter in in vitro studies[6]. Though cyclosporine is well studied for other indications, use for amatoxin mushroom toxicity is limited to case reports.
6. A variety of other therapies, such as intravenous cimetidine or thioctic acid, have been tried but have only animal model support.
(B3)

In selected cases, once a severe liver injury occurs, despite aggressive fluid resuscitation and supportive care, a liver transplant may be the only life-saving option. Rapid progression to hepatic encephalopathy, hepatorenal syndrome, or coagulopathy are indications for liver transplantation. Consideration to transfer to a liver transplant setting and intensive care unit care should be done early in the course of mushroom ingestions.

When renal failure occurs, dialysis should be used, but its use even early after an ingestion does not remove Amatoxin from the blood.

Differential Diagnosis

Confirmatory testing of amatoxin exposure is rarely available and relies on a strong supporting history. Thus, appropriate consideration should be given to other causes of acute hepatitis and liver failure such as acetaminophen overdose, infection, and autoimmune disorders.

Complications

• Renal and liver toxicity
• Encephalopathy
• Dehydration
• Pancreatitis
• Neuropathy