Amatoxins are a group of highly toxic peptides found in several species of mushrooms, including Amanita phalloides, Amanita virosa, Amanita bisporigera, Amanita ocreata, Amanita verna, Galerina autumnalis, Galerina marginata, and some species of Lepiota and Conocybe. Also referred to as cyclopeptide-containing mushrooms, they are responsible for more than 90% of mushroom deaths worldwide. The three main cyclopeptides found in Amanita phalloides are amatoxin, phallotoxin, and virotoxin. Amatoxins, principally alpha-amanitin, are the most toxic and responsible for hepatic and renal toxicity. Phallotoxins are not well absorbed and cause GI symptoms. Virotoxins are not implicated in human poisoning.

Amatoxins are highly stable and resistant to heat and are not removed by any form of cooking. They bind to DNA-dependent RNA polymerase II and inhibit the elongation essential to transcription. The result is a decrease in mRNA that causes an arrest of protein synthesis and cell death. Metabolically active tissue dependent on high rates of protein synthesis, such as cells of the GI tract, hepatocytes, and the proximal convoluted tubules of the kidney, are disproportionately affected. Cellular damage has also been found in the pancreas, adrenal glands, and testes.

1. Pharmacokinetics. Amatoxins are readily absorbed from the intestine and transported across the hepatocytes by bile transport carriers. About 60% undergo enterohepatic recirculation. They have limited protein binding and are eliminated in urine, vomitus, and feces. Toxins are detectable in urine within 90-120 minutes after ingestion. No metabolites of amatoxin have been detected. The half-life in humans is unknown, but in animals there is a rapid decrease in serum, bile and urine levels, with most of the toxin eliminated within the first 24 hours.

Amatoxins are among the most potent toxins known; the minimum lethal dose is about 0.1 mg/kg. One Amanita phalloides cap may contain 10-15 mg. In contrast, Galerina species contain far less toxin; 15-20 caps would be a potentially fatal dose for an adult.

Amatoxin poisoning can be divided into three phases, although not all patients experience phases 2 and 3. There is an initial phase of delayed GI toxicity, followed by a false “recovery” period and then late-onset hepatic failure.

1. Phase 1. Onset of symptoms is 6-24 hours after ingestion. Symptoms include vomiting, severe abdominal cramps, and explosive watery diarrhea, which may become grossly bloody. This GI phase may cause severe volume depletion and hypotension, leading to acute renal failure. Death may occur within the first 24 hours from massive fluid loss.
2. Phase 2 occurs 18-36 hours after ingestion. There is a period of transient clinical improvement in the gastroenteritis but liver enzymes (aminotransferases) are often rising.
3. Phase 3 begins 2-4 days after ingestion and is characterized by markedly elevated transaminases, hyperbilirubinemia, coagulopathy, hypoglycemia, acidosis, hepatic encephalopathy, acute kidney injury, hepatorenal syndrome, multiple-organ failure, disseminated intravascular coagulation, and convulsions. Death usually occurs 6-16 days after ingestion. Encephalopathy, metabolic acidosis, severe coagulopathy, and hypoglycemia are grave prognostic signs and usually predict a fatal outcome.

Is usually based on a history of wild mushroom ingestion and a delay of 6-24 hours before the onset of severe gastroenteritis. However, if a variety of mushrooms have been eaten, stomach upset may occur much earlier owing to ingestion of a different toxic species, making diagnosis of amatoxin poisoning more difficult.

Any available mushroom specimens that may have been ingested should be examined by a mycologist. Pieces of mushroom retrieved from the vomit or even mushroom spores found on microscopic examination may provide clues to the ingested species.

1. Specific levels
   1. Amatoxin can be detected in serum, urine, and gastric fluids by radioimmunoassay or high-performance liquid chromatography (HPLC) with mass spectrometry (LC-MS), but these methods are not readily available to assist in treatment decisions.
   2. A crude qualitative test (Meixner test) for the presence of amatoxins in mushroom specimens has been used in the past, but has unknown reliability and can be misinterpreted or poorly performed.
2. Other useful laboratory studies include electrolytes, glucose, BUN, creatinine, liver aminotransferases (AST and ALT), bilirubin, ammonia, and prothrombin time (PT/INR). Aminotransferases usually peak 60-72 hours after ingestion. Measures of liver function such as the INR are more useful in evaluating the severity of hepatic failure.

The mortality rate is approximately 6-10% with intensive supportive care.

1. Emergency and supportive measures
   1. Maintain an open airway and assist ventilation if necessary. Administer supplemental oxygen.
   2. Treat fluid and electrolyte losses aggressively because massive fluid losses may cause circulatory collapse and contribute to acute kidney injury. Administer normal saline or another crystalloid solution, 10- to 20-mL/kg boluses, with monitoring of central venous pressure to guide fluid therapy.
   3. Provide vigorous supportive care for hepatic failure; orthotopic liver transplant may be lifesaving in patients who develop fulminant hepatic failure. Contact a liver transplant service for assistance.
   4. Use of an extracorporeal bioartificial liver has shown some promise in stabilizing a patient until spontaneous liver regeneration occurs or in serving as a bridge to liver transplant.
2. Specific drugs and antidotes. No antidote has been proven effective for amatoxin poisoning, although over the years many therapies have been promoted. Consult a medical toxicologist or a regional poison control center (1-800-222-1222 in the United States) for further information.
   1. Animal studies and retrospective case series in humans suggest that early treatment with IV silibinin (an extract of milk thistle that is used in Europe [see silibinin]) may be effective in reducing hepatocyte uptake of amatoxin.
   2. Other unproven therapies. High doses of penicillin given before the poisoning showed some hepatoprotective effects in dog and rat studies, but controlled human studies are lacking. A retrospective analysis of 20 years of amatoxin treatment found that high-dose penicillin was the most frequently used chemotherapy but showed little efficacy. The therapies that the authors of this review thought were probably most effective were silibinin, N-acetylcysteine, and detoxification procedures. There are no data to support the use of cimetidine or steroids, and thioctic acid can cause severe hypoglycemia.
3. Decontamination. Administer activated charcoal orally. Gastric lavage may not remove mushroom pieces.
4. Enhanced elimination. There is no proven role for forced diuresis, hemoperfusion, hemofiltration, or hemodialysis in the removal of amatoxins.
   1. Repeat-dose activated charcoal may trap small quantities of amatoxin undergoing enterohepatic recirculation and may be considered in the first 48 hours.
   2. Cannulation of the bile duct or gall bladder to remove bile has been reported effective in dog studies and a few human case reports, but is not without risk, especially in patients with coagulopathy. There has been no direct comparison of the effectiveness of biliary drainage versus repeated-dose activated charcoal.