Mushrooms of two different genera, Gyromitra and Amanita, cause significant toxicity, which characteristically presents several hours after ingestion. Gyromitra esculenta (the false morel) is an uncommon cause of poisoning in North America, but is more common in Scandinavia and Europe.4 G. esculenta has a brown convoluted top resembling a brain and is often mistaken for the tasty morel mushroom. A. phalloides and A. bisporigera are common in the Northern Hemisphere and are particularly common from north central Europe through the Middle East. Mushrooms of these species are found throughout the West Coast, Midwest, and parts of the Northeast of the United States. Immigrants may mistake these mushrooms for edible varieties common in eastern Asia. Mushrooms of the Amanita genus are responsible for 95% of deaths associated with mushrooms. Toxic ingestions in North America occur most commonly in the autumn.
Gyromitrin (N-methyl-N-formylhydrazone) is a volatile heat-labile toxin and primarily responsible for symptoms. Gyromitrin concentration decreases significantly after boiling and desiccation.14 Gyromitrin is hydrolyzed in the stomach to form N-methyl-N-formylhydrazine and N-methylhydrazine. N-Methylhydrazine is chemically identical to rocket fuel, and workers exposed to this compound develop CNS toxicity. N-Methylhydrazine binds to pyridoxine and interferes with enzymes that require pyridoxine as a cofactor. γ-Aminobutyric acid is lowered in the CNS, which may be a cause of associated seizures. N-Methyl-N-formylhydrazine is converted into a free radical in the liver and causes local hepatic necrosis by blocking the activity of the cytochrome P-450 system, glutathione, and other hepatic enzyme systems.14 These two chemicals explain the CNS and hepatic dysfunction characteristic of gyromitrin toxicity. The cause of the initial GI symptoms is not known.
A. phalloides contains several phallotoxins and amatoxins. Phallotoxin is a bi-cyclic peptide that alters the enterocyte cellular membrane, thereby causing early GI symptoms. Its effect is limited to the GI tract, because it is not absorbed by the intestine.15 Amatoxins are bi-cyclic octapeptides that are rapidly absorbed through the intestinal mucosa. They are carried to the liver and undergo enterohepatic circulation, which results in prolonged toxin exposure after ingestion. Nine amatoxins have been identified, but α-amanitin (amanitin) appears the most physiologically active.2 Kinetic studies in humans show that α-amanitin is cleared from the plasma within 48 hours.16 Concentrations in the plasma are quite small. Amatoxins are not protein bound, but are actively transported into hepatocytes, where they bind to RNA polymerase II and inhibit the formation of messenger RNA. Free radical formation may also be involved in toxicity.17 α-Amanitin has the greatest effect on cells that undergo rapid protein synthesis and turnover, including cells of the GI tract mucosa, hepatocytes, and renal tubular epithelium.18 In adults, the dose that causes 50% mortality is 0.1 milligram/kg of body weight, which is commonly contained in a single mushroom.15
Pathologic changes are noted in both gyromitrin and amatoxin toxicity. Patients who ingest gyromitrin-containing mushrooms show diffuse hepatocellular damage and interstitial nephritis. Patients who ingest amatoxin-containing mushrooms show fatty degeneration of the liver, with intranuclear collection of lipids and extensive hepatic necrosis. Electron microscopy shows vacuolization of the mitochondria and clumping of the chromatin in the nucleoli. There are extensive lipid peroxidation changes in both the nucleus and the cytoplasm.
The distinctive characteristics of gyromitrin-containing mushroom toxicity are intense GI signs and symptoms (nausea, vomiting, and watery diarrhea) that develop 6 to 24 hours after ingestion, typically between 6 and 8 hours.
Hypovolemia is common during this phase of toxicity. In severe cases, hepatic failure is evident on day 3 and may result in death as early as day 7. Serum transaminase levels may be significantly elevated. Hypoglycemia occurs during the GI phase and again in the acute hepatic failure phase.
Initial GI symptoms can be accompanied by dizziness, headache, seizures, incoordination, and muscle cramps. The initial GI symptoms resolve within 2 to 5 days.5 In a mild ingestion, the neurologic symptoms persist for several days and resolve without sequelae.
Patients who ingest amatoxin-containing mushrooms also have delayed onset of GI symptoms (6 to 24 hours). The gastroenteritis is intense, often requiring fluid and electrolyte replacement. There are four stages in amatoxin poisoning. The first (latent) stage is characterized by the absence of any signs or symptoms and lasts up to 24 hours after ingestion. During the 12 to 24 hours of the second stage, GI symptoms such as intense cramping abdominal pain, nausea, vomiting, and diarrhea dominate the clinical picture. Both stools and vomitus may become bloody. Although right upper quadrant tenderness and hepatomegaly may be noted, results of liver function tests are usually normal. Patients who present during this stage are frequently misdiagnosed with gastroenteritis. The third, or convalescent, phase lasts 12 to 24 hours. During this stage, the patient feels and looks better, but levels of liver enzymes, such as aspartate aminotransferase, alanine aminotransferase, and bilirubin, begin to rise, heralding the onset of liver damage. Renal function may also deteriorate. In the fourth and final stage, which begins 2 to 4 days after ingestion, transaminase levels rise dramatically, and liver and renal function deteriorate. Hyperbilirubinemia, coagulopathy, hypoglycemia, acidosis, hepatic encephalopathy, and hepatorenal syndrome are noted.2
In both Gyromitra and Amanita toxicity, prothrombin time may be elevated and unresponsive to administration of vitamin K or fresh frozen plasma. Amylase and lipase elevation suggests pancreatic damage, although symptomatic pancreatitis is rare. Abnormal laboratory findings in amatoxin poisoning include a decrease in neutrophils, lymphocytes, and platelets, and abnormal thyroid function results. Hypophosphatemia (primarily noted in children), hypocalcemia, and elevated insulin levels occur. None of these laboratory abnormalities correlates with clinical disease, and their cause is unknown.
The mortality from Gyromitra ingestion is estimated at 15% to 35% and is generally attributed to hepatic failure, renal failure, or fluid and electrolyte disorders.5 More recently, mortality has been reduced to 10% to 15%, because of improved care for hepatic failure and liver transplantation. Patients who survive severe hepatic failure from amatoxin may develop signs of chronic active hepatitis with persistent elevation in liver transaminase levels, development of anti–smooth muscle antibodies, and presence of cryoglobulins. No prolonged effects from gyromitrin toxicity have been reported.
The diagnosis of gyromitrin toxicity is generally assumed from the clinical features and the identification of the mushroom ingested, either by the patient or from samples. Identification of Amanita species generally requires a trained mycologist. The Meixner colorimetric test is used to look for the presence of amatoxin. A drop of fresh mushroom pulp, methanol extract from dried mushrooms, or gastric material is placed on a high-lignin paper (e.g., newspaper) and allowed to dry. A drop of 10-N or 12-N hydrochloric acid is then applied to catalyze the reaction of the amatoxin with the lignin in the paper. The area will turn blue within 1 to 2 minutes if amatoxins are present, but the appearance of color may be delayed up to 30 minutes if the amatoxin concentration is low.2 Although the test is sensitive, it is not very specific, and other nontoxic mushrooms may give a positive test result. Tests using thin-layer chromatography, high-performance liquid chromatography, and radioimmunoassay have been developed to detect amatoxin. Unfortunately, these assays are not generally available to clinicians and are used most often in research settings.2 Amatoxin can be detected in plasma, urine, GI tract contents, and feces. However, its presence merely confirms amatoxin poisoning. Levels do not appear to correlate with clinical severity, and amatoxin is not detected in many patients, presumably because of rapid clearance.
Administer activated charcoal to patient presenting with severe vomiting and diarrhea within a few hours of mushroom ingestion. Repeated doses of charcoal for at least the first 24 hours may be effective, particularly in the presence of amatoxin (because it undergoes enterohepatic circulation).15 Fluid and electrolyte replacement is mandatory. Glucose level should be monitored and glucose replaced as needed. Hypoglycemia is one of the most common causes of death in early mushroom toxicity.
All patients who have ingested amatoxin- or gyromitrin-containing mushrooms should be closely monitored for 48 hours for the development of hepatic and renal failure. Electrolyte levels, liver enzyme levels, and prothrombin time should be monitored several times a day. Patients should be treated with a low-protein diet and should receive standard supportive therapy for hepatic failure. Fresh frozen plasma and vitamin K can be used for the treatment of prolonged prothrombin time, but in many cases, coagulopathy does not respond to treatment.
Patients who develop hepatic failure should be monitored closely, and in severe cases, preparations should be made for liver transplantation. Although no firm criteria exist, progressive coagulopathy, encephalopathy, and renal failure despite maximal medical therapy are frequently listed indications for emergency liver transplantation.19 Many patients have met these criteria and survived without transplantation, and many patients have died without meeting these criteria. Liver transplantation, however, does provide the only option for patients in fulminant hepatic failure and has been quite successful. Auxiliary liver transplantation has also been used. In this case, a portion of the damaged liver is removed and a temporary transplant provided, which allows time for the native liver to regenerate.20
Treat the neurologic symptoms associated with gyromitrin with high-dose pyridoxine. Pyridoxine provides the cofactor required for the regeneration of γ-aminobutyric acid. High doses of pyridoxine, 25 milligrams/kg IV over 30 minutes up to a maximum of 25 grams/d, are recommended, but doses of pyridoxine in excess of 40 grams are associated with severe peripheral neuropathy.21,22 Pyridoxine does not affect the development or course of hepatic failure, and there is no specific therapy for gyromitrin-induced hepatic failure.
Although multiple modalities have been tried in the past with mixed results, activated charcoal, silybinum marianum, and N-acetylcysteine are emerging as the best-supported treatment modalities.15,23 Early in the clinical course, repeated dosing of activated charcoal is thought beneficial by reducing the absorption of amatoxin as it undergoes enterohepatic circulation. Silybinum marianum, a milk thistle isolate, is also thought to prevent toxicity by interfering with transmembrane transport during enterohepatic circulation and inhibiting the binding of α-amanitin to hepatocytes.15,23 There is some evidence that silybinum has additional hepatoprotective effects that result from stimulating protein synthesis and inhibiting tumor necrosis factor-α release in damaged liver cells.23 It is given as a loading dose of 5 milligrams/kg over 1 hour followed by 20 milligrams/kg/d for 6 days. This treatment is not currently approved by the U.S. Food and Drug Administration; it is available in Europe, and phase II/III clinical trials are in progress in the United States.15 N-Acetylcysteine is also beneficial as a means of reducing reactive metabolites by providing sulfhydryl groups for this purpose. It is given intravenously in three sequential doses of 150 milligrams/kg over 1 hour, 50 milligrams/kg over 4 hours, and 100 milligrams/kg over 16 hours.
Despite these therapies, amatoxin toxicity may lead to fulminant liver failure. In cases of amatoxin-induced liver failure, the amatoxin itself is rapidly absorbed and excreted, which limits the utility of hemoperfusion and/or hemodialysis. The Molecular Adsorbent Recirculation System™ can support liver function while hepatocytes recover or until transplantation becomes feasible.24 Although randomized controlled trials are not available, numerous case reports have shown improved liver functioning coinciding with this device.24 Orthotopic liver transplantation (the entire organ is replaced with a graft) and auxiliary partial orthotopic liver transplantation (a portion of the native liver is removed and replaced with a graft until recovery occurs) are both surgical options.15
High-dose penicillin G and ceftazidime have both demonstrated a capacity for decreasing the uptake of amanitin by hepatocytes.18,25 However, these therapies appear to be less effective than using silybinum alone.23 Thioctic acid is a free radical scavenger and has been used for many years but has not yet gained support in the literature.
Patients suspected of ingesting amatoxin- or gyromitrin-containing mushrooms should be admitted and monitored for 48 hours, with monitoring of hepatic and renal function.