Gyromitra Mushroom Toxicity

Etiology

Gyromitra esculenta produces the toxin gyromitrin, the metabolite of which causes the manifestations of Gyromitra syndrome. Gyromitra gigas (Snow morel) and Gyromitra fastigiata also contain gyromitrin, but human poisonings have not been attributed to these 2 mushroom species. The gyromitrin content of other Gyromitra species is unknown.[7]

Gyromitrin is a polar, water-soluble, and volatile mycotoxin. Fresh Gyrometria esculenta mushrooms can contain 50 to 300 mg/kg of gyrometrin. Washing, boiling, and drying can significantly reduce the mushrooms' gyrometrin content and make them safe for human consumption.[8][9] 

Toxicity manifests after gyromitrin hydrolysis to MMH. This metabolite is a rocket propellant ingredient responsible for Gyromitra mushroom toxicity. MMH and other hydrazines are cytotoxic, irreversibly blocking cytochrome P450 enzymes, amine oxidases, and glutathione and producing free methyl radicals.[7] Hydrazine compounds also inhibit pyridoxal 5-phosphate formation, an essential GABA synthesis cofactor derived from pyridoxine (vitamin B6).[10] MMH also prevents folinic acid formation by preventing folic acid biotransformation.[11]  

Epidemiology

Gyromitra poisonings have been recorded in Europe and the US over the centuries, although the species names have changed over time. Further investigation enabled the identification of the Gyromitra esculenta mushroom and its toxin. In 1793, poisonings in France were attributed to the then-named Morchella pleopus. In 1885, an extract was obtained from the same mushroom named "helvellic acid." This toxin is now known as gyromitrin. List and Luft identified gyromitrin's chemical structure and properties in 1968.[12]

Most Gyromitra poisonings occur in Eastern Europe, particularly in Germany, Poland, and Finland's conifer forests. In North America, most exposures have been reported in Michigan. However, a less toxic variety grows west of the Rockies, particularly in Idaho and Western Canada. Exposures occur primarily in the spring, unlike other severe mushroom poisonings like Amanita phalloides, which occur more commonly in the fall.[11]

In Sweden, poisoning is relatively frequent due to the mushroom's wide distribution throughout the country. The Swedish Poisons Information Centre received 706 inquiries about human exposure to Gyromitra esculenta between 1994 and 2002. However, the center never reported life-threatening toxicity, and fatalities have not been reported over the last 50 years.[13]

Data from the North American Mycological Association reveal that only 27 cases of Gyromitra esculenta poisoning have been reported in over 30 years. Liver damage was documented in 9 cases (33%) and kidney failure in 3 (11%). No fatalities were reported. Meanwhile, information from the National Poison Data System (NPDS) shows that mushroom toxin exposures represent about 0.2% of the reported cases and appear stable over time. NPDS data also reveal 133,700 cases (7,428 cases yearly) recorded between 1999 and 2016. Of these cases, 703 (0.55%) were from the Gyrometra species, with no reported fatalities.[14] 

Pathophysiology

Gyromitrin is hydrolyzed to N-methyl-N-formyl hydrazine (MFH) in the stomach, then converted in the stomach or liver by cytochrome P450 oxidation into MMH. This active metabolite inhibits mostly enzymatic processes involving pyridoxine derivatives. Gyromitrin directly binds and inhibits pyridoxal phosphokinase, which catalyzes dietary pyridoxine's phosphorylation to pyridoxal 5-phosphate. Pyridoxine activation is similar to the metabolism of the antituberculosis medication isonicotinic acid hydrazide (isoniazid).

Gastrointestinal irritation results from MFH and MMH exposure, manifesting most commonly as nausea, vomiting, abdominal pain, and diarrhea. Renal injury may arise from direct MMH toxicity and dehydration.

The CNS enzyme glutamic acid decarboxylase cannot convert glutamate into GABA without pyridoxal 5-phosphate as a cofactor. GABA depletion reduces the inhibitory effect of presynaptic GABA neurons on postsynaptic firing, resulting in a relative excitatory state in the brain and predisposing to delayed seizures.[15][16]

Liver failure is due to hepatocyte damage from direct MMH exposure. Free radical production and the formulation of an unstable diazonium compound lead to hepatic cell necrosis. MMH also interferes with cytochrome P450, aminooxidases, and glutathione pathways. 

Toxicokinetics

Gyromitrin has the chemical formula C₄H₈N₂O, and its chemical name is N’-ethylidene-N-methylformohydrazide. Gyromitrin's boiling point is 143°C (289°F). In contrast, MMH boils at a lower temperature of 87.5°C (190°F). Parboiling, with subsequent drying, has been cited by various sources as an effective means to detoxify Gyromitra mushrooms and render them edible. This technique can remove about 99% of the mushroom's gyromitrin content.[17]

Michelot estimated gyromitrin's lethal dose to be 25 to 50 mg/kg in adults and 10 to 30 mg/kg in children based on animal experiments. These values roughly correlate to 0.4 to 1.0 kg of fresh, uncooked mushrooms for adults and 0.2 to 0.6 kg for children, amounts unlikely to be consumed at a given time.

Liver acetylation can detoxify MMH. The acetylation rate is influenced genetically. Fast acetylators may not develop toxicity or experience less severe symptoms due to rapid MMH clearance. Genetically slower acetylators are more likely to present with severe gyromitrin toxicity symptoms due to the MMH's longer elimination time.[18]  

History and Physical

Patients may initially present with nausea, vomiting, and abdominal pain. Diarrhea may or may not be reported.[22] Symptoms usually develop 5 to 12 hours after Gyromitra ingestion or generally adhere to the 6-hour rule for mushroom poisoning. Manifestations may also be observed as early as 2 hours post-ingestion.

The time of mushroom ingestion must be elicited on history, as comparing it with the time of symptom onset can help predict clinical severity. Individuals who report emesis within 6 hours of ingestion will likely develop low systemic toxicity, as emesis reduces intestinal gyromitrin absorption and subsequent circulation. However, systemic toxicity risk rises if vomiting begins 6 hours post-ingestion. Intravenous (IV) access must be established for patients with late-onset symptoms with blood collection for laboratory hepatic or renal assessment. IV fluids may also be started to avoid dehydration.[19] The gastrointestinal symptoms are often self-limiting, with most patients recovering in 2-6 days.

Other information that may be obtained are the kind of mushrooms sought, the season of the year, and the amount consumed. Some knowledgeable foragers may even know Gyromitra esculenta and intentionally seek and consume it. Gyromitra mushrooms emerge during the spring in temperate climate forest areas, often near pines and aspen trees. Meanwhile, the amount eaten can also help approximate the likelihood of toxicity as symptom severity correlates with the ingested toxin's quantity.

If the mushrooms were purchased, the store or seller must be identified to help determine if gyromitrin contamination occurred during collection and distribution. The FDA has prohibited the importation of wild mushrooms since the 1980s. Various US states also regulate and limit the sale of wild mushrooms for human consumption.[20]

Physical examination findings are often nonspecific in the early stages but may include dry mucous membranes, decreased bowel sounds, generalized abdominal tenderness, and confusion. Jaundice is a late finding, typically in more severe cases, occurring 3 days post-ingestion. Signs of extensive CNS involvement, including nervousness, vertigo, ataxia, delirium, seizures, and altered mentation, usually occur after large ingestions. A detailed neurologic examination must be performed for patients with CNS symptoms. The ingested amount must also be elicited. Death, although extremely rare, has been reported as early as 3 days post-ingestion.

Toxicity may often go unrecognized in the initial stages of the illness due to the vague presenting complaints. Thus, a high suspicion index for toxic mushroom ingestion is required for diagnosis. Although a rare occurrence, toxic mushroom ingestion must be considered in patients presenting with gastrointestinal complaints after food consumption.

Evaluation

The diagnosis of Gyromitra syndrome is clinical, relying on associating the patient’s liver, renal, and CNS findings with a history of Gyromitra mushroom ingestion. Specific tests for gyromitrin detection are currently unavailable in the clinical setting.

Common laboratory findings in patients with gyromitrin toxicity include elevated transaminases, lactate dehydrogenase, and total bilirubin within 1 to 2 days of ingestion. Liver transaminases, particularly AST, usually peak around 4 to 5 days post-ingestion. Elevated blood urea nitrogen and creatinine may also occur, reflecting acute kidney injury.

CNS signs may vary from confusion to seizures, but computed tomography and magnetic resonance imaging findings are usually normal. Meanwhile, status epilepticus and persistent lateralizing signs warrant further investigation, and neuroimaging must be performed in such cases once the seizure is controlled.

Treatment / Management

Treatment should be initiated as early as possible, especially if seizure development is likely. Initial treatment is primarily supportive, with close attention to fluid and electrolyte balance. Daily laboratory testing should include liver and kidney function tests.

Gastric decontamination is often not required, as vomiting alone may already clear the intestines of the toxin. Specific treatment for any CNS symptoms is pyridoxine supplementation to overcome the vitamin depletion secondary to MMH's action. Pyridoxine at 25 mg/kg IV can be given to control or prevent seizures. Benzodiazepines are also recommended for ongoing seizures despite pyridoxine replacement. Other first-line anticonvulsants, such as phenytoin, are usually ineffective. Most patients recover uneventfully within 6 days with good supportive care and pyridoxine.

Differential Diagnosis

The differential diagnoses of Gyromitra poisoning include the following:

• Acetaminophen toxicity
• Amatoxin toxicity
• Disulfiram toxicity
• Disulfiram-like mushroom toxicity
• Diabetic ketoacidosis
• Gastroenteritis
• Gallstones (cholelithiasis) and acute cholecystitis 
• Giardiasis
• Hyperemesis gravidarum
• Stimulant abuse
• Iron toxicity
• Isoniazid toxicity
• Orellanine in mushroom toxicity
• Organophosphate and carbamate toxicity
• Pediatric gastroenteritis

A detailed clinical evaluation can help distinguish Gyromitra syndrome from these conditions.

Prognosis

The prognosis of Gyromitra mushroom toxicity is very good, and fatalities have not been documented for decades. Less is known about this mushroom than Amanita phalloides in regards to prognostication. However, encephalopathy, renal failure, lactic acidosis, and gastrointestinal symptom onset longer than 8 hours post-ingestion are associated with poor outcomes.

Complications

The potential complications of severe Gyromitra esculenta intoxication include liver and renal failure. Hemodialysis may be required for severe nephrotoxicity. Repeated and chronic Gyromitra handling may result in typical toxic effects, both systemic and local. Additionally, chronic gyromitrin exposure is possibly oncogenic.[23] Gyromitra consumption has also been linked to the development of amyotrophic lateral sclerosis.[24]