Gyromitra Mushroom Toxicity

Some Gyromitra mushrooms contain hydrazones, including the toxin gyromitrin (N -methyl-N-formylhydrazone). Gyromitrin rapidly decomposes in the stomach to form acetaldehyde and N-methyl-N-formylhydrazine, which is converted to monomethylhydrazine (MMH) by slow hydrolysis. MMH is a water-soluble toxin that causes gastroenteritis, hemolysis, methemoglobinemia, hepatorenal failure, seizures, and coma. MMH is employed in rocket fuel and causes similar toxicity in aerospace industry workers. Cooking can render these mushrooms less toxic, although not reliably so. MMH is volatile and the fumes from cooking may cause toxicity.

Neurotoxicity

MMH exposure is similar to that of isoniazid in that it generates functional pyridoxine deficiency by inhibition of pyridoxine kinase. Pyridoxine kinase inhibition interferes with production of pyridoxal phosphate, an essential cofactor for a number of enzymatic steps, including glutamic acid decarboxylase (GAD).

Gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter of the brain, is produced from glutamate (an excitatory neurotransmitter) by the enzyme GAD. MMH also may inhibit GAD directly. The resultant GABA deficiency, with loss of inhibitory neurotransmission, may lead to seizures.

Gastrointestinal toxicity

Inhibition of diamine oxidase in intestinal mucosa may be responsible for GI effects. Association of individual variability in acetylation rates (eg, slow vs fast acetylators) in hepatotoxicity is not well established.[2]

Hematopoietic toxicity

Hemolysis and methemoglobinemia can occur. Resultant hemoglobinuria may cause acute kidney injury.

MMH poisoning may occur after ingestion of fresh, dried, or raw gyromitrin-containing mushrooms or with inhalation of vapors while cooking gyromitrin-containing mushrooms. 

Severity depends on amount of toxin ingested. Amount of toxin greatly varies among mushrooms, and significant variation in individual susceptibility exists. Raw mushrooms have more toxin than cooked mushrooms. Fresh mushrooms have more toxin than dry mushrooms. Environmental factors appear to influence the amount of toxin, which varies regionally in these mushrooms.

In 2021, the American Association of Poison Control Centers (AAPCC) Toxic Exposure Surveillance System reported 6783 single exposures to mushroom and 3 fatalities.[3]  Unknown mushroom type makes up the majority of exposures each year, usually accounting for well over 70% of mushroom exposures, but deaths in this group remain remarkably low (0-3 per year since 1996).[3, 4, 5, 6, 7, 8, 9, 10]

In the same 2021 report, MMH-containing mushrooms accounted for 32 exposures and no fatalities.[3]

No adequate international database exists. In the past, gyromitrin-containing mushrooms have been associated with significant mortality in Eastern Europe.

Mushroom poisoning is the leading cause of foodborne disease outbreaks and foodborne-related deaths in China. The Chinese Foodborne Disease Outbreak Surveillance System reported a total of 10,036 mushroom poisoning outbreaks between 2010-2020 with over 60% of the outbreaks attributed to unidentified mushrooms. These outbreaks resulted in a cumulative 38,676 illnesses and 788 deaths during that period.  In 2020 there were 2075 mushroom outbreaks reported.[11]  Gyromitra venenata was a new species discovered in two provinces in 2020 and caused poisoning in four patients. Poisonings due to gyromitrins had not been reported in China since 2000.[12]

Children are more sensitive to gyromitrin toxicity than adults. Overall about 60% of mushroom exposures are in children younger than 6 years. Although with Gyromitra species specifically, in 2017 children younger than 6 years account for less than 1% of exposures.[3]

Most patients fully recover after 2-5 days of a gastric illness. Mortality rates from 10-40% have been reported; however, death from gyromitrin-containing mushrooms in North America is exceedingly rare. Toxicity of gyromitrin-containing mushrooms varies by region and season.

Complications of MMH poisoning include:

• Aspiration pneumonia
• Rhabdomyolysis
• Acute kidney injury secondary to hemolysis and rhabdomyolysis
• Liver failure
• Anoxic and hepatic encephalopathy

Inform patients that Gyromitra mushrooms are toxic and potentially lethal.

For patient education information, see visit eMedicineHealth's First Aid and Injuries Center. Also, see eMedicineHealth's patient education articles Poisoning and Activated Charcoal.

Determining history of mushroom exposure is helpful. Query patients presenting with gastroenteritis about mushroom collecting, cooking, and ingestion.

Onset of symptoms typically is delayed with gyromitrin poisoning. GI symptoms typically occur 6-10 hours after ingestion; however, symptoms may begin earlier with severe poisonings. Symptoms may be delayed 48 hours with mild poisonings. Inhalation exposure characteristically produces symptoms within 2 hours of exposure. GI phase of toxicity may be followed by neurologic and hepatorenal toxicity.

Details of ingestion and progression of symptoms are helpful in differentiating ingestions of different mushroom types. Ask the following questions to ascertain specific history:

• When were the mushrooms ingested (or when was patient exposed to vapors of cooking mushrooms)?
• When did each symptom begin?
• Where were the mushrooms found?
• Were other species ingested?
• Did others become ill after eating the mushrooms?

Clinical history includes the following:

• GI symptoms are prominent, with complaints of abdominal pain, bloating, vomiting, and diarrhea.
• Other complaints (eg, weakness, dizziness, headache, confusion, seizures) may be caused by volume depletion, anemia, and renal, hepatic, or neurologic toxicity.
• Typical duration of symptoms is 1-2 days but may be as long as 5 days.

Vital signs in patients with gyromitra mushroom poisoning may include the following:

• Tachycardia
• Hypotension
• Tachypnea (secondary to methemoglobinemia and/or hemolysis)
• Fever

General appearance may include the following:

• Dry skin with poor turgor (from vomiting and fluid losses)
• Pale skin (from hemolysis)
• Cyanosis unresponsive to oxygen (from methemoglobinemia)
• Jaundice (from liver damage and hemolysis)

Neurologic findings may include the following:

• Tremor, muscle spasms
• Seizures, delirium
• Stupor and encephalopathy

Abdominal and rectal findings may include the following:

• Hyperactive bowel sounds, bloating, mild tenderness to palpation
• Hepatomegaly
• Liquid or heme-positive stool

Patients with gyromitra mushroom poisoning may have muddy-colored urine from hemoglobinuria (due to hemolysis) and brown-colored blood (from methemoglobinemia). Blood test results in patients with gyromitra mushroom toxicity include the following:

• Metabolic panel: Patients often are dehydrated. Patients with hemolysis may have impaired kidney function. Hyperglycemia may be present as an acute stress reaction; however, sudden hypoglycemia is a greater concern than hyperglycemia with hepatic injury.
• Complete blood count and/or peripheral blood smear: Assess for anemia from hemolysis or blood loss.
• Hepatic transaminases and serum bilirubin: Levels may be normal at presentation; however, if hepatic injury exists, liver function study results becomes abnormal within days of exposure. Bilirubin may be elevated from hemolysis or liver toxicity. 
• Methemoglobin levels: Measure by co-oximetry (determine need for methylene blue treatment).

Tests for hemolysis

The following for hemolysis may be performed:

• Urinalysis: Positive dip test for blood without red blood cells on microscopic analysis suggests either hemolyzed blood (hemoglobinuria) or myoglobin.
• Free plasma hemoglobin: Level increases with hemolysis
• Serum haptoglobin: Level decreases with hemolysis
• Blood smears: Heinz body formation is observed with special stains, and bite cells are observed with Wright stain.

Determination of mushroom type

If a specimen of the ingested mushroom is available, save it in a paper bag for potential identification. An experienced mycologist may identify the mushroom. Save any food specimen or gastric contents (from emesis); further testing for gyromitrin toxin occasionally may be performed.

Gas-liquid chromatography, gas mass spectrometry, and thin-layer chromatography can be used to identify hydrazone and hydrazine compounds.

Initiate supportive care, including intravenous (IV) fluids and seizure control with pyridoxine and benzodiazepines.

Initiate supportive care and decontamination as follows:

• ABCs (airway, breathing, circulation) and coma protocols
• Correction of fluid and electrolyte imbalances
• Antiemetics (if needed)
• Dextrose (if needed)
• Consideration of activated charcoal (although with typical delayed presentation of poisoning by Gyromitra species, benefit from this intervention is unlikely)

Administer intravenous fluids to maintain brisk urine output and prevent renal damage from hemolysis.

Treat seizures with both pyridoxine (vitamin B6) and benzodiazepines.[13]  Although limited cases exist in which pyridoxine was used as an antidote for gyromitrin-containing mushroom poisoning, pyridoxine is the antidote of choice for isoniazid-induced seizures, which are due to hydrazine and hydrazone metabolites of isoniazid interfering with GABA synthesis.

Phenobarbital has been demonstrated to increase metabolism of hydrazines to toxic metabolites and should be avoided. Phenobarbital metabolism may be decreased if liver failure from gyromitrin toxicity has occurred.

Treatment of methemoglobinemia involves oxygen and methylene blue. Methemoglobin cannot transport oxygen; functional anemia results. Modest levels of methemoglobinemia may be tolerated with supportive care. With higher levels (eg, >20%) and associated symptoms, such as mental status changes, dyspnea, ischemic chest pain, or acidosis, consider treatment with methylene blue.

Anemia due to hemolysis may require blood transfusion.

Theoretically, folinic acid may be beneficial. Hydrazines inhibit metabolism of folic acid to tetrahydrofolate.

Admit all symptomatic patients in whom gyromitrin poisoning is suspected for further management and monitoring. Monitor patients for dehydration, neurologic toxicity, and liver or kidney failure. Consider intensive care unit admission for patients with seizures, coma, severe methemoglobinemia, or hemolysis.

Patients with gyromitrin ingestion who are asymptomatic 8 hours after ingestion and are without clinical or laboratory signs of toxicity may be considered for discharge. Early follow-up care for re-evaluation must be in place at the time of discharge. Instruct patients to return immediately if they become symptomatic. Instruct patients to keep themselves well hydrated.

Consultation with a regional poison control center and toxicologist may be helpful. They may assist in contacting a mycologist for mushroom identification. Obtain a gastroenterology consultation if evidence of liver dysfunction is present.

The goals of pharmacotherapy are to reduce morbidity, prevent complications, and neutralize the effects of the toxin.

Class Summary

Empirically used to minimize systemic adsorption of toxin. May benefit only if administered within 1-2 hours of ingestion.

Activated charcoal (Liqui-Char)

Emergency treatment in poisoning caused by drugs and chemicals. Network of pores present in activated charcoal adsorbs 100-1000 mg of drug per gram of charcoal. Does not dissolve in water. For maximum effect, administer within 30 min of ingesting poison.

Class Summary

Prevents seizure recurrence and terminates clinical and electrical seizure activity. May be used in conjunction with benzodiazepines.

Pyridoxine (Nestrex)

Involved in synthesis of GABA within CNS. Administer with benzodiazepines.

Class Summary

Prevents seizure recurrence and terminates clinical and electrical seizure activity. May be used in conjunction with pyridoxine (vitamin B-6).

Diazepam (Valium)

Depresses all levels of CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA.

Lorazepam (Ativan)

Sedative hypnotic with short onset of effects and relatively long half-life. May depress all levels of CNS, including limbic and reticular formation, by increasing action of GABA, which is a major inhibitory neurotransmitter in the brain. Monitoring patient's blood pressure after administering dose is important. Adjust prn.

Midazolam (Versed)

Used as alternative in termination of refractory status epilepticus. Because water soluble, takes approximately 3 times longer than diazepam to peak EEG effects. Thus clinician must wait 2-3 min to fully evaluate sedative effects before initiating procedure or repeating dose. Has twice the affinity for benzodiazepine receptors than diazepam. May be administered IM if unable to obtain vascular access.

Class Summary

In reduced form, leukomethylene blue is an electron donor to reduce methemoglobin. Reduction of methylene blue is by NADPH generated by G-6-PD.

Methylene blue (Urolene blue)

Used to convert ferrous iron of reduced hemoglobin to ferric form that is the basis for antidotal action.