Gyromitra Mushroom Toxicity


Article Author:
Keahi Horowitz


Article Editor:
B Horowitz


Editors In Chief:
Joshua Gibson
Jim Powers
Kermit Huebner


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Frank Smeeks
Kristina Soman-Faulkner
Radia Jamil
Patrick Le
Sobhan Daneshfar
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
5/12/2019 2:13:04 PM

Introduction

Gyromitra esculenta, the false morel, is a toxic mushroom. The mushroom derives its name (esculenta) from the Latin for edible. Certain cultures, as well as many mushroom guides and websites, consider this mushroom safe to eat provided that proper preparation techniques are used to reduce its toxicity. Unfortunately, several incidences of poisoning have been reported in foragers seeking and ingesting the Gyromitra esculenta. In general, most poisonings occur when foragers search for true morels, such as Morchella species, but instead find and consume Gyromitra.

The Gyromitra syndrome consists of a gastrointestinal prodrome occurring more than 5 hours after eating Gyromitra esculenta. Acute liver injury can occur over the next 2 days in a significant percentage of cases, and acute kidney injury may occur to a lesser degree. Confusion characterizes acute central nervous system (CNS) toxicity. In the most severe instances, refractory seizures are a feared, but rare, a consequence of the pharmacology of gyromitrin’s toxic metabolite, monomethylhydrazine (MMH). Monomethylhydrazine binds to and inhibits pyridoxal phosphokinase, thereby inhibiting activation of vitamin B6 (as pyridoxal 5-phosphate) from functioning as the key co-factor in the synthesis of GABA. The subsequent depletion of GABA leads to CNS excitation and seizures.[1][2][3]

Etiology

Gyromitra esculenta contains the toxin gyromitrin. Other species, such as Gyromitra gigas and Gyromitra fastigiata may also have this toxin, but there have been no documented human poisonings from this species.[4]

Epidemiology

Most poisonings occur in Eastern Europe, particularly in the conifer forests of Germany, Poland, and Finland. In North America, most exposures occur in Michigan, although a less toxic variety grows west of the Rockies and has been clustered in Idaho and Western Canada. Exposures occur mostly in the Spring, unlike other serious mushroom poisonings, such as Amanita phalloides, which occur more commonly in the fall.[5]

Over the centuries, poisonings due to consumption of gyromitra were recorded across those regions of Europe and the United States and, although the name changed over time, these cases allowed for the identification of the mushroom and identification of its toxin. In France in 1793, poisonings were attributed to the then-named Morchella pleopus. In 1885, an extract from the same mushroom was named “helvellic acid," the toxin we now know as gyromitrin, as isolated by List and Luft of Germany in 1968, who identified the chemical nature and structure of the toxin.

From 1953 to 1962, there were 138 documented poisonings with two fatalities in Poland.

Between 1994 to 2002, the Swedish poison center received 706 calls related to gyromitra mushrooms, with no fatalities.

In the United States, from 2001 to 2011, poison centers received 82,140 calls related to mushrooms. Of these, 448 calls involved gyromitrin mushrooms. Over 30 years, the North American Mycological Society (NAMA) reported on 27 cases. None were fatal but nine developed liver injury and three acute kidney injury.

Pathophysiology

In the stomach, gyromitrin is metabolized to monomethylhydrazine (MMH), which is the active metabolite responsible for inhibiting many enzymatic processes, particularly by the inhibition of vitamin B6 (pyridoxine), a key cofactor for many enzymatic processes. Gyromitrin directly binds to and inhibits pyridoxal phosphokinase, the enzyme responsible for transforming dietary vitamin B6 (pyridoxine) into active pyridoxal 5-phosphate. Without the cofactor pyridoxal 5-phosphate, the CNS-enzyme glutamic acid decarboxylase (GAD) cannot convert glutamate to the neurotransmitter gamma-aminobutyric acid (GABA). As GABA is depleted, activation of inhibitory postsynaptic Cl- channel decreases, resulting in a relative excitatory state in the brain, leading to delayed seizures.

This inhibition of vitamin B6 activation is a similar mechanism of action to the anti-tuberculosis medication INH (isonicotinic acid hydrazide).

Other central enzymatic processes for which pyridoxine is a co-factor are:

  • Formation of serotonin from tryptophan
  • Formation of dopamine from DOPA

While these may be inhibited, it is usually not clinically apparent.

Hydrazines, like MMH, may also form hydrazones and hydrazides that can cause further organ damage. Hydrazones induce lipid peroxidation in the liver causing cytotoxic effects and resulting in acute liver injury. Hydrazones may also be oxidizing agents capable of inducing methemoglobinemia. Although the potential for methemoglobin formation in humans is often mentioned as a possible toxic effect of gyromitrin mushroom consumption, only a single case report in a dog exists for this.

Other reported effects of gyromitrin are detailed in studies on rats. Gyromitrin in rats acts as a mild diuretic, with properties of natriuresis and kaliuresis, which may contribute to volume and electrolyte loss in humans. In addition, rats fed gyromitrin for long periods of time develop cancers of the liver, gallbladder, and lung. No definitive human cancer risk has been determined. [6][7]

Toxicokinetics

Gyromitrin has the chemical formula C4H8N2O, and its chemical name is N’-ethylidene-N-methylformohydrazide.

The boiling point of gyromitrin is 143 C (289 F). However, monomethylhydrazine (MMH) boils at a lower temperature of 87.5 C (190 F)

Some websites and mushroom handbooks describe the technique of parboiling then drying, to detoxify the mushroom and render them edible. Patocka [2012] estimates that 99% of the gyromitrin can be removed by either drying or boiling the mushroom before eating it.

Michelot [1991] gives the values of an LD in humans (based on animal experiments) as 25 mg/kg to 50 mg/kg for adults and 10 mg/kg to 30 mg/kg for children. This roughly correlates to between 0.4 kg to 1.0 kg of fresh uncooked mushroom for an adult and 0.2 kg to 0.6 kg fresh mushroom for a child. These are unlikely amounts of mushroom to be ingested at one time.

Cooking hydrolyzes some gyromitrin, but after being ingested, gyromitrin is hydrolyzed rapidly in the stomach to N-methyl-N-formyl hydrazine (MFH), then converted in the liver by cytochrome P-450 oxidation into N-methylhydrazine (MMH). Of interest, this final chemical is also a component in rocket fuel, such as in the propellant mixture Aerozine-50 made by the Aerojet Company, which was used in Titan rockets.

Eleven other hydrazones, in lesser quantities, have been isolated from these mushrooms and may contribute to liver cytotoxicity.

History and Physical

History should ascertain when the mushrooms were eaten, as the time from ingestion to symptom onset can suggest clinical severity.  As with other mushroom poisonings, the classic 6-hour rule usually applies. Specifically, the onset of nausea and vomiting within 6 hours of ingestion suggests that the likelihood of systemic toxicity is low.  However, if vomiting begins after 6 hours, the risk is higher, and these patients often require intravenous (IV) fluid resuscitation and evaluation for signs of hepatic or renal injury.

Specifically concerning gyromitra, the onset of signs and symptoms of toxicity usually occur 5 to 12 hours after ingestion, adhering to the 6-hour rule. The most common presenting complaints are abdominal pain and nausea. Other historical features should focus on which mushrooms were being sought, the season of the year, and the amount consumed. Gyromitra mushrooms emerge in the Spring in temperate climate forest areas, often near pines and aspen trees. Some knowledgeable foragers may even know or recognize Gyromitra esculenta and have intentionally sought and consumed it. The number of mushrooms eaten is also significant as the severity of the patient’s toxicity is proportionally related to the quantity of the toxin ingested.

The physical exam should focus signs of dehydration and the neurologic exam.  Physical exam findings are often non-specific but may include dry mucous membranes, decreased bowel sounds, generalized abdominal tenderness, and confusion. Patients may also experience vomiting and watery diarrhea. Jaundice is a late finding, typically in more severe cases after the 3 days post-ingestion. Large ingestions may exhibit signs of central nervous system involvement, including nervousness, vertigo, ataxia, delirium, seizures, and altered mentation. Death, although extremely rare, has been reported as early as 3 days post-ingestion. Toxicity may often go unrecognized due to the vague presenting complaints and requires a high index of suspicion to make the appropriate inquiries about mushroom ingestion to establish the diagnosis.

Evaluation

The diagnosis of the gyromitra syndrome relies on associating the patient’s liver, renal, or CNS findings with a history of ingestion of the gyromitra mushrooms. Common lab 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 BUN and creatinine may also occur, reflecting acute kidney injury (AKI) secondary to vomiting and volume depletion. While CNS signs may vary from confusion to seizures, there are no findings on imaging modalities such as CT or MRI. However, should the patient experience status epilepticus, neuro-imaging would be warranted after the seizure is controlled.

Treatment / Management

Treatment should be initiated as early as possible, especially if there is a concern of progression to seizures. Initial treatment entails primarily supportive care with close attention to fluid and electrolyte balance.  Liver function tests, blood urea nitrogen, and serum creatinine should be monitored daily. [8]

Specific treatment for any CNS symptoms is the replacement of the vitamin B6 depleted by MMH. Pyridoxine at 25 mg/kg IV can be given either to control or to prevent seizures. Benzodiazepines are also suggested if a patient is seizing despite administration of pyridoxine. Other first-line anticonvulsants such as phenytoin are usually ineffective. Most patients recover uneventfully within 6 days with good supportive care and pyridoxine.

Pearls and Other Issues

Various laboratory techniques like gas chromatography-mass spectrometry and thin-layer chromatography have been used to identify MMH. However, these tests are not generally available outside research laboratories and have neither clinical utility nor correlation with overall toxicity.

Enhancing Healthcare Team Outcomes

Gyromitra poisoning is best managed by a multidisciplinary team that includes neurology nurses. The key is to start treatment immediately with close attention to liver function, electrolyte balance, fluid status and neurological status.

Specific treatment for any CNS symptoms is the replacement of the vitamin B6 depleted by MMH. Pyridoxine at 25 mg/kg IV can be given either to control or to prevent seizures. Benzodiazepines are also suggested if a patient is seizing despite administration of pyridoxine. Other first-line anticonvulsants such as phenytoin are usually ineffective. Most patients recover uneventfully within 6 days with good supportive care and pyridoxine.

Patient education is key. The primary care provider and pharmacist should educate the patient on the potential toxicity of wild mushrooms.


  • Image 5878 Not availableImage 5878 Not available
    Contribute by the Missouri Dept. of Conservation (Public Domain)
Attributed To: Contribute by the Missouri Dept. of Conservation (Public Domain)

Interested in Participating?

We are looking for contributors to author, edit, and peer review our vast library of review articles and multiple choice questions. In as little as 2-3 hours you can make a significant contribution to your specialty. In return for a small amount of your time, you will receive free access to all content and you will be published as an author or editor in eBooks, apps, online CME/CE activities, and an online Learning Management System for students, teachers, and program directors that allows access to review materials in over 500 specialties.

Improve Content - Become an Author or Editor

This is an academic project designed to provide inexpensive peer-reviewed Apps, eBooks, and very soon an online CME/CE system to help students identify weaknesses and improve knowledge. We would like you to consider being an author or editor. Please click here to learn more. Thank you for you for your interest, the StatPearls Publishing Editorial Team.

Gyromitra Mushroom Toxicity - Questions

Take a quiz of the questions on this article.

Take Quiz
A patient develops seizures 8 hours after eating what he thought were morel mushrooms. Which of the following is most likely to control his seizures?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Treatment of seizures due to mushroom poisoning should include which vitamin in addition to anticonvulsants?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which metabolic transformation and anatomic locations are correctly matched?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Seizures occurring after mushroom ingestion are rare but are exclusively due to Gyromitra esculenta mushrooms. What pharmaceutical agent has a similar mechanism of action to the toxin formed by eating these mushrooms?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which enzyme is inhibited by gyromitrin metabolism?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up

Gyromitra Mushroom Toxicity - References

References

Zaraf'iants GN, [Forensic medical diagnostics of intoxication with certain poisonous mushrooms in the case of the lethal outcome in a hospital]. Sudebno-meditsinskaia ekspertiza. 2016 Jan-Feb;     [PubMed]
Saviuc P,Harry P,Pulce C,Garnier R,Cochet A, Can morels (Morchella sp.) induce a toxic neurological syndrome? Clinical toxicology (Philadelphia, Pa.). 2010 May;     [PubMed]
[Mushroom poisonings that we don't think about: Gyromitra poisoning]. Orvosi hetilap. 2007 Nov 4;     [PubMed]
Leathem AM,Dorran TJ, Poisoning due to raw Gyromitra esculenta (false morels) west of the Rockies. CJEM. 2007 Mar;     [PubMed]
Michelot D,Toth B, Poisoning by Gyromitra esculenta--a review. Journal of applied toxicology : JAT. 1991 Aug;     [PubMed]
Toth B,Gannett P, Gyromitra esculenta mushroom: a comparative assessment of its carcinogenic potency. In vivo (Athens, Greece). 1994 Nov-Dec;     [PubMed]
Toth B,Gannett P, Carcinogenesis study in mice by 3-methylbutanal methylformylhydrazone of Gyromitra esculenta. In vivo (Athens, Greece). 1990 Sep-Oct;     [PubMed]
Michelot D, [Poisoning by Geromitra esculenta]. Journal de toxicologie clinique et experimentale. 1989 Mar-Apr;     [PubMed]

Disclaimer

The intent of StatPearls is to provide practice questions and explanations to assist you in identifying and resolving knowledge deficits. These questions and explanations are not intended to be a source of the knowledge base of all of medicine, nor is it intended to be a board or certification review of Environmental and Wilderness. The authors or editors do not warrant the information is complete or accurate. The reader is encouraged to verify each answer and explanation in several references. All drug indications and dosages should be verified before administration.

StatPearls offers the most comprehensive database of free multiple-choice questions with explanations and short review chapters ever developed. This system helps physicians, medical students, dentists, nurses, pharmacists, and allied health professionals identify education deficits and learn new concepts. StatPearls is not a board or certification review system for Environmental and Wilderness, it is a learning system that you can use to help improve your knowledge base of medicine for life-long learning. StatPearls will help you identify your weaknesses so that when you are ready to study for a board or certification exam in Environmental and Wilderness, you will already be prepared.

Our content is updated continuously through a multi-step peer review process that will help you be prepared and review for a thorough knowledge of Environmental and Wilderness. When it is time for the Environmental and Wilderness board and certification exam, you will already be ready. Besides online study quizzes, we also publish our peer-reviewed content in eBooks and mobile Apps. We also offer inexpensive CME/CE, so our content can be used to attain education credits while you study Environmental and Wilderness.