Mushroom Toxicity: Practice Essentials, Pathophysiology, Etiology (2024)

Each poisonous mushroom species contains 1 or more toxins, which may be classified on the basis of the mushroom’s physiologic and clinical effects in humans, the target organ toxicity, and the time to symptom onset. The clinical spectrum and toxicity vary with the following factors:

• Species consumed

• Amount consumed

• Season

• Geographic location where the mushroom was grown

• Preparation method

• Individual response to the toxins

Diaz, in a review of mushroom poisoning cases reported in the literature over 50 years, classified mushroom poisoning into the following 3 major categories on the basis of the time from ingestion to the development of symptoms ^{[3, 4]} :

• Early symptom category – Symptoms generally appear within the first 6 hours of mushroom ingestion and include gastrointestinal (GI), allergic, and neurologic syndromes

• Late symptom category – Signs and symptoms begin to appear between 6 and 24 hours after ingestion and may include hepatotoxic, nephrotoxic, and erythromelalgic syndromes

• Delayed symptom category – Symptoms appear more than 24 hours after ingestion and include mostly nephrotoxic syndromes

Mushroom toxins include the following ^{[3, 4, 5, 6]} :

• Cyclopeptides - Amatoxin

• Gyromitrins (monomethylhydrazine)

• Orellanine

• Muscarine

• Psilocybin

• Muscimol and ibotenic acid

• Coprine

• Nephrotoxins (norleucine)

• Myotoxins

  See Also

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• Immunoactive toxins

• Hemolytic toxins

• GI irritants

GI poisons are the most frequently encountered mushroom toxins. Amatoxins, gyromitrins, and orellanine are the toxins most commonly implicated in fatal mushroom poisonings worldwide. The amatoxins, and to a lesser extent the gyromitrins, are hepatotoxic. Gyromitrins are also epileptogenic. Orellanine and norleucine are nephrotoxic. Muscarine, psilocybin, muscimol, and ibotenic acid are CNS poisons. Coprine causes a disulfiramlike reaction when combined with alcohol.

Cyclopeptides

Cyclopeptides include amatoxins (high toxicity), phallotoxins (medium toxicity), and virotoxins (no toxicity).

Amatoxins, which are responsible for more than 95% of mushroom-related fatalities in the United States, are cyclic octapeptides that are synthesized by some Amanita, Galerina, and Lepiota species (see the list below).

At least 5 subtypes of amatoxins are known, the only significant human toxin being alpha-amatoxin, which inhibits RNA polymerase II and protein synthesis. Alpha-amatoxin is rapidly absorbed by the GI tract, has limited protein binding, and may undergo enterohepatic recirculation. It is excreted in the urine and may be detected in the vomitus and feces. Hepatocellular damage is presumably caused by the formation of free radical intermediates.

Amanita phalloides death cap), Amanita virosa (destroying angel), Amanita verna (fool’s mushroom), Amanita bisporigera, Galerina autumnalis (autumn skullcap), and Galerina sulcipes are the most common mushrooms implicated in liver injury and death amongst the amatoxin-containing mushrooms.

The other associated toxin in Amanita ingestions are the phallotoxins, specifically phalloidin, which produce a choleralike syndrome with vomiting and watery diarrhea, usually starting 6 hours after ingestion, although cases with both earlier and later onset have occurred. Many Lepiota species lack phallotoxins, so ingestion of these may not present with the onset of vomiting and diarrhea until after 12 hours post ingestion, or they may occasionally present only with symptoms of liver failure at 24 hours post ingestion.

Amanitin-containing mushroom species

TheAmanita group includes the following ^[4] :

• Amanita phalloides ^[7] (see the image below)

• Amanita virosa

• Amanita verna

• Amanita ocreata

• Amanita bisporigera

• Amanita suballiacea

• Amanita magniverrucata ^[8]

• Amanita muscaria ^[9]

The Lepiotagroup includes the following:

• Lepiota helveola

  See Also

  Fungus - UNC Lineberger

• Lepiota chlorophyllum

• Lepiota josserandi

• Lepiota fulvella

• Lepiota subincarnata

• Lepiota brunneoincarnata

• Lepiota brunneolilacea

The Galerina group includes the following:

• Galerina autumnalis

• Galerina sulcipes

• Galerina marginata

Gyromitrins

Gyromitrin is a volatile hydrazine derivative synthesized by certain species of false morel (Gyromitra esculenta) and is easily confused with the early false morel (Verpa bohemica). Gyromitrin poisoning typically occurs after ingestion of the toxin-containing mushrooms but may also result from inhalation of the cooking vapors during their preparation.

In the stomach, gyromitrin is rapidly hydrolyzed into acetaldehyde and N-methyl-N-formyl hydrazine (MFH), which is then slowly converted to N-methylhydrazine (MH). Both MFH and MH are toxic to humans. MFH inhibits a number of hepatic systems, including cytochrome P-450 and glutathione, and causes hepatic necrosis. Hepatocellular damage is presumably caused by the formation of free radical intermediates.

MH inhibits pyridoxine kinase and interferes with all the pyridoxine-requiring enzymes in the body, including those involved in the synthesis of gamma-aminobutyric acid (GABA). The reduction of GABA concentrations in the brain leads to CNS hyperexcitability and convulsions. Gyromitrin ingestion may also rarely result in methemoglobinemia, hemolysis, and renal failure.

Orellanine

Orellanine is a nephrotoxic compound that is synthesized by several species of Cortinarius mushrooms. Orellanine-containing species include Cortinarius orellanus and Cortinarius speciosissimus, both of which are commonly found in Europe and Japan but not in North America. Cortinarius species that may contain small amounts of orellanine include Cortinarius gentilis, Cortinarius rainierensis, and Cortinarius splendens henrici; however, there are very few confirmed cases of Cortinarius-induced renal failure in North America. ^{[10, 11]}

Orellanine is colorless and crystalline in nature and may be converted into orelline, which itself may be toxic. Orellanine generates oxygen radicals and simultaneously shuts down the oxidative defence, by down-regulating most anti-oxidative enzymes. ^[12] It is highly kidney-specificand the main effects are on the renal tubular system, where it causes necrosis with relative sparing of the glomerular apparatus. Fatty degeneration of the liver and severe inflammatory changes in the intestine may accompany the renal damage. Cortinarius mushrooms also may elaborate other compounds, such as cortinarin A, B, and C, which exhibit a nephrotoxic potential in laboratory animals.

Norleucine

Other nephrotoxic mushrooms, such as Amanita smithiana and Amanita proxima, have also been associated with an acute oliguric renal failure. Amanita smithiana may be mistaken for the matsutake mushroom (Tricholoma magnivelare) by foragers. These mushrooms cause vomiting and diarrhea 1-12 hours after ingestion, followed by a transient elevation of transaminases, then oliguric renal failure in 3-6 days. It is important to note that renal failure occurs within days of ingestion, as opposed to orellanine-induced renal failure that has an onset over 1-2 weeks. Exposure to norleucine-containing mushrooms may require temporary hemodialysis.

Psilocybin

Psilocybin and psilocin are elaborated by a number of mushroom genera, including Psilocybe cubensis, Psilocybe semilanceata (Liberty cap), Panaeolus cyanescens (previously referred to as Copelandia species), Gymnopilus spectabili (Big Laughing Jim), Conocybe cyanopus, Psathyrella foenisecii, and several species of Pluteus. Psilocybin and psilocin are serotonin (5-HT2) agonists and, when ingested, cause psychedelic effects similar to those of lysergic acid diethylamide (LSD).

Ibotenic acid and muscimol

Amanita muscaria (fly agaric) and Amanita pantherina (panthercap) mushrooms synthesize ibotenic acid and muscimol, both of which are excitatory neurotoxins and may be mildly hallucinogenic.

Ibotenic acid is structurally similar to glutamic acid and acts as an agonist at the glutamic acid receptors (NMDA receptors) in the CNS. Ibotenic acid is decarboxylated in vivo to muscimol. Muscimol is structurally similar to GABA and acts as a GABA-receptor agonist. Amanita muscaria (fly agaric) and Amanita pantherina also may contain some anticholinergic substances and small amounts of muscarine, a cholinergic agent.

Muscarine

Muscarine stimulates M1 and M2 types of postganglionic cholinergic receptors (muscarinic receptors) in the autonomic nervous system. This action results in parasympathetic stimulation similar to that caused by the release of endogenous acetylcholine at postganglionic receptors of smooth muscle and exocrine glands. The action on muscarinic receptors produces a cholinergic syndrome that is characterized by sweating, bronchorrhea with shortness of breath, salivation, lacrimation, diarrhea, miosis, abdominal cramps, and rarely bradycardia.

There is negligible activity on nicotinic receptors; hence, muscle weakness, fasciculations, and paralysis are not present. Because muscarine is a quaternary amine, it does not readily cross the blood-brain barrier and does not directly cause CNS effects. Muscarine is not metabolized by cholinesterase and has a longer biologic half-life than acetylcholine does.

Mushrooms that contain muscarine are commonly found in yards, parks, and wooded areas throughout the United States, Europe, and Asia. Species from the genera cl*tocybe and Inocybe (see the images below) are most commonly responsible for muscarinic mushroom poisoning in the United States.

cl*tocybe dealbata (the sweating mushroom) may be confused with the edible fairy ring champignon (Marasmius oreadus) or sweetbread mushroom (cl*topilus prunulus). Omphalotus olearius (the Jack O’ Lantern mushroom; see the image below) may be confused with the edible chanterelle (Cantharellus cibarius). Other muscarine-containing mushrooms include species from the genera Boletus, Mycena, and Omphalotus. Although Amanita muscaria derives its name from the trace amounts of muscarine it contains, it does not cause clinical cholinergic toxicity.

Muscarine-containing mushrooms typically produce cholinergic symptoms such as sweating, facial flushing, salivation, lacrimation, vomiting, abdominal cramps, diarrhea, urination, and miosis; occasionally, bradycardia, hypotension, and dizziness develop. Symptoms typically occur within 1 hour of ingestion and last for 4-24 hours. In most cases, they resolve without drug therapy or with a dose of atropine. ^[13]

Coprine

A few species of mushrooms, including Coprinopsis atramentaria (formerly known as Coprinus atramentarius), commonly referred to as inky cap or tippler’s bane and mistaken for the edible Coprinus comatus (shaggy mane), produce coprine, an amino acid that is metabolized to 1-aminocyclopropanol in the human body. This metabolite blocks acetaldehyde dehydrogenase, and in the presence of alcohol, acetaldehyde builds up, resulting in a disulfiram reaction. The effects of 1-aminocyclopropanol may last as long as 72 hours after ingestion of the mushroom.

Involutin

Ingestion of Paxillus involutus may result in the acute onset of abdominal pain, nausea, vomiting, and diarrhea within 30 minutes to 3 hours of ingestion, followed by an immune complex-mediated hemolytic anemia with hemoglobinuria, oliguria, anuria, and acute renal failure.

GI toxins

Hundreds of mushrooms contain toxins that can cause GI symptoms (eg, nausea, vomiting, diarrhea, and abdominal pain) similar to those observed with more dangerous mushrooms. They include Chlorophyllum molybdites (green gill), Boletus piperatus (pepper bolete), and Agaricus arvensis (horse mushroom), among many others.

Bronchoalveolar allergic syndrome

An immune reaction is believed to be the cause of the bronchoalveolar allergic syndrome seen after inhalation of spores of some puffball (Lycoperdon) mushroom species.

Erythromelalgia syndrome

Two species of mushrooms, cl*tocybe acromelaga (in Japan) and cl*tocybe amoenolens (in Europe), cause a painful burning sensation with reddening of the skin several days after eating them. In Europe, the cl*tocybe amoenolens mushroom has been mistaken for the edible mushroom Lepista inversa. The suspected toxin is acromelic acid A.