Mushroom Toxicity

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Practice Essentials

Mushroom poisoning (mushroom toxicity) occurs after the ingestion of mushrooms that contain toxins, often in the context of foraging for nontoxic, similarly appearing mushrooms. Mushrooms are the fruiting bodies of a group of higher fungi that have evolved contemporaneously with plants for millions of years. They are widely distributed throughout the world. There are thousands of species of mushrooms, but only about 100 species of mushrooms cause symptoms when eaten by humans, and only 15-20 mushroom species are potentially lethal when ingested.

No simple rule exists for distinguishing edible mushrooms from poisonous mushrooms. In more than 95% of mushroom toxicity cases, poisoning occurs as a result of misidentification of the mushroom by an amateur mushroom hunter. In less than 5% of the cases, poisoning occurs after the mushroom is consumed for its mind-altering properties.

The severity of mushroom poisoning may vary, depending on the geographic location where the mushroom is grown, growth conditions, the amount of toxin delivered, and the genetic characteristics of the mushroom. Boiling, cooking, freezing, or processing may not alter the toxicity of some mushrooms.

Variations in clinical effects may depend on an individual’s susceptibility and on the presence of confounding factors such as contamination or co-ingestion. In general, children are often exposed to nontoxic mushrooms, while older persons are at greater risk for the development of serious complications with mushroom poisoning than are healthy young adults.

Mushroom exposure in children is an infrequent but perennial problem for parents and clinicians. Parental anxiety is generally high because of fears of unknown or untoward effects. The challenges for clinicians are to identify such poisonings, to discern whether poisoning has taken place, to order appropriate diagnostic studies, and to prescribe reasonable therapy. The varied nature of mushroom toxicities, their ubiquitous distribution, and the relative infrequency of the ingestions make these challenges difficult to meet.

Pathophysiology

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:

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[1, 2] :

Mushroom toxins include the following[1, 2, 3, 4] :

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 

The Amanita group includes the following[2] :



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Amanita phalloides.

The Lepiota group includes the following:

The Galerina group includes the following:

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.[8, 9]

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.[10] It is highly kidney-specific and 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 Clitocybe and Inocybe (see the images below) are most commonly responsible for muscarinic mushroom poisoning in the United States.

Clitocybe dealbata (the sweating mushroom) may be confused with the edible fairy ring champignon (Marasmius oreadus) or sweetbread mushroom (Clitopilus 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.



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Omphalotus olearius (Jack O'Lantern mushroom).



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Clitocybe dealbata.



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Inocybe geophylla.



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Inocybe lacera.

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.[11, 12]

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

Etiology

The main causes of mushroom toxicity are as follows:

Rare causes are as follows:

Accidental poisoning accounts for more than 95% of the cases of mushroom intoxications; most of the remaining cases are due to intentional ingestion of the mushrooms for their mind-altering properties.

Cyclopeptide (amatoxin) poisoning most commonly is due to the following:

Gyromitrin (monomethylhydrazine) poisoning is commonly due to Gyromitra esculenta.

Orellanine poisoning is commonly due to Cortinarius orellanus and Cortinarius speciosissimus.

Norleucine nephrotoxicity is due to Amanita smithiana and Amanita proxima.

Psilocybin and psilocin poisoning are commonly due to various Psilocybe species (semilenciata, and cubensis, among others), but it also may be due to the ingestion of many Panaeolus species, Gymnopilusspectabilis, Psathyrella foenisecii, and Psathyrella sepulcharis.

Ibotenic acid and muscimol poisonings are commonly due to some Amanita species (gemmata, muscaria, pantherina, and cokeri).

Muscarine poisoning is commonly due to Clitocybe species (dealbata, dilatata, illudens, and nebulens) and Omphalotus olearius (Jack O’ Lantern mushroom). Most Inocybe species also contain muscarine and may result in muscarinelike symptoms. Additionally, some Amanita species (muscaria, gemmata, pantherina, and parcivolvata) and some Boletus species contain small amounts of muscarine, along with other toxins.

Coprine poisoning is commonly due to ingestion of Coprinus and related mushrooms, including Coprinus atramentaria. Clitocybe clavipes may also contain coprine. Coprine causes a disulfiramlike reaction if ingested with alcohol.

Immunoallergic reactions resulting in hemolysis, hemoglobinuria, and immune-complex–mediated renal failure have occurred after the ingestion of Paxillus involutus. In Europe, Paxillus involutus has been reported to cause severe illness and death due to a Paxillus syndrome, which is characterized by abdominal cramps, diaphoresis, ice-cold extremities, weakness, loss of consciousness, and circulatory collapse.

Bronchoalveolar allergic syndrome results from the inhalation of spores of many Lycoperdon (puffball) species.

Rhabdomyolysis with renal failure has been reported after the ingestion of Tricholomaflavovirens (also know as Tricholoma equestre) in France and with Russula subnigricans in Taiwan and Korea.[13]

Clitocybe acromelaga (in Japan) and Clitocybe amoenolens (in Europe) cause erythromelalgia.

The mushrooms that cause GI symptoms when ingested by humans include many of the “little brown mushrooms.” Additionally, Chlorophyllum species (esculentum and molybdites), Clitocybe nebularis, and Laetarius species cause GI irritation only.

Epidemiology

United States statistics

Because the number of unreported cases is unknown, accurate figures regarding the frequency of mushroom poisoning are difficult to obtain. Cases usually are sporadic, and a few outbreaks have been reported. Accidental poisonings tend to occur most commonly in the spring and fall, when mushroom species are at the peak of their fruiting stage. In general, most ingestions result in minor GI illness, with only the most severe requiring medical attention. According to the 2017 annual report from the AAPCC National Poison Data System, of 5781 total single mushroom exposures 448 had a moderate effects, 34 had a major effects and 2 exposures resulted in death.[9]

During the 10-year period from 2001 to 2011, 83,140 mushroom ingestions were reported to US Poison Control Centers; of these, 64,534 (77.6%) were pediatric ingestions and 48,437 (58.3%) occurred in children younger than 6 years. A total of 48,423 (58.2%) patients were male. The majority of ingestions, 65,255 (78.5%), were unintentional. Identification was made in only 4,232 (5.1%) exposures and included 185 distinct species. The 5 most common species (number of identifications) were (1) Morchella angusticeps (507), (2) Chlorophyllum molybdites (374), (3) Amanita muscaria (319), (4) Lycoperdon candidum (228), and (5) Calvatia lepidophora (175). The toxin group was identified in 12,147 (14.6%) of ingestions.[14]

The toxin groups and number of cases with identification were as follows:

Of the symptomatic cases, effects were minor in 10,953 (56.5%), moderate in 7,804 (40.3%), major in 568 (2.9%), and fatal in 45 (0.2%). Of the 614 cases of major effect or death, a species was identified in 64 (10.4%).[14]

The 5 most common species (number of cases) identified as responsible for major effects or death were Amanita phalloides (27)[5, 15] , Amanita muscaria (22), Amanita pantherina (9), Amanita smithiana/proxima/pseudoporphyria (5), and Amanita bisporigera (3). Of the 97 cases in which Amanita phalloides was identified, 23 (23.7%) resulted in major effects and 4 (4.1%) in death.[14]

International statistics

Mushroom foraging is common in Russia, Asia, and Europe; however, accurate figures regarding the incidence of mushroom toxicity (mushroom poisoning) are difficult to obtain. Outbreaks of severe mushroom poisoning have occurred in Europe, Russia, the Middle East, and the Far East. In April 2008, an outbreak of mushroom poisonings in the Upper Assam part of India claimed more than 30 lives.

In 2018, more than 1200 mushroom poisonings were seen in hospital emergency departments in 13 west and northwestern provinces of Iran; 112 (8.9%) patients were hospitalized and 19 fatalities ere reported. Patients presenting with severe abdominal pain, nausea, vomiting, and diarrhea soon after consumption of wild mushrooms. Lepiota brunneioncarnata, Hypholoma fascicalare, and Coprinopsis atramentaria were involved in this outbreak.[16]  

Age-related demographics

Adults are frequently involved as foragers for edible mushrooms. Because of errors in identification, they may ingest toxin-containing mushrooms that resemble nontoxic varieties. Adults and adolescents may also be inadvertently poisoned when they intentionally consume mushrooms, picked from the ground or purchased dried, to achieve intoxication. Young children may be poisoned by mushrooms when they unintentionally eat mushrooms found outside, typically in yards or outdoor play areas.

Children and elderly patients are at the greatest risk for toxicity. According to the 2016 annual report from the AAPCC National Poison Data System, 3389 of 5979 total single mushroom exposures were reported in those younger than 6 years; 523 exposures were reported in those aged 6-12 years, 392 in those aged 13 to 19, and 1607 were reported in those older than 19 years.[9]

Prognosis

To a great extent, morbidity and mortality depend on the patient’s age and general health. Children and elderly persons are at the greatest risk for toxicity. Rapid diagnosis and treatment can also alter mortality substantially.

Over the course of 2 weeks in December 2016, California Poison Control System (CPCS) investigated 14 suspected A phalloides ingestions in five northern California counties. One of those patients, a child, developed cerebral edema and suffered permanent neurologic sequelae. All the remaining patients recovered completely, although 3 patients received liver transplants because of irreversible fulminant hepatic failure.[17]

With good supportive care, the mortality for amatoxin poisoning may be reduced from 50-60% to less than 5%.[18] In a retrospective analysis of amatoxin-poisoned patients, Giannini found that the evolution of hepatic transaminase levels and the prothrombin time over the initial 4 days were highly predictive of recovery or death.[19]

In a retrospective study of 144 amatoxin-poisoned patients seen between 1996 and 2009, Trabulus et al reported a mortality of 9.7% (14 patients).[20] Factors associated with a greater likelihood of death included the following:

Most patients recover from gyromitrin poisoning. In the United States, death from this event is rare, but in some areas of Europe, mushrooms containing gyromitrins account for the most mushroom fatalities.

Although orellanine poisoning is rare in the United States, mushrooms containing orellanine account for the most mushroom fatalities in some areas of Europe. A shorter time course between ingestion and toxicity portends a worse prognosis. Mild renal insufficiency may resolve a few months after the ingestion.

In a study of long-term effects of orellanine poisoning, the outcomes of 28 patients who ingested mushrooms of the Cortinarius specie in the period from 1979 to 2012 were reviewed.  The researchers reported 22 patients (78%) developed acute kidney injury requiring dialysis of which 15 received a kidney transplantation. No damage was found in any other organs and mortality rates were similar to a control group.[10]   

The prognosis for muscarine poisoning is excellent and fatalities are very rare. Many patients who ingest muscarine-containing mushrooms have minor or no symptoms; when symptoms do occur, they tend to be temporary and self-limited, lasting 6-24 hours.[11, 12] Most patients recover without drug therapy.

However, a case report from Australia described a 53-year-old woman who ate 2 large muscarine-containing Rubinoboletus mushrooms and came to a hospital with a 2-hour history of headache, chest and abdominal pain, vomiting, and profuse sweating.  At 3 hours, she also developed diarrhea, and her condition deteriorated rapidly with hypotension, bradycardia, coma, and respiratory distress.  At 7 hours, the patient remained in shock and did not respond to resuscitative measures. During the first hour of hemodialysis, she developed asystole. At 10 hours after ingestion, the patient died. Her partner had also eaten some of the mushrooms but promptly vomited and did not exhibit any toxic effects. Whether this mushroom grows in North America is unknown.[21]

Patient Education

Education regarding the poisonous nature of wild mushrooms may act as a deterrent to mushroom foraging and ingestion. Patients ingesting coprine-containing mushrooms should be educated regarding the interaction with alcohol.

For patient education resources, see the Poisoning Center and the Poisoning - First Aid and Emergency Center, as well as Poisoning and Activated Charcoal.

History

A careful patient history is the most important aspect of the diagnostic process. Without a history of ingestion, the diagnosis of mushroom poisoning is difficult, but must be considered in the differential diagnosis of liver failure and kidney failure. Although failing to obtain such a history may be inconsequential for most mushroom ingestions, it is detrimental for patients who have ingested mushrooms containing amatoxin, orellanine, or gyromitrin because the early removal of these toxins from the gastrointestinal (GI) tract may alter the outcome of the case.

Every effort should be made to identify the mushroom or mushrooms early. If a sample mushroom is available, use of telemedicine and the Internet may prove valuable in identifying it. If a sample mushroom is not available, questioning patients and their family about the identity of the mushroom they thought they were picking or purchasing may narrow the list of possibilities. An attempt to use an experienced mycologist to identify the mushroom directly or through photos of the mushroom should be considered in symptomatic patients.

Obtain a history of the exposure that includes the following:

The timing of symptom onset has long been considered crucial for differentiating life-threatening or severe mushroom poisonings from less serious ones. Milder poisonings (eg, from muscarine-containing mushrooms) typically become symptomatic early, well within 5 hours of ingestion.[1, 2, 3, 4, 22] In contrast, mushrooms from the cyclopeptide (A phalloides) or orellanine (Cortinarius) groups, which can produce hepatic and renal failure, respectively, typically do not produce symptoms until later, 6-24 hours after ingestion.

There is, however, a growing sense that mushrooms are best classified by the physiologic and clinical effects of their poisons rather than by the timing of symptom onset. The traditional time-based classification may be inadequate. Some serious mushroom syndromes develop soon after ingestion. For example, most of the neurotoxic syndromes, the Coprinus syndrome (ie, concomitant ingestion of alcohol with coprine, and most of the GI intoxications occur within the first 6 hours after ingestion. Amanita smithiana may cause vomiting in as few as 2-4 hours after ingestion and may lead to severe renal toxicity.

Ingestions most likely to require intensive medical care involve mushrooms that contain cytotoxic substances such as amatoxin, gyromitrin, norleucine, and orellanine. Mushrooms that contain involutin may cause a life-threatening immune-mediated hemolysis with hemoglobinuria and renal failure. Inhalation of spores of Lycoperdon species may result in bronchoalveolitis and respiratory failure that necessitates mechanical ventilation.

Mushrooms that contain the GI irritants psilocybin, ibotenic acid, muscimol, and muscarine may cause critical illness in specific groups of people (eg, young persons, elderly persons). Hallucinogenic mushrooms may also  result in major trauma. Finally, coprine-containing mushrooms cause severe illness only when combined with alcohol (ie, Coprinus syndrome).

Identification of mushroom

Although identification of the actual mushroom consumed is important, it is often impossible, because the mushroom in question has already been digested. Nevertheless, the attempt should be made, and to this end, descriptions of the physical characteristics of the mushroom (if available) and the circumstances in which it was obtained are valuable. Clinicians should be careful to not make decisions based on rough descriptions; involve the local Poison Center (800-222-1222), which can identify a local mycologist for identification.

When no specimen is brought in by a patient with a suspected mushroom ingestion, sending an experienced forager to the site to collect any mushrooms growing in the area might be helpful. Different types of mushrooms can be found in the same location, however, and a single sample can lead to false identification of the mushroom that was ingested. Accordingly, all possible mushrooms in the immediate vicinity of where the ingestion occurred must be considered.

When mushrooms are obtained for identification, the entire mushroom should be dug up to preserve the architecture of the bulb, stem, and cap. Individual mushrooms should be carefully placed in a dry paper bag, not a plastic or cloth bag; transporting the mushrooms in this manner minimizes destruction of their natural architecture, discoloration of their caps or gills, and premature release of their spores. The mushrooms must not be refrigerated or crushed.

Collecting the patient’s gastric contents after emesis may yield identifiable spores, but this is rarely a viable means to identification.

Remote viewing of digital images of the mushroom sent over the Internet may facilitate the identification of unknown mushrooms by mycologists.[23]

Amatoxin poisoning

Amatoxin poisoning is characterized by a latent period of 6-12 hours after ingestion (range, 6-48 hours), during which the patient is asymptomatic. However, occasional case reports have shown that some patients may present with GI symptoms earlier than 6 hours, making the differentiation between amatoxin poisoning and other benign mushroom exposure difficult.[24]

At the end of the postingestion latent period, a sudden and severe gastroenteritislike illness phase occurs. The patient experiences abdominal pain, vomiting, and profuse watery diarrhea, which may lead to severe dehydration, electrolyte abnormalities, and, rarely, circulatory collapse in young and elderly persons. This phase, which may last as long as 2-3 days, is either followed by an apparent recovery phase characterized by apparent clinical improvement or rapid deterioration to fulminant liver failure.

The third phase of amanita poisoning (ie, the hepatorenal syndrome) is characterized by jaundice, coagulopathy, hypoglycemia, coma, and multiple organ dysfunction syndrome (MODS) followed by death. With early therapy, mortality may be well below 5%; however, liver transplantation has been necessary in severe liver injury. The course of amatoxin poisoning typically lasts 6-8 days in adults and 4-6 days in children in those that recover without transplantation.

Gyromitrin poisoning

The initial phases of gyromitrin poisoning resemble those of amatoxin poisoning and are characterized by a latent period of 6-10 hours after ingestion (range, 3-48 hours).

At the end of this latent period, the patient experiences a sudden onset of headache, abdominal cramping, vomiting, and diarrhea, which are generally self-limited. This phase may be followed by monomethylhydrazine-related CNS symptoms such as vertigo, delirium, convulsions, and coma. If the toxin has been inhaled, the first phases are usually bypassed, and the patient may exhibit CNS toxicity within 2 hours of exposure.

Hematologic, renal, and hepatic toxicities may also occur, followed by recovery. Hepatotoxicity is heralded by an elevation of transaminase concentrations, followed by signs and symptoms of hepatic insufficiency, and, rarely, death.

Recovery typically begins 2 days after the onset of symptoms but may last as long as 5 days. In a small number of patients, the course may be fulminant, accounting for a 2-4% mortality rate.

Orellanine poisoning

Poisoning begins with a seemingly minor GI illness characterized by mild nausea, vomiting, and, sometimes, diarrhea lasting 24-48 hours after ingestion. This phase is followed by a prolonged latent period lasting from 3 days to 3 weeks. An intense thirst and polyuria herald renal failure. The patient also may experience headaches, myalgias, muscle cramps, loss of consciousness, and convulsions. Dialysis may be required in as many as 50% of patients, and death may occur in 15% of cases.

Norleucine poisoning

Amanita smithiana, a mushroom found in the northwestern region of the United States, is nephrotoxic, but it typically causes GI distress within 2-12 hours.[24] It is almost always mistaken by foragers for the edible nontoxic matsutake pine mushroom (Tricholoma magnivalere), which it closely resembles. These 2 mushrooms usually grow in the same region and are foraged for in the fall. For mushroom ingestions in the Pacific Northwest, patients who have early-onset symptoms (< 3 hours after ingestion) and remain symptomatic should be fully evaluated in a hospital with serial chemistries and renal function tests, until the mushroom identity is confirmed to be nontoxic or the patient’s condition improves.[22]

Patients with Amanita smithiana poisoning present with nausea and vomiting as early as 2-4 hours post ingestion and may demonstrate with early elevations in liver enzymes, making these cases difficult to distinguish clinically from toxicity due to the amatoxin-containing mushrooms. The liver function abnormalities typically resolve over 48 hours, while the creatinine climbs at a linear rate of approximately 2 mg/dL/day.

Other mushrooms that contain norleucine toxin are Amanita proxima (France and Spain), Amanita abrupta, Amanita solitaria, and Amanita pseudoporphyria (Japan). Amanita proxima toxicity is characterized by a latent phase that lasts 12-24 hours, followed by an initial gastroenteritislike illness with nausea, vomiting, and diarrhea. Oliguric renal failure occurs several days after ingestion.

Psilocybin poisoning

After ingestion of psilocybin-containing mushrooms, the onset of hallucinations is usually rapid, and the effects generally subside within 2 hours. Poisoning by these mushrooms is rarely fatal in adults and may be distinguished from ibotenic acid poisoning by the absence of drowsiness or coma. The most severe cases of psilocybin poisoning occur in small children, in whom large doses may cause hallucinations accompanied by fever, convulsions, coma, and death.

Muscarine poisoning

Muscarine poisoning is characterized by increased salivation, perspiration, and lacrimation within 15-30 minutes of mushroom ingestion. With large doses, patients may experience abdominal pain, severe nausea, diarrhea, blurred vision, and labored breathing. Intoxication generally subsides within 2 hours. Death is rare but may result from cardiac or respiratory failure in severe cases.

Ibotenic acid and muscimol poisoning

Symptoms of ibotenic acid and muscimol poisoning generally occur within 1-2 hours of mushroom ingestion. In children, ibotenic-acid (glutaminergic) effects may predominate, including hyperactivity, excitability, illusions, delirium, and convulsions. In adults, muscimol (gamma-aminobutyric acid [GABA]-ergic) effects may predominate, including drowsiness, dysphoria, and vertigo (sometimes accompanied by sleep).

Periods of drowsiness may be interspersed between periods of hyperactivity and periods of delirium. Symptoms generally last for a few hours. Fatalities rarely occur in adults, but in children, accidental consumption of large quantities of these mushrooms may cause convulsions, coma, and other neurologic problems for as long as 12 hours.

Coprine poisoning

The digestion of coprine-containing mushrooms generates a metabolite that inhibits acetaldehyde dehydrogenase. Patients may develop symptoms if an alcoholic beverage is consumed within hours of ingestion of the mushroom. Rarely, symptoms may develop upon drinking ethanol up to 48-72 hours after the mushroom is eaten. Symptoms that develop within 0.5-2 hours after ingesting ethanol include headache, nausea, vomiting, flushing, chest pain, and diaphoresis (as is typical of the disulfiram syndrome) and may last for 2-3 hours.

Miscellaneous GI poisons

Many toxic mushrooms produce symptoms that are similar to those caused by the deadly protoplasmic poisons. Some may cause vomiting, diarrhea, or both that last for several days. Fatalities caused by these mushrooms are rare and are due to dehydration and electrolyte imbalances caused by diarrhea and vomiting; they are especially likely to occur in debilitated, very young, or very old patients. Replacement of fluids and other appropriate supportive measures prevent death in these cases.

Paxillus syndrome may occur after the ingestion of Paxillus involutus. This syndrome begins with gastroenteritislike symptoms within 3 hours of ingestion, followed by an acute hemolytic anemia with hemoglobinuria and renal failure.

Bronchoalveolar allergic syndrome may follow the inhalation of spores of puffball mushroom species (eg, Lycoperdon). This syndrome begins with a nasopharyngitis, which is followed by worsening respiratory symptoms, including dyspnea, cough, fever, and malaise, which may progress to respiratory failure.

Erythromelalgia syndrome is characterized by onset of painful allodynia in the hands about 3-7 days after ingestion and may persist for months. The mushroom Clitocybe acromelalga (Poison Dwarf Bamboo Mushroom) in Japan and the mushroom Clitocybe amoenolens in Alpine areas of Europe cause this syndrome through acromelic acid, which stimulates glutamergic receptors.[18]

Physical Examination

The physical findings depend on the type of mushroom ingested.

Gyromitrin poisoning may cause cyanosis due to methemoglobinemia and occasionally may occur after an intravenous (IV) injection of psilocybin.

Facial flushing may be a manifestation of anticholinergic poisoning and may be noted in a patient’s coprine-related disulfiramlike reaction. Profuse sweating and facial flushing are prominent features of muscarinic poisoning and should raise suspicion of this condition.[11, 12]

Jaundice may be observed in patients with liver failure due to gyromitrin and amatoxin poisoning. Jaundice may also be a manifestation of hemolysis, rarely seen with Paxillus ingestion.

Fever may be observed with psilocybin and muscimol poisonings.

Tachycardia is nonspecific, may be seen with any of the mushrooms, or may be a manifestation of hypoxia or hypovolemia from any cause. Bradycardia may be a manifestation of muscarine poisoning; reflex tachycardia has also been observed in this setting, though less commonly.

Mydriasis is commonly observed with ingestion of mushrooms that contain psilocybin and muscimol (because they also contain anticholinergic substances). Miosis is observed with toxicity caused by muscarine-containing mushrooms.

Toxidromes

A few of the toxic mushrooms may exhibit a known toxidrome, the recognition of which permits early diagnosis and treatment.

Patients with muscarine poisoning may present early with a characteristic cholinergic toxidrome. The acronyms SLUDGE (salivation, lacrimation [with blurred vision and miosis], urinary frequency, diarrhea, GI distress, and emesis) and DUMBBELS (diarrhea, urinary frequency, miosis, bradycardia, bronchorrhea, emesis, lacrimation, and salivation) are potentially useful memory aids for this syndrome.

An anticholinergic syndrome may occur with the ingestion of hallucinogenic mushrooms. Such a syndrome is characterized by fever, tachycardia, agitation, hallucination, hypertension, skin flushing, dry mucous membranes, mydriasis, and blurred vision.

Patients with muscimol-induced GABA-ergic syndrome present with lethargy, ataxia, dysarthria, sleep, and coma. A glutaminergic syndrome may be seen with ibotenic acid poisoning and presents with hallucinations, hyperactivity, ataxia, myoclonic jerks, and convulsions. Because several mushrooms contain both muscimol and ibotenic acid, their ingestion generally results in alternating excitatory and inhibitory symptoms.

Central nervous system

Hallucinations may be caused by poisoning from mushrooms that contain muscimol, ibotenic acid, psilocybin, and psilocin.

Convulsions may be secondary to hypoxia and shock but may also be caused by poisoning from mushrooms that contain gyromitrin, psilocybin, and isoxazole.

Coma may be secondary to hypoxia, hypoglycemia, and hypovolemia but may also be caused by hepatic encephalopathy due to poisoning with amatoxin and gyromitrin.

Muscle fasciculations are commonly observed in poisoning from mushrooms that contain muscarine. Muscarine does not directly cause central nervous system (CNS) symptoms, because it is an ionized quaternary amine and is incapable of crossing the blood-brain barrier. The dizziness and headache occasionally experienced by patients poisoned with muscarine are the consequence of the peripheral cardiovascular and respiratory effects of the toxin.

GI symptoms and hepatotoxicity

Early onset of GI symptoms (eg, cramps, vomiting, and increased bowel activity) and diarrhea (rarely) leading to dehydration commonly occurs with the ingestion of nonlethal toxic mushrooms (eg, those containing muscarine).

Delayed GI symptoms, with vomiting and profuse diarrhea leading to shock, may occur with the ingestion of mushrooms that contain amatoxins and gyromitrins. These mushrooms are also hepatotoxic and may result in fulminant hepatic failure. Hepatomegaly and hepatic tenderness may signal the onset of hepatic failure and may be followed by encephalopathy, coma, bleeding, diatheses, cerebral edema, hepatorenal syndrome, and death.

Complications

Complications of mushroom toxicity include the following:

Approach Considerations

Many patients who ingest a mushroom do not require laboratory testing. Testing should be driven by the patient's clinical condition and the most likely toxin (based on identification of the mushroom by a mycologist, location of the ingestion, and the history).

Several texts describe how to determine whether a suspect botanical contains amatoxin, a potent toxin found in some of the Amanita species.[22]  However, for symptomatic patients, identification of the mushroom by a mycologist is highly desirable.

Botanical identification remains the most reliable method of identifying the mushroom involved in the poisoning. When the mushroom specimen is available, the Meixner test is occasionally used but is unreliable when attempted by inexperienced operators. The test consists of expressing a drop of mushroom juice onto a lignin paper (newspaper) and allowing it to air-dry. A drop of hydrochloric acid (10-12N) is then placed on the same spot, and the area is observed for any color change. The presence of amatoxin is suggested by a bluish color. False-positive results may occur with psilocybin.

By far, the most reliable way to identify a mushroom is to allow examination of the mushroom by an experienced local mycologist. This may be arranged by contacting the local Poison Center (800-222-1222).

Laboratory Studies

In patients with severe diarrhea or vomiting, a basic serum metabolic profile (sodium, potassium, chlorine, carbon dioxide, creatinine, glucose, and calcium) should be obtained for evaluation of fluid and electrolyte disturbances. Electrolyte disturbances (eg, hypokalemia) may occur in patients with severe gastroenteritis. Hypocalcemia may occur with orellanine-induced renal failure and in both gyromitrin and amatoxin poisoning. Hypophosphatemia may occur with amatoxin and gyromitrin poisoning, especially in children.

Hypoglycemia may develop suddenly during the gastroenteritis phase of gyromitrin poisoning, as well as during the hepatic failure phase of both gyromitrin and amatoxin poisoning. Hypoglycemia in the setting of liver failure signals a grim prognosis.

Baseline renal function studies are indicated if nephrotoxic mushroom ingestion cannot be ruled out. Blood urea nitrogen (BUN) concentration, creatinine level, and urinalysis are used as screening tools for renal function.[25]  Renal insufficiency occurs as a result of circulatory collapse from any cause, and in the setting of amatoxin and gyromitrin toxicity, it may be part of the hepatorenal syndrome.

Orellanine is a direct nephrotoxin and may induce oliguric renal failure several days or weeks after ingestion of the toxic mushroom. Mild renal insufficiency also may be observed with intravenous (IV) injection of psilocybin.

Baseline liver function studies may be indicated if hepatotoxic mushrooms are a possibility. For example, hepatic failure is a common complication of amatoxin and gyromitrin ingestions. Biomarkers of hepatocellular necrosis include aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, and lactic dehydrogenase (LDH). With amatoxin- and gyromitrin-induced hepatic necrosis, these biomarkers begin to rise exponentially 36-72 hours after mushroom ingestion. Bilirubin is elevated, as are the prothrombin time (PT) and activated partial thromboplastin time (aPTT).

A complete blood count (CBC) should be obtained if there is suspicion of a mushroom that causes hemolytic anemia. Anemia may be secondary to the acute blood loss associated with hemorrhagic gastroenteritis, or it may be secondary to the hemolysis observed with gyromitrin poisoning. Anemia may also be secondary to the renal failure observed in orellanine poisoning.

Methemoglobinemia may be observed with gyromitrin poisoning and occasionally after an IV injection of psilocybin.

Elevated creatine phosphokinase (CPK) levels are a manifestation of rhabdomyolysis, which may be noted with Tricholoma flavovirins and some Russula species. Evaluation for rhabdomyolysis should be considered if warranted by the signs and symptoms.

Drug screening

Urine drug screening should be considered, especially in the following situations:

Acetaminophen and salicylate levels should be obtained for all patients with an unknown ingestion, and acetaminophen toxicity should be suspected in all patients with fulminant hepatic failure (FHF). Toxicology screening for barbiturates, benzodiazepines, opiates, and alcohol may be obtained to help differentiate the cause of coma. Screening for phencyclidine, LSD, MDMA, and cocaine may help determine the cause of hallucinations and agitation. Screening for phenothiazines may help distinguish the cause of anticholinergic toxicity.

Other tests

Enzyme-linked immunosorbent assay (ELISA) analysis of urinary amanitin appears to be efficacious in confirming amatoxin poisoning, but this is not widely available except in forensic laboratories.

Chromatographic techniques (eg, thin-layer chromatography [TLC], gas-liquid chromatography [GLC], and high-pressure liquid chromatography [HPLC]), as well as mass spectometry, have been used to detect various mushroom toxins (eg, amanitins, orellanine, muscimol and ibotenic acid, psilocybin, muscarine, and gyromitrins).[25]  However, these techniques are typically unavailable, being largely limited to research laboratories.

Hemagglutination inhibition has been used to detect anti-Paxillus immunoglobulin G (IgG).

Imaging Studies

Chest radiography, if clinically indicated, should be performed to assess for aspiration pneumonia or pulmonary edema. Bilateral reticulonodular infiltrates may be seen with puffball (Lycoperdon)-induced allergic bronchoalveolitis. Computed tomography (CT) of the brain is indicated in all patients with encephalopathy in order to rule out structural disease or cerebral edema.

Renal ultrasonography may reveal enlarged kidneys in patients with orellanine poisoning.

Electrocardiography (ECG) may be performed to evaluate the presence of atrioventricular (AV) nodal disease and heart block. ECG may reveal signs of hyperkalemia, which may complicate orellanine-induced renal failure.

Histologic Findings

At autopsy or after transplantation, histologic examination of the liver reveals diffuse hepatocellular damage with gyromitrin toxicity and fatty degeneration of the liver with extensive central zone necrosis and centrilobular hemorrhage in amatoxin poisoning. Electron microscopy reveals changes consistent with extensive lipid peroxidation of the cytoplasm as well as the nucleus, vacuolization of the mitochondria, and clumping of the nucleolar chromatin.

Renal biopsy findings may reveal interstitial nephritis in gyromitrin toxicity. Acute tubular necrosis and dedifferentiation of the proximal tubule is present with orellanine toxicity. Electron microscopy reveals vacuolization of the tubular cells with loss of the brush border.

Gastric contents may be examined, but this is usually impractical as a means of identification. By means of microscopy, a mycologist may be able to identify the spores recovered from the patient’s gastric contents.

Approach Considerations

In the absence of a definitive identification of the mushroom, all toxic ingestions should be considered serious and possibly lethal. Once mushroom toxicity is diagnosed, treatment is largely supportive. Early volume resuscitation is important for liver and kidney toxic syndromes.

Gut decontamination, including whole-bowel irrigation, may be necessary for amatoxins. Beyond the first postprandial hour, orogastric lavage is not recommended, because of its questionable efficacy. Activated charcoal plays a much more important role in limiting absorption of most toxins and is indicated for all patients with amatoxin mushroom poisoning, regardless of the timing of presentation. When amatoxins are suspected, multiple doses of activated charcoal should be administered repeatedly to interrupt enterohepatic circulation of these toxins.

In general, children are more susceptible to volume depletion and mushroom toxicity (mushroom poisoning) than are healthy adults. Elderly patients are more susceptible to volume depletion than are healthy adults.

Supportive Measures

Once a toxin is absorbed, it may potentially be neutralized in the following ways:

Specific therapy depends on the presumed toxin ingested (see Toxin-Specific Management Approaches). Other complications of mushroom poisoning are treated in a standard manner.

Methemoglobinemia, which may occur after the ingestion of gyromitrins and, occasionally, after an intravenous (IV) injection of psilocybin, is treated with IV methylene blue. The US Food and Drug Administration (FDA) warns against the concurrent use of methylene blue with serotonergic psychiatric drugs, unless such therapy is indicated for life-threatening or urgent conditions. Methylene blue may increase CNS serotonin levels, increasing the risk of serotonin syndrome.[26]

Hemolysis, which may occur with gyromitrin toxicity, is usually mild, necessitates the administration of large amounts of IV fluids only to prevent renal complications; blood transfusions are rarely required. Hemolysis due to Paxillus species may be more severe and may result in acute renal failure.

Rhabdomyolysis has been reported with several species. Direct damage to myocytes with resultant onset on rhabdomyolysis occurs after ingestion of the so-called “man-on-horseback” mushroom, Tricholoma equestre (also known as Tricholoma flavovirens). Patients may present with muscle pain and have been reported with elevated creatinine phosphokinase levels, in the 10,000 U/L to 100,000 U/L range.

Other mushrooms implicated in less severe forms of rhabdomyolysis are Russula subnigricans (blackening Russula), Boletus edulis (king boletus), Leccinium versipelle (brown birch boletus), and Albatrellus ovinus (sheep polypore). Many of these are identified in field guides as edible. Treatment is with aggressive IV fluid resuscitation and consideration for IV sodium bicarbonate to alkalinize the urine. In rare cases, dialysis may be needed if renal failure occurs.

Agitation, commonly observed with hallucinogenic mushrooms, is treated with benzodiazepines; phenothiazines are best avoided in this setting. Other causes of agitation (eg, hypoxia, hypovolemia, and shock) should also be sought and corrected.

Anticholinergic poisoning may be treated with benzodiazepines; in rare cases, physostigmine may be required.

Severe muscarinic symptoms may be treated with the infusion of small doses of atropine. In muscarine poisoning, the entire episode usually subsides in 6-8 hours; some symptoms may take up 24 hours to fully resolve. Atropine should be considered only when excessive bronchial secretions compromise breathing and cause shortness of breath. Monitoring with pulse oximetry is indicated. Clinicians should be prepared to support the airway and perform orotracheal suctioning if necessary.[12]

Patients with severe poisoning from disulfiram-containing mushrooms may benefit from fomepizole (4-methylpyrazole), which blocks alcohol dehydrogenase and, hence, the formation of the toxic aldehyde.

Fulminant hepatic failure (FHF) is a common complication observed with amatoxin and gyromitrin poisoning, and it should be treated aggressively because it commonly follows a fatal course. Orthotopic liver transplantation (OLT) may be indicated (see Liver Transplantation).

Renal failure, commonly observed with norleucine and orellanine poisoning, may have to be treated with hemodialysis. Acute kidney injury with mild reversible liver injury may also follow the ingestion of Amanita smithiana and Amanita proxima.

Conventional indications for dialysis include uremic encephalopathy, fluid overload (with pulmonary edema), severe hyperkalemia, and acidosis. Patients with unremitting renal failure are candidates for renal transplantation, but since most cases resolve slowly over time, several months of hemodialysis should occur before this is considered.

The development of renal failure in patients with FHF warrants an attentive search for the cause of the renal failure. Patients with hepatorenal syndrome (HRS) are candidates for liver transplant.

Endotracheal intubation is recommended in all patients at risk of aspiration, and mechanical ventilation should be initiated in all patients with hypoxia, hypercarbia, acidemia, and shock. Aggressive rehydration in the intensive care unit (ICU) may be necessary in patients with choleralike gastroenteritis, and infusions of large amounts of electrolytes with dextrose solutions may be necessary to maintain vital functions.

Blood transfusions may be required in patients with hemorrhagic diarrhea, blood loss, and severe hemolytic anemia. Blood pressure support with dopamine and norepinephrine may be required when crystalloids and colloid infusions fail. Hypoglycemia is treated with infusions of 10% dextrose.

Cerebral edema is also treated in a conventional manner, which is aimed at reducing intracerebral pressure and preventing herniation. Hyperventilation, fluid restriction, osmotic diuresis, hypertonic saline, positioning the head of the bed at 30° from the horizontal plane, barbiturate coma, and anticonvulsants may be necessary.

Toxin-Specific Management Approaches

Amatoxin poisoning

In addition to intensive airway and aggressive rehydration with fluid therapy, correction of coagulation factors, and multiple doses of activated charcoal, a number of therapeutic options for amatoxin poisoning have been proposed, but to date, no controlled studies comparing the efficacy of different modalities have been published.

The IV form of silibinin is not currently available in the United States, but is used in Europe; however, an oral form (silymarin) may be obtained. Silymarin is a dietary supplement found in health food stores as an extract from milk thistle. (Silymarin) is given at 1 g orally 4 times daily, or its purified alkaloid silibinin is given intravenously at 5 mg/kg IV over 1 hour, followed by 20 mg/kg/day as a constant infusion. Silibinin is thought to interfere with hepatic uptake of alpha-amanitin, so early institution of therapy offers the best chance for clinical efficacy.[27]

Other recommended therapies for amatoxin poisoning include the following[28] :

In a murine model, however, none of the proposed antidotal therapies was found to have a significant effect on hepatic aminotransferase levels when compared with controls, nor did any of them demonstrate an important decrease in hepatic necrosis histologically.[29] A large human case series found an association between both silibinin and NAC and higher survival rates.[30]

Corticosteroids, vitamin C, kutkin, aucubin, and thioctic acid have been used in the past but have no proven benefit and are no longer recommended. Charcoal hemoperfusion and hemodialysis are also ineffective in removing toxins because once the toxin is formed, it is rapidly excreted by the kidneys.

Plasma exchange transfusions have been used with some success, but controlled studies are lacking. MARS (Molecular Absorbent Regenerating System), an extracorporeal liver-assistance method using an albumin dialysate to remove albumin-bound toxins, has shown promising survival results in amatoxin-related hepatic failure.[31] The Prometheus (Fresenius Medical Care, Bad Homburg, Germany) fractionated plasma separation and adsorption (FPSA) system also may prove useful for safely eliminating amatoxin and potentially obviating OLT.[32]

Further inpatient care of patients who survive amatoxin poisoning focuses on management of direct complications of poisoning and on management of the liver transplant (if OLT was performed).

Gyromitrin poisoning

In gyromitrin poisoning, in which systemic toxicity results from reduced concentrations of gamma-aminobutyric acid (GABA), seizures may be overcome by the infusions of pyridoxine (vitamin B-6) if they do not respond to benzodiazepines. Hydrazines also inhibit the transformation of folic acid to tetrahydrofolic acid. Therefore, patients with severe gyromitrin toxicity should receive folinic acid, as an adjunctive therapy.

Further inpatient care of patients who survive gyromitrin poisoning focuses on the management of complications of poisoning (eg, rhabdomyolysis, methemoglobinemia, and hemolysis) and management of the liver transplant (if OLT was performed).

Muscarine poisoning

Most patients with poisoning due to mushrooms containing muscarine can be treated without medications. If patients exhibit excessive bronchial secretions or other symptoms of cholinergic excess (bradycardia) that are of significant concern, atropine may decrease these symptoms.

If the patient presents within 1 hour of ingestion, oral administration of activated charcoal may be considered,[33] but adsorption to activated charcoal has not been demonstrated for these constituents.[34] No evidence suggests that routine administration of multiple doses of activated charcoal is useful. Ipecac syrup should generally be avoided, because vomiting often occurs spontaneously and evidence for effectiveness is lacking.

Administer IV fluids if vomiting becomes prominent, though this rarely proves necessary. Provide psychiatric care to patients with intentional ingestions and suicidal thinking.

Liver Transplantation

Indications for immediate OLT include the following:

Other suggested factors to consider include the following:

In patients with these indications, OLT may be the only life-saving therapy. Therefore, transfer to a liver transplantation center should be undertaken early in the setting of amatoxin poisoning and before the development of stage III encephalopathy, jaundice, or renal failure. Patients who develop shock, acidosis, hypoglycemia, and coagulopathy with hemorrhage and those who exhibit marked liver transaminase elevations should also be considered for immediate OLT, even in the absence of hepatic encephalopathy, azotemia, and hyperbilirubinemia.

FHF patients awaiting OLT should be intubated early in order to prevent the added burden of aspiration pneumonia and hypoxia. Hypovolemia is treated with crystalloids. Hemorrhage is treated with blood transfusions and, when accompanied by coagulopathy, infusions of FFP. Lactulose may be administered to patients who exhibit hepatic encephalopathy.

Diet

Patients with FHF have a catabolic rate that is quadruple the reference range; accordingly, they should receive adequate protein and carbohydrates so that hepatocyte regeneration may be optimized. Limiting protein in patients with FHF is associated with an increased mortality. Patients with acute FHF also are at risk for hypoglycemia and require close monitoring of their glucose levels, along with infusion of 10% dextrose solutions. Patients receiving high-carbohydrate solutions also must receive thiamine.

In patients with renal failure, use of essential amino acids is not associated with better outcomes than is the use of standard amino acids. Nutrition of patients with acute kidney injury should include amino acids and glucose, with a relatively normal calorie-to-nitrogen ratio.

Prevention

Prevention is best achieved by eating only commercially cultivated mushrooms, and identification of mushrooms is best left to experts. Mushrooms should be regularly removed from sites where children are routinely present.

Education regarding the poisonous nature of wild mushrooms may act as a deterrent to careless mushroom foraging and ingestion. Mushroom hunters who are appropriately cautious eat only 1 type of mushroom and save a sample in a dry paper bag for later identification, if needed.

Consultations

Specialists from the regional poison center, medical toxicologists, botanists, and mycologists may assist in the identification of the mushroom. A mycologist can be contacted through the local poison center (in the United States, call 800-222-1222), a mycology club, the North American Mycological Association, a botanical garden, or local university. The Internet may also provide answers. However, decontamination and treatment should not wait for the identification of the mushroom.

Other consultations to consider are as follows:

Medication Summary

The goals of pharmacotherapy are to neutralize the toxin, to reduce morbidity, and to prevent complications. Drugs used include anticonvulsants, antiemetics, gastrointestinal (GI) decontaminants, antidotes, and anticholinergic agents.

Lorazepam (Ativan)

Clinical Context:  Lorazepam is a sedative hypnotic with a short time to onset of effects and a relatively long half-life. By increasing the action of gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain, it may depress all levels of the central nervous system (CNS), including the limbic system and the reticular formation. Monitor the patient's blood pressure after administering a dose, and adjust as necessary.

Diazepam (Valium, Diastat)

Clinical Context:  Diazepam depresses all levels of the CNS (eg, the limbic system and the reticular formation), possibly by increasing GABA activity.

Phenobarbital

Clinical Context:  Phenobarbital interferes with the transmission of impulses from the thalamus to the cerebral cortex.

Class Summary

These agents prevent seizure recurrence and terminate clinical and electrical seizure activity.

Prochlorperazine (Compazine)

Clinical Context:  Prochlorperazine may relieve nausea and vomiting by blocking postsynaptic mesolimbic dopamine receptors through anticholinergic effects and depressing the reticular activating system. It is not recommended in children weighing less than 20 lb (9.1 kg), because of the high incidence of extrapyramidal effects.

Metoclopramide (Reglan, Metozolv)

Clinical Context:  Metoclopramide works as an antiemetic by blocking dopamine receptors in the chemoreceptor trigger zone of the CNS.

Class Summary

These agents block the dopamine receptors in the chemoreceptor trigger zone.

Activated charcoal (Charcoal Plus, CharcoCaps, EZ-Char)

Clinical Context:  Activated charcoal is given as emergency treatment in poisoning caused by drugs and chemicals. The network of pores present in activated charcoal absorbs 100-1000 mg of drug for every 1 g of charcoal. Charcoal does not dissolve in water.

For maximum effect, administer activated charcoal within 30 minutes after ingestion of the poison. The first dose is generally given with a cathartic (eg, sorbitol 1 g/kg PO). Additional doses of sorbitol are not administered to children, because they can cause excessive intraintestinal osmotic shifts, electrolyte imbalance, and intravascular volume depletion.

Polyethylene glycol (MiraLAX, Dulcolax Balance)

Clinical Context:  Polyethylene glycol is a laxative with strong electrolyte and osmotic effects that has cathartic actions in the GI tract.

Class Summary

These agents are empirically used to minimize systemic absorption of the toxin.

Pyridoxine (Nestrex)

Clinical Context:  Fomepizole is a Cortinarius antidote that has a better safety profile than ethanol and is easier to dose and administer. In contrast to ethanol, levels need not be monitored during therapy.

Penicillin G (Pfizerpen)

Clinical Context:  Penicillin G is an antibiotic that may work as an antidote by blocking amanitin uptake by hepatocytes and preventing amanitin from binding to RNA polymerase. It interferes with synthesis of cell-wall mucopeptide during active multiplication, resulting in bactericidal activity against susceptible microorganisms.

N-acetylcysteine (Acetadote)

Clinical Context:  N-acetylcysteine may provide a substrate for conjugation with a toxic metabolite.

Methylene blue

Clinical Context:  In reduced form, leukomethylene blue acts as an electron donor to reduce methemoglobin. Reduction of methylene blue is by nicotinamide adenine dinucleotide phosphate (NADPH) generated by glucose-6-phosphodiesterase (G-6-PD). The US Food and Drug Administration (FDA) warns against concurrent use of methylene blue with serotonergic psychiatric drugs, unless it is indicated for life-threatening or urgent conditions. Methylene blue may increase serotonin CNS levels, increasing the risk of serotonin syndrome.

Fomepizole (Antizol)

Clinical Context:  Fomepizole is an antidote that has a better safety profile than ethanol and is easier to dose and administer. In contrast to ethanol, levels need not be monitored during therapy.

Class Summary

Most amatoxin antidotes are experimental, and their use is based on animal studies, anecdotal reports of success in humans, or both.

In addition to the medications listed below, silibinin is made of silymarin, an extract of the milk thistle plant Silybum marianum, and may act as a free radical scavenger or may interrupt enterohepatic circulation. It blocks amanitin uptake by hepatocytes. Silibinin is available in Europe but not in the United States.

Atropine

Clinical Context:  Administered IV/IM, atropine acts at parasympathetic receptor sites to block the actions of acetylcholine and muscarine.

Ipratropium (Atrovent)

Clinical Context:  Ipratropium is chemically related to atropine. It has antisecretory properties and, when applied locally, inhibits secretions from serous and seromucous glands lining the nasal mucosa.

Class Summary

Atropine is a competitive inhibitor of acetylcholine and muscarine in the autonomic nervous system and relieves muscarinic effects, especially bronchorrhea. Inhaled anticholinergic agents (eg, ipratropium) may also be considered.

Author

B Zane Horowitz, MD, FACMT, Professor, Department of Emergency Medicine, Oregon Health and Sciences University School of Medicine; Medical Director, Oregon Poison Center; Medical Director, Alaska Poison Control System

Disclosure: Nothing to disclose.

Coauthor(s)

Robert G Hendrickson, MD, Associate Professor of Emergency Medicine, Oregon Health and Science University School of Medicine; Attending Physician, Medical Director, Emergency Management Program, Department of Emergency Medicine, Oregon Health and Science University Hospital and Health Systems; Associate Medical Director, Director, Fellowship in Medical Toxicology, Disaster Preparedness Coordinator, Oregon Poison Center; Clinical Toxicologist, Alaska Poison Center and Guam Poison Center

Disclosure: Nothing to disclose.

Chief Editor

Sage W Wiener, MD, Assistant Professor, Department of Emergency Medicine, State University of New York Downstate Medical Center; Director of Medical Toxicology, Department of Emergency Medicine, Kings County Hospital Center

Disclosure: Nothing to disclose.

Acknowledgements

William Banner Jr, MD, PhD Medical Director, Oklahoma Poison Control Center; Clinical Professor of Pharmacy, Oklahoma University College of Pharmacy-Tulsa; Adjunct Clinical Professor of Pediatrics, Oklahoma State University College of Osteopathic Medicine

William Banner Jr, MD, PhD, is a member of the following medical societies: American College of Medical Toxicology

Disclosure: Nothing to disclose

Peter A Chyka, PharmD, FAACT, DABAT Professor and Executive Associate Dean, College of Pharmacy, University of Tennessee Health Science Center

Peter A Chyka, PharmD, FAACT, DABAT is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Clinical Pharmacy, and American Society of Health-System Pharmacists

Disclosure: Nothing to disclose.

Timothy E Corden, MD Associate Professor of Pediatrics, Co-Director, Policy Core, Injury Research Center, Medical College of Wisconsin; Associate Director, PICU, Children's Hospital of Wisconsin

Timothy E Corden, MD is a member of the following medical societies: American Academy of Pediatrics, Phi Beta Kappa, Society of Critical Care Medicine, and Wisconsin Medical Society

Disclosure: Nothing to disclose.

Laurie Robin Grier, MD Medical Director of MICU, Professor of Medicine, Department of Emergency Medicine, Anesthesiology and OBGYN, Section of Pulmonary and Critical Care Medicine, Louisiana State University Health Science Center at Shreveport

Laurie Robin Grier, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Society for Parenteral and Enteral Nutrition, and Society of Critical Care Medicine

Disclosure: Nothing to disclose.

Rania Habal, MD Assistant Professor, Department of Emergency Medicine, New York Medical College

Disclosure: Nothing to disclose.

Jorge A Martinez, MD, JD Clinical Professor, Department of Internal Medicine, Louisiana State University School of Medicine in New Orleans; Clinical Instructor, Department of Surgery, Tulane School of Medicine

Jorge A Martinez, MD, JD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Cardiology, American College of Emergency Physicians, American College of Physicians, and Louisiana State Medical Society

Disclosure: Nothing to disclose.

Michael E Mullins, MD Assistant Professor, Department of Emergency Medicine, Washington University School of Medicine

Michael E Mullins, MD is a member of the following medical societies: American Academy of Clinical Toxicology and American College of Emergency Physicians

Disclosure: Johnson & Johnson stock ownership None; Savient Pharmaceuticals stock ownership None

Daniel R Ouellette, MD, FCCP Associate Professor of Medicine, Wayne State University School of Medicine; Consulting Staff, Pulmonary Disease and Critical Care Medicine Service, Henry Ford Health System

Daniel R Ouellette, MD, FCCP is a member of the following medical societies: American College of Chest Physicians and American Thoracic Society

Disclosure: Boehringer Ingleheim Honoraria Speaking and teaching; Pfizer Honoraria Speaking and teaching; Astra Zeneca Honoraria Speaking and teaching

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Jeffrey R Tucker, MD Assistant Professor, Department of Pediatrics, Division of Emergency Medicine, University of Connecticut and Connecticut Children's Medical Center

Disclosure: Merck Salary Employment

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

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Amanita phalloides.

Omphalotus olearius (Jack O'Lantern mushroom).

Clitocybe dealbata.

Inocybe geophylla.

Inocybe lacera.

Amanita phalloides.

Inocybe geophylla.

Inocybe lacera.

Clitocybe dealbata.

Omphalotus olearius (Jack O'Lantern mushroom).