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Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 8e

Chapter 219: Mushroom Poisoning Anne F. Brayer; Lynette Froula

INTRODUCTION AND EPIDEMIOLOGY

Mushrooms are a common toxic exposure, with >6600 poisonous mushroom exposures and six deaths

reported to poison control centers in 2012 and more than half occurring in children <6 years of age.1

Fortunately, the majority of reported mushroom exposures have a benign outcome.2,3 To prevent mushroompoisoning, avoid eating wild mushrooms. There are no easily recognizable di�erences betweennonpoisonous and poisonous mushrooms. Mushroom toxins are not heat labile and so are not destroyed ordeactivated by cooking, canning, freezing, drying, or other means of food preparation.

Depending on the type of mushroom, adverse e�ects from ingestion range from mild GI symptoms to majorcytotoxic e�ects resulting in organ failure and death. Toxicity varies based on the amount ingested, the age ofthe mushroom, the season, the geographic location, and the way in which the mushroom was prepared priorto ingestion. One person may show significant e�ects, whereas others may be asymptomatic a�er ingestingthe same mushroom (Table 219-1).

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TABLE 219-1

Mushrooms: Symptoms, Toxicity, and Treatment

Symptoms Mushrooms Toxicity Treatment

GI symptoms

Onset <2 h Chlorophyllum

molybdites

Omphalotus

illudens

Cantharellus

cibarius

Amanita

caesarea

Nausea, vomiting, diarrhea

(occasionally bloody)

IV hydration

Antiemetics

Onset 6–24 h Gyromitra

esculenta

Amanita

phalloides,

Amanita

bisporigera

Initial: nausea, vomiting, diarrhea

Day 2: rise in AST, ALT levels

Day 3: hepatic failure

IV hydration, glucose; monitor AST,

ALT, bilirubin, BUN, and creatinine

levels, prothrombin time, partial

thromboplastin time

For Amanita: activated charcoal

Consider penicillin G, 300,000–

1,000,000 units/kg/d

Silymarin, 20–40 milligrams/kg/d

Consider cimetidine, 4–10 grams/d

Consider hyperbaric oxygen

therapy

Muscarinic

syndrome

Onset

<30 min

Inocybe

Clitocybe

SLUDGE syndrome (salivation,

lacrimation, urination,

defecation, GI hypermotility, and

emesis)

Supportive; atropine, 0.01

milligram/kg, repeated as needed

for severe secretions

CNS

excitement

Onset

<30 min

Amanita

muscaria

Amanita

pantherina

Intoxication, dizziness, ataxia,

visual disturbances, seizures,

tachycardia, hypertension, warm

dry skin, dry mouth, mydriasis

(anticholinergic e�ects)

Supportive; sedation with

diazepam, 0.1 milligram/kg IV for

children; diazepam, 2–5

milligrams IV, or phenobarbital, 30

milligrams IV for adults

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Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase.

Symptoms Mushrooms Toxicity Treatment

Hallucinations

Onset

<30 min

Psilocybe

Gymnopilus

Visual hallucinations, ataxia Supportive; sedation with

diazepam, 0.1 milligram/kg or 5

milligrams IV for adults, or

phenobarbital, 0.5 milligram/kg or

30–60 milligrams IV for adults

Disulfiram

reaction

2–72 h

a�er

mushroom,

and <30 min

a�er alcohol

Coprinus Headache, flushing, tachycardia,

hyperventilation, shortness of

breath, palpitations

Supportive; IV hydration

β-Blockers for supraventricular

tachycardia

Norepinephrine for refractory

hypotension

Dermatitis

1–2 d

a�er ingestion

Shiitake Whip-like, linear, erythematous

wheals, blanching erythematous

patches, scattered petechiae,

pruritus

Oral antihistamines, 0.1%

triamcinolone ointment twice

daily; spontaneously resolves

within 1–3 wk

Mushroom toxicity is divided into early toxicity (within 2 hours a�er ingestion) and delayed toxicity (6 hoursto 20 days later).

Mushroom poisoning occurs in four main groups of individuals: young children who ingest poisonousmushrooms inadvertently, wild mushroom foragers, individuals attempting suicide or homicide, andindividuals looking for a hallucinatory "high." Identification of the mushroom ingested may be di�icult andtime consuming. Very o�en, foragers mix di�erent species of mushrooms together, so it is not always clearthat the species being identified is the same one that was ingested. Therefore, direct treatment by a patient'ssymptoms rather than by attempts at mushroom identification. Treatment for mushroom poisoning is based

on case reports and small series.3

Nearly all fatalities in the United States and Europe occur from ingestion of mushrooms of the Amanita

species (Amanita phalloides, Amanita virosa, and Amanita bisporigera).4 If Amanita ingestion is suspected,identification of the species may be helpful but is di�icult because there are many Amanita mushrooms thatare nontoxic. Amanita species generally have warts on the cap (remnants of the membrane covering theemerging mushroom), which give it a spotted appearance. The gills are "free," ending before the stem begins.The stem characteristically has a membrane ring around it and widens as it enters the soil. In most cases, theLoading [Contrib]/a11y/accessibility-menu.js

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stem of the mushroom is contained in a cup or volva, which may be underground (Figures 219-1, 219-2 and219-3).

FIGURE 219-1.

Amanita muscaria. [Photo used with permission of Jilber Barutciyan.]

FIGURE 219-2.

Amanita pantherina. [Photo used with permission of Jilber Barutciyan.]

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FIGURE 219-3.

Amanita phalloides. [Photo used with permission of Jilber Barutciyan.]

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EARLY-ONSET GI SYMPTOMS

PATHOPHYSIOLOGY

Most wild mushroom ingestions cause mild GI irritation, and mushrooms that cause GI irritation can be ofmany types. In North America and in almost every country, Chlorophyllum molybdites is particularly

common and is sometimes mistaken for an Amanita.3 Many little brown mushrooms found commonly inlawns, and o�en accidentally ingested by children, are in this category. Omphalotus, Boletus, Entoloma,Gomphus, Hebeloma, Lactarius, and Verpa genera are other examples for this group (Figure 219-4). Theactual toxin varies with the species of mushroom, but most toxins are poorly described.

FIGURE 219-4.

Omphalotus olearius. [Photo used with permission of Jilber Barutciyan.]

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CLINICAL FEATURES

The majority of mushroom-induced intoxications are mild and do not prompt a visit to the ED. C. molybdites,

however, is an exception that may cause severe symptoms.5 Typically, patients present with acute onset ofvomiting and diarrhea <2 hours a�er ingesting the mushroom. There may be intestinal cramping, chills,headaches, and myalgias. Diarrhea is usually watery, but occasionally bloody with fecal leukocytes. Mostcommonly, symptoms are mild and self-limited. Symptoms usually resolve within 24 hours but may last up toseveral days. Vomiting and diarrhea can cause dehydration and electrolyte imbalance. The presentation maybe confused with acute gastroenteritis or acute food poisoning if the patient does not o�er the history ofmushroom ingestion.

TREATMENT

Treat symptomatic toxic mushroom ingestion with activated charcoal 0.5 to 1.0 gram/kg, PO or by

nasogastric tube. There is no role for prophylactic decontamination therapy of asymptomatic patients.6

Other treatment is largely supportive and includes IV fluid and electrolyte replacement when necessary.Antiemetics can be given, but do not give antidiarrheal agents, because they may prolong exposure to the

toxin.2 In most cases, symptoms are self-limited, resolving within 12 to 24 hours. Some cases of Amanitasmithiana ingestion present with early GI symptoms (between 30 minutes and 12 hours) and can progress to

renal failure within 3 to 5 days.7

Once vomiting has subsided and the patient is tolerating oral fluids, discharge from the ED is safe. Rarely,symptoms may persist and hospitalization may be needed for fluid and electrolyte replacement.Loading [Contrib]/a11y/accessibility-menu.js

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Recommend outpatient follow-up within 5 days, and provide return precautions (urinary changes, lumbar or

flank pain).7

EARLY-ONSET NEUROLOGIC SYMPTOMS

PATHOPHYSIOLOGY

Several classes of mushrooms can cause neurologic symptoms. These include the hallucinogenicmushrooms ("magic mushrooms") that contain the chemical psilocybin, which is rapidly dephosphorylated

by alkaline phosphatase to the more psychoactive chemical psilocin.8 Psilocin acts on serotonergic neuronsin the CNS, causing e�ects similar to those of lysergic acid diethylamide. Mushrooms of the Psilocybe genus,which are the most commonly ingested in this class, are small brown or gold mushrooms that commonlygrow on dung in warmer climates throughout the Pacific Northwest and southeastern United States as well

as warm regions of Central America, South America, Asia, and Australia.9 They characteristically turn agreenish blue when bruised or cut. They may also be cultivated at home from purchased spores. Nontoxicmushrooms may also be laced with phencyclidine or lysergic acid diethylamide and sold as hallucinogenicmushrooms.

Mushrooms containing the isoxazole derivatives ibotenic acid and muscimol also possess neurologic e�ects,which are thought to be mediated by γ-aminobutyric acid and anticholinergic activity. Amanita muscaria isthe principle representative of this group of mushrooms and is easily identified (Figure 219-1). It has anorange or red cap with white warts (remnants of the universal veil present in young specimens), as well as aring (annulus) and cup (volva) on the stem. Amanita pantherina, another member of the group, is 5 to 14 cmin length and diameter, with a white to brown cap, and has the ring and cup on the stem (Figure 219-2). Bothspecimens grow under trees in woodlands throughout North America.

CLINICAL FEATURES

Symptoms typically develop within 2 hours of ingestion of hallucinogenic mushrooms. Euphoria, aheightened imagination, a loss of the sense of time, and visual distortions or hallucinations are common.Tachycardia and hypertension may be noted because of the presence of phenylethylamine in psilocybin-

containing mushrooms.10 Fever and seizures have been reported in rare cases. Symptoms generally last 4 to

6 hours but can persist up to 12 hours.11 There are infrequent reports of flashbacks for up to 4 months a�eringestion, particularly in association with other substances that alter cognition such as alcohol or

marijuana.9

Patients ingesting isoxazole-containing mushrooms usually present with symptoms within 30 minutes ofingestion. Signs of muscarinic poisoning are the first apparent (nausea, vomiting, diarrhea, vasodilation,diaphoresis, salivation). These are replaced by an atropine-like symptom complex about 30 minutes a�eringestion (mydriasis, xerostomia, elevated temperature, increased blood pressure), along with drowsiness,amentia, dizziness, photosensitivity, euphoria, motor hyperactivity, ataxia, muscle jerking, hallucinations,

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and delirium with di�iculty with perception of size, time, and place. Seizures have been reported in children.Symptoms are typically self-limited, resolving within 4 to 6 hours a�er ingestion. Headache and fatigue are

reported to occur the day following ingestion, with headache lasting up to a few weeks.9

TREATMENT

Treatment for ingestion of hallucinogenic mushrooms is largely supportive. Place the patient in a darkened,quiet room, devoid of visual stimuli, and provide reassurance. If sedation is required, benzodiazepines suchas diazepam or lorazepam are preferred. Do not give anticholinergic agents because they may aggravatedelirium.

Treat symptomatic ingestion of isoxazole-containing mushrooms with activated charcoal. Do not give syrupof ipecac because of the potential for CNS depression and seizures, which place the patient at risk foraspiration. In patients with severe vomiting and diarrhea, replace fluids and electrolytes. Appropriatelyrestrain patients who are agitated, and provide sedation as necessary with benzodiazepines (diazepam orlorazepam). Treat seizures with benzodiazepines.

Consider treatment with physostigmine only for patients with severe anticholinergic symptoms.Physostigmine can produce bradycardia, hypotension, and seizures, so administration should be reservedfor severely symptomatic patients. The dose is 1 to 2 milligrams IV in adults and 0.5 milligram IV in children,administered slowly. Monitor continuous cardiorespiratory e�ects and blood pressure during administration.Base the decision to discharge from the ED on duration of symptoms and need for ongoing pharmacologicsedation or intubation.

EARLY-ONSET MUSCARINIC SYMPTOMS

Muscarine was the first mushroom toxin to be identified.12 Mushrooms of the Inocybe and Clitocybe generaare common causes of muscarinic poisoning (Figure 219-5). The Inocybe mushrooms are small brownmushrooms with conical caps, typically found under hardwoods and conifers. The Clitocybe mushrooms areusually found individually on lawns and in parks and are white to gray, with a cup-shaped cap. A. muscaria,despite its name, contains far less muscarine than these other groups and only rarely causes cholinergicpoisoning symptoms. Isoxazole-containing mushrooms can cause transient muscarinic symptoms early a�eringestion.

FIGURE 219-5.

Clitocybe candicans. [Photo used with permission of Jilber Barutciyan.]

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PATHOPHYSIOLOGY

Muscarine is a parasympathomimetic compound that is heat stable and acetylcholine like. It is not degraded

by cholinesterase and, therefore, has a long duration of action.13 Acetylcholine receptors on the heart,

apocrine glands, and smooth muscle are activated by muscarine.12 Mushrooms containing muscarine causeneurologic symptoms and muscarinic or cholinergic e�ects.

CLINICAL FEATURES

The symptoms of muscarinic intoxication are characterized by the SLUDGE syndrome (salivation,lacrimation, urination, defecation, GI hypermotility, and emesis). In addition to the SLUDGE syndrome,patients with muscarine ingestions can develop diaphoresis, muscle fasciculations, miosis, bradycardia, andbronchorrhea. Symptoms typically present within 30 minutes of ingestion and spontaneously resolve in 4 to12 hours.

TREATMENT

In most cases, muscarinic symptoms are mild and self-limited. Supportive care is su�icient. Because emesisis a common presenting symptom, activated charcoal administration is o�en di�icult. Patients with severevomiting may require IV fluid and electrolyte replacement.

Atropine is an antidote for muscarinic symptoms and can be administered to patients with severe symptoms.It can be e�ective in treating bradycardia and hypotension unresponsive to IV fluid administration. AtropineLoading [Contrib]/a11y/accessibility-menu.js

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is helpful in the treatment of diaphoresis, increased oral secretions, and bronchorrhea. It may also helpreduce GI cramping, emesis, and diarrhea. The dose is 0.5 to 1.0 milligram IV for adults and 0.01 milligram/kgIV for children (minimum dose, 0.1 milligram; maximum does, 1 milligram). The dose can be repeated asnecessary to control bronchorrhea, bradycardia, or hypotension. Large doses may be necessary to treatsevere toxicity. Patients should be carefully monitored during administration. Oxygen and inhaled β agonists(albuterol) are recommended for the treatment of patients with increased pulmonary secretions andbronchospasm.

Because symptoms of muscarinic poisoning frequently resolve within 12 hours of ingestion, many patientscan be safely discharged from the ED a�er observation when symptoms have subsided.

DELAYED-ONSET GI SYMPTOMS

Mushrooms of two di�erent genera, Gyromitra and Amanita, cause significant toxicity, whichcharacteristically presents several hours a�er ingestion. Gyromitra esculenta (the false morel) is an

uncommon cause of poisoning in North America, but is more common in Scandinavia and Europe.4 G.esculenta has a brown convoluted top resembling a brain and is o�en mistaken for the tasty morelmushroom. A. phalloides and A. bisporigera are common in the Northern Hemisphere and are particularlycommon from north central Europe through the Middle East. Mushrooms of these species are foundthroughout the West Coast, Midwest, and parts of the Northeast of the United States. Immigrants maymistake these mushrooms for edible varieties common in eastern Asia. Mushrooms of the Amanita genus areresponsible for 95% of deaths associated with mushrooms. Toxic ingestions in North America occur mostcommonly in the autumn.

PATHOPHYSIOLOGY

Gyromitrin (N-methyl-N-formylhydrazone) is a volatile heat-labile toxin and primarily responsible for

symptoms. Gyromitrin concentration decreases significantly a�er boiling and desiccation.14 Gyromitrin ishydrolyzed in the stomach to form N-methyl-N-formylhydrazine and N-methylhydrazine. N-Methylhydrazineis chemically identical to rocket fuel, and workers exposed to this compound develop CNS toxicity. N-Methylhydrazine binds to pyridoxine and interferes with enzymes that require pyridoxine as a cofactor. γ-Aminobutyric acid is lowered in the CNS, which may be a cause of associated seizures. N-Methyl-N-formylhydrazine is converted into a free radical in the liver and causes local hepatic necrosis by blocking the

activity of the cytochrome P-450 system, glutathione, and other hepatic enzyme systems.14 These twochemicals explain the CNS and hepatic dysfunction characteristic of gyromitrin toxicity. The cause of theinitial GI symptoms is not known.

A. phalloides contains several phallotoxins and amatoxins. Phallotoxin is a bi-cyclic peptide that alters theenterocyte cellular membrane, thereby causing early GI symptoms. Its e�ect is limited to the GI tract,

because it is not absorbed by the intestine.15 Amatoxins are bi-cyclic octapeptides that are rapidly absorbedthrough the intestinal mucosa. They are carried to the liver and undergo enterohepatic circulation, whichLoading [Contrib]/a11y/accessibility-menu.js

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results in prolonged toxin exposure a�er ingestion. Nine amatoxins have been identified, but α-amanitin

(amanitin) appears the most physiologically active.2 Kinetic studies in humans show that α-amanitin is

cleared from the plasma within 48 hours.16 Concentrations in the plasma are quite small. Amatoxins are notprotein bound, but are actively transported into hepatocytes, where they bind to RNA polymerase II and

inhibit the formation of messenger RNA. Free radical formation may also be involved in toxicity.17 α-Amanitinhas the greatest e�ect on cells that undergo rapid protein synthesis and turnover, including cells of the GI

tract mucosa, hepatocytes, and renal tubular epithelium.18 In adults, the dose that causes 50% mortality is

0.1 milligram/kg of body weight, which is commonly contained in a single mushroom.15

Pathologic changes are noted in both gyromitrin and amatoxin toxicity. Patients who ingest gyromitrin-containing mushrooms show di�use hepatocellular damage and interstitial nephritis. Patients who ingestamatoxin-containing mushrooms show fatty degeneration of the liver, with intranuclear collection of lipidsand extensive hepatic necrosis. Electron microscopy shows vacuolization of the mitochondria and clumpingof the chromatin in the nucleoli. There are extensive lipid peroxidation changes in both the nucleus and thecytoplasm.

CLINICAL FEATURES

The distinctive characteristics of gyromitrin-containing mushroom toxicity are intense GI signs andsymptoms (nausea, vomiting, and watery diarrhea) that develop 6 to 24 hours a�er ingestion, typicallybetween 6 and 8 hours.

Hypovolemia is common during this phase of toxicity. In severe cases, hepatic failure is evident on day 3 andmay result in death as early as day 7. Serum transaminase levels may be significantly elevated. Hypoglycemiaoccurs during the GI phase and again in the acute hepatic failure phase.

Initial GI symptoms can be accompanied by dizziness, headache, seizures, incoordination, and muscle

cramps. The initial GI symptoms resolve within 2 to 5 days.5 In a mild ingestion, the neurologic symptomspersist for several days and resolve without sequelae.

Patients who ingest amatoxin-containing mushrooms also have delayed onset of GI symptoms (6 to 24hours). The gastroenteritis is intense, o�en requiring fluid and electrolyte replacement. There are four stagesin amatoxin poisoning. The first (latent) stage is characterized by the absence of any signs or symptoms andlasts up to 24 hours a�er ingestion. During the 12 to 24 hours of the second stage, GI symptoms such asintense cramping abdominal pain, nausea, vomiting, and diarrhea dominate the clinical picture. Both stoolsand vomitus may become bloody. Although right upper quadrant tenderness and hepatomegaly may benoted, results of liver function tests are usually normal. Patients who present during this stage are frequentlymisdiagnosed with gastroenteritis. The third, or convalescent, phase lasts 12 to 24 hours. During this stage,the patient feels and looks better, but levels of liver enzymes, such as aspartate aminotransferase, alanineaminotransferase, and bilirubin, begin to rise, heralding the onset of liver damage. Renal function may alsodeteriorate. In the fourth and final stage, which begins 2 to 4 days a�er ingestion, transaminase levels riseLoading [Contrib]/a11y/accessibility-menu.js

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dramatically, and liver and renal function deteriorate. Hyperbilirubinemia, coagulopathy, hypoglycemia,

acidosis, hepatic encephalopathy, and hepatorenal syndrome are noted.2

In both Gyromitra and Amanita toxicity, prothrombin time may be elevated and unresponsive toadministration of vitamin K or fresh frozen plasma. Amylase and lipase elevation suggests pancreaticdamage, although symptomatic pancreatitis is rare. Abnormal laboratory findings in amatoxin poisoninginclude a decrease in neutrophils, lymphocytes, and platelets, and abnormal thyroid function results.Hypophosphatemia (primarily noted in children), hypocalcemia, and elevated insulin levels occur. None ofthese laboratory abnormalities correlates with clinical disease, and their cause is unknown.

The mortality from Gyromitra ingestion is estimated at 15% to 35% and is generally attributed to hepatic

failure, renal failure, or fluid and electrolyte disorders.5 More recently, mortality has been reduced to 10% to15%, because of improved care for hepatic failure and liver transplantation. Patients who survive severehepatic failure from amatoxin may develop signs of chronic active hepatitis with persistent elevation in livertransaminase levels, development of anti–smooth muscle antibodies, and presence of cryoglobulins. Noprolonged e�ects from gyromitrin toxicity have been reported.

DIAGNOSIS

The diagnosis of gyromitrin toxicity is generally assumed from the clinical features and the identification ofthe mushroom ingested, either by the patient or from samples. Identification of Amanita species generallyrequires a trained mycologist. The Meixner colorimetric test is used to look for the presence of amatoxin. Adrop of fresh mushroom pulp, methanol extract from dried mushrooms, or gastric material is placed on ahigh-lignin paper (e.g., newspaper) and allowed to dry. A drop of 10-N or 12-N hydrochloric acid is thenapplied to catalyze the reaction of the amatoxin with the lignin in the paper. The area will turn blue within 1to 2 minutes if amatoxins are present, but the appearance of color may be delayed up to 30 minutes if the

amatoxin concentration is low.2 Although the test is sensitive, it is not very specific, and other nontoxicmushrooms may give a positive test result. Tests using thin-layer chromatography, high-performance liquidchromatography, and radioimmunoassay have been developed to detect amatoxin. Unfortunately, these

assays are not generally available to clinicians and are used most o�en in research settings.2 Amatoxin canbe detected in plasma, urine, GI tract contents, and feces. However, its presence merely confirms amatoxinpoisoning. Levels do not appear to correlate with clinical severity, and amatoxin is not detected in manypatients, presumably because of rapid clearance.

TREATMENT

Administer activated charcoal to patient presenting with severe vomiting and diarrhea within a few hours ofmushroom ingestion. Repeated doses of charcoal for at least the first 24 hours may be e�ective, particularly

in the presence of amatoxin (because it undergoes enterohepatic circulation).15 Fluid and electrolytereplacement is mandatory. Glucose level should be monitored and glucose replaced as needed.Hypoglycemia is one of the most common causes of death in early mushroom toxicity.Loading [Contrib]/a11y/accessibility-menu.js

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All patients who have ingested amatoxin- or gyromitrin-containing mushrooms should be closely monitoredfor 48 hours for the development of hepatic and renal failure. Electrolyte levels, liver enzyme levels, andprothrombin time should be monitored several times a day. Patients should be treated with a low-proteindiet and should receive standard supportive therapy for hepatic failure. Fresh frozen plasma and vitamin Kcan be used for the treatment of prolonged prothrombin time, but in many cases, coagulopathy does notrespond to treatment.

Patients who develop hepatic failure should be monitored closely, and in severe cases, preparations shouldbe made for liver transplantation. Although no firm criteria exist, progressive coagulopathy, encephalopathy,and renal failure despite maximal medical therapy are frequently listed indications for emergency liver

transplantation.19 Many patients have met these criteria and survived without transplantation, and manypatients have died without meeting these criteria. Liver transplantation, however, does provide the onlyoption for patients in fulminant hepatic failure and has been quite successful. Auxiliary liver transplantationhas also been used. In this case, a portion of the damaged liver is removed and a temporary transplant

provided, which allows time for the native liver to regenerate.20

Gyromitrin-Specific Treatment

Treat the neurologic symptoms associated with gyromitrin with high-dose pyridoxine. Pyridoxine providesthe cofactor required for the regeneration of γ-aminobutyric acid. High doses of pyridoxine, 25 milligrams/kgIV over 30 minutes up to a maximum of 25 grams/d, are recommended, but doses of pyridoxine in excess of

40 grams are associated with severe peripheral neuropathy.21,22 Pyridoxine does not a�ect the developmentor course of hepatic failure, and there is no specific therapy for gyromitrin-induced hepatic failure.

Amatoxin-Specific Treatment

Although multiple modalities have been tried in the past with mixed results, activated charcoal, silybinum

marianum, and N-acetylcysteine are emerging as the best-supported treatment modalities.15,23 Early in theclinical course, repeated dosing of activated charcoal is thought beneficial by reducing the absorption ofamatoxin as it undergoes enterohepatic circulation. Silybinum marianum, a milk thistle isolate, is alsothought to prevent toxicity by interfering with transmembrane transport during enterohepatic circulation

and inhibiting the binding of α-amanitin to hepatocytes.15,23 There is some evidence that silybinum hasadditional hepatoprotective e�ects that result from stimulating protein synthesis and inhibiting tumor

necrosis factor-α release in damaged liver cells.23 It is given as a loading dose of 5 milligrams/kg over 1 hourfollowed by 20 milligrams/kg/d for 6 days. This treatment is not currently approved by the U.S. Food andDrug Administration; it is available in Europe, and phase II/III clinical trials are in progress in the United

States.15 N-Acetylcysteine is also beneficial as a means of reducing reactive metabolites by providingsulfhydryl groups for this purpose. It is given intravenously in three sequential doses of 150 milligrams/kgover 1 hour, 50 milligrams/kg over 4 hours, and 100 milligrams/kg over 16 hours.

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Despite these therapies, amatoxin toxicity may lead to fulminant liver failure. In cases of amatoxin-inducedliver failure, the amatoxin itself is rapidly absorbed and excreted, which limits the utility of hemoperfusion

and/or hemodialysis. The Molecular Adsorbent Recirculation System™ can support liver function while

hepatocytes recover or until transplantation becomes feasible.24 Although randomized controlled trials are

not available, numerous case reports have shown improved liver functioning coinciding with this device.24

Orthotopic liver transplantation (the entire organ is replaced with a gra�) and auxiliary partial orthotopicliver transplantation (a portion of the native liver is removed and replaced with a gra� until recovery occurs)

are both surgical options.15

High-dose penicillin G and ce�azidime have both demonstrated a capacity for decreasing the uptake of

amanitin by hepatocytes.18,25 However, these therapies appear to be less e�ective than using silybinum

alone.23 Thioctic acid is a free radical scavenger and has been used for many years but has not yet gainedsupport in the literature.

Patients suspected of ingesting amatoxin- or gyromitrin-containing mushrooms should be admitted andmonitored for 48 hours, with monitoring of hepatic and renal function.

DELAYED-ONSET RENAL FAILURE

Delayed-onset renal failure is seen a�er ingestion of Cortinarius (Cortinarius orellanus, Cortinarius

speciosissimus, and Cortinarius gentilis) and A. smithiana mushrooms.26 Cortinarius species are foundprimarily in Europe. This mushroom is o�en mistaken for a pine mushroom and grows commonly in the

Pacific Northwest. A. smithiana mushrooms are common in forest areas of western North America.7

PATHOPHYSIOLOGY

Orellanine and ortinarin A and B are the nephrotoxic compounds in species of Cortinarius (C. orellanus, C.speciosissimus, and C. gentilis). These toxins are heat stable, and their mechanisms of action are not wellknown. Orellanine and its derivatives are believed to inhibit protein synthesis in the kidneys. Histopathologicexamination indicates interstitial nephritis with edema and leukocyte infiltration, tubular necrosis, basalmembrane rupture, and fibrosis without glomerular injury in patients poisoned with orellanine-containing

mushooms.18,22,27

Allenic norleucine (aminohexadienoic acid) and chlorocrotylglycine are the nephrotoxins found in A.

smithiana.26 Allenic norleucine has been shown to induce renal tubular epithelial necrosis and tends to exert

its e�ect earlier than orelline in cultured cell lines.7

CLINICAL FEATURES

Patients who ingest mushrooms containing nephrotoxins o�en present initially with GI symptoms, includingnausea, vomiting, and nonbloody diarrhea. Symptoms begin several hours to days a�er ingestion and may

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persist for 3 days. Occasionally, paresthesias, abnormal taste, and cognitive dysfunction are reported.Symptoms of renal failure, including lumbar and flank pain, oliguria, or more rarely polyuria, begin between3 and 20 days a�er ingestion. Patients who ingest A. smithiana tend to develop GI symptoms earlier, with arange of symptom onset between 30 minutes and 12 hours (median, 5 to 6 hours). Orellanine ingestion tendsto present with GI symptoms later, with a range of 12 hours to 14 days a�er ingestion. Similarly, renal failureis noted to develop earlier in allenic norleucine cases (within 3 to 5 days) and occurs within 4 to 15 days of

orellanine ingestion.7 Orellanine poisoning can be confirmed by thin-layer chromatography of renal biopsyspecimens or by plasma assays for orellanine or orelline, but these tests are not commonly available in

clinical practice.5 Many patients who ingest these mushrooms never develop renal dysfunction, whichsuggests variability in host sensitivity to their toxic e�ects. Consider allenic norleucine or orellanine toxicityfrom wild mushroom ingestion in a patient with unexplained acute renal failure.

TREATMENT

There is no specific treatment for patients who develop renal failure from ingestion of Cortinarius or A.smithiana mushrooms. Monitor urine output and electrolyte, calcium, magnesium, BUN, and creatininelevels. Hemodialysis is indicated for refractory hyperkalemia, refractory acidosis, uremic symptoms, orsevere renal dysfunction. Supportive hemodialysis may be required, but many patients experience aspontaneous return of normal renal function. Because spontaneous improvement is reported, renaltransplantation should be withheld for several months to monitor patient response. Renal transplantation

has been used in several patients with good success.28

Monitor patients suspected of ingesting orellanine- or ortinarin-containing mushrooms for at least 72 hoursfor electrolyte abnormalities and renal failure.

DELAYED-ONSET DISULFIRAM REACTION

Perhaps most interesting, although clinically least important, is a mushroom toxin contained in the Coprinusgenus. This mushroom, which is very common in North America, is known as "inky cap" or "shaggy mane." Itis a tall, white, thin mushroom with a shaggy cap. As the mushroom ages, the cap liquefies and blackens, andblack liquid drips from the necrosing cap. The mushroom contains coprine, which is chemically related todisulfiram.

PATHOPHYSIOLOGY

Coprine causes inhibition of alcohol dehydrogenase within 2 hours of ingestion, and activity may last up to72 hours. If alcohol is consumed during this sensitive period, patients develop a typical disulfiram reaction.Mushrooms ingested at the same time as alcohol produce no toxicity.

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Because of the delay between mushroom consumption and alcohol consumption, few patients link theirsymptoms to the ingestion of a mushroom. Symptoms include headache, paresthesias of distal extremities,metallic taste, flushing, palpitations, chest pain, nausea, vomiting, and diaphoresis and generally occurwithin minutes to several hours a�er alcohol consumption. Symptoms generally last for 2 to 4 hours but may

last up to 2 days.5 Most symptoms are mild. Diagnosis is made based on presence of the symptom complexand its association with alcohol consumption.

Because alcohol is readily absorbed from the GI tract, GI decontamination has no role and charcoaladministration is not beneficial. Patients occasionally become hypotensive and respond to administration ofIV fluids or, in refractory cases, norepinephrine. Excessive sympathetic activity can be inhibited by β-

blockers.5

Most cases are self-limited, and patients can be discharged once they can tolerate oral fluids. Prior todischarge, educate patients about the link between alcohol consumption and mushroom ingestion.

SHIITAKE DERMATITIS

Shiitake dermatitis is a well-known entity in Japan, China, and Korea, and cases have been reported in

Europe and the United States.29,30 Shiitake dermatitis is a characteristic flagellate erythema appearing aswhip-like, linear wheals that appear within 1 or 2 days of ingesting raw or cooked shiitake mushrooms. Therash tends to be pruritic and can also involve branching patches of erythema and scattered petechiae. Thepathophysiology is not fully understood but is thought to be toxin-induced, involving the thermolabile

polysaccharide lentinan that is found in the shiitake mushroom. Skin biopsy results are nonspecific.29,30

Allergy testing in a�ected individuals is negative.30

Treat symptoms with 0.1% triamcinolone ointment twice daily and oral antihistamines. Regardless of

treatment, the rash resolves spontaneously without hyperpigmentation in 1 to 4 weeks.29,30

The rash is self-limited, and no sequelae have been reported.

SPECIAL POPULATIONS

Toxic mushroom exposure during pregnancy has been reported.28 In one series, a slightly lower birth weightwas noted in infants born to mothers with toxic mushroom exposure than in infants of mothers with no suchexposure. Most infants appeared to be healthy and developmentally normal, in keeping with the findings

that amatoxins do not cross the placental barrier.31,32

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USEFUL WEB RESOURCES

http://www.mushroomexpert.com/ (MushroomExpert.Com [Web site run by Michael Kuo, PhD, an amateurmycologist, with extensive information on and photographs of mushroom species for aid in identification])

http://www.fda.gov/Food/FoodborneIllnessContaminants/CausesOfIllnessBadBugBook/default.htm(Mushroom Toxins, U.S. Food and Drug Administration, Center for Food Safety and Applied Nutrition [sectionof the Bad Bug Book containing information on mushroom toxins])

http://www.namyco.org/ (North American Mycology Association [information on toxicology, photographs ofmushrooms, and information on how to report a case to the national mushroom poisoning registry])

RogersMushrooms: Web site based on Roger Phillips's publications on mushrooms, with information onspecies identification, extensive photographs of mushrooms, and even a global chat room—http://www.rogersmushrooms.com/ (RogersMushrooms [Web site based on Roger Phillips's publications onmushrooms, with information on species identification, extensive photographs of mushrooms, and even aglobal chat room])

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