eMedicine Specialties > Emergency Medicine > Toxicology

Toxicity, Mushroom - Amatoxin

Andrew K Chang, MD, Associate Professor, Department of Emergency Medicine, Albert Einstein College of Medicine, Montefiore Medical Center

Updated: Nov 9, 2009

Introduction

Background

Of more than 5000 species of mushrooms in the United States, approximately 100 are poisonous, and less than a dozen are deadly.

Most fatalities resulting from mushroom ingestion are associated with amatoxins within the mushrooms. Amatoxins (cyclic octapeptides) represent 1 of 3 major groups of cyclopeptides (in addition to phallotoxins and virotoxins) and are heat-stable, insoluble in water, and not destroyed by drying. At least 5 subtypes of amatoxins exist; alpha and beta amatoxins are the most significant subtypes.

Alpha amatoxin inactivates RNA polymerase II and inhibits protein synthesis, which ultimately leads to cell death. Amanita toxins are found in several Amanita species (A phalloides, A bisporigera, A hygroscopia, A ocreata, A suballiacea, A tenuifolia, A verna, A virosa) and some members of the genera Galerina (G autumnalis, G marginata, G venenata) and Lepiota (L brunneoincarnata, L chlorophyllum, L helveola, L josserandii). Even experienced mushroom pickers may mistake death cap (Amanita phalloides), which is generally considered the most toxic of the world's cyclopeptide-containing mushrooms, for one of its benign cousins.

Amanita phalloides.

Pathophysiology

Amatoxin poisoning can be divided into 3 stages.

• Amatoxin poisoning has a characteristic latent period of 6-12 hours postingestion before onset of clinical symptoms. After this asymptomatic period, abdominal cramping, vomiting, and profuse watery diarrhea (rice water, choleralike) occur. Fluid losses may be severe enough to cause profound dehydration and even circulatory collapse.
• Once this acute gastrointestinal phase is over (usually after 24 h), the second stage begins. Although the patient appears to have improved clinically, ongoing liver damage is occurring as indicated by laboratory abnormalities (elevation of serum aminotransferase levels, prothrombin time). This stage may last as long as 2-3 days.
• Hepatic and renal injury become clinically apparent and may progress to fulminant hepatic failure in the third phase. Death may occur in 3-7 days.

Frequency

United States

In 2007, 7351 single exposures to mushrooms were reported to the American Association of Poison Control Centers.¹

In 1996, 10,584 mushroom exposures were reported to the American Association of Poison Control Centers.² Eighty-eight percent of reported mushroom exposures were unidentified. Only 54 were identified as amatoxin exposures; however, this number is undoubtedly an underestimation given the number of unknown mushroom exposures.

One author estimates incidence of mushroom exposures at 5 exposures per 100,000 population per year.

International

No adequate database exists to estimate worldwide exposures.

• Mushroom foraging is more common in parts of Europe and Russia than in other parts of the world.
• From mid-July to September of 1998, 9 people died and 180 were poisoned from mushrooms in Russia.
• In July and August of 1997, 34 people died of mushroom poisoning across Russia.

Mortality/Morbidity

Ninety-five percent of all mushroom fatalities in North America are associated with cyclopeptide-containing species (amatoxins). Worldwide, most mushroom fatalities are ascribed to amatoxins. Amatoxins are associated with mortality rates ranging from 10-60%.

Ingestion of a single Amanita phalloides mushroom can be lethal.

No deaths due to mushroom exposures were reported in the 2007 American Association of Poison Control Centers National Poison Data System annual report.¹

Age

• Most unintentional mushroom exposures occur in children younger than 6 years.
• Mortality is higher in children because they absorb a larger dose of toxins per body weight.

Clinical

History

With amatoxin ingestion, onset of GI symptoms typically is delayed 6-12 hours or more. An earlier onset of symptoms suggests that another mushroom is responsible for symptomatology. However, if the patient's meal included several different mushrooms, an earlier onset of symptomatology does not rule out concomitant amatoxin ingestion.

• Presenting complaints include severe abdominal pain, cramping, nausea and vomiting, profuse diarrhea, and weakness.
• With delayed presentation, complaints may include symptoms attributable to hepatic dysfunction, such as jaundice, lethargy, or bruising.
• If a mushroom sample is available, place it in a dry paper bag (do not moisten or refrigerate).

Physical

Assessing the patient's volume status is an important component of the initial evaluation. With delayed presentations, look for signs of hepatic or CNS dysfunction.

• Vital signs
  • Tachycardia
  • Hypotension
• Skin
  • Poor turgor
  • Jaundice, bruising (with hepatic failure)
• Abdomen
  • Mild tenderness
  • Diarrhea, may have a positive result on a Hemoccult test (guaiac positive)
• Neurologic (if hepatic failure or hypoglycemia)
  • Confusion
  • Lethargy
  • Coma

Causes

• Unintentional childhood ingestions
• Misidentification of mushroom by forager
• Deliberate seeking of psychotropic mushrooms

Differential Diagnoses

Workup

Laboratory Studies

• Obtain liver function tests because hepatic damage is the main concern with amatoxin poisoning.
  • Prothrombin time (PT) (most reliable indicator for severity of poisoning)
  • Aminotransferase levels
  • Bilirubin level
  • Alkaline phosphatase level
• Complete blood count (CBC)
• Electrolytes, BUN, and creatinine levels (dehydration from vomiting and diarrhea)
• Glucose level (monitor very closely with hepatic failure)
• Urinalysis (hematuria and proteinuria signifying renal involvement)
• Amylase/lipase level (pancreatitis)
• Serum ammonia level in patients with evidence of hepatic encephalopathy
• Urinary amanitin analysis (a pilot study suggests high specificity and positive predictive value) is not clinically feasible in most cases.

Imaging Studies

• Abdominal radiographs may be obtained if bowel obstruction or ileus appears in the differential diagnosis. Mushrooms are not radiopaque and, therefore, will not be seen on abdominal radiographs.

Other Tests

• Melzer reagent in contact with amatoxin containing mushroom produces a dark blue color
• Meixner test also can be performed if a specimen of the ingested mushroom is available for analysis. However, false-negative and false-positive tests are raising the question of its reliability.
  • Place a drop of liquid expressed from the mushroom on lignin-containing paper (ie, paper derived from wood pulp, such as newspaper but not filter paper).
  • After the drop has dried, place a drop of 10-12 N HCl on the spot.
  • The appearance of a blue color within several minutes suggests the presence of amatoxins.
  • A delayed appearance of a blue color suggests that amatoxin is present but in lower concentrations.
  • Presence of psilocybin can lead to a false-positive result.
  • Gastric contents are not suitable for this test.
• An experienced mycologist may analyze and identify spores in gastric contents.

Treatment

Prehospital Care

Institute supportive measures if needed, such as intravenous access and oxygen.

Emergency Department Care

Aggressively treat a patient with suspected amatoxin ingestion because the mortality rate of ingested amatoxin is as high as 60%.

• Reduction of amatoxin absorption
  • Consider gastric lavage if the patient has not already vomited. In general, lavage should be attempted within 1 hour of ingestion. Given the delayed presentation of these intoxications, efficacy of this procedure is uncertain.
  • Administer activated charcoal. Amatoxins appear to undergo enterohepatic circulation and repeat dose activated charcoal may interrupt this cycle and reduce toxicity.
• The mainstays of treatment of amatoxin ingestion include aggressive intravenous fluids and electrolytes to correct and maintain adequate hydration. Serum electrolyte and glucose levels should be closely monitored.
• Several drugs have been postulated to reduce uptake of amatoxin into hepatocytes. Animal data support the use of some of these drugs, but only anecdotal support is available for humans.
  • The lowest mortality rate was reported in patients treated with N-acetylcysteine and silibinin (water-soluble milk thistle extract, not available in the United States) that were both administered as monotherapy.³
  • Poly-therapies with the lowest mortality rate included combination of high-dose penicillin G along with silibinin.³
  • It is interesting to note that an isolated administration of high-dose penicillin did not show improved survival.³
  • Vitamin K (if coagulopathy is present)
  • Cimetidine (unproven, but relatively benign treatment)

Consultations

• Consult a regional poison center or toxicologist for assistance in case management.
• Contacting a mycologist for possible mushroom identification may be helpful. Possible sources for mushroom identification include the following:
  • North American Mycological Association
  • Local botanical garden
  • Local mycology club
  • Regional poison control center
• Consult a gastroenterologist if hepatic dysfunction is present. If hepatic failure is present, medical personnel who work with a liver transplant program should be consulted to facilitate a preoperative evaluation should spontaneous recovery not occur.
• For fulminant hepatic failure, consult a liver transplant service.

Medication

Management of amatoxin poisoning is primarily supportive.

GI decontaminants

These agents bind toxin in the GI tract and limit systemic adsorption. Repeat doses may effectively interrupt enterohepatic circulation.

Activated charcoal (Liqui-Char)

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

Dosing

Adult

1 g/kg (30-100 g) PO; repeat 0.5-1 g/kg q2-4h

Pediatric

1-2 g/kg (15-30 g) PO; repeat 0.5-1 g/kg q2-4h

Interactions

May inactivate ipecac syrup if used concomitantly; effectiveness of other medications decreases with coadministration; do not mix charcoal with sherbet, milk, or ice cream (decreases adsorptive properties)

Contraindications

Documented hypersensitivity; poisoning or overdosage of mineral acids and alkalies; unprotected airway with absent gag reflex

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Not very effective in poisonings of ethanol, methanol, and iron salts; induce emesis before giving activated charcoal; after emesis with ipecac, patient may not tolerate activated charcoal for 1-2 h; can administer in early stages of gastric lavage; without sorbitol, gastric lavage returns are black; check for presence of bowel sounds before repeat administration to minimize risk of charcoal ileus

Pharmacologic antidotes - experimental

Medications documented in case reports and literature reviews without solid clinical evidence for use.

Penicillin G (Pfizerpen)

Use based on animal studies in mice, rats, and dogs. Somewhat protective against lethal doses of amatoxin.

Dosing

Adult

Up to 1 million U/kg/d IV

Pediatric

Infants (<30 lb): 600,000 U IV
Children (30-60 lb): 900,000-1.2 million U IV

Interactions

Probenecid can increase effects of penicillin; coadministration of tetracyclines can decrease effects of penicillin

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in impaired renal function

Silibinin (Milk thistle)

Thought to competitively antagonize toxin binding to liver cell membrane receptors in mushroom poisoning and other hepatotoxic exposure. Some recommend a water-soluble preparation of silymarin, which inhibits penetration of amatoxins into liver cells.

Dosing

Adult

20-50 mg/kg/d

Pediatric

Not established

Interactions

May decrease effectiveness of oral contraceptives

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

None reported

Antidote, Mushroom Induced Liver Toxicity

N-acetylcysteine

May provide substrate for conjugation with toxic metabolite.

Dosing

Adult

Loading dose: 150 mg/kg IV infused over 15 min (dilute in 200 mL D5W) (Some authors recommend administration of loading dose over 60 min in order to reduce chances for anaphylactoid reaction) follow with maintenance doses
First maintenance dose: 50 mg/kg IV infused over 4 h (dilute in 500 mL D5W), followed with second maintenance dose
Second maintenance dose: 100 mg/kg IV infused over 16 h (dilute in 1000 mL D5W).
For continuation of NAC administration, consult with poison control center or medical toxicologist

Pediatric

Administer as in adults except decrease total volume of D5W with each dose for pediatric patient
Contact poison control center and medical toxicologist for the recommendations prior administration of IV NAC to pediatric population

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

IV administration may cause anaphylactoid reaction, vasodilatation, rash, bronchospasm and angioedema. (discontinue/slower IV and administer antihistamine, epinephrine, then follow local anaphylaxis protocol if symptoms persist); IV administration may also cause acute flushing or erythema within 30-60 min after initiating infusion, which typically resolves spontaneously despite continued infusion; adjust total fluid volume for IV in patients <40 kg

Follow-up

Further Inpatient Care

• Admission criteria: Admit all patients with amatoxin poisoning for aggressive supportive care and monitoring of hepatic function.
• Administer multiple doses of activated charcoal every 2-4 hours if the patient is not vomiting and has a protected airway. Control nausea and vomiting with antiemetics, preferably ondansetron.
• Administer IV NAC and silibinin until hepatic injury resolves.
• A retrospective review of 105 patients with amatoxin poisoning from 1988-2002 in Italy showed that all patients treated within 36 hours after ingestion were cured without sequelae. Two patients died; both were admitted more than 60 hours after ingestion. Their treatment protocols included intensive fluid and supportive therapy, restitution of altered coagulation factors, multiple-dose activated charcoal, mannitol, dexamethasone, glutathione, and penicillin G.⁴
• Others have described additional treatments including extracorporeal liver assist device (ELAD), charcoal hemoperfusion, and plasma exchange.

Transfer

• Consider transfer of any patient with amatoxin poisoning to a facility with a medical toxicologist.
• Consider transfer of any patient with progressive hepatic dysfunction to a facility that has a liver transplant service.

Deterrence/Prevention

• No single test can be used to determine the edibility of wild mushrooms.
• Foragers should abide by the following: "No rule is the only rule."
• Immigrants, even if very experienced in their countries of origin, may not be able to distinguish poisonous mushrooms from edible mushrooms in the United States.

Complications

• Liver failure is the most serious complication of amatoxin ingestion.
• Hepatic coma and hypoglycemia can complicate liver failure.
• Progressive hepatic failure can lead to hepatorenal syndrome.
• A recent retrospective study concluded that the prothrombin index in combination with the serum creatinine level from day 3 to day 10 after ingestion may help predict those patients needing liver transplantation. In this study, an international normalized ratio (INR) of 2.5 or higher along with a serum creatinine level greater than 106 µmol/L was predictive of fatal outcome.⁵

Prognosis

• Mortality rates of 10-60% have been reported. With good supportive care, mortality rates are now lower than in the past.
• Liver transplant can save the life of a patient with the most severe amatoxin poisoning.

Patient Education

• For excellent patient education resources, visit eMedicine's Poisoning Center and Poisoning - First Aid and Emergency Center. Also, see eMedicine's patient education articles Poisoning and Activated Charcoal.

Miscellaneous

Medicolegal Pitfalls

• Failure to consider mushroom ingestion with acute gastroenteritis or signs of hepatic injury
• Failure to consider an amatoxin mushroom poisoning when a patient presents with symptoms early (meal may have included several different mushrooms)
• Failure to provide aggressive symptomatic therapy in addition to IV NAC and silibinin
• Failure to involve liver transplant team early in the course of disease
• Relying on Meixner test to rule out or rule in exposure to amatoxin containing mushrooms
• Failure to contact regional poison control center or medical toxicologist to assist you in the management of poisoned patient

Multimedia

Media file 1: Amanita phalloides.

References

1. Bronstein AC, Spyker DA, Cantilena LR Jr, Green JL, Rumack BH, Heard SE. 2007 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 25th Annual Report. Clin Toxicol (Phila). Dec 2008;46(10):927-1057. [Medline]. [Full Text].

2. Litovitz TL, Smilkstein M, Felberg L, Klein-Schwartz W, Berlin R, Morgan JL. 1996 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. Sep 1997;15(5):447-500. [Medline].

3. Enjalbert F, Rapior S, Nouguier-Soulé J, Guillon S, Amouroux N, Cabot C. Treatment of amatoxin poisoning: 20-year retrospective analysis. J Toxicol Clin Toxicol. 2002;40(6):715-57. [Medline].

4. Giannini L, Vannacci A, Missanelli A, Mastroianni R, Mannaioni PF, Moroni F. Amatoxin poisoning: a 15-year retrospective analysis and follow-up evaluation of 105 patients. Clin Toxicol (Phila). Jun-Aug 2007;45(5):539-42. [Medline].

5. Ganzert M, Felgenhauer N, Zilker T. Indication of liver transplantation following amatoxin intoxication. J Hepatol. Feb 2005;42(2):202-9. [Medline].

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7. Butera R, Locatelli C, Coccini T, Manzo L. Diagnostic accuracy of urinary amanitin in suspected mushroom poisoning: a pilot study. J Toxicol Clin Toxicol. 2004;42(6):901-12. [Medline].

8. Diaz JH. Syndromic diagnosis and management of confirmed mushroom poisonings. Crit Care Med. Feb 2005;33(2):427-36. [Medline].

9. Feinfeld DA, Mofenson HC, Caraccio T, Kee M. Poisoning by amatoxin-containing mushrooms in suburban New York--report of four cases. J Toxicol Clin Toxicol. 1994;32(6):715-21. [Medline].

10. Floersheim GL. Treatment of human amatoxin mushroom poisoning. Myths and advances in therapy. Med Toxicol. Jan-Feb 1987;2(1):1-9. [Medline].

11. Goldfrank LR. Mushrooms: toxic and hallucinogenic. In: Goldfrank's Toxicologic Emergencies. 5^th ed. Appleton & Lange; 1994:951-961.

12. Olesen LL. Amatoxin intoxication. Scand J Urol Nephrol. 1990;24(3):231-4. [Medline].

13. Paydas S, Kocak R, Erturk F, Erken E, Zaksu HS, Gurcay A. Poisoning due to amatoxin-containing Lepiota species. Br J Clin Pract. Nov 1990;44(11):450-3. [Medline].

14. Pond SM, Olson KR, Woo OF, et al. Amatoxin poisoning in northern California, 1982-1983. West J Med. Aug 1986;145(2):204-9. [Medline].

15. Warden CR, Benjamin DR. Acute renal failure associated with suspected Amanita smithiana mushroom ingestions: a case series. Acad Emerg Med. Aug 1998;5(8):808-12. [Medline].

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Keywords

amatoxin toxicity, death cap, mushroom ingestion, poisonous mushroom, mushroom toxicity, mushroom poisoning, amatoxin, toxin, cyclopeptide-containing species, amatoxin poisoning, mushroom exposure,

Contributor Information and Disclosures

Author

Andrew K Chang, MD, Associate Professor, Department of Emergency Medicine, Albert Einstein College of Medicine, Montefiore Medical Center
Andrew K Chang, MD is a member of the following medical societies: American Academy of Emergency Medicine, American Academy of Neurology, American College of Emergency Physicians, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Medical Editor

Jeffrey Glenn Bowman, MD, MS, Consulting Staff, Highfield MRI, Columbus, Ohio
Disclosure: Nothing to disclose.

Pharmacy Editor

John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart & St. Joseph's Hospitals
John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists
Disclosure: Nothing to disclose.

Managing Editor

Michael Hodgman, MD, Assistant Clinical Professor of Medicine, Department of Emergency Medicine, Bassett Healthcare
Michael Hodgman, MD is a member of the following medical societies: American College of Medical Toxicology, American College of Physicians, Medical Society of the State of New York, and Wilderness Medical Society
Disclosure: Nothing to disclose.

CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD, Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital
Disclosure: Nothing to disclose.

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