Brandon K. Wills and Steven E. Aks
Serious poisoning from mushroom ingestion is relatively infrequent. Exposures most often involve (1) unintentional ingestion of toxic species obtained by inexperienced foragers, (2) individuals seeking mind-altering effects of some species, or (3) unintentional ingestion by children. Differentiating poisonous from nonpoisonous species can be difficult even for experts and often requires microscopic examination of the spores. For the clinician, evaluating a patient for suspected poisoning, identifying the fungus in question is even more challenging.
In 2011, there were 6,818 exposures to mushrooms reported to US poison centers, which included 5,560 cases of unknown species (1). There were two deaths, both from cyclopeptide species. There are several hundred toxic mushroom species, and these can be categorized into a syndromic presentation based on their mycotoxin (see Table 354.1).
TABLE 354.1
Presenting Symptoms/Signs, and Treatment by Mushroom Species
The most deadly class is the cyclopeptide-containing, or amatoxin-containing, Amanita species. Cyclopeptide poisoning is a rare event in the United States, but exposures are much more common in Europe. Amatoxins are classically found in Amanita phalloides and A. virosa species but are also found in Galerina autumnalis, G. venenata, Lepiota sp, and Conocybe filaris. Amatoxins are bicyclic octapeptides that noncompetitively inhibit RNA polymerase II in the liver and, to a lesser extent, the kidney. Protein synthesis is interrupted, causing hepatocellular necrosis and acute tubular necrosis. Severe poisoning can result in fulminant hepatic and renal failure. Phallotoxins are another cyclopeptide toxin found in Amanita sp, which are thought to produce the gastrointestinal (GI) symptoms seen 6 to 10 hours after ingestion.
Mushrooms containing coprine include members of the Coprinus sp, including C. atramentarius. Metabolites of coprine can inhibit aldehyde dehydrogenase and result in a disulfiram-like reaction if ethanol is consumed concurrently or within 3 days of the meal (see Chapter 297).
There is a diverse group of mushrooms whose toxins are irritants that cause primarily GI symptoms. Nausea, vomiting, diarrhea, and abdominal pain usually occur within 2 to 3 hours of the meal, and because the course is generally self-limited, identification of the specific species is unimportant.
Amanita muscaria, A. pantherine, and A. gemmata contain the toxins ibotenic acid and muscimol. Ibotenic acid is similar to the excitatory neurotransmitter glutamate and is an agonist at the N-methyl-D-aspartate (NMDA) receptor, whereas muscimol is a γ-aminobutyric acid (GABA) agonist. Symptoms can be diverse and may include somnolence, hallucinations, myoclonus, and seizures. Patients may seek to consume A. muscaria and A. pantherinespecies intentionally for their hallucinogenic effects.
Gyromitra esculenta or “false morel” and other species represent one-third of fatal mushroom poisonings in Eastern Europe; however, they are quite rare in the United States. These mushrooms contain gyromitrins, a family of hydrazones that are metabolized to monomethylhydrazine, which is structurally related to isoniazid and some types of rocket fuel. Hydrazines inhibit pyridoxine phosphokinase, which prevents the activation of pyridoxine (vitamin B6). Activated B6 is required for GABA synthesis, resulting in decreased GABA production. Poisoning results in delayed GI symptoms and hepatic and renal toxicity, and like isoniazid, often include seizures (see Chapter 317).
Muscarine is an alkaloid found in both Clitocybe and Inocybe genera that is structurally similar to acetylcholine. Symptoms are typically less severe than, yet similar to, the peripheral muscarinic effects seen in organophosphate/carbamate insecticide exposures (see Chapter 318).
Species of Cortinarius contain the toxin orellanine, whose metabolites cause damage to renal tubules and result in interstitial nephritis and renal failure several days to weeks after ingestion. The majority of these cases have been in Europe.
A. smithiana mushrooms contain alienic norleucine and pentanoic acid, which can cause renal failure several days after ingestion. Unlike Cortinarius, these mushrooms may cause GI effects as early as 2 hours of ingestion.
Psilocybe species, as well as Concocybe smithii, Gymnopilus spectabilis, and Panaeolus subbalteathus, are all known to contain psilocybin. Ingestion of this class of mushroom is often intentional for its hallucinogenic effects. Psilocin is a serotonin agonist that often causes an initial sympathomimetic-like effect including tachycardia, hypertension, mydriasis, and tremor, followed by hallucinations.
Rhabdomyolysis has been attributed to a myotoxin found in Tricholoma equestre mushrooms.
CLINICAL PRESENTATION
Patients often present within several hours of a mushroom meal with nonspecific GI symptoms including nausea, vomiting, and diarrhea. Fortunately, the majority of these patients are suffering from GI irritants and require only supportive care. Patients who have consumed the more toxic mushrooms containing cyclopeptides, orellanine, or monomethylhydrazine generally have a delay of more than 6 hours before the onset of symptoms. A short time to symptom onset gives the clinician some reassurance that patients presenting early are likely to have a benign clinical course. A notable exception is with A. smithiana ingestion; patients ingesting this mushroom are likely to have GI symptoms within hours of ingestion but subsequently develop renal failure over the next 48 hours to several weeks. Fortunately, A. smithiana ingestions are rare, and the only cases reported in the United States have been in the Pacific Northwest. Another caveat applies to those who have consumed a “mushroom salad” that contained several species including both cytotoxic and GI irritant species and thus present with symptoms earlier than 6 hours.
Each class of toxic mushroom has a distinctive constellation of presenting symptoms, signs, laboratory abnormalities, and end-organ involvement (Table 354.1). Patients who have ingested cyclopeptide- or amatoxin-containing mushrooms will typically present after more than 6 hours of ingestion with nausea, vomiting, abdominal pain, and severe watery diarrhea. Symptoms may improve 24 to 48 hours into the illness, followed by hepatic injury marked by elevated transaminases, bilirubin, and often renal dysfunction (2). Within 2 to 6 days, fulminant hepatic and renal failure may develop, with subsequent hepatic encephalopathy, coagulopathy, seizures, and death. With intensive supportive therapy, survival may be as high as 90% (3); however, with fulminant hepatic failure, orthotopic liver transplant may be required (4).
Mushrooms containing coprine are typically edible and cause no symptoms. If ethanol is consumed between several hours to 3 days after the ingestion, however, a disulfiram-like reaction may be seen. Symptoms include nausea, vomiting, facial flushing, hypotension, tachycardia, headache, vertigo, and metallic taste. Symptoms typically last up to several hours.
Mushrooms containing GI irritants cause symptoms similar to gastroenteritis, usually beginning 30 minutes to 6 hours after ingestion. Vomiting and diarrhea, sometimes bloody, may last for 48 hours and are typically self-limited.
Patients consuming mushrooms containing ibotenic acid and muscimol can have a varied presentation as a result of both GABAergic and glutamate effects. Symptoms usually begin within 30 to 180 minutes of ingestion and may include a combination of euphoria, mild hallucinations, obtundation, agitation, myoclonus, and seizures.
The “false morel” G. esculenta is often confused with the edible true morel or Morchella species and results in significant toxicity. The severity of symptoms depends on the amount ingested and method of preparation. Parboiling or drying may eliminate the gyromitrin toxins. Patients often become symptomatic 5 to 8 hours after ingestion and present with nausea, vomiting, and diarrhea. These symptoms may last up to several days before resolving. Central nervous system (CNS) effects, including fatigue, headache, ataxia, tremor, and (rarely) seizures, may be seen. After 24 to 72 hours, there may be evidence of hepatic and/or renal damage, as well as hemolysis and methemoglobinemia.
The onset of symptoms following ingestion of muscarine-containing mushrooms is rapid, usually within 30 minutes. Cholinergic signs and symptoms include those identified by the commonly used mnemonic DUMBELS: diaphoresis, urination, miosis, bronchorrhea/bradycardia, emesis, lacrimation, and salivation. With supportive treatment, patients typically recover with no long-term effects.
Rhabdomyolysis with myalgias, weakness, and fatigue begins 24 to 74 hours after ingesting T. equestre mushrooms. Symptoms usually improve over the following 2 weeks, but death can occur. Fatal cases have had persistent creatine kinase (CK) elevations and evidence of myocardial damage on autopsy.
Toxicity from orellanine-containing Cortinarius sp is most often seen in Europe and is relatively uncommon in the United States. GI symptoms, including nausea, vomiting, diarrhea, and abdominal or flank pain, begin 2 to 14 days after ingestion, at which time renal damage has already occurred. Progression to end-stage renal failure may ensue.
Similar to poisoning by Cortinarius sp, the ingestion of alienic norleucine–containing A. smithiana produces renal damage 2 to 4 days after ingestion. One distinguishing feature is that A. smithiana may cause early GI symptoms.
Abuse of psilocin-containing mushrooms is common among young adults, frequently in combination with alcohol and other drugs. Patients often present to the emergency department with severe anxiety from the unpleasant hallucinations. Other signs and symptoms may include mydriasis, tachycardia, GI symptoms, coma, and seizures. As with other hallucinogens, an increased association with high-risk behavior and poor decision-making often leads to other traumatic injuries (see Chapter 346, “Hauucinogens”).
DIFFERENTIAL DIAGNOSIS
Toxic mushroom ingestion should be considered in the differential diagnosis of patients presenting with GI symptoms, hepatic or renal damage, delirium or hallucinations, disulfiram-like reactions, seizures, or rhabdomyolysis. The GI symptoms from both GI irritant and the more toxic mushrooms will often be indistinguishable from gastroenteritis. The history of recent wild mushroom ingestion may be the only clue to the diagnosis.
Hepatotoxicity similar to that caused by Amanita ingestion can occur with overdose of acetaminophen and iron, chronic isoniazid (INH) therapy, and many nontoxicologic etiologies, including viral hepatitis. In addition to coprine-containing mushrooms, a large number of chemicals and pharmaceuticals can cause a disulfiram-like reaction when ethanol is consumed (see Chapter 297). Other hallucinogens, CNS depressants, γ-hydroxybutyrate (GHB), or withdrawal syndromes may cause symptoms similar to those seen after the ingestion of mushrooms containing ibotenic acid and muscimol. Agents causing toxicity similar to hydrazine-containing mushrooms include isoniazid and some types of rocket fuel. Direct muscarinic agonists or acetylcholinesterase inhibitors produce cholinergic toxicity similar to that seen with muscarine-containing mushrooms. The differential diagnosis of renal failure includes prerenal causes, intrinsic nephrotoxins, and postrenal causes. Conditions that may be confused with psilocin intoxication include use of LSD, mescaline, morning glory, hallucinogenic amphetamines (e.g., methylenedioxymethamphetamine [MDMA]), synthetic cathinones, tryptamines (e.g., dimethyltryptamine [DMT]); alcohol withdrawal; or medical causes of delirium.
ED EVALUATION
The goal of evaluation is to identify patients who may have ingested a cyclopeptide, amatoxin, or other potentially dangerous mushroom. Of greatest importance is the time interval between ingestion of the mushroom and the onset of GI symptoms. Other information that may be helpful include the quantity consumed, cooked versus raw, fresh versus dried, and if ethanol was consumed within 3 days of the meal. Positive identification of the mushroom involved will be very difficult but may be possible if the patient brings a sample of the offending mushroom. The Illinois Poison Center can consult a mycologist to review digital images of the mushroom in three planes that the physician has sent electronically to the poison center (5). The mushroom does not have to be positively identified if the most toxic species can be ruled out. Contacting a regional poison center (800-222-1222) can be helpful in this regard.
Patients with prolonged GI symptoms or clinical evidence of dehydration should have measurement of serum electrolyte, blood urea nitrogen (BUN), creatinine, and glucose as well as a urinalysis. Evaluation of patients presenting with weakness or myalgias should include a serum creatine phosphokinase (CK). Those with possible amatoxin poisoning should have liver function tests, chemistries, and coagulation studies. A serum creatinine >1.2 mg/dL with an international normalized ratio (INR) >2.5 may predict mortality (6). Except for muscarine, which can be identified by thin-layer chromatography, other mushroom toxins are not easily detected by routine toxicology screening. Thus, the best strategy is to have the mushroom in question identified by a mycologist.
KEY TESTING
• Mushroom identification if possible
• For dehydrated patients: serum electrolytes, BUN, creatinine, urinalysis
• For patients with weakness or myalgias: CK
• For suspected cyclopeptide exposure: transaminases, INR
ED MANAGEMENT
Supportive care is the mainstay of management for any toxic mushroom ingestion. Most patients will need no treatment other than intravenous (IV) fluids if dehydrated and antiemetics. Benzodiazepines should be administered for seizures, severe agitation, or hallucinations. Activated charcoal should be considered for patients presenting within 1 to 2 hours of ingestion.
There is no clear antidote for amatoxin-containing mushrooms though many therapies are empirically used (7). Multiple-dose activated charcoal has been recommended because amatoxins are enterohepatically recirculated. Charcoal hemoperfusion may also enhance toxin elimination if performed in the first 24 hours. High-dose IV penicillin (1 million units per kilogram per day for the first day, followed by 0.5 million units per kilogram per day for 2 more days) appears to have variable efficacy. The mechanism is postulated to prevent or reduce hepatic uptake of amatoxins. Silibinin is thought to reduce hepatic uptake and interrupt enterohepatic circulation of amatoxins (8). Intravenous silibinin can be obtained in North America by calling the Madaus-sponsored hotline at (866) 520-4412. N-Acetylcysteine (NAC), traditionally used for the treatment of acetaminophen poisoning, may also be effective for nonspecific causes of hepatic injury. One comparative animal model demonstrated no benefit from NAC, penicillin, cimetidine, thioctic acid, or silymarin (9). When fulminant hepatic failure occurs, orthotopic liver transplantation is the only successful therapy (4,6).
Patients with coprine-containing mushroom ingestion should be counseled to avoid alcohol. Antihistamines may provide symptomatic relief.
Monomethylhydrazine-containing mushrooms (Gyromitra spp) may cause seizures. If benzodiazepine therapy is not immediately successful, the patient should be given IV vitamin B6 (10). Gyromitrin causes an inhibition of glutamic acid decarboyxylase, similar to isoniazid, and B6 is effective in this setting. Suggested doses are 1 g for children and 5 g for adults.
Muscarine-containing mushrooms (e.g., Clitocybe sp) will generally respond well to supportive care alone. Atropine may be used for severe cholinergic symptoms. Atropine dosing should be continued until reversal of pulmonary symptoms of bronchorrhea and bronchospasm.
Patients with hallucinations should be placed in a quiet, low-stimulus environment, if possible. Haloperidol or droperidol and lorazepam or another benzodiazepine can be used for severe agitation and hallucinations.
The treatment of rhabdomyolysis includes maintenance of urine output by infusion of IV fluids, consideration of urinary alkalinization, and possibly dialysis.
CRITICAL INTERVENTIONS
• Determine the time of onset of symptoms with respect to the time of ingestion.
• Consult a regional poison center, toxicologist, or mycologist to assist with mushroom identification and management.
• Administer IV fluids and antiemetics to patients with GI symptoms and dehydration.
• Admit patients with symptoms that begin 6 to 8 hours after ingestion and monitor for liver and renal dysfunction.
DISPOSITION
Patients who present with GI symptoms that begin within 2 hours after ingestion, have not had a mixed mushroom ingestion, and have low likelihood of A. smithiana ingestion may be considered for discharge after favorable response to IV fluids and oral challenge. Patients who have ingested hallucinogenic mushrooms may be safely discharged when their mental status returns to normal. Those who develop GI symptoms 6 to 8 hours after ingestion or whose ingestion is identified as a possible cyclopeptide-containing species should be admitted to the hospital, and liver and renal function should be followed. In the case of delayed presentation with hepatotoxicity from A. phalloides or other cyclopeptide-containing mushroom, consultation with a gastroenterologist and transfer to a transplant center is prudent.
Common Pitfalls
• Failure to include wild mushroom ingestion in the differential diagnosis of gastroenteritis, altered mental status, and liver or renal dysfunction of unknown cause.
• Assuming that a potentially lethal mushroom has not been ingested along with less toxic species because symptoms began soon after ingestion.
• Failure to appreciate that therapy is based primarily on clinical symptoms and should not be delayed or withheld until the mushroom is identified.
REFERENCES
1. Bronstein AC, Spyker DA, Cantilena LR, et al. 2011 annual report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 29th annual report. Clin Toxicol (Phila).2012;50(10):911–1164.
2. Diaz JH. Syndromic diagnosis and management of confirmed mushroom poisoning. Crit Care Med. 2005;33(2):427–436.
3. Enjalbert F, Rapior S, Nouguier-Soule J, et al. Treatment of amatoxin poisoning: 20-year retrospective analysis. J Toxicol Clin Toxicol. 2002;40(6):715–757.
4. Broussard CN, Aggarwal A, Lacey SR, et al. Mushroom poisoning—From diarrhea to liver transplantation. Am J Gastroenterol. 2001;96(11):3195–3198.
5. Fischbein CB, Mueller GM, Leacock PR, et al. Digital imaging: A promising tool for mushroom identification. Acad Emerg Med. 2003;10(7):808–811.
6. Ganzert M, Felgenhauer N, Zilker T. Indication of liver transplantation following amatoxin intoxication. J Hepatol. 2005;42(2):202–209.
7. Ward J, Kapadia K, Brush E, et al. Amatoxin poisoning: Case reports and review of current therapies. J Emerg Med. 2013;44(1):116–121.
8. Mengs U, Pohl R, Mitchell T. Legalon SIL: The antidote of choice in patients with acute hepatotoxicity from amatoxin poisoning. Curr Pharm Biotechnol. 2012;13(10):1964–1970.
9. Tong TC, Hernandez M, Richardson WH, 3rd, et al. Comparative treatment of alpha-amanitin poisoning with N-acetylcysteine, benzylpenicillin, cimetidine, thioctic acid, and silybin in a murine model. Ann Emerg Med.2007;50(3):282–288.
10. Levine M, Ruha AM, Graeme K, et al. Toxicology in the ICU: Part 3: Natural toxins. Chest. 2011;140(5):1357–1370.