This chapter does not address molds, mildews, and yeasts, which in addition to mushrooms are all categorized as fungi. The unifying principle for fungi is the lack of the photosynthetic capacity to produce nutrition. Survival is achieved by the enyzymatic capacity of these organisms to integrate into living materials and digest them. Molds are ubiquitous and often associated with varied adverse health effects such as rhinitis, rashes, headaches, and asthma.21 Trichothecenes are mold-related mycotoxins that are discussed in Chap. 133 as potential biological weapons. All other molds are not associated with toxicologic emergencies concerns and are not addressed in this chapter.
Because mushroom species vary widely with regard to the xenobiotics they contain, and because identifying them with certainty is difficult, a clinical system of classification is more useful than a taxonomic system (Table 120–1). The text and tables that follow utilize the commonest species associated with a particular syndrome or xenobiotic and are not meant to be inclusive of all the exceptionally diverse mushrooms associated with many xenobiotics. In many instances the taxonomy has changed, confusing readers and investigators. For example, the text will use the current nomenclature, whereas the citations will obviously utilize prior nomenclature. In many cases, management and prognosis can be determined with a high degree of confidence from the history and the geographic origin of the mushroom, the initial signs and symptoms, the organ system or systems involved, and coexistent factors or conditions.31,58,75,76,104
TABLE 120–1.Mushroom Toxicity Overview |Favorite Table|Download (.pdf) TABLE 120–1. Mushroom Toxicity Overview
|Representative Genus/Species ||Xenobiotic ||Time of Onset of Symptoms ||Primary Site of Toxicity ||Symptoms ||Mortality ||Specific Therapya |
|I || || || || || || |
Amanita phalloides, A. tenuifolia, A. virosa
Galerina autumnalis, G. marginata, G. venenata
Lepiota josserandi,L. helveola
|5–24 hours ||Liver || |
Phase I: GI toxicity—N/V/D
Phase II: Quiescent
Phase III: N/V/D, jaundice, ↑ AST, ↑ ALT
|0%–30% || |
|II || || || || || || |
|Gyromitra ambigua,G. esculenta, G. infula ||Gyromitrin (metabolite: monomethylhydrazine) ||5–10 hours ||CNS ||Seizures, abdominal pain, N/V, weakness, hepatorenal failure ||Rare ||Benzodiazepines, Pyridoxine 70 mg/kg IV |
|III || || || || || || |
|Clitocybe dealbata, Omphalotus olearius, most Inocybe spp ||Muscarine ||0.5–2 hours ||Autonomic nervous system ||Muscarinic effects—salivation, bradycardia, lacrimation, urination, defecation, diaphoresis ||Rare ||Atropine–Adults: 1–2 mg Children: 0.02 mg/kg with a minimum of 0.1 mg |
|IV || || || || || || |
|Coprinopsis atramentaria ||Coprine (metabolite: 1-aminocyclopropanol) ||0.5–2 hours ||Aldehyde dehydrogenase ||Disulfiramlike effect with ethanol, tachycardia, N/V ||Rare ||Symptomatic care |
|V || || || || || || |
|Amanita gemmata,A. muscaria, A. pantherina ||Ibotenic acid, muscimol ||0.5–2 hours ||CNS ||GABAergic effects, rare delirium, hallucinations, dizziness, ataxia ||Rare ||Benzodiazepines during excitatory phase |
|VI || || || || || || |
|Psilocybe cyanescens,P. cubensis ||Psilocybin, psilocin ||0.5–1 hours ||CNS ||Ataxia, N/V, hyperkinesis, hallucinations, illusions ||Rare ||Benzodiazepines |
|Gymnopilus spectabilis || || || || || || |
|Psathyrella foenisecii || || || || || || |
|VII || || || || || || |
|Clitocybe nebularis ||Various ||0.3–3 hours ||GI ||Malaise, N/V/D ||Rare ||Symptomatic care |
|Chlorophyllum molybdites, C. esculentum ||Gl irritants || || || || || |
|Lactarius spp, Paxillus involutus || || || || || || |
|VIII || || || || || || |
|Cortinarius orellanus, C. rubellus ||Orelline, orellanine ||>1 day–weeks ||Renal ||Phase I: N/VPhase II: Oliguria, kidney failure ||Rare ||Hemodialysis for acute kidney injury |
|IX || || || || || || |
|Amanita smithiana |
|Allenic norleucine ||0.5–12 hours ||Renal ||Phase I: N/VPhase II: Oliguria, kidney failure ||None ||Hemodialysis for acute kidney injury |
|X || || || || || || |
|Tricholoma equestre ||Unidentified ||24–72 hours ||Muscle (skeletal and cardiac) ||Fatigue, nausea, muscle weakness, myalgias, ↑ CK, facial erythema, diaphoresis, myocarditis ||25% ||Sodium bicarbonate, hemodialysis for acute kidney injury |
|XI || || || || || || |
|Clitocybe acromelalga,C. amoenolens ||Acromelic acids ||24 hours ||Peripheral nervous system ||Erythromelalgia paresthesias—hands and feet, dysesthesias, erythema, edema ||None ||Symptomatic care |
|XII || || || || || || |
|Pleurocybella porrigens ||Unknown ||1–31 days ||CNS ||Encephalopathy, convulsions, myoclonus in patients with chronic kidney failure ||High (30%) ||Hemodialysis |
|Hapalopilus rutilans ||Polyporic acid ||>12 hours ||GI, CNS ||N/V, abdominal pain, vertigo, ataxia, drowsiness, encephalopathy ||None ||Symptomatic care |
|XIII || || || || || || |
|Paxillus involutus,? Clitocybe claviceps,? Boletus luridus ||Immune mediated response to involutin ||Following repeated exposure 0.5–3 hours ||Red blood cell, kidney ||Hemolytic anemia, acute kidney injury ||Rare ||Hemodialysis |
|XIV || || || || || || |
|Lycoperdon perlatum, L. pyriforine L. gemmatum ||Spores ||Hours ||Pulmonary, GI ||Cough, shortness of breath, fever, nausea, vomiting ||None ||Corticosteroids |
Group I: Cyclopeptide Containing Mushrooms
Worldwide most mushroom fatalities are associated with cyclopeptide-containing species.5,32,138 In the United States, there are two distinct ranges of the fungus Amanita species along the West Coast (California to British Columbia) and along the East Coast (Maryland to Maine).136 These cyclopeptide-containing species mushrooms include a number of Amanita species, including A. verna, A. virosa, and A. phalloides; Galerina spp, including G. autumnalis, G. marginata, and G. venenata; and Lepiota species, including L. helveola, L. josserandi, and L. brunneoincarnata (Fig. 120–1).
Amanita virosa. (Used with permission of John Plischke III.)
Early differentiation of cyclopeptide poisonings from other types of mushroom poisoning is difficult (Fig. 120–2). Patients poisoned with cyclopeptides may be ill enough to seek health care for nausea, vomiting, abdominal pain, and diarrhea, which in the absence of a rigorous detailed history often is attributed to other causes as the patient improves with supportive care. Such patients may be sent home, only to return moribund on a subsequent day. The delayed onset of more serious symptoms is typical of cyclopeptide toxicity and is a critical consideration in assessing the toxicologic potential of any exposure.
In the more highly specialized and evolved mushrooms, various protective tissues cover the fruit body and its constituent parts during its development. In the mushroom shown, an Amanita species, two veils of tissue are involved—one an outer enclosing bag, the universal veil, which ruptures as the fruit body expands to leave a volva at the base and fragments on the cap; the other an inner partial veil covering the developing gills that is pulled away as the cap opens to leave a ring on the stem. (Redrawn, with permission, from Kibby G: Mushrooms and Toadstools, A Field Guide: Oxford: Oxford University Press, 1979, p. 14.)
A. phalloides contains 15 to 20 cyclopeptides, each with an approximate weight of 900 Da. The amatoxins (cyclic octapeptides), phallotoxins (cyclic heptapeptides), and virotoxins (cyclic heptapeptides) are the best studied.37,71,131 There is no evidence for the toxicity of virotoxins in humans. Of these three chemically similar cyclopeptide molecules, phalloidin (theprincipal phallotoxin) appears to be a rapid-acting toxin, whereas amanitin tends to cause more delayed manifestations.108 Phalloidin crosses the sinusoidal plasma membranes of hepatocytes by a carrier-mediated process. This process is shared by bile salts and can be prevented in the presence of extracellular bile salts, suggesting competitive inhibition. A sodium-independent bile salt transporting system may be responsible forphalloidin hepatic uptake, elimination, and detoxification.85 Phalloidin interrupts actin polymerization and impairs cell membrane function, but becauseof its limited oral absorption it appears to have minimal toxicity, restricted mostly to GI dysfunction.
The amatoxins are the most toxic of the cyclopeptides, leading to hepatic, renal, and central nervous system (CNS) damage. These polypeptides are heat stable.34 α-Amanitin is the principal amatoxin responsible for human toxicity following ingestion. Approximately 1.5 to 2.5 mg amanitin can be obtained from 1 g of dry A. phalloides, and as much as 3.5 mg/g can be obtained from some Lepiota spp.92,96,131 A 20-g mushroom contains well in excess of the 0.1 mg/kg amanitin considered lethal for humans.33 α-Amanitin and β-amanitin have comparable toxicity in animal models.36
The amanitins are poorly but rapidly absorbed from the GI tract.63 Amatoxins show limited protein binding and are present in the plasma at low concentrations for 24 to 48 hours.63 α-Amanitin hepatocellular entry appears to be facilitated by a sodium-dependent bile acid transporter. Several studies demonstrate that the sodium taurocholate cotransporter polypeptide, a member of the organic anion–transporter polypeptide OAT polypeptide family localized in the sinusoidal membranes of human hepatocytes, facilitates hepatocellular α-amanitin uptake.57,78 Once inside the cells the cytotoxicity amanitin results from its interference with RNA polymerase II,preventing the transcription of DNA.81,114 α-Amanitin may be enterohepatically recirculated. Target organs are those with the highest rate of cell turnover, including the GI tract epithelium, hepatocytes, and kidneys. Amatoxins do not appear to cross the placenta, as demonstrated by the absence of fetal toxicity in severely poisoned pregnant women.7,14,118
In an intravenous radiolabeled amatoxin study in dogs, 85% of the amatoxin was recovered in the urine within the first 6 hours, whereas less than 1% was found in the blood at that time.38 Amatoxins can be detected by high-performance liquid chromatography,63 thin-layer chromatography, ion trap mass spectrometry,42 and radioimmunoassay in gastroduodenal fluid, serum, urine, stool, and liver and kidney biopsies for several days following an ingestion.36,37,70
Some of the toxicokinetic analyses following unquantified ingestions demonstrate 12 to 23 μg amatoxin excretion in the urine over 24 to 66 hours, of which 60% to 80% occurred during the first 2 hours of collection. The extreme variabilities of the type and quantity of ingestant, the host, and the management make interpretations exceedingly difficult.125 In another series, total maximal urinary α- and β-amanitin excreted over 6 to 72 hours were 3.19 and 5.21 mg, respectively. Two-thirds of the patients had total amanitin excretion greater than 1.5 mg.63 Urinary amanitin excretion concentrations differ by several orders of magnitude. Whether the variation results from exposure dose, time following ingestion, or laboratory technique is unclear. Several techniques for quantitative and qualitative evaluation of urinary amanitin are under investigation.17,18,96,118
Phase I of cyclopeptide poisoning resembles severe gastroenteritis, with profuse watery diarrhea not occurring until 5 to 24 hours after ingestion. Some consider the early onset (less than 8 hours) of diarrhea as a predictive factor for hepatic failure and the need for liver transplantation,34 whereas this is not supported by most other case series reviewed. It is typically considered that the onset of symptoms before 5 hours is strong support for another non-Amanita species cause for the gastrointestinal distress. Supportive fluid and electrolyte replacement leads to transient improvement during phase II, which occurs between 12 and 36 hours after ingestion.96,138 However, despite such supportive care, phase III, manifested by hepatic and renal toxicity and death, may ensue 2 to 6 days after ingestion.5 Pancreatic toxicity may rarely occur.48 The initial hepatotoxicity begins within the second phase, but clinical hepatotoxicity (Chap. 23) with elevated concentrations of bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT), hypoglycemia, jaundice, and hepatic coma are not manifest until 2 to 3 days after ingestion. Pathologic manifestations include steatosis, central zonal necrosis, and centrilobular hemorrhage, with viable hepatocytes remaining at the rims of the larger triads. Lobular architecture remains intact (Fig. 23–3).5
Cyclopeptide toxicity alters the hormones that regulate glucose, calcium, and thyroid homeostasis, resulting in widespread endocrine abnormalities.68 Insulin and C-peptide concentrations are elevated at a stage of poisoning prior to hepatic and renal compromise.29,68 These findings are suggestive of direct toxicity to pancreatic β cells, resulting in release of preformed hormone or induction of hormone synthesis. This insulin release necessitates vigilance for hypoglycemia prior to hepatocellular damage. Serum calcitonin concentrations may be elevated, and hypocalcemia may be present. Thyroxine concentrations may be depressed and triiodothyronine concentrations undetectable, whereas thyroid-stimulating hormone concentrations may not be elevated. These thyroid-related findings were reported in a single study and merit further investigation.68
In a series of 10 patients exposed to diverse Lepiota spp, 50% developed a mixed sensory and motor polyneuropathy. Most of the patients spontaneously recovered within one year, although a single patient developed progressive clinical and electromyographic deterioration.98 These neuropathic findings have not been recognized in other case reports.
The search for treatments has been vigorously pursued in Europe because of the persistently large number of amatoxin victims each year.47 Survival rates in case series of variable numbers of patients poisoned by A. phalloides who received supportive care, fluid and electrolyte repletion, high-dose penicillin G, dexamethasone, or thioctic acid are between 70% and 100%.47,56,62,88,90,100,138 Many of these case series have excellent survival rates with extremely variable therapeutic interventions, limiting the capacity to determine the need for or efficacy of most of the standard conservative therapeutic regimens.
Fluid and electrolyte repletion and treatment of hepatic compromise are essential. Intravenous 0.9% sodium chloride solution and electrolytes usually are necessary because of substantial fluid loss due to vomiting and diarrhea. Dextrose repletion may be necessary because of nutritional compromise, hepatic failure, or glycogen depletion. Activated charcoal both adsorbs the amanitins and improves survival in laboratory animals.36 Emesis, lavage, and catharsis are not necessary unless the patient presents within several hours after the ingestion because any substantial quantity of ingested toxin almost invariably induces emesis and catharsis. In an analysis11 of the AAPCC Toxic Exposure Surveillance System (TESS) database of unintentional mushroom exposures in children from 1992 to 2005 it is suggested that a syrup of ipecac treated subgroup compared to an activated charcoal or no intervention group showed the smallest percentage of moderate or major outcomes. Activated charcoal is safe, logical, and a valuable therapeutic strategy. Although the clinical presentation often is delayed, 1 g/kg body weight of activated charcoal should be given orally every 2 to 4 hours (if the patient is not vomiting) or by continuous nasogastric infusion. Continuous nasogastric duodenal aspiration is used by multiple groups (mainly European) to remove amatoxins secreted in the bile; others use an even more difficult biliary drainage approach to disrupt the enterohepatobiliary recirculation of the amatoxin.84 Although there is theoretical support for early quantitative toxin removal due to substantial biliary concentration, the total quantity and actual gastroduodenal concentration remains low, offering inadequate clinical data to support gastroduodenal or biliary drainage.64
Thioctic (α-lipoic) acid initially was reported to be beneficial in treating the amatoxin-induced liver toxicity in several different animal models, and a number of uncontrolled clinical trials in humans followed.5 Because of its potential effects as a coenzyme in the tricarboxylic acid cycle or as a free radical scavenger, thioctic acid was credited for the survival of 39 of 40 patients reportedly, but not definitively, poisoned by A. phalloides.73 Hypoglycemia is a common feature of thioctic acid therapy for Amanita poisoning, but whether hypoglycemia results from direct toxicity of the drug or is secondary to hepatic damage is unclear. Despite the initial success, thioctic acid was not effective in various other studies and is no longer recommended.45,46
Several laboratory investigations in mice and rats suggest that 1 g/kg penicillin G (l g = 1,600,000 Units) may have a time- and dose-dependent protective effect.49,50 These results are limited because the amatoxins were administered intraperitoneally, resulting in the death of untreated animals 12 to 24 hours later. Additional investigations demonstrated that 1 g/kg penicillin G administered 5 hours after sublethal doses of α-amanitin decreased clinical and laboratory toxicity.49 The mechanisms suggested include displacing α-amanitin from albumin, blocking its uptake from hepatocytes, binding circulating amatoxins, and preventing α-amanitin binding to RNA polymerase. None of these mechanisms is substantiated,32 and we no longer recommend penicillin G be used unless it is used very shortly after an ingestion as a temporizing gesture.
The active complex of milk thistle (Silybum marianum) is silymarin, which is a lipophilic extract composed of three isomeric flavonolignans: silibinin, silychristin, and silydianin. Silibinin represents approximately 50% of the extract, but represents about 70% to 80% of the marketed products.61 Silibinin, a mixture of Silibinin A and B, competitively inhibits the organic anion transporter (OATP1B3) that is responsible for the uptake and enterohepatic recycling of α-amanitin. Use of silibinin 50 mg/kg in dogs 5 and 24 hours following exposure to α-amanitin suppressed chemical evidence of hepatotoxicity and lethality. These same studies suggest silibinin diminishes α-amanitin enterohepatic circulation. Although silibinin is routinely available as a nonprescription supplement in most pharmacies and appears to be safe and well tolerated in patients with chronic liver disease, no reduction in mortality, improvement in histology at liver biopsy, or biochemical marker has been identified in a systematic review and meta-analysis.61 A dose of silibinin 20 to 50 mg/kg/d should be used in humans, even though it is not approved as a therapeutic for hepatic disease by the Food and Drug Administration (FDA) in the United States.70,129 Currently there is an amatoxin poisoning clinical trial utilizing Legalon SIL (Silibinin) at 20 mg/kg/day IV60 (Antidotes in Depth: A36).
Because of its hepatoprotective effects, N-acetylcysteine should be given as an antidote, but no evidence for any specific benefit has been demonstrated. When fulminant hepatic failure is present, N-acetylcysteine should be administered until the patient recovers from the encephalopathy because of its presumptive benefits under these circumstances (Antidotes in Depth: A3).
In animals, cimetidine (a potent CYP2C9/2D6 inhibitor) may have a hepatoprotective effect against α-amanitin,106 but it shows no protective effect against phalloidin toxicity.108 Cimetidine is proposed as a therapeutic intervention,107 but no available human data support its use, and it is not currently recommended.
A recent randomized murine model of intraperitoneal α-amanitin poisoning comparing treatment with rescue postexposure N-acetylcysteine, benzylpenicillin, cimetidine, thioctic acid, or silybin was unable to show any laboratory benefit with regard to hepatotoxic manifestations such as aminotransferase concentrations or histologic evidence of hepatonecrosis.119
Forced diuresis, hemodialysis, plasmapheresis,64,65 hemofiltration, and hemoperfusion40 may be effective shortly after ingestion, but most studies offer neither clinical evidence of benefit nor supportive pharmacokinetic data for any of these therapies.70,95,96,110,125,128 Most studies suggest that no circulating amatoxins are present by the time the need for transplantation is evident.30 “Shortly after” is not defined, although these techniques are indicated within 24 hours of a documented ingestion.41 Plasmapheresis, which is dependent on effective clearance, high plasma protein binding, and a low volume of distribution, does not remove more than 10 μg of amatoxin. Because of the absence of prospective, controlled studies of exposure to amatoxins, in addition to the extreme variability of success with many regimens, multiple-dose activated charcoal, and supportive care remain the standard therapy. Early recognition of exposure to amanitin is an indication for hemodialysis or hemoperfusion, but most patients likely will no longer have the potential for benefit at the time they develop clinical manifestations of toxicity.65 Future therapeutic interventions may be dependent on improved understanding of the hepatocellular bile acid transporter, which is a member of the OAT polypeptide family.57,74,78
Extracorporal albumin dialysis,39 molecular adsorbent recirculating system (MARS),26,84,113,135 and fractionated plasma separation and adsorption system (FPSA; Prometheus system),35,124,126 are variant detoxification techniques used in patients with fulminant hepatic failure to remove water-soluble and albumin-bound xenobiotics while providing renal support. The typical delayed time to onset of use of MARS and other extracorporeal liver assist devices in amanitin poisoning invariably limits the potential effects of these systems not to toxin removal but to correction or stabilization of hepatic dysfunction. None of the available studies of these bridging systems are randomized or controlled. The clinical experience is solely in the care of patients with grave hepatotoxicity at a delayed stage limiting any potential for significant conclusions. These two techniques permit time for hepatic regeneration or sufficient bridging time to orthotopic liver transplantation. The criteria and timing for liver transplantation following amatoxin poisoning are far less established than for fulminant viral hepatitis, where grade III or IV hepatic encephalopathy, marked hyperbilirubinemia, and azotemia are the well-established criteria for transplantation (Chap. 23).94 Successful transplantations were performed in individuals whose resected livers showed 0% to 30% hepatocyte viability. In these cases, the authors did not wait for progression past grade II encephalopathy or for development of azotemia or marked hyperbilirubinemia.94 Criteria for patient selection are essential to avoid unnecessary risk while offering the potential for survival to appropriate candidates who have no functional liver. The grim prognosis associated with hepatic coma secondary to Amanita poisoning has led several transplant groups to consider hepatic transplantation for encephalopathic patients with prolonged international normalized ratios (INRs; greater than 6), persistent hypoglycemia, metabolic acidosis, increased concentrations of serum ammonia and AST, and hypofibrinogenemia.34,53,54,69,94 There are now case reports of successful liver transplantation for fulminant63,67,94 hepatic failure from presumed A. ocreata,69,137 A. phalloides, A. virosa,16 Lepiota helveola,86 and L. brunneoincarnata poisoning.98
To enhance the likelihood of success, individuals who manifest symptoms suggestive of hepatotoxic Amanita, Galerina, or Lepiota spp exposure should be told of the potential need for transplantation and, with their consent, be rapidly transferred to a regional liver transplantation center.16,34,94
Group II: Gyromitrin Containing Mushrooms
Members of the gyromitrin group include Gyromitra esculenta, Gyromitra ambigua, and Gyromitra infula. G. esculenta enjoys a reputation of being edible in the Western United States but of being toxic in other areas. The most common error occurs in the spring, when an individual seeking the nongilled, brainlike Morchella esculenta (morel) finds the similar G. esculenta (false morel) (Fig. 120–3).
Group II: Gyromitrin containing mushrooms. A true morel (Morchella spp) on the left is compared to a false morel (Gyromitra esculenta) on the right. (Used with permission of John Trestrail.)
These mushrooms are found commonly in the spring under conifers and are easily recognized by their brainlike appearance. Poisonings with these mushrooms are exceptionally uncommon in the United States, representing less than 1% of all recognized events, whereas these poisonings are considered more common in Europe. Certain cooking methods may destroy the toxin, but because of the potential for toxicity, all members of this mushroom family should be avoided.
Gyromitra mushrooms contain the nonvolatile insoluble gyromitrin which on hydrolysis yields a family of N-methyl-N-formyl hydrazones, which on subsequent hydrolysis split into aldehydes and N-methyl-N-formyl hydrazine.3 Subsequent hydrolysis of N-methyl-N-formyl hydrazine yields monomethylhydrazine (Fig. 120–4). The hydrazine moiety reacts with pyridoxine, resulting in inhibition of pyridoxal phosphate-related enzymatic reactions (Figs. 58–2 and 58–3). This interference with pyridoxal phosphate disrupts the function of the inhibitory neurotransmitter γ-aminobutyric acid (GABA).75 This decrease in GABA is thought to contribute to the diverse neurological manifestations typically associated with this ingestion.
Gyromitra mushrooms contain gyromitrin which undergoes hydrolysis to yield a family of N-methyl-formyl hydrazines. These molecules on subsequent hydrolysis yield N-methyl-N-formyl hydrazine and monomethylhydrazine.
The initial signs of toxicity for these mushrooms occur 5 to 10 hours after ingestion and include nausea, vomiting, diarrhea, and abdominal pain.Patients manifest headaches, weakness, and diffuse muscle cramping. Rarelyin the first 12 to 48 hours, patients develop delirium, stupor, convulsions, and coma. Most patients improve dramatically and return to normal function within several days. Infrequently, patients develop a hepatorenal syndrome and require extensive in-hospital care.
Activated charcoal 1 g/kg body weight should be given. Benzodiazepines are appropriate for initial management of seizures. Under most circumstances, supportive care is adequate treatment. Pyridoxine in doses of 70 mg/kg IV up to 5 g may be useful in limiting seizures (Antidotes in Depth: A14).
There are no rapid diagnostic strategies in the laboratory, although thin-layer chromatography, gas-liquid chromatography, and mass spectrometry can be used for subsequent identification of the various hydrazine and hydrazone metabolites.
Group III: Muscarine Containing Mushrooms
Mushrooms that contain muscarine include numerous members of the Clitocybe species, such as C. dealbata (the sweater) and C. illudens (Omphalotus olearius) (Fig. 120–5A and 5B), and the Inocybe species, which includeI. iacera, I. lanuginosa, and I. geophylla. A. muscaria and A. pantherina contain limited quantities of muscarine, although A. muscaria contains substantial amounts of muscimol.
Omphalotus olearius. (Used with permission of John Plischke III.)
Clinical manifestations, which typically are mild, usually develop within 0.25 to 2 hours, typically last several additional hours with complete resolution within 24 hours. Muscarine and acetylcholine are similar structurally and have comparable clinical effects at the muscarinic receptors. Peripheral manifestations typically include bradycardia, miosis, salivation, lacrimation, vomiting, diarrhea, bronchospasm, bronchorrhea, and micturition. Central muscarinic manifestations do not occur because muscarine, a quaternary ammonium compound, does not cross the blood–brain barrier. No nicotinic manifestations such as diaphoresis or tremor occur. The effects of muscarine often last longer than those of acetylcholine. Because muscarine lacks an ester bond, it is not hydrolysed by acetylcholinesterase.
Significant toxicity is uncommon, limiting the need for more than supportive care. Rarely, atropine (1–2 mg given IV slowly for adults or 0.02 mg/kg with a minimum of 0.1 mg IV for children) can be titrated and repeated as frequently as indicated to reverse symptomatology.
No current, clinically available, analytic techniques can identify muscarine, although high-performance liquid chromatography would be appropriate for investigative purposes.
Group IV: Coprine Containing Mushrooms
Coprinus mushrooms, particularly C. atramentarius, (Coprinopsis atramentaria) contain the xenobiotic coprine (Fig. 120–6A). These mushrooms grow abundantly in temperate climates in grassy or woodland fields. They are known as “inky caps” because the gills that contain a peptidase autodigest into an inky liquid shortly after picking. The edible member of this group, Coprinus comatus (shaggy mane) (Figs. 120–6B and 6C) is nontoxic, and probably its misidentification results in collectors’ errors. Coprine, an amino acid, its primary metabolite, 1-aminocyclopropanol,20,83,120 or, more likely, a secondary in vivo hydrolytic metabolite, cyclopropanone hydrate, has a disulfiramlike effect (Fig. 120–7, see Chap. 79).134 Although both of these metabolites appear to inhibit aldehyde dehydrogenase, the most stable in vivo inhibitory effect is manifested by cyclopropane hydrate.134 Inhibition of acetaldehyde dehydrogenase results in accumulation of acetaldehyde and its accompanying adverse effects, which takes at least 0.5 to 2 hours if the patient ingests alcohol and a coprine containing mushroom concomitantly. For the subsequent 48 to 72 hours following coprine-containing mushroom ingestion if ethanol ingestion occurs toxicity may ensue. Within 0.5 to 2 hours of ethanol ingestion, an acute disulfiram effect is noted, with tachycardia, flushing, nausea, and vomiting. The simultaneous ingestion of the mushroom and alcohol does not result in immediate clinical manifestations because inhibition of aldehyde dehydrogenase occurs following coprine metabolism and the in vivo production of cyclopropane hydrate. Treatment is symptomatic with fluid repletion and antiemetics such as metoclopramide or ondansetron, although clinical manifestations usually are mild and resolve within several hours. Prophylactic use of fomepizole immediately following ingestion of ethanol and coprine-containing mushrooms has a theoretical basis, but no case reports or studies are published. This group of mushrooms rarely causes fatalities.
Group IV: Coprine containing mushrooms. (A) Coprinopsis atramentaria; (B) and (C) show Coprinus comatus (shaggy mane). Image (B) shows an early form which later is self digested demonstrating the gill liquefaction in image (C). (Image A Used with permission of John Plischke III, and images B and C used with permission of Lewis Nelson.)
The Coprinus mushrooms contain coprine, an amino acid which is rapidly hydrolysed to 1-aminocyclopropanol and subsequently cyclopropane hydrate. It is this last metabolite which most likely has the disulfiramlike effect.
Group V: Ibotenic Acid andMuscimol Containing Mushrooms
Most of the mushrooms in this class are primarily in the Amanita species, which includes A. muscaria (fly agaric), A. pantherina, and A. gemmata (Fig. 120–8). They exist singly and are scattered throughout the US woodlands. The brilliant red or tan cap (pileus) is that of the mushroom commonly depicted in children’s books and is easily recognized in the fields during summer and fall.
Group V: Muscimol containing mushrooms. This image of Amanita muscaria highlights different developmental forms and colors. (Used with permission of John Plischke III.)
Small variable quantities of the isoxazole derivatives ibotenic acid and muscimol are found in these mushrooms, which have been used in religious customs throughout history. Ibotenic acid is structurally similar to the stimulatory neurotransmitter glutamic acid. The stereochemistry of muscimol is very similar to that of the neurotransmitter GABA and may act as a GABA agonist.
Most patients who develop symptoms intentionally ingested large quantities of these mushrooms while seeking a hallucinatory experience. Within 0.5 to 2 hours of ingestion, these mushrooms produce the GABAergicmanifestations of somnolence, dizziness, hallucinations, dysphoria, and delirium in adults, and the excitatory glutamatergic manifestations of myoclonic movements, seizures, and other neurologic findings predominate in children.8
Treatment is invariably supportive. Most symptoms respond solely to supportive care, although a benzodiazepine is appropriate for excitatory CNS manifestations.
Group VI: Psilocybin Containing Mushrooms
Psilocybin-containing mushrooms include Psilocybe cyanescens, Psilocybe cubensis, Conocybe cyanopus, Panaeolus cyanescens, Gymnopilus spectabilis, and Psathyrella foenisecii (Fig. 120–9). These mushrooms have been used for native North and South American religious experiences for thousands of years. They grow abundantly in warm, moist areas of the United States. Drug culture magazines and Internet sources advertise mail-order kits containing P. cubensis spores to grow “magic mushrooms” domestically.
Group VI: Psilocybin containing mushrooms. Three examples of hallucinogenic mushrooms: (A) Psilocybe cyanescens, (B) Psilocybe caerulipes, and (C) Gymnopilus spectabilis. (Used with permission of John Plischke III.)
Toxicity from this group is common because of the popularity of hallucinogens.12 Psilocybin is rapidly and completely hydrolyzed to psilocin in vivo. Serotonin, psilocin, and psilocybin are very similar structurally and presumably act at a similar 5-HT2 receptor site. The effects of psilocybin as a serotonin agonist and antagonist are discussed in Chaps. 14 and 82.
The psilocybin and psilocin indoles, like those of lysergic acid diethylamide (LSD), rapidly (within one hour of ingestion) produce CNS effects, including ataxia, hyperkinesis, visual illusions, and hallucinations. Some patients manifest gastrointestinal distress, tachycardia, mydriasis, anxiety, lightheadedness, tremor, and agitation. Most manifestations are recognized within 4 hours of ingestion with a return to normalcy within 6 to 12 hours.59 Rare cases of renal failure,51,97 seizures, and cardiopulmonary arrest12 are associated with psilocybin-containing species. However, such associations should always be questioned when reported in a substance-using individual potentially simultaneously exposed to other xenobiotics.
A single patient who intravenously administered an extract of Psilocybe mushrooms experienced chills, weakness, dyspnea, headache, severe myalgias, vomiting associated with hyperthermia, hypoxemia, and mild methemoglobinemia.27
Treatment for hallucinations usually is supportive, although a benzodiazepine may be necessary when reassurance proves inadequate.
Group VII: Gastrointestinal Toxin Containing Mushrooms
By far the largest group of mushrooms is a diverse group that contains a variety of ill-defined GI toxins. Many of the hundreds of mushrooms in this group fall into the “little brown mushroom” category. Some Boletus spp, Lactarius spp, O. olearius, Rhodophyllus spp, Tricholoma spp, Chlorophyllum molybdites, and Chlorophyllum esculentum are mistaken for edible or hallucinogenic species. A frequently reported error4,52,123 is the confusion of the jack-o’-lantern (Omphalotus illudens) with the edible species of chanterelle (Cantharellus cibarius).
The toxins associated with this group are not identified. The malabsorption of proteins and sugars, such as trehalose, and the ingestion of a mushroom infected or partially digested by microorganisms or allergy may be responsible for symptoms. GI toxicity occurs 0.3 to 4 hours after ingestion when epigastric distress, malaise, nausea, vomiting, and diarrhea are evident. Treatment includes fluid resuscitation with control of vomiting and diarrhea. The clinical course is brief and the prognosis excellent. Those mushroom ingestions resulting in gastrointestinal toxicity more than 4 hours after ingestion are considered in Table 120–2. When symptoms seem to persist, the clinician must consider a mixed ingestion of another potentially toxic mushroom group.
TABLE 120–2.Mushroom Toxicity: Correlation between Organ System Affected, Time of Onset of Symptoms, and Mushroom Constituent Responsible |Favorite Table|Download (.pdf) TABLE 120–2. Mushroom Toxicity: Correlation between Organ System Affected, Time of Onset of Symptoms, and Mushroom Constituent Responsible
|Time of Onset |
|Organ System ||Early: <5 hours ||Middle: 5–24 hours ||Late: >24 hours |
|Gastrointestinal ||Allenic norleucine ||Allenic norleucine ||Orellinine and orellanine |
| ||Coprine ||Amatoxin || |
| ||Gastrointestinal toxins ||Gyromitrin || |
| ||Muscarine || || |
|Hepatic || || ||Amatoxin |
|Immunologic ||Involutin || || |
| ||Spores || || |
|Neurologic ||Ibotenic acid and muscimol ||Gyromitrin ||Acromelic acid |
| ||Psilocybin || || |
|Renal || || || |
Orellinine and orellanine
Rarely, clinical presentations are life threatening, with hypovolemic shock necessitating fluids and vasopressors.115 Resolution of symptoms usually occurs within 6 to 24 hours. The clinical courses associated with specific mushroom ingestions are variable.8 Death is rare.
Group VIII: Orellanine and Orellinine Containing Mushrooms
Cortinarius mushrooms, such as C. rubellus (Fig. 120–10) and C. orellanus, are commonly found throughout North American and Europe.19,66,109 The C. orellanus toxin orellanine is reduced by photochemical degradation to orellinine a bipyridyl molecule that is further reduced to the nontoxic orelline.2,91,101 The toxic compound orellanine is a hydroxylated bipyridine compound activated by its metabolism through the cytochrome P450 system. Toxicologically, these molecules are similar to paraquat and diquat and may have comparable mechanisms of action, although precise knowledge is limited (Chap. 112). Other nephrotoxins, such as cortinarines, are isolated from certain Cortinarius spp107 and result in tubular damage, interstitial nephritis, and tubulointerstitial fibrosis.
Group VIII Orellanine and Orellinine containing mushrooms: Cortinarius rubellus. (Used with permission of Astrid Holmgren, Swedish Poisons Information Centre.)
Orellanine is rapidly removed from the plasma within 48 to 72 hours and concentrated in the urine in a soluble form. It can be detected in the plasma at the time of clinical symptoms by some investigators99 but not by other investigators.102 Thin-layer chromatography on renal biopsy material can detect orellanine long after clinical exposure.99,102
Initial symptoms occur 24 to 36 hours after ingestion and include headache, chills, polydipsia, anorexia, nausea, vomiting, and flank and abdominal pain. The largest case review demonstrated that numerous patients repetitively ingested the Cortinarius spp prior to diagnosis.28 Oliguric renal failure may develop several days to weeks after initial symptoms.13 The only initial laboratory abnormalities may be hematuria, leukocyturia, and proteinuria. Nephrotoxicity is characterized by interstitial nephritis with tubular damage and early fibrosis of injured tubules with relative glomerular sparing.19,109 Hepatotoxicity is rarely reported.13 Hemoperfusion, hemodialysis, and renal transplantation are used for the treatment of renal failure.13,28 No evidence suggests that secondary detoxification by plasmapheresis or hemoperfusion is of any benefit in preventing chronic renal failure even when initiated in the first 48 hours.28,70,99 The data are inadequate to define management or prognosis precisely, as many patients improve rapidly, while some require temporary intermittent hemodialysis and others require chronic therapy for persistent renal failure.13 No laboratory or clinical parameters predicting the individual reactions to the toxins are available. Although case reports in the literature commonly lack definitive proof of ingestion or confirmation of toxin presence, the more rapid the onset of GI and renal manifestations, the greater the risk of both acute and chronic renal failure.28
Group IX: Allenic Norleucine Containing Mushrooms
Amanita smithiana poisoning is reported in the Pacific Northwest (Fig. 120–11).77,122,127,130 Because the mature specimen often lacks any evidence of a partial or universal veil, these mushrooms are not recognized as Amanita species. It appears that all of the poisoned individuals were seeking the edible pine mushroom matsutake (Tricholoma magnivelare), a highly desirable look-alike. The A. smithiana, A. proxima, A. abrupta and A. pseudoporphyria, and A. abrupta possess two amino acid toxins: allenic norleucine (amino-hexadienoic acid) and possibly 1,2-amino-4-pentynoic acid.23,93,139 A similar case report following the ingestion of A. proxima in Southern France resulted in gastrointestinal and renal manifestations.25 In vitro renal epithelial tissue cultured with allenic norleucine developed necrotic morphologic changes similar to those that occur following A. smithiana ingestion.93 In mice the extract of A. abrupta is hepatotoxic, which suggests that hepatotoxins and nephrotoxins are present in this species.139
Group IX Allenic norleucine containing mushrooms: (A) Amanita smithiana compared to (B) Tricholoma magnivelare (matsutake, the mushroom with which it has been mistaken). (Used with permission of John Plischke III.)
Initial symptoms were noted from 0.5 to 12 hours following ingestion of either raw or cooked specimens. GI manifestations, including anorexia, nausea, vomiting, abdominal pain, and diarrhea, occurred frequently, accompanied by malaise, sweating, and dizziness. In some cases, vomiting and diarrhea persist for several days. The patients typically presented for care 3 to 6 days after ingestion, at which time they were oliguric or anuric. Acute kidney injury manifested 4 to 6 days following ingestion with marked elevation of BUN and creatinine. Lactate dehydrogenase and ALT concentrations frequently were elevated, whereas amylase, AST, alkaline phosphatase, and bilirubin were only infrequently abnormal.
Risk of toxicity was greatest in older patients and in patients with underlying renal insufficiency. Patients who required hemodialysis underwent the procedure two to three times per week for approximately one month until recovery. None of the patients in the three series died.
There is no known antidote for these nephrotoxins. Activated charcoal, although of no proven benefit, should be used in standard doses when a patient in the Northwest United States presents with early GI manifestations after mushroom ingestions. The clinician will be forced to consider the circumstances of ingestion to assess the probability of A. smithiana ingestion as opposed to ingestion of mushrooms containing a GI toxin.
In view of the substantial morbidity associated with A. smithiana ingestions, historic, clinical, and/or temporal evidence of this ingestion should lead to charcoal hemoperfusion or hemodialysis as a strong consideration when the patient presents in the early phase of exposure. When a patient presents with renal compromise several days, as opposed to weeks, following mushroom ingestion and with a history of early, as opposed to delayed, GI manifestations, the clinician may be able to suggest A. smithiana as the etiology compared to Cortinarius spp exposure.
Group X: Rhabdomyolysis Associated Mushrooms
There are several reports of Tricholoma equestre (Tricholoma flavovirens) ingestions in Poland and France, where although this mushroom is considered “edible choice,” it has resulted in significant myotoxicity.24,89 In the first report 12 patients who ingested T. equestre mushrooms for 3 consecutive days developed severe rhabdomyolysis that was lethal in three cases.6 All patients developed fatigue, muscle weakness, and myalgias 24 to 72 hours following the last mushroom meal. The individuals also developed facial erythema, nausea without vomiting, and profuse sweating. The mean maximal creatine phosphokinase (CK) was 226,067 U/L in women and 34,786 U/L in men, with some values greater than 500,000 U/L. Electromyography revealed muscle injury with evidence of myotoxic activity. The biopsies showed myofibrillar injury and edema consistent with an acute myopathy.
Dyspnea, muscle weakness, acute myocarditis, dysrhythmias, congestive heart failure, and death ensued in three patients. Autopsy demonstrated myocardial lesions identical to those found in the peripheral muscles. Although muscle toxicity was reproduced using T. equestre extracts in amouse model, the etiology of the toxicity is not defined.6 All the triterpenoids, sterols, indoles, and acetylenic compounds extracted from these mushrooms previously were assumed to be without toxicity. Currently all the clinical experience originates from Europe where these mushrooms are considered choice and eaten extensively; no cases are reported in the United States.
Group XI: Erythromelalgia Acromelic Acid Containing Mushrooms
A poorly defined syndrome originally recognized in Japan,87 recently in France9 following the ingestion of various Clitocybe species (C. acromelalga and C. amoenolens), and not recognized currently in the United States. The toxic substances acromelic acids A–E have been isolated. These molecules are similar to kainic acid and are of the pyrrolidine dicarboxylic acid family, which act as ionotropic glutamate receptors. The syndrome typically occurs more than 24 hours following ingestion. Patients typically develop paraesthesias of distal extremities followed by paroxysms of severe burning dysesthesias lasting several hours. The extremities show edema and erythema. These manifestations respond variably to symptomatic and supportive care and resolve completely within several months.
Group XII: Polyporic Acid and Other Mushroom Constituents Resulting in Encephalopathy
Two groupings of toxic mushroom ingestion syndromes result in encephalopathy. In the first group, Pleurocybella porrigens is commonly eaten in Japanese miso soup without any adverse effects. However, their ingestion by patients with chronic renal failure resulted in delayed manifestations of encephalopathy.55 Three-quarters (24 of 32) of the affected patients were undergoing hemodialysis at the time of the presumed poisoning. The delay from time of ingestion to the development of an altered consciousness, convulsions, myoclonus, dysarthria, dysesthesias, ataxia, respiratory failure, or death was between 1 and 31 days. No prior toxic link or known toxin in these commonly ingested mushrooms is recognized.
The second group of mushrooms associated with encephalopathy is the Hapalopilus rutilans reported in a German case series. More than 12 hours after ingestion an adult and two children developed nausea, vomiting, and abdominal pain; aminotransferase and creatine concentration elevations; and CNS abnormalities. Vertigo, ataxia, visual disturbances, and somnolence were reported.72,104 In each case the urine was a violet color, the color being noted when polyporic acid is placed in an alkaline solution. Polyporic acid, a dehydroquinone derivative (2,5-dihydroxy-3,6-diphenyl-1,4 benzoquinone), a constituent of these mushrooms, is a dehydroorotate dehydrogenase (an enzyme in the biosynthesis of pyrimidine) inhibitor that resulted in comparable clinical and biochemical manifestation when administered to rats.72 Symptomatic treatment is indicated with more specific therapy should hepatic or renal compromise be significant.
Group XIII: Immune Mediated Hemolytic Anemia
A small number of patients with ingestions of Paxillus involutus, and possibly Clitocybe claviceps and Boletus luridus, develop early onset mild GI symptoms followed by an immune-mediated hemolytic anemia, hemoglobinuria, oliguria, and renal failure. IgG antibodies to a Paxillus extract-containing involutin70 were detected by a hemagglutination test in these patients.132,133 This syndrome occurs in Europe, typically among those who have eaten P. involutus numerous times in the past.
Group XIV: Lycoperdonosis
Puffball mushrooms (Lycoperdon perlatum, Lycoperdon pyriforme, or Lycoperdon gemmatum) are edible in the fall and can (upon decay or drying) release large numbers of spores following compression, fracture, or shaking (Fig. 120–12). Lycoperdonosis is directly related to massive exposure to spores, although many consider the syndrome an allergic bronchoalveolitis. This syndrome occurs in patients following acute inhalation of spores as an alternative or complementary therapy for epistaxis117 and in adolescents for various experimental reasons.22 Massive inhalation, insufflation, and chewing of spores can lead to the development of nasopharyngitis, nausea, vomiting, and pneumonitis within hours. Over a period of several days, cough, shortness of breath, myalgias, fatigue, and fever develop. Rarely, patients require intubation because of pulmonary compromise associated with diffuse reticulonodular infiltrates.22 Lung biopsy demonstrates an inflammatory process with the presence of Lycoperdon spores.117 Patients treated with corticosteroids such as prednisone and antifungals such as amphotericin B recovered within several weeks without sequelae.
Puff balls: (A) Lycoperdon pyriforme and (B) Lycoperdon perlatum. (Used with permission of John Plischke III.)