Poisonous Mushrooms · 2017-08-26 · Poisonous Mushrooms Gholamreza Karimia* and Bibi Marjan Razavib aMedical Toxicology Research Center and Pharmacy School, Mashhad University of

Poisonous Mushrooms

Gholamreza Karimia* and Bibi Marjan RazavibaMedical Toxicology Research Center and Pharmacy School, Mashhad University of Medical Sciences, Mashhad, IranbDepartment of Pharmacodynamy and Toxicology, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

Mushrooms are the sexual organs or fruiting bodies of fungi. Although some mushrooms areconsidered to be a rich source for nutrients and biologically active compounds, some species areknown because of their toxicity that may cause fatalities every year generally due to misidenti-fication. Among thousands of mushroom species, fewer than a hundred are toxic. Mushroompoisoning is associated with different signs and symptoms that are mainly attributed to some activesubstances belonging to poisonous mushrooms. Most mushroom toxins cause mild or moderatesigns and symptoms such as nausea, vomiting, abdominal pain, fever, and headache. However, somespecies result in severe poisoning. Renal failure, neurotoxicity, hepatotoxicity, rhabdomyolysis, andother toxic effects were identified in toxicity studies with various species.

The toxicity of mushroom is influenced by many factors including genus and species, geographiclocation, preparation prior to ingestion, and the human’s susceptibility. This chapter is aimed toaddress various types of mushroom toxins, thus providing some information about their toxicmechanisms, a brief description of the toxicokinetics (absorption, distribution, metabolism, excre-tion) of mushroom toxins, and management of mushroom poisonings.

Introduction

Mushrooms are large and highly diverse group of organisms called fungi which are similar in manyaspects to the plants. Among thousands of mushroom species in the world, fifty to a hundred areknown to be toxic (Brent and Palmer 2007). It is very difficult to verify exposure to mushroomtoxins, because clinical reports of mushroom poisoning are uncommon and there are manyunreported cases (Beuhler and Graeme 2005). Serious poisoning and lethality induced by somemushroom species along with the misidentification of toxic species have greatly raised fear inclinicians (Beuhler and Graeme 2005). Proper identification is very important to avoid accidentalmushroom poisoning. Diagnosis of toxic signs and symptoms provides the success of treatment.Recently, modern technology of intensive care medicine has reduced the mortality and morbidity ofmushroom toxicity (Table 1).

It is very important to consider the time period for exhibition of clinical presentations rather thanthe time of consumption in patients with suspected mushroom poisoning. Based on these findings,toxic mushrooms are generally classified as follows (Beuhler and Graeme 2005):

1. Mushrooms which exhibit symptoms within 4 h. Generally they do not induce serious toxicity.2. Mushrooms which show symptoms more than 6 h following ingestion. Typically these mush-

rooms induce life-threatening syndromes.

*Email: [email protected]

ToxinologyDOI 10.1007/978-94-007-6288-6_42-1# Springer Science+Business Media Dordrecht 2014

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Based on the mechanism of toxicity and clinical presentations, poisonous mushrooms can becategorized as follows.

Mushrooms-Induced Delayed Nephrotoxicity

Species of genus Cortinarius (including C. splendens, C. orellanus, C. gentilis, andC. speciosissimus) and Amanita smithiana cause delayed renal toxicity (Danel et al. 2001; Beuhlerand Graeme 2005) (Fig. 1).

Cortinarius spp.Cortinarius spp. poisoning is characterized by a delayed acute renal failure (Danel et al. 2001).

Table 1 Main toxins, clinical features, and treatments related to mushroom poisonings

Mushrooms Toxins Clinical presentations Treatments

Cortinarius spp., Amanita smithiana Orellanine,cortinarinsA and B, andaminohexadienoicacid

GI disturbances, chills,headache, myalgia,paresthesia, and renaldysfunction

Hemodialysis,hemoperfusion,plasmapheresis, andkidney transplantation

Clitocybe and Inocybe Muscarine Bradycardia, miosis,salivation, lacrimation,diarrhea and bronchospasm

Supportive,anticholinergic agentssuch as atropine in thepresence of severetoxicity

Coprinus atramentarius Coprine Flushing, headache, dyspnea,sweating, arrhythmia,hypotension, and confusion

Propranolol, fomepizole

Amanita gemmata, Amanitapantherina, Amanita muscaria

Ibotenic acid andmuscimol

Continues periods ofexcitation and inhibition in thenervous system

Supportive, sedative, andhypnotic agents

Gymnopilus spectabilis, Panaeolusfoenisecii, Conocybe cyanopus,Psilocybe caerulescens, Psilocybecubensis

Psilocybin andpsilocin

Euphoria, hallucinations,tachycardia and bloodpressure, mydriasis, tremors,and fever

Supportive, diazepam

Omphalotus olearius, Chlorophyllummolybdites

Gastroenteritis Supportive

Tricholoma equestre, Russulasubnigricans

Russuphelins GI disturbances, weakness,myalgia, rhabdomyolysis andrenal failure

Supportive

Amanita verna, Amanita virosa,Amanita phalloides, Lepiota helveola,Galerina marginata

Amanitin Initial phase: latency 2ndphase: GI disturbances 3rdphase: recovery 4th phase:liver and renal failure

Silibinin, PCN and NAC

Gyromitra esculenta Gyromitracalifornica

Gyromitrin GI irritations, neurotoxicity,liver/renal failures, andhemolysis

Methylene blue,pyridoxine, folinic acid,NAC, vitamin K

Supportive management includes gut decontamination, fluid therapy, cardiac monitoring, etc.NAC N-acetyl cysteine, PCN penicillin, GI gastrointestinal


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ToxicologyThe genus Cortinarius contains the cyclopeptide orellanine (Danel et al. 2001), which is a heat-stable bipyridine N-oxide (3, 30, 4, 40-tetrahydroxy-2, 2-bipyridine-N, N0-dioxide). Orellaninechemically resembles the pyridine herbicides paraquat and diquat. In vitro studies revealed thatorellanine produces oxygen-free radicals at the target site through redox cycling and/or redoxactivation of iron. Furthermore, it is indicated that a metabolite of the toxin can inhibit proteinsynthesis (Nilson et al. 2008).

In addition to orellanine, cortinarins A and B are cyclopeptides which may involve inCortinarius-induced renal toxicity (Beuhler and Graeme 2005).

Clinical PresentationsThe signs and symptoms of Cortinarius poisoning may appear between 2 and 14 days after theingestion of mushrooms (mean 6 days and maximum 17 days) (Beuhler and Graeme 2005). Thesigns and symptoms include nausea, vomiting, abdominal pain, intense thirst, chills, headache,myalgia, paresthesia, polyuria or oliguria, and possibly anuria. Hemodialysis may be necessary untilkidney function has returned (Michelot and Tebbett 1990; Tegzes and Puschner 2002; Beuhler andGraeme 2005; Brent and Palmer 2007).

Although it was shown that renal dysfunction may be improved several weeks followingpoisoning, chronic renal failure had been observed in nearly 30–46 % of population who werepoisoned by Cortinarius (Beuhler and Graeme 2005; Brent and Palmer 2007).

TreatmentBecause the onset of toxicity is delayed, patients usually do not present symptoms early afterthe ingestion. It is unlikely that gastric lavage with activated charcoal is helpful (Brent andPalmer 2007). Hemodialysis is indicated in cases of acute renal failure. There is currently no specifictreatment for such mushroom poisoning; however, hemoperfusion and plasmapheresis have beenrecommended (Beuhler and Graeme 2005). At the late stage of chronic renal failure, kidneytransplantations might be carried out (Michelot and Tebbett 1990; Danel et al. 2001).

Fig. 1 Cortinarius speciosissimus (http://en.wikipedia.org)


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http://en.wikipedia.org/

Amanita smithianaAmanita smithiana is a mushroom which is also found to induce delayed nephrotoxicity(Goldfrank 2009; Fig. 2).

ToxicologyIt is established that aminohexadienoic acid (allenic norleucine) present in Amanita smithiana isresponsible for toxicity. Mechanism of A. smithiana toxicity is similar to that of orellanine (Beuhlerand Graeme 2005; Goldfrank 2009).

Clinical PresentationsUsually the patients experience asymptomatic period which ranges from 30 min to 12 h (mean 6 h).The onset of symptoms is earlier than orellanine toxicity. Toxic ingestion causes a syndrome ofgastroenteritis including nausea, vomiting, abdominal pain, lethargy, headache, and myalgiafollowed by delayed onset renal failure within 1 week (2–5 days) with increase in BUN andcreatinine. ALT and LDH are found to be increased as well, which may be due to liver damage(Beuhler and Graeme 2005; Goldfrank 2009; Brent and Palmer 2007; West et al. 2009). However,the increase in amylase, ALP, and bilirubin is uncommon (Donnelly and Wax 2005).

TreatmentNo specific treatment has been reported. In most patients, renal failure would be recovered after4 weeks (80 %), but sometimes dialysis is recommended (Beuhler and Graeme 2005).

Mushroom-Induced Muscarinic Syndrome

Species of genus Clitocybe (including C. illudens and C. dealbata) and Inocybe (includingI. geophylla and I. iacera) cause muscarinic syndrome (Young 1994; Beuhler and Graeme 2005;

Fig. 2 Amanita smithiana (http://en.wikipedia.org)


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Goldfrank 2009; Fig. 3). Also, Rhodophyllus rhodopoliuswhich is found in Japan causes muscarinicsyndrome (Beuhler and Graeme 2005; Goldfrank 2009). The amount of muscarine in Amanitapantherina and Amanita muscaria is not sufficient to induce toxicity in human (Michelot andMelendez-Howell 2003).

ToxicologyMuscarine is a quaternary ammonium compound which is found in the abovementioned mush-rooms. Similar to acetylcholine, muscarine activates postganglionic muscarinic receptors and pro-duces cholinergic syndromes (Young 1994).

Clinical PresentationsClinical signs develop within 30 min to 2 h of ingestion (Lima et al. 2012). Because of its quaternarystructure, muscarine does not cross the blood–brain barrier, and its cholinergic effects are entirelyperipheral. The signs and symptoms include bradycardia, miosis, salivation, lacrimation, diarrhea,nausea, vomiting, and bronchospasm (Stallard and Edes 1989; De Haro et al. 1999; Salhab 2007).Muscarine is poorly absorbed after oral exposure; therefore, the severity of cholinergic syndromedue to the consumption of these mushrooms is less than organophosphate compounds. Moreover thestimulation of nicotinic receptors was not observed (Beuhler and Graeme 2005; Goldfrank 2009;Brent and Palmer 2007). Muscarine is not susceptible to inactivation by acetylcholinesterase, so theduration of its effect could be more prolonged compared to acetylcholine. Clinical signs are usuallyself-limited and would last for about 6–24 h if large amounts were consumed (Brent and Palmer2007).

TreatmentSever poisoning is rare. Treatment includes early decontamination, administration of activatedcharcoal, and fluid therapy. If life-threatening clinical signs are present, atropine should be admin-istered. The dose in adults and children are 1–2 mg and 0.02 mg/kg via continuous i.v. injections,respectively (Goldfrank 2009; Beuhler and Graeme 2005). The best criteria for therapeutic endpointwith atropine include ease of respiration and lack of respiratory secretions. It has been shown thatglycopyrrolate is safer than atropine because it does not cross the blood–brain barrier. The doses in

Fig. 3 Inocybe geophylla (http://en.wikipedia.org)


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adults and children are 0.05–0.1 mg and 0.005–0.01 mg/kg via continuous i.v. injections,respectively. In patients with bronchospasm, inhalation of ipratropium bromide is alsorecommended (Beuhler and Graeme 2005; Goldfrank 2009; Brent and Palmer 2007).

Mushroom-Induced Disulfiram-Like Syndrome

Coprinus atramentarius is a well-known mushroom which produces disulfiram-like syndrome(Carlsson et al. 1978; Fig. 4).

ToxicologyCoprinus atramentarius contains amino acid coprine. Coprine is metabolized to the active com-pound named as aminocyclopropanol (ACP). ACP inhibits aldehyde dehydrogenase which isresponsible for acetaldehyde hydrolysis. As a result of coprine ingestion, acetaldehyde accumulatesin the body. When ethanol is consumed simultaneously or during 24–72 h after coprine, disulfiram-like syndrome will occur. Although coprine acts similar to that of disulfiram, it is an alkylating agentandmutagenic (Beuhler and Graeme 2005). Coprine is heat stable and remains toxic even after beingcooked (Carlsson et al. 1978; Michelot 1992; Beuhler and Graeme 2005; Brent and Palmer 2007).

Clinical PresentationsSigns and symptoms begin within minutes of ethanol ingestion and include flushing (face and neck),headache, metal taste, nausea/vomiting, dyspnea, chest pain, sweating, tachycardia, prematureventricular contraction, atrial fibrillation, hypotension, hypothermia, confusion, and coma. Thesymptoms could improve within 24 h (Michelot 1992; Beuhler and Graeme 2005; Goldfrank2009; Brent and Palmer 2007).

TreatmentTreatment is supportive. The effectiveness of activated charcoal is not established. There is noevidence regarding the beneficial use of antihistamines to reduce flushing. Propranolol is

Fig. 4 Coprinus atramentarius (http://en.wikipedia.org)


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recommended to treat sympathomimetic syndrome but may be dangerous in severe toxicity (Beuhlerand Graeme 2005). Fomepizole, known as an alcohol dehydrogenase inhibitor, may reduce toxicitydue to the decrease in acetaldehyde production. Fluid therapy is recommended for hypotension, andvasopressors may be required for patients in shock status. Dopamine can be preferentially usedbecause coprine does not inhibit dopamine b-hydroxylase. In life-threatening poisoning, hemodi-alysis might be recommended to remove ethanol and acetaldehyde (Michelot 1992; Beuhler andGraeme 2005; Goldfrank 2009; Brent and Palmer 2007).

Mushrooms-Induced Isoxazole Syndrome

Species of genus Amanita including A. gemmata, A. pantherina, and A. muscaria cause neurotox-icity. The major toxins of these mushrooms are ibotenic acid and muscimol (Beuhler and Graeme2005; Tsujikawa et al. 2006; Lima et al. 2012; Fig. 5).

ToxicologyIbotenic acid and muscimol are pseudoneurotransmitters. Ibotenic acid is a potent agonist ofN-methyl-D-aspartic-acid (NMDA) receptor, and muscimol is a powerful GABA (gamma-aminobutyric acid) agonist (Tsujikawa et al. 2006). After rapid absorption, muscimol and ibotenicacid cross the blood–brain barrier via an active transport system. Ibotenic acid decarboxylates toform muscimol in the stomach, liver, and brain (Nielsen et al. 1985). Therefore, the main toxinresulting in clinical signs of poisoning is muscimol. Muscimol and ibotenic acid can be detectedin urine within 1 h of exposure. Lethal dose of muscimol in rats is 25 mg/kg (Beuhlerand Graeme 2005).

Fig. 5 Amanita muscaria (http://en.wikipedia.org)


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Clinical PresentationsMuscimol is a potent agonist of GABAA, which is an inhibitory neurotransmitter. Typical clinicalsigns and symptoms of muscimol toxicity begin within 30 min to 2 h after ingestion and includemydriasis, dry mouth, ataxia, confusion, euphoria, dizziness, and drowsiness. Vomiting is notconsistently seen in cases of isoxazole poisoning. Ibotenic acid activates glutamate receptors.After a brief period of sedation, glutamatergic manifestations appear and include muscle spasmsand seizures. Continuous periods of excitation and inhibition in the nervous system could be seenduring poisoning. Recoveries are recorded within 6–12 h (Stormer et al. 2004; Beuhler and Graeme2005; Tsujikawa et al. 2006; Brent and Palmer 2007; Tsujikawa et al. 2007).

Although patients may manifest features similar to cholinergic or anticholinergic toxidromes, it isnot known whether these symptoms are due to the presence of large amounts of muscarine, anunidentified compound, or due to the isoxazoles (Brent and Palmer 2007; Beuhler and Graeme2005).

TreatmentTreatments are mainly symptomatic and supportive. Gastric decontamination should be considered.In human poisoning, the use of atropine is contraindicated because of the absence of cholinergic-likesymptoms. Furthermore, physostigmine is rarely recommended because humans do not manifesttrue anticholinergic symptoms.

Patients with unstable clinical signs or obvious mental disorders should be admitted to intensivecare unit until complete recovery (Beuhler and Graeme 2005; Brent and Palmer 2007).

Mushroom-Induced Hallucination

Mushrooms including Gymnopilus spectabilis, Panaeolus foenisecii, Conocybe cyanopus,Psilocybe caerulescens, and Psilocybe cubensis are known as mushrooms that induced hallucino-genic manifestations (Fig. 6).

Fig. 6 Psilocybe cubensis (http://en.wikipedia.org)


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ToxicologyActive toxic substances in these mushrooms include psilocybin which is an indole-like serotoninsimilar to LSD (lysergic acid diethylamide) and biologic amines, namely, baeocystin andnorbaeocystin. Psilocybin is 50 % absorbed via orally and is rapidly dephosphorylated to psilocin.According to the literature, the main toxin is psilocin because it is lipid soluble and crossesblood–brain barrier. Psilocin is responsible for the central nervous system toxicities (Beuhler andGraeme 2005). Psilocin is excreted unchanged or as psilocin glucuronide in urine and to some extentunchanged via the bile (Hasler et al. 2002).

Clinical signs and symptoms of hallucinogenic mushroom poisoning are attributed to theindole–tryptamine derivatives including psilocybin and psilocin which are chemically similar toLSD and serotonin. These agents are 5HT2A agonists, thus inducing hallucinogenic effects(Musshoff et al. 2000; Brent and Palmer 2007).

Clinical PresentationsThe most common manifestation is euphoria. In humans, the psychoactive effects of psilocin aresimilar to those induced by LSD. The clinical manifestations are observed within 20–30 minfollowing ingestion and include visual and auditory hallucinations. Visual hallucinations are morecommon. Other autonomic nervous system effects are increased heart rate and blood pressure,mydriasis, tremors, and increased temperature. The effects can last up to 8 h, but hallucinogenicactivity rarely exceeds 1 h. It is reported that difficulty in concentration and visual and auditoryhallucinations could occur 2 weeks after ingestion due to neuronal demyelinization (Beuhler andGraeme 2005; Goldfrank 2009; Brent and Palmer 2007).

TreatmentThe management of hallucinogenic mushrooms poisoning is primarily supportive, and in mostcases, treatment is not necessary. Agitated patients should be maintained in a calm environment.Gastric lavage is not recommended. The beneficial effect of activated charcoal in such poisonings isnot approved, but its administration can be considered. If severe neurologic signs such as seizuresoccur, diazepam is recommended (Beuhler and Graeme 2005; Brent and Palmer 2007).

Mushrooms-Induced Gastrointestinal Irritation

This group includes species such as Omphalotus olearius and Chlorophyllum molybdites whichresult in gastroenteritis as the primary clinical sign (Fig. 7).

ToxicologyAlthough muscarine is not found inO. olearius, sometimes it is considered as muscarine-containingmushrooms. Similar to the muscarinic symptoms, clinical features of poisoning are vomiting,nausea, diarrhea, abdominal pain, lethargy, and blurred vision (French and Garrettson 1988). Themost common signs of muscarinic syndrome are shown except salivation and lacrimation (Beuhlerand Graeme 2005).

Clinical PresentationsThese mushrooms exhibit gastroenteritis early after ingestion. It was shown that ingestion of onlypart of one C. molybdites may result in gastroenteritis along with clinical signs and symptoms ofnausea, vomiting, and diarrhea which occur 1–2 h after ingestion. Diarrhea is a common sign.


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Moreover some cases exhibited bloody diarrhea (Blayney et al. 1980). Other clinical signs andsymptoms include electrolyte abnormalities, abdominal pain, sweating, and dizziness. Althoughmost patients could recover after 4–6 h, complete recovery had been shown to be as late as 24–48 hpost-ingestion in severe cases (Beuhler and Graeme 2005).

TreatmentTreatment is nonspecific and should focus on rehydration and correction of serum electrolyteabnormalities. Antiemetics should be recommended. Vasopressors are often useful in hypotensivepatients. Vomiting is a hallmark of poisoning by gastrointestinal irritant mushrooms. Thus, emeticsare not recommended. Activated charcoal is thought to have benefit when administered within 1 hafter ingestion (Beuhler and Graeme 2005; Goldfrank 2009).

Mushroom-Induced Rhabdomyolysis

Tricholoma equestre and Russula subnigricans are known as mushrooms that induced rhabdomy-olysis (Beuhler and Graeme 2005; Brent and Palmer 2007; Fig. 8).

ToxicologyAlthough the mechanism of toxicity is not fully known, it is indicated that russuphelins is probablyresponsible for R. subnigricans toxicity (Beuhler and Graeme 2005; Goldfrank 2009; Brent andPalmer 2007).

Clinical PresentationsClinical signs and symptoms in humans appear 2 h after ingestion and include diarrhea, nausea, andvomiting. Complete recovery could occur after 24 h. In severe poisoning, muscular weakness,fatigue, myalgia, and rhabdomyolysis have been reported. Renal failure and metabolic acidosiscould also be present (Bedry et al. 2001; Karlson-Stiber and Persson 2003).

Fig. 7 Chlorophyllum molybdites (http://en.wikipedia.org)


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TreatmentTreatment is completely supportive and is recommended as soon as possible (Beuhler andGraeme 2005).

Mushroom-Induced Delayed Gastroenteritis and Liver Failure

Most fatalities are reported by exposure to cyclopeptide-containing mushrooms. Species of genusAmanita (including A. verna, A. virosa, and A. phalloides), Lepiota helveola, and Galerinamarginata are known asmushrooms that contain cyclopeptides (Donnelly andWax 2005; Goldfrank2009; Fig. 9).

ToxicologyThe most toxic cyclopeptide-containing mushroom is A. phalloides, the ubiquitous “death cap.”Amanitin was isolated from A. phalloides in 1940 by Hallermayer. There are three groups ofcyclopeptides, including the amatoxins, phallotoxins, and virotoxins. Amatoxins are bicyclicoctapeptides and include the amanitins (a, b, g,). Severe poisonings and lethality are mainlyattributable to the amanitins. Phallotoxins are bicyclic heptapeptides and potent hepatotoxin.Phallotoxins are thought to be the cause for gastrointestinal toxicity (Barbato 1993; Donnelly andWax 2005). Because of heat stability of amatoxins, poisoning could and usually occur after cooking(Jaeger et al. 1993; Donnelly and Wax 2005). Amanitins exert their toxicity by the inhibition ofnuclear RNA polymerase II (Lindell et al. 1970; Wieland 1983), which results in impaired proteinsynthesis and cell death. Other toxic mechanisms include the induction of apoptosis (Leistet al. 1997), production of reactive oxygen species (ROS), and depletion of hepatic glutathione(Enjalbert et al. 2002). Amanitins are poorly but rapidly absorbed from the gastrointestinal tract.a-Amanitin may be enterohepatically recirculated (Goldfrank 2009). Excretion is particularly renal,but significant amounts are also excreted in bile and feces (Jaeger et al. 1993).

Fig. 8 Tricholoma equestre (http://en.wikipedia.org)


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Clinical PresentationsThe clinical signs and symptoms can be divided into four phases: The initial phase or the latencyperiod lasted for about 6–24 h (mean 8–12 h). The second phase is recognized by severe gastroin-testinal manifestations including nausea, vomiting, bloody diarrhea, and severe abdominal pain.Gastrointestinal signs improved after 60 h (Vogel et al. 1984). The gastroenteric phase is oftenfollowed with a lag time of several hours to a few days. During this phase, the patients will seem tohave recovered. Within the third phase, monitoring of liver and kidney functions is recommended toavoid misdiagnosis. The final stage or fourth phase begins approximately 36–84 h after exposure toamanitins. In this stage, liver, renal, andmultiorgan failure may occur. Elevation in serumAST, ALT,ALP, and bilirubin are commonly observed (Vogel et al. 1984; Mas 2005). Coagulopathy, enceph-alopathy, and coma are also present with liver failure (Vogel et al. 1984). If patients survive beyondhepatic failure, renal failure may happen as a result of proximal and distal tubular necrosis (Tegzesand Puschner 2002). Clinical signs of renal failure include polyuria, polydipsia, vomiting, andanorexia (Santi et al. 2012). Severe hypoglycemia may occur after the gastrointestinal phase and isaccompanied with the breakdown of liver glycogen (Donnelly and Wax 2005; Mas 2005). Deathusually occurs due to cyclopeptide-containing mushrooms at days of 6–16 after ingestion (Donnellyand Wax 2005; Brent and Palmer 2007).

TreatmentThe use of activated charcoal may be beneficial in adsorbing toxins within the gastrointestinal tractas well as those that reenter it due to enterohepatic recirculation. The recommended dose is 1 g/kgevery 2–4 h for speeding the rate of toxin elimination (Goldfrank 2009). Also a number ofdecontamination procedures have been applied in humans and include hemodialysis,hemoperfusion, plasmapheresis, forced diuresis, and nasoduodenal suctioning. Close monitoring,fluid replacement, and supportive care nevertheless are the essential parts of the treatment ofamanitin poisoning. As part of vigorous supportive care, i.v. fluids, correction of hypoglycemiaand electrolyte abnormalities, vitamin K1, and plasma transfusions should be considered dependenton the clinical presentations of each poisoned patient. Liver transplantation has been used

Fig. 9 Amanita phalloides (http://en.wikipedia.org)


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successfully in patients with severe liver failure (Donnelly and Wax 2005; Goldfrank 2009; Brentand Palmer 2007).

Some antidotes are available to treat amanitin poisoning. These include silibinin, penicillin, andN-acetylcysteine (NAC) which are most commonly recommended along with decontaminationprocedures and supportive care (Ward et al. 2013). Although the exact mechanisms of silibininand penicillin are not fully understood, both compounds reduce the uptake of amanitins intohepatocytes. Silibinin (also known as silybin) is the main component of silymarin and providesmost of the hepatoprotection that is related to milk thistle (Silybum marianum). Silibinin is a freeradical scavenger and has immunostimulatory and iron-binding properties (Mayer et al. 2005;Karimi et al. 2010). It is reported that silibinin could interact with the enterohepatic recirculationof amanitin. Experimentally, silibinin was shown to be effective. The recommended i.v. dose ofsilibinin in humans is an initial bolus infusion of 5 mg/kg followed by a continuous infusion of20 mg/kg/day for a minimum of 3 days (Karlson-Stiber and Persson 2003; Donnelly and Wax 2005;Brent and Palmer 2007). The recommended dose for oral preparations is 140 mg, two to three timesper day. Side effects of silibinin administration are rare but may include anaphylactic reactions, mildlaxative effects, and interactions with certain phase I and phase II metabolic enzymes(Venkataramanan et al. 2000). Recently, the efficacy of penicillin G alone, not in combinationwith silibinin, was shown to be ineffective in humans with amanitin poisoning (Enjalbertet al. 2002). Based on animal and retrospective human studies, the recommended dose of penicillinG is 300,000–1,000,000 IU/Kg/day (Brent and Palmer 2007). Research has shown that the admin-istration of silibinin appears to have greater therapeutic benefit than penicillin G at least in humans(Enjalbert et al. 2002). The use of antioxidants in amanitin poisoning was also established. It wasshown that NAC is as useful as silibinin in reducing mortality in humans after amanitin poisoning(Enjalbert et al. 2002). It is believed that NAC could be beneficial to reduce the development ofencephalopathy, renal failure, and coagulopathy. Thioctic acid is also used in the treatment ofamanitin poisoning and could increase the rate of survival of poisoned patients. Steroids, hyperbaricoxygen, cimetidine, ascorbic acid, D-penicillamine, and diethyldithiocarbamate are alsorecommended (Donnelly and Wax 2005; Brent and Palmer 2007). Controversy still remains aboutthe efficacy of many of these procedures as specific data do not exist.

Mushroom-Induced Central Nervous System Abnormalities andHemolysis

Gyromitrin is found in species including Gyromitra esculenta and Gyromitra californica. It isreported that G. esculenta is thought to be one of the mushroom species which induce severepoisoning (Brooks and Graeme 2005; Goldfrank 2009; Fig. 10).

ToxicologyThis group of mushrooms produces gyromitrin (acetaldehyde N-methyl N-formylhydrazine). It isa toxin which can be partly removed by boiling and/or drying. After hydrolysis of gyromitrin in thestomach, methylformylhydrazine and monomethylhydrazine are formed. Hydrazines caused toxic-ity similar to that of isoniazid. As soon as hydrazines reach the liver, they are further metabolized toreactive intermediates, such as methyl cations and free methyl radicals (Gannett et al. 1991). It isestablished that monomethylhydrazine can inhibit pyridoxal phosphokinase, an enzyme responsiblefor the formation of pyridoxal phosphate. Enzyme inhibition results in decreased pyridoxal 5-phosphate concentration (Lheureux et al. 2005). The inhibition of glutamic acid decarboxylase, an


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enzyme responsible for the formation of g-aminobutyric acid (GABA), was also reported. Depletionof GABA and an increase in glutamic acid concentration lead to seizures (Michelot and Toth 1991;Brooks and Graeme 2005; Goldfrank 2009; Brent and Palmer 2007).

Clinical PresentationsGyromitrin is considered as a gastrointestinal irritant which leads to clinical signs of vomiting,abdominal pain, and diarrhea 6–48 h after ingestion of the poisonous mushroom. Most patientsexhibit only mild gastrointestinal symptoms and recover fully within several days after exposure.However, in some cases, especially in patients with severe poisoning, neurotoxicity, liver and renalfailures as well as hemolysis could also occur (Brooks and Graeme 2005; Goldfrank 2009; Brent andPalmer 2007). Other clinical signs and symptoms that may be present include vertigo, sweating,diplopia, headache, dysarthria, incoordination, ataxia, seizures, coma, hemolysis, methemoglobi-nemia, rhabdomyolysis, myalgia, hypoglycemia, and electrolyte abnormalities (Berger and Guss2005). N-methyl-N-formylhydrazine is found to inhibit cytochrome P450 and glutathione-metabolizing enzymes (Braun et al. 1979) and can lead to liver necrosis. Moreover, the highlyreactive metabolites, such as methyl cations generated in the liver, may significantly contribute tohepatic injury (Toth and Gannett 1994).

TreatmentManagement is mainly supportive. Because of the delayed onset of clinical symptoms, earlydecontamination is not possible. Activated charcoal has been recommended, although its efficacyhas not been proved. Fluid therapy and correction of electrolyte imbalances are also important. Inpatients with methemoglobinemia, methylene blue should be provided. The recommended dose is1–2 mg/kg via i.v. injection (maximum 7 mg/kg). Caution is recommended because higher doses ofmethylene blue could induce oxidative stress. In patients with G6PD deficiency, methylene blue iscontraindicated (Brooks and Graeme 2005). Administration of pyridoxine is also provided. Therecommended dose in humans is 25–50 mg/kg i.v. over 15–30 min. The dosing can be repeated inpatients manifesting coma or recurrent seizures but should not exceed 20 g/day. While pyridoxine

Fig. 10 Gyromitra esculenta (http://en.wikipedia.org)


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can effectively control seizures, it has no benefit in preventing liver injury (Brooks and Graeme2005; Goldfrank 2009; Brent and Palmer 2007). Pyridoxine can be used alone or in combinationwith diazepam for the control of seizures. It is believed that the efficacy of combination therapy isbetter than that of pyridoxine alone (Villar et al. 1995; Goldfrank 2009; Brent and Palmer 2007).Phenobarbital is not recommended for the management of seizures because of its cytochrome P450-inducing capability (Brooks and Graeme 2005). Administration of folinic acid has beenrecommended in humans because hydrazine inhibits the formation of activated folate. Therecommended dose is 5–15 mg/kg (i.v., i.m., or orally) for 5–7 days. The cytochrome P450inhibitors such as cimetidine and also NAC should be considered to prevent hepatic injury(Brooks and Graeme 2005). Thioctic acid is also recommended due to its antioxidative property.Vitamin K (0.5–10 mg/kg, i.v., i.m., or orally) could be used in the presence of liver injury (Brooksand Graeme 2005).

Conclusion and Future Directions

Toxicities induced by some commonly consumed mushrooms are described with more emphasis onthe mechanisms of toxicity, main toxins, clinical signs, and therapeutic approaches. Because of theoccurrence of many accidental poisonings, proper identification is very important to avoid acciden-tal mushroom poisoning. Furthermore, the prompt identification of signs and symptoms of mush-room poisoning provides the success of treatment. In severe poisoning induced by agents such asamatoxins, intensive care is necessary to save lives, and rapid toxin identification would helpclinicians to confirm the diagnosis earlier and then commence proper management. Currently,therapeutic approaches are primarily based on both the mechanisms of toxicity and clinical signsof mushroom poisoning. Our knowledge regarding appropriate analytical techniques for specificmushroom toxins should be updated frequently, and further research is necessary in order to developtimely analytical techniques that are based on toxin characterizations.

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Index Terms:

Amatoxin 11, 15Coprine 6–7Gyromitrin 13–14Muscarine 5, 8–9Mushroom 1Phallotoxin 11


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