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Home , Amanita, Amanita phalloides, Amatoxin

Maxwell Moor-Smith, BSc, Raymond Li, BSc(Pharm), MSc, Omar Ahmad, MD, FRCPC

The world’s most poisonous , phalloides, is growing in BC

The expanded range of death cap —previously found on the roots of imported European trees but now found in association with native Garry —puts amateur foragers at risk, and recognition of poisoning is essential to preventing future fatalities.

ABSTRACT: in Amanita acute failure occurs. Manage- shown some benefit in a retro-­ phalloides, commonly known as the ment of the symptomatic patient spective survival analysis. With the death cap mushroom, are responsi- consists of providing supportive expanded range of A. phalloides in ble for 90% of the world’s mushroom- care, promoting renal elimination of BC, physicians should be alert to related fatalities. The most deadly amatoxins, interrupting enterohe- the possibility of amatoxin - amatoxin for humans is α-amanitin, patic recirculation of amatoxins, and ing and include it in the differential a bicyclic octapeptide that irrevers- administering proposed . diagnosis of a patient presenting ibly binds RNA polymerase II, thus Although no established with gastroenteritis or hepatotoxic- preventing protein synthesis and for A. phalloides has been identified, ity and a history of ingesting foraged causing cell death. Three recent N- and have mushrooms. poisoning cases in British Columbia show how the death cap can be eas- ily mistaken for edible mushrooms The world’s most poisonous mushroom such as the and the paddy is growing in British Columbia straw mushroom. Since being intro- duced from to the west and mid-Atlantic coasts of North Ameri- , commonly known as the death cap mushroom, ca, A. phalloides has spread to south is responsible for 90% of the world’s mushroom-related fatalities. coastal BC, and has the potential to spread to vast areas of the continent. Following ingestion of A. phalloides, Clinical presentation is triphasic: there is a latency period (6 hours) followed by intoxication, classically described as triphasic: a dysentery phase (6 to 24 hours), a false recov- 6–24 24–72 4–9 ery phase (24 to 72 hours), and a HOURS HOURS DAYS hepatorenal phase (4 to 9 days) con- Dysentery phase False recovery phase Hepatorenal phase sisting of multisystem organ failure, , , and death. Management of symptomatic patients includes supportive measures, promoting Treatment is based on decontami- renal elimination of amatoxins, and early consultation with a liver transplant centre. nation and if Maxwell Moor-Smith, BSc, Raymond Li, MSc, Omar Ahmad, MD This article has been peer reviewed. BCMJ 2019;61:20-24

20 bc medical journal vol. 61 no. 1, january/february 2019 bcmj.org The world’s most poisonous mushroom, Amanita phalloides, is growing in BC

manita phalloides, known tion of A. phalloides in North Amer- As an ectomycorrhizal , A. commonly as the death cap ica was in northern California at the phalloides forms an obligate symbiot- A mushroom, causes life- Hotel Del Monte in 1935, a location ic relationship with the roots of trees, threatening hepatorenal dysfunction famous for its exotic and unusual gar- which have been mostly nonnative, when ingested. Considered the most dens.5 Since then, the death cap has broad-leaf trees.4,5 This association poisonous mushroom in the world, been introduced to multiple sites in may have limited the mushroom’s A. phalloides contains amatoxins, a the Pacific Northwest. spread so far. However, in Victoria group of bicyclic octapeptides that A. phalloides specimens were first A. phalloides has now been found in are responsible for 90% of global collected in BC in 1997 from under association with native BC Garry mushroom-related fatalities. One cap European trees at Lake Er- trees, which may allow the mushroom of A. phalloides is sufficient to cause rock in the upper Fraser Valley. The to expand its range even further.4 death in an adult.1-3 first identification of A. phalloides Pringle and colleagues estimate the The death cap was first introduced in Victoria was in 1998 from under speed of A. phalloides spread among to British Columbia on the roots of a large European tree on the native California coastal oak at 5 imported European trees and has landscaped grounds of Government km per year on average (range 3 to since spread to North American oak House, the residence of BC’s lieu- 9 km/year).5 Additionally, predictive trees.4,5 Death caps are now found in- tenant governor. A. phalloides was climate suitability mapping shows creasingly in urban settings. In 2017 detected in Vancouver in 2008 under that most of south coastal BC is ap- the Canadian Forest Service and Oak European trees that had propriate habitat for A. phalloides5 Bay parks department reported that been planted by the city in the 1960s.4 ( Figure 1 ). death caps in the Victoria area sprout- Since these first specimens were Mushroom foragers and health ed earlier and in greater numbers than collected, there have been numer- care providers should be aware of the in previous years.6 The spread of this ous reports of A. phalloides found in expanded range for this highly toxic invasive has led to cases of Vancouver and the Fraser Valley, on mushroom in order to prevent fatali- morbidity and mortality from inges- Southern Vancouver Island, and on ties from the death cap in the future.7 tion of the mushroom and an ongoing the Gulf Islands. risk of misidentification. Health care providers need to be aware of this risk, as prompt recognition and ap- propriate management are critical for positive patient outcomes.

Distribution A. phalloides is not native to North America. First identified in Europe, the species has now traveled to Aus- tralia, Asia, Southern , and the Americas on the roots of imported trees.5 The first confirmed collec-

Mr Moor-Smith is a medical student (class of 2020) in the University of British Colum- bia Island Medical Program. Mr Li is a drug Death cap mushroom, Amanita phalloides and poison information pharmacist at the Known location, single site BC Drug and Poison Information Centre. Dr Known location, multiple sites Ahmad is a physician with Island Health and Potential distribution head of Critical Care and Emergency Medi- cine. He is also a clinical associate profes- Figure 1. Amanita phalloides distribution in BC. sor in the Department of Emergency Medi- Map: © Province of British Columbia. All rights reserved. Reproduced with permission of the Province cine at the University of British Columbia. of British Columbia. Image: Adolf Ceska, used with permission.

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Identification and misidentification A. phalloides typically grows from June to November in BC and looks different depending on its stage of maturity. The immature mushroom may be totally encased in a “univer- sal veil,” giving it the egg-like ap- pearance of a puffball mushroom if not cut in half to reveal the growing mushroom inside. As the mushroom Figure 2. Amanita phalloides specimens at various stages of growth. matures, the ruptures Image: Paul Kroeger, used with permission. and remains in the ground as a mem- branous sac (). The cap may binds RNA polymerase II, thus pre- ized by abdominal pain, , and grow up to 16 cm in diameter, becom- venting protein synthesis and caus- severe, cholera-like that may ing broad and slightly convex. The ing cell death. None of the amatoxins contain blood and mucus, and often cap can be white or have a green or are destroyed by cooking, drying, results in profound .2,10 yellow hue, and is often darker in the or freezing. The presence of organic The second (false recovery) phase centre. A. phalloides specimens typ- anion transporting polypeptide 1B3 occurs 24 to 72 hours after ingestion ically feature white gills and spores, (OATP1B3) in hepatic sinusoidal with the patient demonstrating symp- a ring of tissue (annulus) near the top membranes results in the active trans- tomatic improvement despite clinical of the stalk, and a volva at the base8 port of into hepatocytes, causing signs and biochemical markers of liv- ( Figure 2 ). massive centrilobular necrosis and er damage progressing, peaking at 60 Death caps can easily be misiden­ vascular degeneration.2,9 Amatoxins to 72 hours after ingestion.11 The third tified as an edible variety of mush- are primarily eliminated by renal ex- (hepatorenal) phase occurs 4 to 9 days room, as seen in three cases of cretion, with a portion undergoing after ingestion and is characterized by amateur foragers who mistook the biliary excretion and enterohepatic acute liver and multisystem organ death cap for other species. In 2003 recirculation.9 The kidneys may also failure that can lead to convulsions, a 43-year-old man in Victoria con- be affected and show signs of acute hemorrhage, coma, and death.2,3 sumed an immature death cap he tubular necrosis and hyaline casts in thought was a puffball mushroom. In the tubules.2 Diagnosis and 2008 a 63-year-old woman in Van- management couver consumed a mature death cap Triphasic clinical Amatoxin can she assumed was a paddy straw mush- presentation be fatal. The best prognosis results room, a common variety in Asia but Symptoms following the ingestion from prompt recognition and appro- one not native to North America. Both of nonfatal mushroom species gener- priate management. The foundation patients recovered following hospital- ally occur within 6 hours. In contrast, of diagnosis is an accurate history and ization. In 2016 a 3-year-old boy died symptoms of A. phalloides poisoning recognition of the toxidrome. Speci- after consuming a death cap foraged arise 6 to 24 hours after ingestion. mens or photographs of the mush- from a residential street in Victoria.4 Symptoms occurring within 6 hours room consumed can help confirm the of ingestion do not exclude the possi- diagnosis, but often samples are par- Toxicity bility of A. phalloides ingestion, how- tially decomposed or do not represent Three classes of are present ever, as multiple species of foraged the ingested species. Assays to detect in A. phalloides: amatoxins, phallo- toxic mushrooms are often ingested amatoxins are not available locally.3 toxins, and . Of the three, together.3 After this initial latency For asymptomatic patients, gas- amatoxins exert the greatest ef- period, there are three phases in the trointestinal decontamination with fect, and the most toxic for humans clinical presentation of A. phalloides activated charcoal should be con- is α-amanitin.1,2,8 Like all the major poisoning. sidered, even if the patient presents amanitins (α, β, γ), α-amanitin is a Most patients present in the first several hours after ingestion.9 For bicyclic octapeptide that irreversibly (dysentery) phase, which is character- symptomatic patients, management

22 bc medical journal vol. 61 no. 1, january/february 2019 bcmj.org The world’s most poisonous mushroom, Amanita phalloides, is growing in BC

should include providing supportive vated charcoal. High-dose for hepatoprotection if IV silibinin is care, promoting renal elimination of G and cyclosporine are other potential not an option.9 amatoxins, interrupting enterohe- antidotes as they inhibit OATP1B3 N-acetylcysteine is thought to patic recirculation of amatoxins, and and thus can prevent transport of limit hepatic damage through its free- administering proposed antidotes amatoxin into hepatocytes. Penicillin radical or oxygen scavenging capa- ( Table ).12-14 In addition, early consul- has been one of the most commonly bilities. Due to the benign side-effect tation with the local poison control centre and a liver transplant centre is advised. No established antidote for ama- toxin poisoning has been identified. Several have been proposed, but their efficacy is not proven. A meta-analysis Death caps can easily of 2108 hospitalized patients with be misidentified as an edible amatoxin poisoning found therapies with silibinin or the hepatoprotectant variety of mushroom. N-acetylcysteine (NAC) were the most effective in a retrospective sur- vival analysis.2 Silibinin (extract of milk thistle) inhibits OATP1B3 and prevents up- take of amatoxins into hepatocytes.9 While intravenous silibinin (Leg- used therapies, despite showing lim- profile of NAC, the benefits of its use alon SIL) has been used in Europe ited benefit in a retrospective sur- are thought to outweigh any risks.7,13 for many years, in Canada it is only vival analysis.2 Although the risks Once acute occurs, available through the Special Access associated with high-dose penicillin liver transplantation is the only defini- Programme. Oral silibinin is avail- (hypernatremia, seizures) are more tive treatment.1,3,10,14 able at health food stores, but it may significant than other proposed thera- be inactivated when given with acti- pies, penicillin use can be considered Summary The physician’s role in preventing Table. Managing symptomatic amatoxin poisoning after Amanita phalloides ingestion. fatalities from A. phalloides inges- tion lies in prompt recognition of Provide • Aggressively replace fluids and . Patients may be severely amatoxin poisoning in a patient. Clin- supportive dehydrated. icians should be particularly alert if care • Correct and .1,3,9,10,13 the patient reports consuming for- Promote renal • Establish and maintain brisk urine output with a minimum of 1.5 mL/kg/h, aged puffball mushrooms or paddy elimination weighing the risks and benefits in patients who may not tolerate aggressive straw mushrooms, as both of these volume loading.9 mushrooms are known to resemble • Although cannot remove amatoxin, it may be necessary as the death cap. With the expanded part of supportive care.2,7,10 range of A. phalloides in BC, phys- Interrupt • Administer multiple doses of activated charcoal.1,3,9,10 icians should include amatoxin tox- enterohepatic • Consider other interventions supported by anecdotal evidence: giving icity in the differential diagnosis of recirculation patients nothing by mouth, administering octreotide to sequester amatoxins in the gall bladder, initiating percutaneous biliary drainage.9,14 a patient presenting with gastroenter- itis or hepatotoxicity and a history Administer • Consider administering agents that block OATP1B3: intravenous silibinin, of ingesting foraged mushrooms. proposed high-dose penicillin, cyclosporine.2,7,9 Management of the symptomatic pa- antidotes • Consider administering the hepatoprotectant N-acetylcysteine.2,7,9,13 tient involves providing supportive Consult • Contact local poison control: In BC, call the Drug and Poison Information measures, promoting renal elimina- Centre at 1 800 567-8911 (24 hours). tion of amatoxins, interrupting entero- • Contact liver transplant centre. hepatic recirculation of amatoxins,

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administering proposed antidotes, News. 11 October 2017. Accessed 20 11. Giannini L, Vannacci A, Missanelli A, et al. and consulting with the local poison November 2018. www.cbc.ca/news/can Amatoxin poisoning: A 15-year retrospec- control centre and a liver transplant ada/british-columbia/death-cap-mush tive analysis and follow-up evaluation of centre. room-boom-deadly-fungi-victoria-oak 105 patients. Clin Toxicol (Phila) 2007; -bay-garry-oak-1.4349883. 45:539-542. 7. Ward J, Do KK, Brush E, Salhanick SD. 12. Kieslichova E, Frankova S, Protus M, et al. Amatoxin poisoning: Case reports and re- due to Amanita phalloi- The best prognosis view of current therapies. J Emerg Med des poisoning: Therapeutic approach and results from 2013;44:116-121. outcome. Transplant Proc 2018;50:192- 8. French LK, Hendrickson RG, Horowitz BZ. 197. prompt recognition Amanita phalloides poisoning. Clin Toxicol 13. Stein CM, Wu PE, Scott JA, Weinerman and appropriate (Phila) 2011;49:128-129. AS. Fulminant hepatic failure following in- 9. Zilker T, Faulstich H. Cyclopeptide-con- gestion of wild mushrooms. CMAJ 2015; management. taining mushrooms: The deadly Amani- 187:822-824. tas. In: Brent J, Burkhart K, Dargan P, et al. 14. Vo KT, Montgomery M, Mitchell ST, et. al. (eds). Critical care toxicology. 2nd ed. New Amanita phalloides mushroom poison- Acknowledgments York: Springer; 2017. p. 2129-2148. ings—Northern California December The authors would like to thank Dr Daniel 10. Diaz JH. Syndromic diagnosis and man- 2016. MMWR Morb Mortal Wkly Rep Ovakim for his assistance in developing agement of confirmed mushroom poison- 2017;66:549-553. this article. Dr Ovakim is affiliated with ings. Crit Care Med 2005;33:427-436. Critical Care Medicine at Island Health, and Medical Toxicology at the BC Drug and Poison Information Centre.

Competing interests None declared.

References 1. Garcia J, Costa VM, Carvalho ATP, et al. A breakthrough on Amanita phalloides poi- soning: An effective antidotal effect by polymyxin B. Arch Toxicol 2015;89:2305- 2323. 2. Enjalbert F, Rapior S, Nouguier-Soulé J, et al. Treatment of amatoxin poisoning: 20- year retrospective analysis. J Toxicol Clin Toxicol 2002;40:715-757. 3. Berger KJ, Guss DA. revisit- ed: Part I. J Emerg Med 2005;28:53-62. 4. Berch SM, Kroeger P, Finston T. The death cap mushroom (Amanita phalloides) moves to a native tree in Victoria, British Columbia. Botany 2017;95:435-440. 5. Pringle A, Adams RI, Cross HB, Bruns TD. The ectomycorrhizal fungus Amanita phalloides was introduced and is expand- ing its range on the west coast of North America. Mol Ecol 2009;18:817-833. 6. Brend Y. Death cap mushrooms boom 1 year after child’s death in Victoria. CBC

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