Research Amanita phalloides poisoning and treatment with silibinin in the Australian Capital Territory and New South Wales Darren M Roberts manita phalloides (“deathcap” Abstract PhD, FRACP, Clinical Toxicology Fellow1 or “whitecap”) is a cyclopep- Objectives: To report the frequency and clinical outcomes of Amanita phalloides A tide variety of mushroom poisoning in the Australian Capital Territory and New South Wales, and the Michael J Hall FACEM, that is responsible for more than 90% treatments used (including silibinin). Clinical Director, of mushroom-related fatalities; one Design, setting and patients: Retrospective case series of patients admitted to Department of Emergency Medicine2 mushroom cap can cause fulminant public hospitals in Canberra and Sydney for suspected A. phalloides poisoning hepatic failure and death in an adult.1 between 1999 and 2012 (identified from hospital records and calls to the New Morna M Falkland South Wales Poisons Information Centre). BPharm, Most reported A. phalloides poison- Senior Pharmacist, ings occur in Europe. In Australia, Main outcome measures: Frequency of poisoning and the clinical outcomes. Medicines Information Centre2 most occur in Canberra as A. phal- Results: Twelve patients presented with a history suggesting A. phalloides loides grows in the Australian Capital poisoning, 10 with probable poisoning and two with possible poisoning. Eight of Simone I Strasser those with probable poisoning developed significant hepatotoxicity and four MD, FRACP, Territory, particularly in the older died. Silibinin was administered to nine of those with probable poisoning (the Clinical Associate Professor suburbs of Canberra (which has been and Hepatologist3 other presented before 2005). Maintaining silibinin supply became a challenge attributed to imported oak trees). during two clusters of poisoning. Eight of the patients with probable poisoning Nick A Buckley Cases have also been reported in MD, FRACP, were not long-term residents of the ACT, and six were immigrants from Asia. 1 Clinical Toxicologist, and Victoria. Public health campaigns are Conclusions: The mortality rate due to A. phalloides poisoning in this case series Professor4 commonplace in the ACT in summer was high despite treatment according to current standards, including use of and autumn (“mushroom season”). silibinin, and the frequency of hepatotoxicity was more than double that for the 1 New South Wales Poisons Amatoxin is the most potent hepa- previous decade. Ongoing public health campaigns are required. Information Centre, Children’s Hospital at totoxin in cyclopeptide mushrooms; Westmead, Sydney, NSW. it irreversibly binds to RNA polymer- action and some supporting evidence poisoning who were treated at pub- 2 Canberra Hospital, 1 Canberra, ACT. ase II, causing hepatic necrosis. The from animal studies, and silibinin is lic hospitals in Canberra and the 3 Australian National Liver clinical features of A. phalloides poi- regarded as the standard of care in Australian National Liver Trans- Transplantation Unit, Royal soning are well described (Box 1). Europe. In 2010, the silibinin stock plantation Unit at Royal Prince Prince Alfred Hospital, Sydney, NSW. The most recent report of A. phal- level at Canberra Hospital was Alfred Hospital between January 4 Professorial Medicine loides poisonings in Australia was increased so that there was sufficient 1999 and May 2012. Patients were Unit, Prince of Wales Hospital, University of New from the ACT over 10 years ago, stock to treat two patients and, in identified from clinical databases in South Wales, Sydney, NSW. describing seven poisonings that Sydney, Royal Prince Alfred Hospital departments of emergency medicine [email protected] occurred between 1988 and 1998.5 also stocked it. and clinical toxicology in the ACT Since then, a chemically modified Here, we review cases of A. phal- and from call records of the New MJA 2013; 198: 43–47 derivative of silibinin (silibinin-C- loides poisoning that occurred in the South Wales Poisons Information doi: 10.5694/mja12.11180 2',3-dihydrogen succinate, disodium ACT and New South Wales between Centre. A diagnosis of A. phalloides salt [Legalon SIL, Madaus], referred 1999 and 2012, including patients poisoning was suspected on the to hereafter as silibinin) — a pur- treated with silibinin. basis of a history of mushroom ported antidote to A. phalloides poi- ingestion and subsequent delayed soning that is derived from the milk Methods onset of gastroenteritis and hepati- thistle Silybum marianum — has been tis; blood tests confirming the pres- stocked by hospitals in the ACT. In We reviewed the clinical records of ence of amatoxin are not available in 2005, Canberra Hospital imported patients with possible A. phalloides Australia. The Medical Journalsilibinin of Australia for use ISSN: as 0025-an antidote 729X 21 Januarythrough 2013 198 the 1 43-47Special Access Scheme ©The Medicalof Journal the Therapeutic of Australia Goods 2013 Adminis- 1 Clinical features of acute Amanita phalloides poisoning1-4 www.mja.com.autration because it is not registered Research 0 to 6–18 hours after ingestion: Asymptomatic for use in Australia. Sufficient stock 6–24 hours after ingestion: Gastroenteritis, including abdominal pain, nausea, vomiting, was purchased to treat one patient diffuse diarrhoea, dehydration with or without hypotension, metabolic acidosis and for at least 96 hours at a dosage of electrolyte disturbance; normal or mildly deranged renal function and levels of hepatic 20 mg/kg/24 h, given in 6-hourly enzymes doses. This decision was made 1–7 days after ingestion: Resolving gastrointestinal symptoms, but progressive hepatic (despite a lack of good-quality evi- failure, coagulopathy, kidney injury (including hepatorenal syndrome); possible progression to dence of efficacy) because there was multisystem organ failure and a 10%–30% mortality rate no approved treatment in Australia, > 7 days after ingestion: Complete resolution of symptoms occurs in most survivors over weeks or months; chronic hepatitis may persist ◆ there was a plausible mechanism of MJA 198 (1) · 21 January 2013 43 Research 2 Patients with a history suggesting Amanita phalloides poisoning, Australian Capital Teritory and New South Wales, 1999–2012* No. of Peak abnormal results mushrooms Onset of of renal and liver Predicted Patient ingested symptoms function tests Treatment to die† Outcome A 1 8.5 h Cr, 137 mol/L; ALT, IV fluids, analgesia, antiemetics, MDAC, NAC, No Survived, no sequelae 7814 U/L; INR, 3.4; La, penicillin, silibinin (36 h after ingestion) then 4.6 mmol/L silymarin, ICU admission, care by liver transplantation unit B 10 9 h Cr, 192 mol/L; ALT, IV fluids, penicillin, silibinin (23 h after ingestion) No Died 6 days after ingestion 3914 U/L; INR, 2.2; La, then silymarin, ICU admission, care by liver (shock, acute abdomen and 16 mmol/L transplantation unit cerebral oedema; hepatic failure was resolving) C 1 8.5 h Cr, 98 mol/L; ALT, IV fluids, antiemetics, analgesia, MDAC, NAC, No Survived, no sequelae 4913 U/L; INR, 1.7; La, penicillin, silibinin (46 h after ingestion) 1.6 mmol/L D211hCr, 88mol/L; ALT, IV fluids, penicillin, silibinin (21 h after ingestion), No Survived 3701 U/L; INR, 1.7; La, cimetidine, antibiotics and antifungal, care by liver 2.3 mmol/L transplantation unit E Unclear, 25 h after first Cr, 73 mol/L; ALT, IV fluids, MDAC, acetylcysteine, silibinin (31 h after No Survived, persistent but various meal; 9 h after 7067 U/L; INR, 2.6; La, second meal), ICU admission, care by liver asymptomatic hepatitis at last mushrooms second meal 4.4 mmol/L transplantation unit review (5 days after ingestion) ingested in two meals F Unclear; 10 h Cr, 179 mol/L; ALT, IV fluids, NAC, MDAC, silibinin (19 h after No (died Died 2.5 days after ingestion, perhaps 8–10 7253 U/L; INR, 8.4; La, ingestion), ICU admission, care by liver early) fulminant hepatic failure and 18 mmol/L transplantation unit, plasma products lactic acidosis G Unclear Unknown; had Cr, 232 mol/L; ALT, IV fluids, then heparin and interhospital transfer for Yes Died 4 days after suspected time symptoms for 3793 U/L; INR, 12.6; La, investigation and treatment of an ischaemic foot of ingestion, fulminant hepatic 48 h before 13.4 mmol/L that resolved without other intervention‡ failure and lactic acidosis presentation H Unclear; 10 h Cr, 119 mol/L; ALT, IV fluids, NAC, MDAC, silibinin (19 h after Yes (based Died 3 days after ingestion, perhaps 8–10 7511 U/L; INR, >12; La, ingestion), ICU admission, care by liver on terminal fulminant hepatic failure and 22 mmol/L transplantation unit, plasma products blood test lactic acidosis results) I Unclear 14 h Cr, 77 mol/L; ALT, IV fluids, MDAC, NAC, silibinin (23 h after No Survived, no sequelae 63 U/L; INR, 1.0; La, ingestion), ICU admission 1.3 mmol/L J 510hCr, 111mol/L; ALT, IV fluids, MDAC, NAC, silibinin (33 h after No Survived 52U/L; INR, 1.1; La, ingestion), ICU admission 1.5 mmol/L K Part of a 12 h Urea and ALT levels Observed for 4 h, no follow-up No Survived mushroom mildly elevated L 1 6 h (very mild) No changes Observed overnight, no progression of symptoms No Survived ALT= serum alanine aminotransferase (reference interval, < 55 U/L). Cr = serum creatinine (reference interval, 60–110 mol/L). ICU = intensive care unit. INR = international normalised ratio (reference interval, 0.8–1.2). IV = intravenous. La = blood lactate (reference interval, < 2.5 mmol/L). MDAC = multiple doses of activated charcoal. NAC = acetylcysteine. * Poisoning was probable