a) In patients with severe hepatocellular failure, shock is mostly related to hemorrhage or occurs in the terminal phase.

a) Tachycardia has been reported (Aygul et al, 2010). In the gastrointestinal phase, vomiting and diarrhea can produce severe fluid losses resulting in hypovolemic shock with tachycardia and decreased central venous pressure.
b) In a retrospective review of 144 amatoxin poisonings, 7 patients developed tachycardia (Trabulus & Altiparmak, 2011).

a) Patients may present with hypotension in the first phase of poisoning (Aygul et al, 2010; Scalzo et al, 1998). When shock occurs later, during the hepatitis phase, it is mostly due to hemorrhage secondary to severe coagulation disorders. Cardiovascular collapse also accompanies a severe hepatic failure at the terminal stage (Nicholson & Korman, 1997). Death may result from multiple organ failure (CDC, 1997; Nicholson & Korman, 1997).
b) In a retrospective review of 144 amatoxin poisonings, 21 patients developed hypotension (Trabulus & Altiparmak, 2011).

a) In a retrospective review of 144 amatoxin poisonings, 2 patients developed bradycardia (Trabulus & Altiparmak, 2011).

a) In a retrospective review of 144 amatoxin poisonings, 2 patients developed ventricular dysrhythmia (Trabulus & Altiparmak, 2011).
b) Transient impairment in cardiac systolic function developed in 3 of 45 patients with acute kidney injury and hepatic injury after ingesting amatoxin mushrooms. All 3 patients had acute reversible left ventricular dysfunction and mildly elevated cardiac enzymes (Altintepe et al, 2014).

a) CASE REPORT: A 24-year-old woman presented with abdominal pain, nausea, vomiting, and weakness 6 hours after ingesting Amanita phalloides mushrooms (unknown quantity). Despite supportive therapy, including 4 sessions of hemodialysis, her condition did not improve. Her condition deteriorated very quickly and she developed multiorgan failure, including liver, renal, and cardiac failure. At this time, she was orthopneic, cyanotic, somnolent, tachycardiac (130 beats/min), and hypotensive (BP 70/50 mmHg). An ECG revealed sinus tachycardia with nonspecific ST-T wave changes in anterior leads. Laboratory results revealed a prolonged prothrombin time (INR 5.19) and elevated liver enzymes and serum creatinine. Borderline cardiomegaly with bilateral pleural effusions at the costophrenic angles was observed in a chest x-ray. An echocardiogram showed a global left ventricular hypokinesia with left ventricular ejection fraction (EF) of 24%, end-diastolic diameter of 6.2 cm, and systolic pulmonary artery pressure of 50 mmHg. At this time, an intra-aortic balloon counterpulsation catheter was inserted and a marked improvement was noted within 1 hour. In addition, she was treated with 4 units of fresh-frozen plasma and a peritoneal dialysis catheter was inserted. Her condition continued to improve and both intra-aortic balloon counterpulsation and peritoneal dialysis were removed on day 5. She was discharged on day 12 (Aygul et al, 2010).

a) Respirations are usually normal, but hyperventilation accompanies fulminant hepatitis. Respiratory failure with hypoventilation or apnea may occur in patients presenting with hepatic coma and is a sign of poor prognosis.

a) CASE REPORT: Hemorrhagic pulmonary alveolitis was seen in a 14-year-old fatality with massive liver necrosis (Sanz et al, 1988).

a) Adult respiratory distress syndrome (ARDS) may develop in the later stages of cyclopeptide mushroom poisoning, in conjunction with severe hepatic impairment and coagulopathies. ARDS resulting in death has been reported (Zevin et al, 1997; Ramirez et al, 1993).
b) CASE REPORT: Seven days after eating Amanita phalloides mushrooms, a 32-year-old man developed adult respiratory distress syndrome requiring intubation and mechanical ventilation. He died 9 days after ingestion (CDC, 1997).

a) Neurologic symptoms are related to hepatic encephalopathy and may occur in patients developing severe hepatic failure. Encephalopathy usually occurs 5 to 7 days after ingestion (Mottram et al, 2010; Hydzik et al, 2008; Burton et al, 2002; CDC, 1997; Ramirez et al, 1993).
b) CASE REPORT: A 54-year-old man who ingested 2 to 4 Amanita phalloides mushrooms, developed necrotic liver, encephalopathy, severe coagulopathy, and acute renal failure. He was treated with 7 sessions of Molecular Absorbents Recirculating Systems (MARS) starting 63 hours after ingesting mushrooms, as well as standard supportive care (eg, fluid resuscitation, NAC, oral activated charcoal). He also underwent liver transplantation 9 days postingestion. After the surgery, he experienced persistent acute renal failure (requiring hemodialysis), rhabdomyolysis, and heparin-induced thrombocytopenia. He recovered and was discharged home after 128 days of hospitalization (Kantola et al, 2009).
c) CASE REPORT: A 65-year-old woman developed acute renal failure, liver encephalopathy, and hypoprothrombinemia after ingesting Amanita phalloides mushrooms. Following supportive care, her liver function recovered completely. However, acute renal failure persisted, necessitating hemodialysis (started on day 10). She still required hemodialysis at 2-year follow-up (Garrouste et al, 2009).
d) In a retrospective review of 144 amatoxin poisonings, 10 patients developed encephalopathy (Trabulus & Altiparmak, 2011).
e) CASE REPORT: A 71-year-old man presented with nausea, vomiting, diarrhea, and weakness within 48 hours of ingesting an unknown amount of Amanita mushrooms while camping in northwestern Iowa. Laboratory results revealed elevated liver enzymes, total bilirubin of 1.5 mg/dL (normal range, 0 to 1 mg/dL), INR of 1.3 (normal range, 0.8 to 1.2), and a serum creatinine of 2.7 mg/dL (normal range, 0.51 to 1.2 mg/dL). Despite treatment with IV N-acetylcysteine and penicillin G, he developed encephalopathy, acute renal injury, coagulopathy, and worsening transaminase elevations. He was transported to the liver transplant center and received multidose activated charcoal and IV silibinin (loading dose: 5 mg/kg over 1 hour, continued for 3 days at 20 mg/kg/day) starting 96 hours postingestion. His condition gradually improved by day 3 and he was discharged 5 days after presentation. On a follow-up visit a month later, his liver enzymes were normal (Gores et al, 2014).
f) SOMNOLENCE
g) COMA

a) Seizures may be observed in hepatic coma.
b) Meningeal signs with anisocoria and miosis are often present prior to seizures (Mitchell & Rumack, 1978).

a) CASE REPORT: Langer et al (1997) reported intracranial hypertension on the 5th day following amanita phalloides ingestion in a 9-year-old boy which was adequately controlled for 12 hr. After 36 hours, intracranial hypertension (above 80 mm Hg) became resistant to therapy and the child died (Langer et al, 1997).

a) Polyneuropathy, developing 8 days after mushroom ingestion, has been reported in 5 patients. Loss of strength in the lower extremities, absence of deep tendon reflexes and alteration of pain, temperature and proprioceptive sensitivity was noted in all 5 patients. EMG readings showed a decrease in sensitive conduction speed and, to a lesser extent, motor speed. Two of these patients did not improve after 1 year (Ramirez et al, 1993).

a) Asthenia has been reported in some patients after ingestion of these mushrooms (Kervegant et al, 2013; Krenova et al, 2007; Trabulus & Altiparmak, 2011).
b) CASE SERIES: In a study of 34 patients with amanita phalloides poisoning, weakness developed in 4% of patients (Krenova et al, 2007).
c) In a retrospective review of 144 amatoxin poisonings, 16 patients developed weakness (Trabulus & Altiparmak, 2011).

a) In a retrospective review of 144 amatoxin poisonings, 27 patients developed vertigo (Trabulus & Altiparmak, 2011).

a) In a retrospective review of 144 amatoxin poisonings, 10 patients developed headache (Trabulus & Altiparmak, 2011).

a) Gastrointestinal symptoms, including nausea, vomiting, diarrhea, and abdominal pain, appear after a latent period of 6 to 24 hours (mean 12.3 hours) (Vanooteghem et al, 2014; Kervegant et al, 2013; Kantola et al, 2009; Hydzik et al, 2008; Himmelmann et al, 2001; Yamada et al, 1998; Scalzo et al, 1998; Omidynia et al, 1997; Serne et al, 1996; Aji et al, 1995; Cappell & Hassan, 1992; Rivett & Boon, 1988). One patient developed rectal bleeding after ingesting a meal containing Lepiota brunneoincarnata mushrooms (Kervegant et al, 2013).
b) INCIDENCE: In a study of 205 Amanita intoxications, gastrointestinal symptoms were present in 199 (97%) patients (Floersheim et al, 1982).
c) CASE REPORT: A 71-year-old man presented with nausea, vomiting, diarrhea, and weakness within 48 hours of ingesting an unknown amount of Amanita mushrooms while camping in northwestern Iowa. Laboratory results revealed elevated liver enzymes, total bilirubin of 1.5 mg/dL (normal range, 0 to 1 mg/dL), INR of 1.3 (normal range, 0.8 to 1.2), and a serum creatinine of 2.7 mg/dL (normal range, 0.51 to 1.2 mg/dL). Despite treatment with IV N-acetylcysteine and penicillin G, he developed encephalopathy, acute renal injury, coagulopathy, and worsening transaminase elevations. He was transported to the liver transplant center and received multidose activated charcoal and IV silibinin (loading dose: 5 mg/kg over 1 hour, continued for 3 days at 20 mg/kg/day) starting 96 hours postingestion. His condition gradually improved by day 3 and he was discharged 5 days after presentation. On a follow-up visit a month later, his liver enzymes were normal (Gores et al, 2014).

a) There is a sudden onset of colicky abdominal pain rapidly followed by nausea, frequent vomiting, and diarrhea, usually beginning 10 to 12 hours after ingestion (Vanooteghem et al, 2014; Mottram et al, 2010; Hanrahan & Gordon, 1984; Gazzero & Goos, 1991; Scalzo et al, 1998; Nicholls et al, 1995; Cappell & Hassan, 1992; Nicholson & Korman, 1997; Omidynia et al, 1997).
b) In a 15-year retrospective analysis of amatoxin mushroom poisoning (n=111), 93 (83.8%) patients developed nausea and vomiting, with the average delay in onset of 12.4 +/- 0.8 hours (Giannini et al, 2007).
c) CASE SERIES: In a study of 34 patients with amanita phalloides poisoning, vomiting developed in 76% of patients (Krenova et al, 2007).
d) In a retrospective review of 144 amatoxin poisonings, 139 patients developed nausea and 129 developed vomiting (Trabulus & Altiparmak, 2011).

a) In many cases, diarrhea is severe, watery, and cholera-like (up to 2 to 4 L/day) (Mottram et al, 2010; Kaneko et al, 2001; Olesen, 1990; Nicholson & Korman, 1997; Omidynia et al, 1997) or may be bloody (Nicholls et al, 1995). In the absence of fluid replacement, diarrhea may induce rapid dehydration, hemoconcentration, and hypovolemic shock. Diarrhea may persist for 2 to 4 days.
b) In a 15-year retrospective analysis of amatoxin mushroom poisoning (n=111), 102 (91.9%) patients developed diarrhea, with the average delay in onset of 16.7 +/- 1.8 hours (Giannini et al, 2007).
c) CASE SERIES: In a study of 34 patients with amanita phalloides poisoning, diarrhea developed in 62% of patients; 22% experienced abdominal cramping (Krenova et al, 2007).
d) In a retrospective review of 144 amatoxin poisonings, 82 patients developed diarrhea (Trabulus & Altiparmak, 2011).

a) CASE REPORT: A 71-year-old man inadvertently ingested mushrooms containing amanita phalloides, and developed typical gastrointestinal symptoms and laboratory evidence of severe hepatic damage. Although hepatic injury slowly resolved, the patient had evidence of toxic megacolon (ie, intractable diarrhea, dilatation of the intestine {6 cm noted in small intestine; 8 cm dilatation in the colon}). Antibiotic and systemic steroid therapy were not successful, but clinical improvement was observed with decompression of the colon via a catheter. No permanent sequelae was reported (Eyer et al, 2004).

a) Transient elevation of pancreatic enzyme levels, without the presence of clinical signs and symptoms of pancreatitis, were reported in a 6-year-old child approximately 5 days after ingesting the Galerina species of mushrooms (Kaneko et al, 2001).
b) CASE REPORT: A 43-year-old woman, with a medical history significant for hepatitis B carrier status, developed fulminant hepatic failure with pancreatitis, coagulopathy, profound metabolic acidosis, and renal insufficiency, 36 hours after ingesting approximately 170 g of sauteed Lepiota subincarnata mushrooms. Following supportive care and a liver transplant, she was discharged home on day 12 (Mottram et al, 2010).

a) Abdominal pain developed in a patient after ingesting a meal containing Lepiota brunneoincarnata mushrooms (Kervegant et al, 2013).
b) In a retrospective review of 144 amatoxin poisonings, 78 patients developed abdominal pain (Trabulus & Altiparmak, 2011).

a) Clinical signs of hepatocellular damage usually become evident only on the third to fourth day after ingestion. Clinical presentation may only include a mild jaundice and a mild hepatomegaly (Burton et al, 2002; Nicholls et al, 1995). Elevated liver enzyme levels are common, and sometimes are accompanied with coagulopathy (Stein et al, 2015; Gores et al, 2014; French et al, 2011; Aygul et al, 2010; Madhok et al, 2006; Lim et al, 2000; Cappell & Hassan, 1992; Scalzo et al, 1998; O'Brien & Khuu, 1996; Nicholson & Korman, 1997; Zevin et al, 1997; Aji et al, 1995; Serne et al, 1996; Ramirez et al, 1993).
b) Fulminant hepatic failure, developing very quickly, often within 4 days, and requiring liver transplantation has been reported following severe intoxications (Stein et al, 2015; Hydzik et al, 2008; Donnelly et al, 2000; Zilker et al, 1999; Yamada et al, 1998).
c) In a 15-year retrospective analysis of amatoxin mushroom poisoning (n=111), patients were graded according to the Poisoning Severity Score (PSS) and transaminase levels: PSS 1 (patients (n=62) with mild intoxication and transaminase of less than 1000 International Units/L); PSS 2 (patients (n=18) with moderate intoxication and transaminase of 1000 to 2000 International Units/L); PSS 3 (patients (n=31) with severe intoxication and transaminase of greater than 2000 International Units/L). The majority of patients reached the highest PSS 60 hours after mushroom ingestion. Two patients (graded as PSS 3) died; both patients were hospitalized very late (more than 60 hours after ingestion). The most clinically useful indicators of prognosis were hepatic transaminases and prothrombin activity (PTA). Overall, patients with PSS3 grade (higher transaminase levels) had lower PTA. In most patients, peak hepatic transaminase levels and minimum PTA were reached on day 3 postingestion. Patients treated within 36 hours of mushroom ingestion had lower transaminase peak, higher PTA, lower PSS grading, and earlier discharge from hospital. At follow-up, 12 to 180 months (89.6 +/- 6.7) after discharge, all patients had normal hepatic transaminase and PTA levels, including those classified as PSS 3 (Giannini et al, 2007).
d) In severe cases, hepatitis follows an explosive course with marked jaundice, and hepatic coma. It may be accompanied by renal failure and cardiovascular collapse. In fatal cases death occurs within 6 to 16 days (mean 8 days). CDC (1997) reported 2 cases of poisoning, both developing hepatic encephalopathy and one developing renal failure, with death occurring 6 and 9 days after ingestion.
e) PROGNOSTIC INDICATOR: In a small study (n=12; 4 fatalities; 8 recovered) of amanita phalloid poisonings, transaminase levels and severity of clinical features were examined. In all patients, transaminase levels were increased usually 2 days after exposure and the highest values were reached by days 4 to 6. In the group that died, the average value of AST was 4456 +/- 534 (range 2260-6328) and ALT was 3758 +/- 1054 (range 1870-6388) with a De Ritis index (AST to ALT ratio) generally higher than 1 (mean 1.41 +/- 0.28, range 0.96 to 1.6.). In the surviving group, the average value of AST was 271.5 +/- 110 (range 67-661) and ALT was 1235.37 +/- 212 (range 63-4641) with a De Ritis index of less than 1.0 (mean 0.32 +/- 0.0085; range 0.14 to 0.46). The authors concluded that aminotransferases are important biological markers, and suggested that monitoring transaminases and measuring their ratio may be of prognostic value (Petkovska et al, 2003).
f) Liver biopsies carried out during the acute phase of the poisoning do NOT offer any substantial advantage over current clinical and biochemical criteria with respect to assessment of short- or medium-term prognosis. Prothrombin time appears to be a more useful prognostic marker for clinical outcome than serum aminotransferase levels, although close monitoring of both are recommended (Lim et al, 2000).
g) CASE REPORTS

a) In a retrospective review of 144 amatoxin poisonings, 9 patients developed jaundice (Trabulus & Altiparmak, 2011).

a) Mice given a single dose of alpha-amanitin, 0.6 mg/kg or 1.2 mg/kg, demonstrated hepatotoxicity based on liver histology and enzymes that were concentration dependent. Hyperbaric oxygen therapy provided no protection against liver damage (Thomas et al, 1997).

a) Two kinds of renal failure may be observed. During the gastrointestinal phase, a functional renal failure is frequently observed. It is associated with hypovolemia, and is secondary to fluid losses and hypoperfusion of the kidneys. This renal failure improves if dehydration and hypovolemia are treated rapidly and aggressively.
b) In a retrospective review of 144 amatoxin poisonings, 19 patients developed acute renal failure; 5 patients developed oliguria-anuria (Trabulus & Altiparmak, 2011).
c) It is sometimes possible to avoid acute tubular necrosis by the correct administration of fluids (Constantino et al, 1978) (Vesconi et al, 1985). A direct nephrotoxic effect of amatoxins is possible.
d) AMANITA BISPORIGERA
e) AMANITA PHALLOIDES

a) HYPOURICEMIA seen after A. phalloides poisoning in children is probably due to proximal tubule injury. A possible mechanism is tubular hypersecretion. The tubular injury/defect may endure long after liver function tests are normalized (Zawadzki et al, 1993).

a) During the gastrointestinal phase, metabolic acidosis may occur as a result of bicarbonate losses from the gut. Metabolic acidosis, hypotension, and severe liver dysfunction were reported 6 days after ingestion of Amanita phalloides mushrooms (CDC, 1997) and within a week of ingestion of Amanita bisporigera (Scalzo et al, 1998).
b) CASE REPORT: Severe metabolic acidosis (pH 7.05) occurred in a 61-year-old female several hours after ingesting several mushrooms that had been dried and frozen for approximately 7 to 8 months. The diagnosis of Amanita phalloides poisoning was confirmed by detection of amatoxin in the patient's urine (Himmelmann et al, 2001).
c) CASE REPORT: Severe metabolic acidosis (pH 6.98, pCO2 17.9 mmHg, bicarbonate 10 mEq/L, lactate 10.9 mmol/L, anion gap 28 mEq/L) developed in a 43-year-old woman who also experienced fulminant hepatic failure with pancreatitis, coagulopathy, profound metabolic acidosis, and renal insufficiency, 36 hours after ingesting approximately 170 g of sauteed Lepiota subincarnata mushrooms. Following supportive care and a liver transplant, she was discharged home on day 12 (Mottram et al, 2010).

a) CASE REPORT: Lactic acidosis has been reported during the hepatic phase in a 90-year-old woman. The patient was in fulminant hepatic failure (Feinfeld et al, 1994).
b) CASE REPORT: A 68-year-old man was reported with marked lactic acidosis and severe renal impairment during the hepatic phase of Amanita phalloides poisoning. He died 24 hours after hospital admission of multiorgan failure (Nicholson & Korman, 1997).

a) Coagulation defects with hypofibrinogenemia and hypoprothrombinemia occur in hepatic failure and may result in local or general bleeding.
b) Usually the earliest indication of coagulopathy is persistent bleeding from intravenous puncture sites (Bivins et al, 1985). Other types of bleeding include epistaxis and gastrointestinal hemorrhage.
c) Manifested by marked coagulation defects secondary to impaired synthesis of clotting factors, this condition usually signifies a poor prognosis in that it indicates extensive hepatocellular damage (Floersheim, 1987; Scalzo et al, 1998; Serne et al, 1996).
d) CASE SERIES: A woman and her 2 children (an 8-year-old boy and an 11-year-old girl) ingested a meal containing Lepiota brunneoincarnata mushrooms and presented about 9 hours later with stomach cramps and vomiting. The mother reported that she ate most of the mushroom meal and her son ate a smaller portion and her daughter only had a bite. They had normal laboratory results and were discharged with a prescription for antiemetics and spasmolytic agents. The next day, the son's condition deteriorated and he developed asthenia, fever, abdominal pain, and watery diarrhea. He presented to a pediatric ED on day 4 with the same symptoms, as well as rectal bleeding, somnolence, and confusion. Laboratory results revealed major liver failure with elevated transaminase concentrations (aspartate transaminase, 1018 International Units/L; alanine transaminase, 3205 International Units/L) and a clotting disturbance (prothrombin time, 18 seconds [normal values: 10 to 14 seconds]). The mother and daughter also had transient minor liver impairment. All patients received activated charcoal, penicillin G (0.1 MIU/kg x 6/day for 12 hours), silibinin (5 mg/kg x 4/day for 24 hours), and N-acetylcysteine (IV loading dose for 150 mg/kg, followed by 50 mg/kg every 4 hours for 12 hours). They gradually improved and were discharged 11 days postingestion (Kervegant et al, 2013).
e) CASE REPORT: A 54-year-old man who ingested 2 to 4 Amanita phalloides mushrooms, developed necrotic liver, encephalopathy, severe coagulopathy, and acute renal failure. He was treated with 7 sessions of Molecular Absorbents Recirculating Systems (MARS) starting 63 hours after ingesting mushrooms, as well as standard supportive care (eg, fluid resuscitation, NAC, oral activated charcoal). He also underwent liver transplantation 9 days postingestion. After the surgery, he experienced persistent acute renal failure (requiring hemodialysis), rhabdomyolysis, and heparin-induced thrombocytopenia. He recovered and was discharged home after 128 days of hospitalization (Kantola et al, 2009).
f) CASE REPORT: A 65-year-old woman developed acute renal failure, liver encephalopathy, and hypoprothrombinemia after ingesting Amanita phalloides mushrooms. Following supportive care, her liver function recovered completely. However, acute renal failure persisted, necessitating hemodialysis (started on day 10). She still required hemodialysis at 2-year follow-up (Garrouste et al, 2009).
g) CASE REPORT: A 61-year-old woman developed a decrease in prothrombin time, from 47% to 32% despite administration of vitamin K, approximately 2 days after ingesting several mushrooms that had been frozen for approximately 7 to 8 months. The speculative diagnosis of Amanitas phalloides was confirmed by urinary detection of amatoxin at a level of 37.3 mcg/L (measured approximately 4 days postingestion). Despite aggressive supportive care, the patient continued to deteriorate with a prothrombin time of less than 10% on day 3 of hospitalization (approximately 6 days postingestion) and subsequently died on day 4 of hospitalization (Himmelmann et al, 2001).
h) CASE SERIES: In a study of 34 patients with amanita phalloides poisoning, hepatic failure with coagulopathy and encephalopathy developed in 24% of patients. One patient developed fulminant hepatic failure 2 days after ingesting mushrooms. He died of circulatory failure during liver transplantation (Krenova et al, 2007).
i) CASE REPORT: A 33-year-old woman developed hepatic failure with coagulopathy and encephalopathy after ingesting Amanita phalloides mushrooms. She underwent liver dialysis and a successful liver transplantation was performed 6 days postingestion (Hydzik et al, 2008).
j) CASE REPORT: A 71-year-old man presented with nausea, vomiting, diarrhea, and weakness within 48 hours of ingesting an unknown amount of Amanita mushrooms while camping in northwestern Iowa. Laboratory results revealed elevated liver enzymes, total bilirubin of 1.5 mg/dL (normal range, 0 to 1 mg/dL), INR of 1.3 (normal range, 0.8 to 1.2), and a serum creatinine of 2.7 mg/dL (normal range, 0.51 to 1.2 mg/dL). Despite treatment with IV N-acetylcysteine and penicillin G, he developed encephalopathy, acute renal injury, coagulopathy, and worsening transaminase elevations. He was transported to the liver transplant center and received multidose activated charcoal and IV silibinin (loading dose: 5 mg/kg over 1 hour, continued for 3 days at 20 mg/kg/day) starting 96 hours postingestion. His condition gradually improved by day 3 and he was discharged 5 days after presentation. On a follow-up visit a month later, his liver enzymes were normal (Gores et al, 2014).

a) CASE REPORT: Disseminated intravascular coagulation (DIC) was observed in a patient who died from massive liver necrosis (Sanz et al, 1988).

a) Mild jaundice with sclera icterus is present in most patients at the hepatic phase of the intoxication. Marked jaundice occurs when hepatitis progresses to severe hepatic failure.

a) Serum insulin and C-peptide levels were elevated after ingestion (Kelner & Alexander, 1987).

a) In severe hepatic failure, glucose metabolism is often disturbed.
b) CASE REPORT: A 9-year-old boy was reported to have severe hypoglycemia and hepatic failure on the second day after ingestion of amanita phalloides (Langer et al, 1997).
c) CASE REPORT: Hypoglycemia was reported in a 61-year-old woman who had ingested several mushrooms that had previously been frozen for approximately 7 to 8 months (Himmelmann et al, 2001).
d) Hyperglycemia may also occur when highly concentrated dextrose solutions are infused.
e) In in vivo and in vitro studies it was noted that amanita phalloides toxins can induce insulin release. Although the exact effect of amanita poisoning related to clinical presentation (ie, insulin levels and glucose metabolism) cannot be determined, the results indicate that amanita toxins can induce a direct insulin-releasing effect and a cytotoxic effect on beta cells (DeCarlo et al, 2003).
f) In a retrospective review of 144 amatoxin poisonings, 8 patients developed hypoglycemia (Trabulus & Altiparmak, 2011).

a) Serum calcitonin levels were elevated in conjunction with hypocalcemia in 4 patients who ingested alpha-amanitin containing mushrooms (Kelner & Alexander, 1987).

a) Serum parathyroid hormone was elevated at first (during hypocalcemia), but normalized when the hypocalcemia was corrected (Kelner & Alexander, 1987).

a) Serum thyroxine concentrations were depressed in 4 patients who ingested alpha-amanitin containing mushrooms (Kelner & Alexander, 1987).

a) CASE REPORT: Kaufmann et al (1978) reported an Amanita phalloides ingestion in a 25-year-old woman at 9 weeks gestation. The patient developed a toxic hepatitis (transaminase 1800 Units/L). After life-threatening maternal toxicity was treated, a therapeutic abortion was carried out at 12 weeks gestation. Histologic examination of fetal liver showed cellular damage related to amanitin toxicity. Amatoxins appear to cross the placental barrier (Kaufmann et al, 1978).

a) CASE REPORT: A 22-year-old woman in the 11th week of pregnancy was diagnosed with medium severity Amanita phalloides poisoning (eg, vomiting, diarrhea, persistent increases in liver enzymes, severe decreases in prothrombin factor V, II, VII, and X). Following treatment with intravenous hydration, silymarine and N-acetylcysteine, her condition gradually improved. On day 10, no fetal abnormalities were seen during an obstetric examination. She delivered a healthy baby in the 38th week of pregnancy (Boyer et al, 2001).

a) CASE REPORT: A 26-year-old woman in her 23rd week of pregnancy was diagnosed with medium severity Amanita phalloides intoxication, requiring hydration, forced diuresis, and administration of silibinin, penicillin, thioctic acid, hydrocortisone, vitamin K and fresh frozen plasma. No fetal abnormalities were seen on sonographic and obstetric controls. A healthy baby was born in the 38th week of pregnancy (Nagy et al, 1994).
b) CASE REPORT: A 27-year-old woman who was 20 weeks pregnant was admitted for amanita poisoning and developed hepatic encephalopathy. Despite aggressive supportive care and extracorporeal detoxification by hemodialysis plus hemoperfusion (performed daily), the patient's clinical status (hepatic and neuro function) did not improve. Uterine contraction was noted on day 5, with threatened abortion anticipated. The patient then underwent three courses of albumin dialysis using MARS intermittently starting from the 8th day of hospitalization. Liver function was noted to immediately improve, as well as clinical features; uterine contraction ceased. The patient was discharged with normal liver function and fetal evaluation appeared normal. Upon follow-up, a healthy baby was born at 36 weeks and had normal development at 7 months (Wu & Wang, 2004).

a) CASE REPORT: A 21-year-old woman in the eighth month of pregnancy, ingested Amanita phalloides. Blood tested positive for amatoxin, but the amniotic fluid tested negative. She gave birth to a healthy baby without biochemical evidence of hepatotoxicity (Belliardo et al, 1983).
b) CASE REPORT: Four family members presented with gastrointestinal symptoms 2 days after ingesting Amanita phalloides mushrooms. One patient, a pregnant woman (at 39 weeks' gestation) developed only elevated liver enzymes and was treated with silibin (2 g/24 hour for 3 days). She delivered a healthy baby who had a slight temporary increase in liver enzymes activity. All samples of amniotic fluid, umbilical vein blood, peripheral venous blood, and urine of mother and newborn tested negative for amatoxin. Two family members died from liver failure and lethal brain edema (Wacker et al, 2009).

a) Concentrations were mean 73 +/- 69 ng/mL for alpha amanitin (range 8 to 190 ng/mL) and mean 55.6 +/- 60 ng/mL for beta-amanitin (range 16 to 162 ng/mL).
b) In all cases except one, amanitins were only found in serum before the 48th hour following ingestion.
c) In 45 patients, amatoxins were found in the plasma of 11 and the urine of 22. Amatoxins were present in the plasma until the 36th hour, but could be found in urine for up to 4 days using HPLC (Jaeger et al, 1989).

a) Hepatic enzymes usually reach a peak between the 60th and 72nd hours and then decrease. Enzyme activity may be low in massive liver necrosis (Bivins et al, 1985).
b) Alkaline phosphatase (AP) activity is often within normal limits. An AP ISO enzyme study will show increases in the hepatic-2 fraction as an indicator of severity of hepatic damage (Parra et al, 1992).
c) Szponar et al (1999) reported that decreased prothrombin index, significant increase of bilirubin, and increased ALT, AST and AFP levels correlated with the clinical stage of illness.
d) PROGNOSTIC INDICATOR: In a small study (n=12; 4 fatalities; 8 recovered) of amanita phalloid poisonings, transaminase levels and severity of clinical features were examined. In all patients, increased transaminase levels were increased usually 2 days after exposure and the highest values were reached by days 4 to 6. In the group that died, the average value of AST was 4456 +/- 534 (range 2260-6328) and ALT was 3758 +/- 1054 (range 1870-6388) with a De Ritis index (AST to ALT ratio) generally higher than 1 (mean 1.41 +/- 0.28, range 0.96 to 1.6.). In the surviving group, the average value of AST was 271.5 +/- 110 (range 67-661) and ALT was 1235.37 +/- 212 (range 63-4641) with a De Ritis index of less than 1.0 (mean 0.32 +/- 0.0085; range 0.14 to 0.46). The authors concluded that aminotransferases are important biological markers, and suggested that monitoring transaminases and measuring their ratio may be of prognostic value (Petkovska et al, 2003).

a) In serial determinations, urinary amatoxins were found 24 to 66 hours postingestion. Total urinary output of amatoxins in this period ranged from 12,000 to 23,000 ng.

a) In some cases, serial determinations showed that amanitins were excreted up to 72 to 96 hours postingestion.
b) Concentrations as high as 4800 ng/mL (alpha amanitin) and 4300 ng/mL (beta amanitin) were observed.
c) Mean total amounts excreted in urine: alpha amanitin (0.95 mg) and beta amanitin (1.7 mg).

a) In patients presenting with seizures, EEG should be considered.

a) 13C-MBT has been used experimentally to evaluate cytochrome P450-dependent liver function in patients with Amanita phalloides poisoning. Methacetin, a substrate that undergoes extensive first-pass clearance, is metabolized by cytochrome P450 (isoform CYP1A2) into carbon dioxide by single dealkylation. The appearance of 13CO2 in exhaled breath suggests that 13C-methacetin has undergone oxidation. Exhaled breath samples are collected and 13C content are measured using an isotope ratio mass spectrometer. The breath test shows a cumulative percentage of the administered dose of 13C recovered over time, which corresponds to 13C-methacetin cumulative oxidation percentage and reflects metabolic liver capacity (Hydzik et al, 2008).

1) Perform indoors away from sunlight and excessive heat.
2) Squeeze a drop of juice from fresh mushroom tissue onto a piece of pulp paper such as newsprint. A garlic press is recommended. If only a small fragment of tissue is available, mash it onto the paper so the juice will be absorbed.
3) Encircle the wet spot with a pencil to mark location.
4) Dry the spot with gentle warm air such as from a hair dryer.
5) Add a drop of concentrated hydrochloric acid to the dry spot. The presence of amatoxins is indicated by the formation of a blue color.
6) For dry mushrooms, crush a part in absolute methanol and apply a drop of the methanol to the paper.
7) This test may NOT be used on mushroom parts that have been removed from the stomach (Lampe & McCann, 1987).
8) The test's sensitivity is 0.2 mg/mL (Lampe & McCann, 1987).

1) Melzer's reagent is used to detect an amyloid reaction in cyclopeptide containing Amanitas.
2) REAGENT CONTAINS: 1.5 g iodine, 5 g potassium iodide, 100 g (mL) chloral hydrate; add to 100 mL of warm water. Do NOT boil.
3) A drop of this solution is placed on the spores of suspected mushrooms. The cyclopeptide-containing species spores turn blue (amyloid), other mushroom types turn brown (dextrinoid) or do NOT change color (non-amyloid) (Lincoff & Mitchell, 1977).

1) Column chromatography procedure on Sephadex LH-20 followed by thin-layer chromatography has been used for the determination of amatoxins in A. phalloides (Faulstich et al, 1975).
2) One study applied high-performance thin-layer chromatography for the determination of alpha, beta, and gamma amanitins in A. phalloides and A. verna (Seeger & Stijve, 1979).

1) Grade 1: GI upset only, no indications of liver or kidney failure. Symptomatic treatment only (Spoerke & Rumack, 1994).
2) Grade 2: Show all signs of intoxication, with a mild to moderate rise in transaminases (less than 500 units/L). Symptomatic treatment only (Spoerke & Rumack, 1994).
3) Grade 3: Severe hepatic damage with a great increase in transaminases (> 500 units/L), plus an impaired plasma clotting function (e.g. a prolonged prothrombin time) (Spoerke & Rumack, 1994). Can be divided into two groups based on bilirubin values:
4) Grade 4: Steep rise in transaminases, accompanied by a steep decline in clotting function, a steep rise in bilirubin, and the onset of kidney dysfunction. These patients have a poor prognosis, and many die in spite of intensive care (Spoerke & Rumack, 1994).

a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
b) ADVERSE EFFECTS/CONTRAINDICATIONS

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
b) ADVERSE EFFECTS/CONTRAINDICATIONS

a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.

a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.

a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.

a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).

a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.

a) ADULT DOSE: Optimal dose not established. After an initial dose of 50 to 100 grams of activated charcoal, subsequent doses may be administered every 1, 2 or 4 hours at a dose equivalent to 12.5 grams/hour (Vale et al, 1999), do not exceed: 0.5 g/kg charcoal every 2 hours (Ghannoum & Gosselin, 2013; Mauro et al, 1994). There is some evidence that smaller more frequent doses are more effective at enhancing drug elimination than larger less frequent doses (Park et al, 1983; Ilkhanipour et al, 1992). PEDIATRIC DOSE: Optimal dose not established. After an initial dose of 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) (Chyka & Seger, 1997), subsequent doses may be administered every 1, 2 or 4 hours (Vale et al, 1999) in a dose equivalent to 6.25 grams/hour in children 1 to 12 years old.
b) Activated charcoal should be continued until the patient's clinical and laboratory parameters, including drug concentrations if available, are improving (Vale et al, 1999). The patient should be frequently assessed for the ability to protect the airway and evidence of decreased peristalsis or intestinal obstruction.
c) Use of cathartics has not been shown to increase drug elimination and may increase the likelihood of vomiting. Routine coadministration of a cathartic is NOT recommended (Vale et al, 1999).
d) AGENTS AMENABLE TO MDAC THERAPY: The following properties of a drug that are likely to allow MDAC therapy to be effective include: small volume of distribution, low protein binding, prolonged half-life, low intrinsic clearance, and a nonionized state at physiologic pH (Chyka, 1995; Ghannoum & Gosselin, 2013).
e) Vomiting is a common adverse effect; antiemetics may be necessary.
f) CONTRAINDICATIONS: Absolute contraindications include an unprotected airway, intestinal obstruction, a gastrointestinal tract that is not intact and agents that may increase the risk of aspiration (eg, hydrocarbons). Relative contraindications include decreased peristalsis (eg, decreased bowel sounds, abdominal distention, ileus, severe constipation) (Vale et al, 1999; Mauro et al, 1994).
g) COMPLICATIONS: Include constipation, intestinal bleeding, bowel obstruction, appendicitis, charcoal bezoars, and aspiration which may be complicated by acute respiratory failure, adult respiratory distress syndrome or bronchiolitis obliterans (Ghannoum & Gosselin, 2013; Ray et al, 1988; Atkinson et al, 1992; Gomez et al, 1994; Mizutani et al, 1991; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Mina et al, 2002; Harsch, 1986; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002).

a) All patients with cyclopeptide mushroom ingestion have the potential to develop severe toxicity. Administer activated charcoal for recent ingestions, and consider multiple dose activated charcoal or nasogastric suction to interrupt enterohepatic recirculation of the toxins. N-acetylcysteine may be beneficial and is associated with little toxicity. Silibinin is currently undergoing a clinical trial for amatoxin poisoning. In studies, NAC and silibinin were the most effective agents. High-dose penicillin G has also been used. All of these therapies should be instituted as soon as possible in patients with the potential for significant toxicity.

a) There are several drugs that have been proposed as antidotes in the management of cyclopeptide containing mushroom poisoning. In studies, silibinin and NAC each administered as monotherapy, and silibinin with benzylpenicillin as bi-, tri-, and polytherapies were associated with the lowest mortalities. Overall, NAC and silibinin were the most effective agents.
b) N-ACETYLCYSTEINE: High doses of N-acetylcysteine have been used in humans in the setting of amatoxin poisoning. The dose most often used is 150 mg/kg infusion over 60 minutes followed by 50 mg/kg infusion over 4 hours followed by 6.25 mg/kg/hour infusion which is continued until the patient has clinically improved.
c) SILIBININ: Silibinin is being studied as a potential antidote for amatoxin. It is an extract from milk thistle and thought to inhibit the uptake of amatoxin into hepatocytes. The most common dose is 5 mg/kg IV loading dose followed by 20 mg/kg/day via continuous infusion. There is some human data showing promise of silibinin as an antidote, and it is currently available as part of an open label, multicenter clinical trial. To obtain silibinin, contact 866-520-4412.
d) PENICILLIN G: Penicillin G appears to displace amatoxin from plasma protein binding sites and possibly inhibit its uptake into hepatocytes. The dose with some evidence of effectiveness is 300,000 to 1,000,000 units/day, though mortality is not significantly affected in preliminary studies.
e) THIOCTIC ACID: Thioctic acid is a coenzyme in the Krebs cycle used in Eastern Europe for the treatment of amatoxin poisoning with some data showing a possible reduction in mortality. The dose is 50 to 150 mg every 6 hours. Its efficacy remains unproven. It has been reported to cause hypoglycemia and is not readily available in the US.

1) Careful correction of fluid, electrolyte, glucose, and acid base imbalances
2) correction of altered coagulation factors with fresh frozen plasma as needed and intravenous vitamin K1 20 to 40 mg/day in patients with INR greater than 2.1
3) multiple dose activated charcoal 20 to 40 g every 4 hours for at least 3 days after ingestion
4) Fluid therapy (1 liter crystalloid/10 kg/day) and mannitol 18% (0.25 to 0.5 g/kg/hr) to maintain urine output of 200 ml/hr for 2 days after ingestion
5) intravenous dexamethasone (8 to 16 mg/day)
6) intravenous glutathione (4.8 g/day in two divided doses)
7) continuous intravenous administration of penicillin g (1,000,000 international units/kg for the first day, then 500,000 international units/kg for the next 2 days)
8) metoclopramide for nausea and vomiting (up to 10 mg three times/day

a) In this series, only two patients died, both of whom presented to the hospital more than 60 hours after ingestion with high transaminase and bilirubin concentrations and low prothrombin activity. Patients who were hospitalized within 36 hours of ingestion had lower peak aminotransferase concentrations and higher prothrombin activity, and were discharged earlier, suggesting that early use of this treatment regimen may impact the severity of illness (Giannini et al, 2007).

a) DOSES: This is the standard FDA-approved dosing regimen for the treatment of acetaminophen poisoning. LOADING DOSE: 150 mg/kg in 200 mL of 5% dextrose, infuse intravenously over 60 minutes. MAINTENANCE DOSE: 50 mg/kg in 500 mL of 5% dextrose, infuse intravenously over 4 hours followed by 100 mg/kg (6.25 mg/kg/hour) in 1000 mL of 5% dextrose, infuse intravenously over 16 hours (Daly et al, 2008; Prod Info ACETADOTE(R) IV injection, 2006; Prescott et al, 1979).

a) An open-label, multicenter, clinical trial (start date: February 2010; anticipated end date December, 2015), sponsored by Madaus Inc, (a division of Madaus GmbH, Cologne, Germany), is evaluating the safety and efficacy of intravenous silibinin (Legalon(R) SIL) for treating patients with amatoxin mushroom poisoning diagnosed by history, GI symptoms, elevated liver enzymes, and/or diagnostic assay. Patients will be treated with 5 mg/kg loading dose of silibinin followed by 20 mg/kg/day via continuous infusion. Treatment will be discontinued when coagulopathy has resolved, and when liver enzyme concentrations have significantly improved. Patients will be monitored for 7 to 14 days after the end of silibinin therapy with follow up lab studies. For more information on this clinical trial, check the following website: http://clinicaltrials.gov/ct2/show/NCT00915681 (Madaus Inc., 2009).
b) To obtain silibinin, a 24-hour hotline is available for physicians: 866-520-4412 (Madaus Inc., 2009).

a) A hepatic specialist should be contacted about the appropriateness of a liver transplant.
b) PROGNOSTIC INDICATORS
c) PARTIAL LIVER TRANSPLANT
d) CASE REPORTS
e) INTRAPORTAL HEPATOCYTE TRANSPLANTATION

a) In a retrospective study, the effects of MARS and therapeutic plasma exchange (TPE) therapies were evaluated in 9 patients (age range, 22 to 51 years old) with Amanita phalloides-induced fulminant liver failure. All patients were also treated with standard treatments, including gastric lavage, naso-duodenal tube with continual aspiration, multiple doses of activated charcoal, penicillin G, and vitamin K. Seven patients received 12 MARS treatments (time from intoxication to MARS: 52 to 138 hours). Seven patients received 12 TPE treatments (time from intoxication to TPE: 68 to 122 hours). Five of these patients received both TPE and MARS. Overall, 6 (66.7%) patients survived. Although both TPE and MARS removed toxins and improved liver functions, a single session of TPE produced a greater improvement in liver function as compared with MARS therapy. Patients with severe liver failure and renal failure had worse outcomes (Zhang et al, 2014)
b) CASE SERIES: Ten patients presented with vomiting, stomach cramps, and diarrhea within 2 days (median 18 hours, range 14 to 36 hours) of ingesting 2 to 4 Amanita phalloides mushrooms. Within 4 days (range, 26 to 78 hours) of mushroom ingestions, all patients were treated with MARS albumin dialysis (a median of 3 MARS sessions (range, 1 to 7 sessions) lasting for 15.4 hours) and standard supportive care (eg, fluid resuscitation, NAC, oral activated charcoal, silibinin in 7 patients and penicillin G in 4 patients). Nine patients recovered completely (days in hospital, 3 to 14 days). One patient with necrotic liver, encephalopathy, severe coagulopathy, and acute renal failure underwent liver transplantation 9 days postingestion. After the surgery, he experienced persistent acute renal failure (requiring hemodialysis), rhabdomyolysis, and heparin-induced thrombocytopenia. He recovered and was discharged home after 128 days of hospitalization (Kantola et al, 2009).
c) CASE SERIES: One retrospective study compared the outcomes of 6 patients (age range, 16 to 61 years) with Amanita Phalloides poisoning treated with either MARS (n=3; three 6-hour sessions per patient) plus optimal intensive care (OIC) or OIC alone (n=3). All 3 patients in the MARS plus OIC group had statistically significant reductions in ammonia (p value 0.011), ALT (p less than 0.01) and prothrombin time (p value 0.004). However, 2 of these patients had a significant rebound in bilirubin a day after MARS therapy. Five patients (3 from OIC group and 2 from MARS plus OIC group) who ingested 150 to 250 grams of mushrooms died within 9 days of mushroom ingestion. Mortality was 67% in the MARS group compared to 100% in the OIC group. One patient who ingested 50 grams of mushrooms and was treated with MARS plus OIC recovered and was discharged with good liver function (Sorodoc et al, 2010).
d) CASE SERIES: In a series of 6 patients with fulminant hepatic failure secondary to cyclopeptide mushroom ingestion, use of MARS was associated with improvement in serum transaminase, bilirubin, ammonia and creatinine levels and improved prothrombin time. Two patients had sustained improvement in native liver function, two had orthotopic liver transplantation and survived, and two died (Faybik et al, 2003).
e) CASE REPORT/PREGNANCY: A 27-year-old woman who was 20 weeks pregnant was admitted for amanita poisoning and developed hepatic encephalopathy. Despite aggressive supportive care and extracorporeal detoxification by hemodialysis plus hemoperfusion (performed daily), the patient's clinical status (hepatic and neuro function) did not improve. Uterine contraction was noted on day 5, with threatened abortion anticipated. The patient then underwent three courses of albumin dialysis using MARS intermittently starting from the 8th day of hospitalization. Liver function was noted to immediately improve, as well as clinical features; uterine contraction ceased. The patient was discharged with normal liver function and fetal evaluation appeared normal. Upon follow-up, a healthy baby was born at 36 weeks and had normal development at 7 months (Wu & Wang, 2004).
f) CASE REPORT/PEDIATRIC: An 11-year-old boy with amanita phalloides poisoning developed fulminant liver failure and CNS depression, and was placed on a waiting list for emergent liver transplant. During this period, the patient was started on continuous albumin dialysis with MARS (Terakilin AG combined with BM25, Baxter); no neurological changes were observed after the first session. On day two of therapy the parameters for the MARS sessions were modified (ie, increased blood, albumin and dialysate flows), and the patient had a dramatic improvement in neurological function approximately 1 hour after the session was completed; preparation for emergent transplant was temporarily halted. Despite a presumed rebound deterioration in brain function, the patient had a third session and the patient continued to make neurological and clinical improvement on days 4 through 7. On day 24, the patient was discharged to home with normal liver function and intact neurological functioning; 12 month follow-up revealed no clinical or developmental deficits (Rubik et al, 2004).
g) CASE REPORTS: MARS was reportedly used in another amanita phalloides poisoning with a favorable outcome (Catalina et al, 2003). MARS appears to be a promising bridging technique until the patient's liver can spontaneously recover or until liver transplantation can occur.

a) CASE REPORT: An 18-year-old man unintentionally ingested 11 amanita bisporigera mushrooms, and developed hepatotoxicity. Laboratory findings approximately 20 hours after exposure included: aspartate aminotransferase (AST) 42 Units/L, total bilirubin 0.9 mg/dL, total protein 5.1 g/dL and ammonia level of 62 micromol/L. Due to concern of developing severe hepatotoxicity, the patient was transferred to a higher level of care. Severe liver dysfunction developed within 72 hours (AST 2459 U/L, ALT 3649, U/L, INR of 5.96, ammonia of 67 micromol/L) and aggressive treatment including possible liver transplantation. The patient underwent an upper gastrointestinal endoscopy with nasobiliary drain placement to interrupt the enterohepatic circulation of amatoxins. The total amount of bile was 240 mL. Total amatoxin (including alpha-amatoxin {1.81 mg} and beta-amatoxin {2.22 mg} as determined by high performance liquid chromatography) excreted from the bile was 4.03 mg over 3 days. Charcoal hemoperfusion was also performed to enhance elimination. The patient recovered completely with normal liver enzymes and was discharged to home on day 8 (Madhok et al, 2006).

a) CASE REPORT: A 24-year-old woman presented with abdominal pain, nausea, vomiting, and weakness 6 hours after ingesting Amanita phalloides mushrooms (unknown quantity). Despite supportive therapy, including 4 sessions of hemodialysis, her condition did not improve. Her condition deteriorated very quickly and she developed multiorgan failure, including liver, renal, and cardiac failure. At this time, she was orthopneic, cyanotic, somnolent, tachycardiac (130 beats/min), and hypotensive (BP 70/50 mmHg). An ECG revealed sinus tachycardia with non-specific ST-T wave changes in anterior leads. Laboratory results revealed a prolonged prothrombin time (INR 5.19) and elevated liver enzymes and serum creatinine. Borderline cardiomegaly with bilateral pleural effusions at the costophrenic angles was observed in a chest x-ray. An echocardiogram showed a global left ventricular hypokinesia with left ventricular ejection fraction (EF) of 24%, end-diastolic diameter of 6.2 cm, and systolic pulmonary artery pressure of 50 mmHg. At this time, an intra-aortic balloon counterpulsation catheter was inserted and a marked improvement was noted within 1 hour. In addition, she was treated with 4 units of fresh-frozen plasma and a peritoneal dialysis catheter was inserted. Her condition continued to improve and both intra-aortic balloon counterpulsation and peritoneal dialysis were removed on day 5. She was discharged on day 12 (Aygul et al, 2010).

a) Experimentally, thioctic acid was totally ineffective as an antidote against amatoxins in mice or dogs (Floersheim, 1987). There seems to be little reason to continue the use of thioctic acid in Amanita intoxication.
b) For those who still wish to consider it, administer thioctic acid (alpha-lipoic acid) 50 to 150 mg every 6 hours in intravenous glucose (Roldan & Lloret, 1986) Becker et al, 1976, Finestone et al, 1972). It must be protected from light (wrap intravenous bottle and tubing in aluminum foil).
c) Thioctic acid is NOT commercially available for use in humans. The technical material may be available through chemical supply companies.

a) Three groups of 10 mice each were given 0.5 mg/kg of amanitin and either 1) saline before and after, 2) cimetidine both before and after, or 3) saline before and cimetidine 6 hours after.
b) Group 1 mice were injected intraperitoneally with saline 1 milliliter, then 60 minutes later with 2.5 mg/kg of phallodin.
c) Group 2 mice were injected intraperitoneally with 120 mg/kg of cimetidine, then 60 minutes later with 2.5 mg/kg phallodin. The cimetidine pretreatment group had a statistically worse survival rate than the control group (Schneider et al, 1991).
d) Two mice in group 2 died due to reaction to the 120 mg/kg intraperitoneal dose. The surviving 18 mice appeared to have decreased fatty changes compared to the unprotected group.
e) No comparison was made to other forms of therapy. The actual mechanism that produced this reduction is unknown.
f) If the 120 mg/kg dose used in the experiment were applied to a 70 kg human, this would be 8,400 mg, well above the 800 to 1200 mg therapeutic dose.
g) Much more work needs to be done before cimetidine can be recommended as a standard therapy.

a) In 1957, Dr Bastien proposed a treatment where a patient is given intravenous vitamin C (ascorbic acid) 3 grams/day, oral nifuroxazide 1,200 mg/day, and dihydrostreptomycin 1500 mg/day.
b) The three drugs are given for 3 days during which carrot broth is the only source of nutrition. He had treated himself and other patients using this technique (Laing, 1984).
c) Some poison centers in France use the technique combined with fluid, electrolytes, and penicillin. It can NOT recommend this technique at this time.

a) Four hours later they were given 1 milliliter of solutions containing the following combination therapies.
b) All were tested versus controls who received no treatment. Seven day survival is indicated below. Caution should be used when interpreting these results.
c) Similar to previous studies, the dose of cimetidine was approximately 28 times the usual single therapeutic human dose.

a) Kutkin is a mixture of the iridoid glycosides picroside 1 and kutkoside.
b) When mice were given lethal doses of lyophilized Amanita phalloides, the protective effect of kutkin was comparable to that seen with silibinin (Floersheim et al, 1990).

a) Aucubin has shown to be protective against Amanita intoxication when tested in dogs and mice (Chang et al, 1984) Chang & Yun, 1985; (Chang & Yamaura, 1993).
b) No human testing has been done.

1) Nine of 10 patients given hemodialysis died in one case series. This treatment was not thought to be responsible for the poor outcome (Paydas et al, 1990).

1) MUSHROOM POISON CASE REGISTRY

1) Woodle et al (1985) reported a 3-year-old girl who ingested Amanita phalloides. She developed abdominal pain, vomiting, diarrhea, and then hepatitis. Laboratory data showed a marked hepatitis (AST 16.648 Units/L; ALT 9.844 Units/L), and coagulation disorders (prothrombin time: 34.2 sec). Serum bilirubin was 23 mg/L and ammonia was 122 mcg/dL. Despite supportive treatment, the patient deteriorated rapidly and developed an encephalopathy (grade III). An orthotopic liver transplantation was performed on the fifth day. After transplantation, hepatic parameters improved rapidly. However, some neurologic abnormalities remained (Woodle et al, 1985).
2) ORGAN DONATION: Langer et al (1997) reported a case of a 9-year-old boy who died on the 7th day from liver failure and intracranial hypertension following amanita phalloides ingestion. There was no evidence of renal, pulmonary or cardiac dysfunction. Consequently, his kidneys, heart, and corneas were transplanted (Langer et al, 1997).

a) SERUM AMATOXIN LEVELS were detectable in 65 percent of patients in one study (Vesconi et al, 1985) even as late as 30 hours postingestion. Concentrations were 0.5 to 24 nanograms/milliliter. Only 4 of 19 had levels greater than 3 nanograms/milliliter.
b) In another study, serum amatoxin levels were detected in only 10 of 30 patients (Jaeger et al, 1988). Concentrations were 8 to 190 nanograms/milliliter for alpha amanitin (6 patients) and 16 to 162 nanograms/milliliter for beta amanitin (5 patients).
c) Urinary amatoxin level of 37.3 mcg/L (measured approximately 4 days post-ingestion) confirmed a suspected diagnosis of Amanitas phalloides poisoning following ingestion of several mushrooms that had been previously frozen for 7 to 8 months (Himmelmann et al, 2001).

a) In animals fatally poisoned by oral amatoxins, amatoxin levels are always below 30 nanograms/milliliter even in the first hour of poisoning (Vesconi et al, 1985).

a) Begin treatment immediately.
b) Keep animal warm and do not handle unnecessarily.
c) Remove the patient and other animals from the source of contamination or remove dietary sources.

a) ASPCA Animal Poison Control Center, 1717 S Philo Road, Suite 36 Urbana, IL 61802
b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
c) Contact information: (888) 426-4435 (hotline) or www.aspca.org (A fee may apply. Please inquire with the poison center). The agency will make follow-up calls as needed in critical cases at no extra charge.

a) EMESIS/GASTRIC LAVAGE -
b) ACTIVATED CHARCOAL/CATHARTIC -

a) HORSES/DIAZEPAM: Neonates: 0.05 to 0.4 milligrams/kilogram; Adults: 25 to 50 milligrams. Give slowly intravenously to effect; repeat in 30 minutes if necessary.
b) CATTLE, SHEEP AND SWINE/DIAZEPAM: 0.5 to 1.5 milligrams/kilogram intravenously to effect.

a) DIAZEPAM: 0.5 to 2 milligrams/kilogram intravenous bolus; may repeat dose every ten minutes for four total doses. Give slowly over 1 to 2 minutes to effect.
b) PHENOBARBITAL: 5 to 30 milligrams/kilogram over 5 to 10 minutes intravenously to effect.
c) REFRACTORY SEIZURES: Consider anaesthesia or heavy sedation. Administer pentobarbital to DOGS & CATS at a dose of 3 to 15 milligrams/kilogram intravenously slowly to effect. May need to repeat in 4 to 8 hours. Be sure to protect the airway.

1) SUMMARY
2) Treatment should always be done on the advice and with the consultation of a veterinarian.
3) Additional information regarding treatment of poisoned animals may be obtained from a Veterinary Toxicologist or the National Animal Poison Control Center.
4) ASPCA ANIMAL POISON CONTROL CENTER

1) GENERAL TREATMENT

a) Kinetics of amatoxins have been studied in dogs after IV administration, and in mice after IP administration (Faulstich et al, 1985; pp 1233-1234).
b) Animal species differ in their ability to absorb amatoxins from the gastrointestinal tract.
c) In mice and rats, the poison is absorbed extremely slowly or NOT at all.
d) In guinea pigs, cats, and dogs, doses of a few milligrams per kilogram cause death.

a) Phallotoxins are NOT absorbed from the gastrointestinal tract.