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Amatoxin-containing mushroom poisoning (eg, Amanita phalloides): Clinical manifestations, diagnosis, and treatment

Amatoxin-containing mushroom poisoning (eg, Amanita phalloides): Clinical manifestations, diagnosis, and treatment
Literature review current through: Jan 2024.
This topic last updated: Sep 08, 2023.

INTRODUCTION — The clinical manifestations, diagnosis, and treatment of amatoxin-containing mushroom poisoning will be reviewed here.

Clinical manifestations, diagnosis, and management of poisoning caused by other types of mushroom toxins are presented separately.

(See "Clinical manifestations and evaluation of mushroom poisoning".)

(See "Management of mushroom poisoning (except amatoxin-containing mushrooms)".)

EPIDEMIOLOGY — More than 35 mushroom species across three genera (Amanita, Galerina, and Lepiota) contain amatoxin [1-4]. Amatoxin-containing mushrooms (eg, Amanita phalloides (picture 1 and figure 1), A. virosa, A. bisporigera (picture 2), Galerina autumnalis) annually cause approximately 50 deaths in Europe and Asia and, on average, one to two deaths in the United States [1,5-12]. This difference in frequency of lethal exposures reflects the relative popularity of mushroom foraging in Europe and Asia rather than significant variance in intrinsic toxicity or prevalence of harmful mushroom species among the regions. In a study of presumed cyclopeptide-containing mushroom poisoning in the United States between 2008 and 2018, the fatality rate was 8.8 percent [10].

When serious toxicity due to mushroom ingestion does occur, it typically results from consumption of a meal of misidentified mushrooms in adult foragers and others who shared their food [2,13,14]. Amatoxins are not removed by boiling or otherwise cooking the mushroom. A common scenario involves amateur mushroom hunters or recent immigrants who mistake a toxic mushroom for an edible variety with similar morphologic features (eg, Amanita species (picture 1 and picture 2 and figure 1) mistaken for Agaricus species). (See "Clinical manifestations and evaluation of mushroom poisoning", section on 'Epidemiology'.)

By contrast, pediatric exposures to amatoxin-containing mushroom exposures (picture 1 and picture 2), rarely cause serious toxicity because of the limited amount of toxins available in the small amount of mushroom typically ingested. In the United States, no pediatric fatalities due to ingestion of a single mushroom have been reported in over 25 years of National Poison Data System surveillance [15].

AMATOXIN-CONTAINING MUSHROOMS — Common amatoxin-mushroom species include [16-18]:

Amanita – The "deadly white Amanitas" (eg, A. phalloides ["death cap" or "death cup"] (picture 1), A. bisporigera (picture 2), A. virosa ["destroying angel"], A. ocreata, and A. verna ["fool's mushroom"]) are most commonly involved in human exposures and fatalities worldwide [6,19,20]. Physical characteristics of these mushrooms include a symmetric cap (pileus) and stem (stipe) with a bulbous base (volva) surrounded by remnants of a universal veil and free gills (figure 1). They have no offensive taste or odor and typically grow as single mushroom in moist, hardwood chestnut or oak forests. They mature throughout the mid-summer and fall in temperate regions. Despite sometimes colored gills, white spores may be detected if a cap is left right side up on colored filter paper for 1 hour (ie, spore print). Immature amatoxin-containing Amanita mushrooms are egg-shaped "buttons" that reveal their developing structures when bisected. Not all Amanita mushrooms contain amatoxin, including several edible types (A. vaginata).

Lepiota – Lepiota, including L. josserandii, are similar in appearance to the deadly white Amanitas and also have significant amatoxin content [2,7]. They are far less prevalent and are implicated in human exposures less frequently. Their caps are more pointy (umbonate) and more heavily covered in concentrically ringed scales.

Galerina – Galerina mushrooms (eg, G. autumnalis, G. marginata, G. venenata) are smaller and have lower concentrations of amatoxin. Galerina are brown and grow in groups directly from decaying wood.

PATHOPHYSIOLOGY AND TOXICOKINETICS — Cyclopeptide-containing mushrooms contain cyclic octapeptides (amatoxins) and cyclic heptapeptides (phallotoxins and virotoxins) [1,21,22]. Alpha-amanitin is the predominant toxin responsible for most toxic effects seen in human exposures [21]. Phallotoxins have limited absorption but may contribute to early gastrointestinal (GI) dysfunction following Amanita ingestion [18,23].

Amatoxins are heat stable and insoluble in water, thus "parboiling" does not make cyclopeptide-containing mushrooms safe. The minimum lethal human dose of amanitin is 0.1 mg/kg or approximately one to two medium-sized mushroom caps [22].

Limited observations following human poisoning and animal models suggest that amatoxins are absorbed from the intestinal lumen and then are transported to the liver through the portal circulation. Active transport by the hepatocyte membrane proteins such as organic anion transporting polypeptide (OATP) and sodium taurocholate co-transporter (NTCP) concentrates the toxin within the liver cells [24-26].

Amatoxins have a low volume of distribution (0.3 L/kg), and very low protein binding (0.3 percent) [5,27,28]. They can be detected in urine up to 48 hours after mushroom consumption. Biliary excretion and enterohepatic recirculation occurs; high levels of amatoxins can be measured in gastroduodenal fluid in poisoned patients [5,6,27]. Diverting or reducing biliary circulation (eg, biliary suctioning, octreotide) and repeated doses of activated charcoal are strategies for the reduction of circulating amatoxin. (See 'Elimination enhancement' below.)

Once inside the cell, amatoxins bind to DNA-dependent RNA polymerase type II and halt intracellular protein synthesis, ultimately resulting in apoptosis [22,26,29]. Other organs with high output protein synthesis (rapid cellular turnover), including intestinal endothelium or proximal convoluted renal tubules may be affected. In human cases of severe toxicity, centrilobular hepatocyte necrosis leads to fulminant hepatic failure and death [30]. Prevention of amatoxin uptake is the most important strategy to reduce toxicity after ingestion. In vitro evidence of inhibition of amatoxin OATP hepatocyte uptake is strongest for silibinin dihemisuccinate and cyclosporin [31], whereas rifampin [32], paclitaxel, and penicillin G may reduce uptake as well [26]. (See 'Amatoxin uptake inhibitors' below.)

Based upon mice studies, polymyxin B may reverse alpha-amanitin binding of RNA polymerase type II and prevent toxicity up to 12 hours after exposure [33]. However, in humans, polymyxin B has significant toxicity including nephrotoxicity and neurotoxicity that is amplified in the presence of renal injury as may occur with amatoxin-containing mushroom poisoning. Thus, further studies in humans are needed before its use can be recommended.

Amatoxins do not appear to cross the placenta based on normal neonatal outcomes observed in poisoned pregnant women [34]. Amatoxin does not appear in breast milk [35].

CLINICAL MANIFESTATIONS — Delayed onset of signs and symptoms more than 6 to 12 hours after mushroom consumption is consistent with a potentially serious amatoxin-containing mushroom ingestion [2,13,36]. However, early onset of gastrointestinal (GI) symptoms after mushroom ingestion does not exclude amatoxin-containing mushroom poisoning if multiple toxic mushroom species were ingested. In some instances, patients do not present for treatment until 2 to 3 days after mushroom consumption when signs and symptoms of acute liver injury have occurred.

Clinical manifestations of amatoxin-containing mushroom poisoning may be categorized into three phases [5,37]:

Phase I: Dysentery (6 to 24 hours post-ingestion) – Patients typically develop abdominal pain, vomiting, and severe, cholera-like diarrhea that may contain blood and mucous. Profound GI fluid losses may lead to hypovolemia, acute renal failure, and circulatory shock. Hematuria may also be present.

Right upper quadrant tenderness may be found, but liver enzymes and bilirubin are initially normal. Electrolyte losses consistent with a secretory diarrhea (eg, hypokalemia and metabolic acidosis) may also occur. Earlier onset of gastroenteritis before 12 hours after mushroom consumption may correlate with more severe hepatotoxicity [38].

Phase II: Apparent recovery (24 to 36 hours post-ingestion) – Patients will experience a gradual resolution of dysentery within 24 hours which falsely suggests resolution of their toxicity. However, elevations in the liver enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT) become evident; typically seen by 24 to 36 hours after ingestion, with peak levels occurring at 60 to 72 hours post-ingestion [38]. In patients with severe poisoning, the patient may go from Phase I directly to Phase III.

Phase III: Fulminant hepatic and multisystem organ failure (48 to 96 hours post-ingestion) – Typically 2 to 4 days after mushroom consumption, severely poisoned patients may develop irreversible hepatic failure, often accompanied by acute renal failure.

Massive hepatocyte cell death disrupts hepatic venous and biliary flow and raises portal pressures. Peak transaminase elevations are typically seen by 72 hours post-ingestion [38]. Direct nephrotoxic effects are seen in the proximal and distal convoluted renal tubules. Pancreatitis occurs in half of all severe cases.

Loss of hepatic synthetic function over the following days causes hypoglycemia, coagulopathy, encephalopathy, and fluid shifts with progression to multi-organ failure. In up to 30 percent of patients, death occurs, typically within 1 to 2 weeks of mushroom ingestion [39,40]. A decrease in serum transaminase levels at this stage reflects that no further cell injury is occurring but irreversible liver damage is still present.

EVALUATION — Except for children with small exploratory ingestions, all patients with suspected ingestion of amatoxin-containing mushrooms should undergo the following baseline testing:

Serum electrolytes including glucose, calcium, magnesium and phosphate

Liver studies (eg, AST, ALT, total protein, albumin, total and direct bilirubin)

Prothrombin time (PT), partial thromboplastin time (PTT)

Complete blood count with platelets

Blood urea nitrogen and serum creatinine

Urinalysis

In addition, patients with evidence of hepatotoxicity warrant additional evaluation including:

Arterial or venous blood gas

Blood ammonia

Lactate

Lactate dehydrogenase (LDH)

Lipase

If encephalopathy is present, neuroimaging should performed; additional studies may also be indicated as discussed separately (see "Hepatic encephalopathy in adults: Clinical manifestations and diagnosis", section on 'Diagnosis')

In patients who are candidates for liver transplantation, other testing to evaluate for the appropriateness of transplantation and to exclude alternative diagnoses may also be required and are discussed separately. (See "Liver transplantation in adults: Patient selection and pretransplantation evaluation", section on 'Pretransplantation evaluation' and "Acute liver failure in children: Management, complications, and outcomes", section on 'Laboratory monitoring'.)

DIAGNOSIS — The acute diagnosis of amatoxin-containing mushroom poisoning relies on clinical findings and should be suspected in any patient with delayed onset of gastrointestinal symptoms and/or hepatotoxicity after mushroom ingestion. (See 'Clinical manifestations' above.)

As discussed below, the clinical diagnosis should be confirmed, whenever possible, by amatoxin detection in the urine, which is the gold standard for the diagnosis of amatoxin-mushroom poisoning but is not rapidly available. Mushroom identification is also supportive but difficult to achieve in a timely manner.

Consultation with a regional poison control center is strongly encouraged whenever amatoxin-containing mushroom poisoning is suspected. (See 'Regional poison control centers' below.)

Amatoxin detection – Laboratory confirmation of amatoxin poisoning is not routinely available at many hospital laboratories but can be obtained through reference laboratories. However, treatment should not wait for these results. Urine testing is preferred, although amatoxins can also be detected in blood or gastric aspirates. Detection methods include polymerase chain reaction, high-performance liquid chromatography/mass spectrophotometry, lateral flow immunoassay (LFIA) [41], enzyme-linked immunoassay (ELISA), or radioimmunoassay. A point-of-care test has been developed but has not received approval by the US Food and Drug Administration [42]. Historically, ELISA testing for amanitin in the urine is the least technically challenging and has good sensitivity [43]. ELISA testing for amatoxins is most reliable within 36 hours of mushroom ingestion [43,44]. Amatoxins are typically not detectable in the blood or urine more than four days after mushroom consumption [27].

The Meixner bedside test is unreliable and should not be performed. Specific laboratory testing for mycotoxins is discussed in greater detail separately. (See "Clinical manifestations and evaluation of mushroom poisoning", section on 'Mushroom identification'.)

Mushroom identification – Historically, mushroom identification usually has not been readily available during the acute phase of care, and most mushrooms causing toxicity are never correctly identified. Nevertheless, mushroom identification can be attempted in consultation with a medical toxicologist to supplement clinical and laboratory findings; identification may sometimes be possible using digital pictures of the mushroom. However, these attempts should not detract from providing timely supportive care and presumptive treatment when amatoxin-containing mushroom ingestion is suspected. We do not endorse the use of the internet for identification of toxic mushroom species without expert consultation [45].

The determination of some morphological features of the mushroom ingested can be helpful to guide treatment recommendations and prognosis. Fresh, uncooked samples of all potentially ingested mushrooms that are harvested carefully or photographed in situ are ideal samples for identification but are rarely retrieved in practice. When instructing family members to bring in mushroom species that have been foraged, whole mushrooms are preferred, but identification can sometimes be made on parts of the mushroom, especially the underside of the cap and intact base. Storage is facilitated by placing them in a paper bag and refrigerating the sample. Storage in plastic bags should be avoided. Unfortunately, patients often forage and ingest multiple mushrooms. Furthermore, mushrooms that have been cooked, or otherwise damaged, are difficult to be identified.

Mushroom identification is discussed in greater detail separately. (See "Clinical manifestations and evaluation of mushroom poisoning", section on 'Mushroom identification'.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of amatoxin-mushroom poisoning includes toxicity from ingestion of other mushrooms and other causes of acute gastroenteritis or hepatotoxicity with liver failure.

The table provides a description of the various mushroom poisoning syndromes (table 1). Of note, early onset of symptoms does not exclude the possibility of amatoxin-mushroom poisoning. Furthermore, several other mushrooms cause delayed toxicity. Thus, consultation with a regional poison control center is advised when trying to identify the mushroom responsible for toxicity. A discussion of the clinical recognition and management of poisoning by other mushroom species is discussed in detail separately. (See "Clinical manifestations and evaluation of mushroom poisoning" and "Management of mushroom poisoning (except amatoxin-containing mushrooms)".)

A history of amatoxin-containing mushrooms ingestion typically differentiates mushroom poisoning from other causes of acute gastroenteritis or hepatotoxicity with liver failure. However, when this history is not available or is questionable, evaluation includes a comprehensive history, careful physical examination, laboratory evaluation, and imaging studies as discussed separately. (See "Diagnostic approach to diarrhea in children in resource-abundant settings" and "Approach to the adult with acute diarrhea in resource-abundant settings" and "Approach to the patient with abnormal liver biochemical and function tests" and "Acute liver failure in adults: Etiology, clinical manifestations, and diagnosis", section on 'Determining the cause of acute liver failure'.)

MANAGEMENT — Management is determined by the presence of symptoms. (See 'Clinical manifestations' above.)

Asymptomatic — Management of asymptomatic patients after amatoxin-containing mushroom consumption is determined by the estimated size of the ingestion:

Exploratory pediatric exposures – Pediatric exposures commonly consist of a single bite of a large white mushroom by a young child. These patients warrant a single dose of activated charcoal (AC). Once AC is given, they can be observed at home by a reliable caregiver for vomiting, diarrhea, or abdominal pain and assured follow-up within 24 hours. Baseline laboratory studies are usually unnecessary.

Other exposures – Larger exposures in asymptomatic patients (eg, ingestion of one cap or more of an amatoxin-containing mushroom as part of a meal) are concerning. These patients should undergo baseline testing, be admitted for observation and, in consultation with a medical toxicologist, receive treatment as described below for symptomatic patients.

Symptomatic (gastroenteritis, delayed hepatotoxicity) — The treatment of symptomatic poisoning with amatoxin-containing mushrooms is summarized in the table and described in detail below (table 1). Early consultation with a regional poison control center is strongly encouraged (see 'Regional poison control centers' below). After stabilization and initiation of specific therapy, patients with signs of acute liver failure warrant timely transfer to a liver transplant center.

Recommendations for care of children and adults with amatoxin-containing mushroom poisoning are primarily derived from observational studies, including case series and reports [37].

Supportive care — Historical mortality rates of up to 50 percent are seen in older case series of amatoxin-containing mushroom poisoning [1,30]. Mortality can be reduced to approximately 10 percent with supportive care measures; these include fluid resuscitation for hypovolemic shock caused by severe vomiting and diarrhea, correction of electrolyte disturbances associated with these fluid losses, elimination enhancement with multiple dose activated charcoal (MDAC), and supportive care related to liver dysfunction [10].

Supportive care of liver toxicity includes (see "Acute liver failure in adults: Management and prognosis"):

Treatment of hypoglycemia

Lactulose administration for hyperammonemia

Vitamin K replacement and infusions of fresh frozen plasma for significant coagulopathy

Management of other common comorbidities include acute renal failure, sepsis, metabolic disturbances, hepatic encephalopathy, and cerebral edema

Gastrointestinal decontamination — We recommend that alert patients with a suspected amatoxin-containing mushroom ingestion receive AC. Because of adverse effects, such as vomiting, diarrhea, and volume depletion, patients with mushroom poisoning should not receive a cathartic (eg, sorbitol, magnesium citrate). Amatoxins bind well to AC in vitro. In patients with amatoxin-containing mushroom poisoning, multiple doses of AC administered for up to 24 hours are associated with improved survival compared with supportive care alone [28,30]. The recommendation for AC also derives from indirect evidence of benefit in volunteers, animal studies, and evidence of benefit following ingestions of other poisonous substances. (See 'Elimination enhancement' below and "Gastrointestinal decontamination of the poisoned patient", section on 'Activated charcoal'.)

Patients who ingest an amatoxin-containing mushroom should not undergo gastric emptying by gastric lavage or syrup of ipecac in the emergency department. Randomized controlled trials show minimal benefit and possible risk to patients who undergo gastric emptying after poisoning. Furthermore, syrup of ipecac may delay or complicate the administration of MDAC. (See "Clinical manifestations and evaluation of mushroom poisoning", section on 'Mushroom identification' and "Gastrointestinal decontamination of the poisoned patient", section on 'Indications' and "Gastrointestinal decontamination of the poisoned patient", section on 'Syrup of Ipecac'.)

Elimination enhancement — In addition to a single dose of AC, we recommend that patients who ingest amatoxin-containing mushrooms receive MDAC to decrease the enterohepatic circulation of amatoxin. The dose is 0.5 g/kg (maximum dose 50 g) every four hours. We typically continue MDAC for two days after mushroom consumption. Because amatoxin-containing mushroom ingestion usually is associated with severe diarrhea, co-administration of cathartics with MDAC should be avoided. Optimum benefit is expected if MDAC is started within six hours of mushroom ingestion.

The charcoal dosing regimen is often limited by patient tolerance. In patients with vomiting, smaller, more frequent doses or slow continuous nasogastric infusion may be better tolerated and effective. Antiemetics (eg, ondansetron 0.15 mg/kg, maximum single dose 8 mg) may also be helpful. MDAC should not be used in patients with gastrointestinal ileus (such as may occur from shock), perforation, obstruction, or in patients with depressed mental status and an unprotected airway. (See "Enhanced elimination of poisons", section on 'Multiple-dose activated charcoal'.)

This recommendation is based upon the following observations:

Amatoxins are excreted in the bile and recirculated in humans [27]. The duration of biliary excretion may be up to 5 days after mushroom consumption.

MDAC administration permits binding of amatoxins and elimination in the feces [27].

In one case series, MDAC administration alone without other specific therapies was associated with 9 percent mortality (2 out of 22 patients) [30].

In a critical review of 2100 cases of amatoxin-containing mushroom poisoning, detoxification procedures alone, including MDAC, were associated with a mortality rate of 10 versus 47 percent when supportive care alone was provided [1].

Other methods of elimination enhancement in patients with acute liver failure have also been reported, but evidence is lacking regarding benefit because of the delivery of concomitant therapies in these cases. Until more evidence is available, the use of these techniques should be decided in consultation with a medical toxicologist and a transplant team in patients with acute liver failure or rapidly progressing acute liver injury (see 'Liver transplantation' below):

Biliary drainage – Nasal jejunal suction placed endoscopically or percutaneous biliary drainage have been proposed by some experts as a temporizing measure until other techniques such as fractionated plasma separation and adsorption system (FPSA) or molecular adsorbent recirculating system (MARS) can be established [46]. If used, biliary drainage is most likely to be helpful in patients who present for medical care within 24 hours of ingestion of definitively identified amatoxin-containing mushrooms or those with acute liver failure [47]. However, there are no published reports of outcomes following biliary drainage in patients with mushroom poisoning and no evidence to suggest that biliary drainage is additive to or better than MDAC alone or FPSA, MARS, or therapeutic plasma exchange. In one case series of 18 patients with acute liver failure or acute liver injury following amatoxin-containing mushroom poisoning with 16 surviving with or without liver transplantation, nasobiliary drainage was performed in only one patient [48].

Fractionated plasma separation and adsorption system (FPSA) – In a small trial of 20 patients with acute liver failure due to Amanita phalloides ingestion, FPSA reduced urinary amanitin levels from approximately 43 ng/mL to 1 ng/mL with no need for liver transplantation and survival in all 9 patients in whom it was used compared to 1 death and 1 patient requiring prolonged dialysis in the comparison group [49]. Patients receiving FPSA did not experience hemodynamic instability, coagulopathy, or pulmonary edema.

Molecular absorbent recirculating system (MARS) – MARS has been associated with recovery from acute liver failure after amatoxin-containing mushroom poisoning in case reports and series, [50-52]. (See 'Liver transplantation' below.)

Therapeutic plasma exchange – Therapeutic plasma exchange alone or combined with MARS was associated with improvement in liver function in a series of 9 patients with amatoxin-containing mushroom poisoning but was associated with a decrease in hemoglobin, serum albumin, and platelet count [52].

Extracorporeal elimination with hemodialysis or hemoperfusion are ineffective at removing significant amounts of amatoxin in patients with normal renal function and have not been shown to improve survival [1,30,53-56].

Amatoxin uptake inhibitors — Several compounds have been shown to decrease amatoxin uptake by animal and human hepatocytes in experimental models [26]. Of these, silibinin dihemisuccinate and penicillin G have been used the most in human poisoning [57]. Single drug therapy with intravenous (IV) silibinin dihemisuccinate is associated with the lowest mortality.

Preferred: Silibinin dihemisuccinate — We recommend that patients with amatoxin-containing mushroom poisoning receive IV silibinin dihemisuccinate (Legalon SIL), if available in a timely fashion (ie, six hours). Silibinin appears to be most effective when given within 24 hours of ingestion [58]. Silibinin is widely available in many countries and is administered as an initial IV loading dose of 5 mg/kg followed by a continuous IV infusion at a dose of 20 mg/kg per day for 6 days or until the patient shows clinical signs of recovery [59]. Each vial contains the equivalent of 350 mg of silibinin [60].

The availability of IV silibinin varies by region. In the United States, IV silibinin (Legalon SIL) may be obtained by application for an Emergency Investigational New Drug to the US Food and Drug Administration (FDA) Expanded Access Program (call FDA Center for Drug Evaluation and Research at 301-796-3400 during business hours or the FDA Emergency Call Center at 866-300-4374 after hours and generate a shipping label by sending an email to [email protected] or calling customer service at 484-754-7500). In Canada, use the Special Access Program (telephone: 613-946-8711, email: [email protected]; emergency request [outside normal hours]: 613-410-9186).

Silibinin infusion appears to be well tolerated in humans. Skin flushing is the most common adverse reaction reported by the manufacturer. Nausea, stomach and joint pains, headache, and itching have also been described [61]. Anaphylactic reactions are rare.

Silibinin is an extract of the Mediterranean milk thistle (Silybum marianum) and inhibits amatoxin uptake by organic anion transporting polypeptide (OATP) 1B3 and sodium taurocholate co-transporter (NTCP) located in hepatocyte membranes. It improves cellular survival in human hepatocytes exposed to alpha-amanitin [26,62]. Intracellular effects also include stimulation of RNA polymerase type I, antioxidant effects, and enhanced amatoxin excretion into the bile [63].

This recommendation for silibinin is supported by a systematic review of 2100 cases that showed lower mortality in the 624 patients who received silibinin than those who did not (6 versus 12 percent, respectively) [39]. In an observational study of 118 patients, not included in the systematic review, who received silibinin alone, 5 percent died or underwent liver transplantation. Mortality or transplantation was not significantly different in patients who received silibinin more than 24 hours after mushroom ingestion (odds ratio [OR] 3.0, 95% CI 0.96-9.2) [58].

Alternatives

Penicillin G — In human and animal models of amatoxin toxicity, high-dose IV penicillin G may inhibit amatoxin uptake by OATP [26] and prevent cellular toxicity [62]. In canine experiments, penicillin G appears to have a time and dose-dependent effect on survival [64,65]. Penicillin G is a less specific inhibitor of human hepatocyte amatoxin uptake than silibinin in vitro [26]. If IV silibinin is available, then there may be no additional benefit associated with high-dose penicillin therapy, and our practice is to not give penicillin G.

We recommend that, when IV silibinin is not available within six hours, patients with amatoxin-containing mushroom poisoning receive a continuous IV infusion of high-dose penicillin G. Recommended dosing varies from 300,000 to 1,000,000 units/kg per day (maximum dose: 40 million units) given as a continuous infusion [1]. Penicillin G should not be given to patients with a known penicillin allergy. As discussed below, limited evidence suggests that IV ceftazidime 4.5 g every 2 hours may be an alternative for such patients.

Although high doses of penicillin G may be beneficial for the treatment of amatoxin-containing mushroom poisoning when IV silibinin is not available, the potential risk of this therapy is higher than for silibinin infusion. High-dose penicillin G infusion may be associated with coma, seizures, electrolyte imbalance (hyperkalemia or hypernatremia, depending upon excipient), severe granulocytopenia, acute interstitial nephritis, and/or renal tubular damage, although the frequency of these adverse effects are not known [1].

Based upon case series and observational studies of patients with amatoxin-containing mushroom poisoning, high-dose penicillin, when combined with aggressive supportive care, MDAC, and other therapies, such as glutathione or acetylcysteine but not silibinin, may be associated with marginally lower mortality. For example, in a systematic review of treatments given to 2100 patients with amatoxin-containing mushroom poisoning, of the 1411 patients who received benzylpenicillin 10.7 percent died compared to the average mortality rate of 11.6 percent among all patients [39].

However, penicillin, when given with silibinin, does not appear to improve outcomes compared to silibinin alone. As an example, in an observational study of patients with amatoxin-containing mushroom poisoning, death or organ transplantation occurred in 9 percent of 249 patients who received both silibinin and high-dose penicillin G infusions compared to 5 percent of 118 patients who received silibinin alone [58]. Mortality was not significantly different between these regimens.

Ceftazidime administration has been proposed as an alternative beta-lactam antibiotic that may be used to prevent amatoxin uptake in the liver. Ceftazidime administration in combination with silibinin has been reported in 12 patients with amatoxin-containing mushroom poisoning [39]. Although the impact on mortality appears favorable, the low number of patients treated and the co-administration of silibinin in all patients do not permit firm conclusions regarding efficacy. The use of other antibiotics, such as aminoglycosides (eg, gentamicin), macrolides (eg, erythromycin), or vancomycin, has not been shown to be beneficial [39].

Oral milk thistle products — IV silibinin dihemisuccinate (Legalon SIL) is preferred to oral formulations such as silymarin and should be obtained if at all possible. We suggest that, if IV silibinin dihemisuccinate is not available, symptomatic patients with amatoxin-containing mushroom poisoning receive oral silymarin capsules in addition to MDAC, IV penicillin G, and acetylcysteine. Silymarin should not be given within two hours of AC administration. Silymarin should not be given to patients with allergy to thistle, kiwi, artichoke, or other members of the Asteraceae family [66].

Silymarin is an extract of the Mediterranean milk thistle (Silybum marianum) that contains several flavonolignans, including silibinin (the natural form of the drug, silibinin dihemisuccinate). Silymarin capsules are available in 100, 150, and 300 mg concentrations online and at a variety of stores in the United States that stock health food and complementary medicine items. It is not typically available from United States hospital pharmacies. Because the manufacture of these formulations is not regulated in the United States, the concentration of silibinin in formulations varies. However, most silymarin capsules contain approximately 50 percent silibinin [67]. Oral absorption is approximately 20 to 40 percent in humans [68] and administration of silymarin capsules to healthy volunteers resulted in peak plasma levels of silibinin at 3 to 5 hours with an elimination half-life of approximately 6 hours [67].

No clear guidance for oral dosing of silymarin for amatoxin-containing mushroom poisoning is available. Given the 50 percent concentration of silibinin in most silymarin extracts and the low absorption, oral dosing of approximately 10 g of silymarin capsules daily would be required to achieve plasma concentrations equivalent to the typical IV dose of silibinin (20 mg/kg/day). This dose is much higher than the usual silymarin dose of 150 to 360 mg three times daily that is used for other liver diseases [66]. High doses of silymarin may produce significant diarrhea and may complicate management in some patients. Thus, the clinician may initially start with a trial dose of 50 to 100 mg/kg (maximum single dose: 2 g) of oral silymarin in capsule form every 8 hours and if tolerated, increase to a maximum of 200 mg/kg per dose (maximum single dose; 3 g) for a duration of 6 days or until the patient shows signs of clinical improvement. In patients who do not tolerate the trial dose, lower doses may be attempted but may not provide adequate hepatic protection. Successful oral administration may require aggressive treatment of vomiting with antiemetics (eg, ondansetron 0.15 mg/kg; maximum dose; 16 mg) and replacement of fluid losses caused by diarrhea.

Evidence for the benefit of oral administration derives indirectly from the potential benefit of IV administration of silibinin (see 'Preferred: Silibinin dihemisuccinate' above). Although silymarin has not been studied in a controlled fashion in humans, it has shown a protective effect in animal models of Amanita phalloides poisoning [69,70]. Silymarin may cause nausea, abdominal pain, and diarrhea, but no serious toxic effects at doses less than 1.5 g per day have been reported [68]. Toxicity at higher doses has not been studied.

Dilute liquid formulations of silymarin are sold as liver tonics in health food stores, but these formulations are of no value in amatoxin-containing mushroom poisoning because they contain low doses of silibinin and should not be used [71].

Antioxidant therapy — Amatoxins are known to enhance lipid peroxidation that contributes to membrane instability and cell death. A number of antioxidants have been used historically in the treatment of amatoxin poisoning including acetylcysteine, ascorbic acid (vitamin C), cimetidine, and thioctic acid. Thioctic acid is no longer recommended because it is associated with hypoglycemia and does not improve clinical outcomes [39]. (See 'Cimetidine and vitamin C' below.)

Acetylcysteine — We suggest that patients with amatoxin-containing mushroom poisoning and evidence of hepatotoxicity receive acetylcysteine. When administering acetylcysteine for this indication, we typically use a continuous front-loaded infusion over 20 hours identical to the two-bag IV regimen for acetaminophen poisoning (see "Acetaminophen (paracetamol) poisoning: Management in adults and children", section on 'Simplified 20-hour (two-bag) intravenous protocol'):

First, administer a four-hour infusion at 50 mg/kg per hour IV (ie, total of 200 mg/kg over four hours; maximum 20 grams).

Next, administer a 16-hour infusion at 6.25 mg/kg per hour IV (ie, total of 100 mg/kg over 16 hours; maximum 10 grams). The 16-hour dose may be repeated if significant hepatic dysfunction persists.

This treatment protocol provides a total of 300 mg/kg over 20 hours. Weight-based dilution should be performed in children who weigh less than 40 kg. (See "Acetaminophen (paracetamol) poisoning: Management in adults and children", section on 'Intravenous acetylcysteine dilution in children'.)

This recommendation for acetylcysteine is supported by the following observations:

A systematic review of treatments given to 2100 patients with amatoxin-containing mushroom poisoning found that 192 patients who received acetylcysteine had a mortality rate of 6.8 percent, which was significantly lower than the average mortality rate of 11.6 percent among all patients [39].

A systematic review that included 506 patients who received acetylcysteine found a composite endpoint of mortality and liver transplantation of 11 percent; this endpoint was lower in patients who presented within 24 hours compared with those who presented later (6 versus 23 percent) [72]. A subsequent systematic review (877 patients) that included all therapies (overall mortality of 16 percent) suggested that acetylcysteine added to other treatment regimens may not confer benefit; however, one-third of patients were from case reports potentially biasing towards a sicker population [73].

IV acetylcysteine is generally well-tolerated although anaphylactoid reactions have been described. (See "Acetaminophen (paracetamol) poisoning: Management in adults and children", section on 'Adverse reactions to acetylcysteine'.)

Cimetidine and vitamin C — We suggest that patients with amatoxin-containing mushroom poisoning and evidence of hepatotoxicity receive L-ascorbic acid (vitamin C) and cimetidine. These agents have antioxidant and cytoprotective effects in animal models of amatoxin-containing mushroom poisoning [1]. However, improved outcomes in humans have not been established [39]. Because they are not associated with significant adverse effects, we use them in combination with silibinin and acetylcysteine in the following doses:

Cimetidine: 300 mg IV every 8 hours until clinical improvement

Vitamin C: 3 g IV daily until clinical improvement

Certain therapies are associated with no benefit or worsening outcomes in animal models or clinical reports of amatoxin-containing mushroom poisoning and should be avoided including thioctic acid, glucocorticoids, insulin in combination with glucagon or growth hormone, vitamin E, and amifostine [39,74,75].

Reduced biliary circulation (octreotide) — Some contributors on this topic administer octreotide to a patient with amatoxin-containing mushroom poisoning who has not developed liver injury, but not all contributors use it routinely. It is administered as a 50 mcg/hr IV infusion for up to 48 hours after ingestion. Octreotide inhibits gallbladder emptying, reduces hepatic bile secretion, and is generally well tolerated, but evidence of clinical benefit does not exist [76].

Liver transplantation — The physician should contact a liver transplant center early in the course of treating symptomatic patients with suspected amatoxin-containing mushroom poisoning. Transfer to a tertiary care center capable of performing liver transplantation or other bridging liver failure therapies (eg, MARS, FPSA, and renal replacement therapy) should occur if clinical signs of hepatic injury are moderate to severe.

Liver transplant centers in the United States may be found using the United Network for Organ Sharing directory.

Case reports and one small trial describe full recovery despite severe poisoning by employment of bridging liver failure therapies (eg, MARS, fractionated plasma separation and adsorption system [Prometheus]), therapeutic plasma exchange, renal replacement therapy, or auxiliary partial liver transplantation [48-50,77-80]. (See 'Elimination enhancement' above.)

In a critical review of treatment for amatoxin-containing mushroom poisoning in 2100 patients, liver transplantation was performed in approximately 2 percent of cases [1]. The decision to perform liver transplantation or provide other advanced supportive therapies to permit liver regeneration in such patients is complex and the criteria for liver transplantation after amatoxin-containing mushroom poisoning may not correspond with that used for other liver diseases [80-83]. For example, encephalopathy may not represent an appropriate prerequisite for transplantation in all poisoned patients [48]. Liver transplantation may occur without any danger of toxicity to the transplanted liver when performed ≥4 days after ingestion [1].

Experimental therapies — The following agents have been proposed for the treatment of amatoxin-containing mushroom poisoning, but evidence in humans is lacking. They should only be given after consultation with a medical toxicologist and as part of an experimental protocol:

Cyclosporine – In a case series of three patients in a Canadian hospital treated with cyclosporine (5 mg/kg IV over four to six hours, every 24 hours), in vitro analysis confirmed good OATP 1B3 inhibition [31]. Additional clinical experience is needed to support routine cyclosporine administration over other hepatic uptake inhibitors.

Resveratrol – Based upon one study in a mouse kidney tissue, early resveratrol administration (within 12 hours after alpha-amanitin ingestion) may reverse the effects of alpha-amanitin-induced nephrotoxicity, partly through its antioxidant action [84].

Polymyxin B – Based upon one animal study, polymyxin B may reverse alpha-amanitin binding of RNA polymerase type II and prevent toxicity [33]. However, the safety, efficacy, and appropriate dosing of polymyxin B for this indication in humans have not been established.

Other amatoxin uptake inhibitors – Experimental studies in isolated human hepatocytes indicate that paclitaxel and rifampin are significant inhibitors of amatoxin uptake into liver cells, but their use in human mushroom poisoning has not been described [26].

Aucubin – Plant-derived iridoid glycosides, such as aucubin, have shown benefit as antioxidants in animal studies of alpha-amanitin toxicity, but clinical utility in humans is unknown [85,86].

DISPOSITION — Prompt consultation with a regional center is advised to assist with disposition decisions. (See 'Additional resources' below.)

All patients with suspected or confirmed ingestion of a significant amount of amatoxin-containing mushrooms (eg, one to two whole mushrooms) based upon clinical findings, amatoxin detection, or mushroom identification warrant hospital admission with initiation of therapies described above. (See 'Management' above.)

Children who are asymptomatic after ingestion of a small amount (eg, one bite) of a suspected Amatoxin-containing mushroom and who present within a few hours of ingestion may receive a single dose of activated charcoal and be discharged to home if follow-up within 24 hours is assured.

ADDITIONAL RESOURCES

Regional poison control centers — Regional poison control centers in the United States are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately. (See "Society guideline links: Regional poison control centers".)

SUMMARY AND RECOMMENDATIONS

Specialty consultation – When amatoxin-containing mushroom ingestion is suspected, a medical toxicologist (if available) or the regional poison control center should be contacted to assist with the diagnosis of amatoxin-containing mushroom ingestion based upon clinical findings, to assist with confirmation of the diagnosis, and to provide treatment recommendations and resources. (See 'Regional poison control centers' above.)

Amatoxin-containing mushrooms – Amatoxins are found in a variety of Amanita and non-Amanita species mushrooms (eg, Amanita phalloides (picture 1), A. bisporigera (picture 2), A. virosa, Galerina autumnalis). (See 'Amatoxin-containing mushrooms' above and 'Pathophysiology and toxicokinetics' above.)

Clinical manifestations – The onset of signs and symptoms >6 hours after mushroom consumption should increase suspicion for amatoxin-containing mushroom poisoning. However, early onset of gastrointestinal (GI) symptoms after mushroom ingestion does not exclude this diagnosis, especially when several different mushrooms have been consumed, resulting in a mixed clinical picture. The natural history of amatoxin-poisoning has been grouped into three phases along a timeline (see 'Clinical manifestations' above):

Phase I: Dysentery (6 to 24 hours post-ingestion) – Epigastric abdominal pain, vomiting, and severe, cholera-like diarrhea

Phase II: Apparent recovery (24 to 36 hours post-ingestion) – Clinical improvement but elevation in liver enzymes

Phase III: Fulminant hepatic and multisystem organ failure (48 to 96 hours post-ingestion) – Irreversible liver failure often accompanied by renal failure

Diagnosis – The diagnosis of amatoxin-containing mushroom poisoning relies on clinical findings and should be suspected in any patient with delayed onset of GI symptoms and/or hepatotoxicity after mushroom ingestion. The clinical diagnosis should be confirmed, whenever possible, by amatoxin detection in the urine. Mushroom identification is also supportive but difficult to achieve in a timely manner. (See 'Diagnosis' above.)

Differential diagnosis – The differential diagnosis of amatoxin-mushroom poisoning includes toxicity from ingestion of other mushrooms and other causes of acute gastroenteritis or hepatotoxicity with liver failure. (See 'Differential diagnosis' above.)

Asymptomatic patients

Exploratory pediatric exposure – An asymptomatic child who has recently ingested a small amount (eg, one bite) of a mushroom after an exploratory ingestion may receive a single dose of activated charcoal (AC) and be discharged to home if follow-up within 24 hours is assured. (See 'Asymptomatic' above.)

Larger exposure Larger exposures in asymptomatic patients (eg, ingestion of one cap or more of an amatoxin-containing mushroom as part of a meal) are concerning. These patients should undergo baseline testing and be admitted for observation. Initiation of treatment as described below for symptomatic patients should be determined in consultation with a medical toxicologist. (See 'Asymptomatic' above.)

Management of symptomatic patient – The treatment of a patient with gastroenteritis and hepatoxicity is provided in the table (table 1) (see 'Symptomatic (gastroenteritis, delayed hepatotoxicity)' above):

Supportive care of amatoxin-containing mushroom poisoning includes management of fluid losses caused by vomiting and diarrhea and anticipation of hepatotoxicity and multisystem organ failure. (See 'Supportive care' above.)

In an alert patient with a suspected amatoxin-containing mushroom ingestion, we recommend administering AC without cathartic (Grade 1B). A patient who ingests an amatoxin-containing mushroom should not undergo gastric emptying by gastric lavage or syrup of ipecac in the emergency department. (See 'Gastrointestinal decontamination' above.)

In an alert patient with a suspected amatoxin-containing mushroom ingestion, we recommend administering multiple dose activated charcoal (MDAC) without cathartic (Grade 1B) (after the initial dose of AC). (See 'Elimination enhancement' above.)

The use of other techniques to enhance elimination (eg, biliary diversion) should be decided in consultation with a medical toxicologist and/or transplant team in patients with acute liver failure or rapidly progressing acute liver injury.

In a patient with a suspected amatoxin-containing mushroom ingestion, we recommend administering intravenous (IV) silibinin dihemisuccinate (Legalon SIL), whenever available (Grade 1C). (See 'Preferred: Silibinin dihemisuccinate' above.)

In a patient with a suspected amatoxin-containing mushroom ingestion, if IV silibinin dihemisuccinate is not available within six hours, we recommend administering a continuous IV infusion of high-dose penicillin G (Grade 1C) and suggest administering an oral milk thistle product (eg, silymarin capsules, typically not stocked by hospital pharmacies) (Grade 2C). In the United States, milk thistle products contain small amounts of active ingredients and must be obtained from health food stores. (See 'Penicillin G' above and 'Oral milk thistle products' above.)

In a patient with evidence of hepatocellular injury due to amatoxin-containing mushroom poisoning, we suggest administering IV N-acetylcysteine (Grade 2C) and IV L-ascorbic acid (vitamin C) and cimetidine (Grade 2C). (See 'Acetylcysteine' above and 'Cimetidine and vitamin C' above.)

Some contributors on this topic administer octreotide to a patient with amatoxin-containing mushroom poisoning who has not developed liver injury to reduce hepatic bile secretion, but not all contributors use it routinely. (See 'Reduced biliary circulation (octreotide)' above.)

Consultation for liver transplantation – The clinician should contact a liver transplant center early on in the course of treatment of patients with suspected amatoxin-containing mushroom symptomatic poisoning. Transfer to a tertiary care center capable of performing liver transplantation or other bridging liver failure therapies (eg, molecular absorbent recirculating system [MARS], fractionated plasma separation and adsorption system [FPSA], or plasma exchange) should occur if clinical signs of hepatic injury are moderate to severe. (See 'Liver transplantation' above.)

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Topic 13893 Version 32.0

References

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