Amanitins: The Most Poisonous Molecules of the Fungal World.

Among the toxic metabolites of the fungal world, those that, due to their strong biological effect, can seriously (even fatally) damage the life processes of humans (and certain groups of animals) stand out. Amatoxin-containing mushrooms and the poisonings caused by them stand out from the higher fungi, the mushrooms. There are already historical data and records about such poisonings, but scientific research on the responsible molecules began in the middle of the last century. The goals of this review work are as follows: presentation of the cosmopolitan mushroom species that produce amanitins (which are known from certain genera of four mushroom families), an overview of the chemical structure and specific properties of amanitins, a summary of the analytical methods applicable to them, a presentation of the "medical history" of poisonings, and a summary of the therapeutic methods used so far. The main responsible molecules (the amanitins) are bicyclic octapeptides, whose structure is characterized by an outer loop and an inner loop (bridge). It follows from the unusual properties of amanitins, especially their extreme stability (against heat, the acidic pH of the medium, and their resistance to human, and animal, digestive enzymes), that they are absorbed almost without hindrance and quickly transported to our vital organs. Adding to the problems is that accidental consumption causes no noticeable symptoms for a few hours (or even 24-36 h) after consumption, but the toxins already damage the metabolism of the target organs and the synthesis of nucleic acid and proteins. The biochemical catastrophe of the cells causes irreversible structural changes, which lead to necrotic damage (in the liver and kidneys) and death. The scientific topicality of the review is due to the recent publication of new data on the probable antidote molecule (ICR: indocyanine green) against amanitins. Further research can provide a new foundation for the therapeutic treatment of poisonings, and the toxicological situation, which currently still poses a deadly threat, could even be tamed into a controllable problem. We also draw attention to the review conclusions, as well as the mycological and social tasks related to amanitin poisonings (prevention of poisonings).

Early diagnosis of amanitin exposure (amatoxicosis) in a dog with a point-of-care diagnostic test.

OBJECTIVE: To describe the rapid diagnosis, treatment, and clinical course of a dog that ingested an amanitin-containing mushroom. CASE SUMMARY: A 2-month-old female intact Australian Shepherd presented with diarrhea and vomiting, along with a possible mushroom exposure. Upon presentation, the dog's urine was collected and tested positive by a point-of-care rapid diagnostic test specific for detecting amanitins, the causative agents of amatoxicosis. NEW OR UNIQUE INFORMATION PROVIDED: This is the first reported case of amatoxicosis that was diagnosed using a point-of-care test prior to starting treatment. An early diagnosis helps to guide early treatment decisions in this frequently fatal toxicosis.

Clinical recovery of 5 dogs from amatoxin mushroom poisoning using an adapted Santa Cruz protocol for people.

OBJECTIVE: To describe the clinical course, treatment, and outcome of 5 dogs following ingestion of toxic Amanita spp. mushrooms containing amatoxins using an adapted version of the Santa Cruz protocol developed for people. CASE SERIES SUMMARY: Five dogs were presented with clinical signs compatible with amanitin toxicity with witnessed ingestion noted in 3 of 5 dogs. Clinical findings included acute onset vomiting and diarrhea, lethargy, and hepatopathy including signs of fulminant hepatic failure (increased liver enzyme activities, hyperbilirubinemia, prolonged clotting times, and hypoglycemia were noted among these cases). Urine toxicological screening confirmed the presence of Amanita toxins in 4 cases with expert mycologist speciation in the fifth. Core interventions included percutaneous biliary drainage, use of octreotide, and early nil per os orders. All dogs survived to discharge with this treatment strategy. NEW OR UNIQUE INFORMATION PROVIDED: This case series describes the use of a modified version of the Santa Cruz protocol to address amatoxin-induced fulminant hepatic failure in dogs. The protocol was safe, well tolerated, and all patients made a full clinical recovery.

Successful treatment with tumor necrosis factor-α blockers for poison-induced liver injury: case report and literature review.

Acute poisoning could result in hepatic dysfunction which is potentially life threatening. We reviewed three cases of poison-induced liver injury with gastrointestinal disorder on admission. Two cases were poisoned by mushroom α-Amanitin while the other was poisoned by acetaminophen (APAP). They were cured under the close monitor of laboratory examinations and other supportive therapies, as well as the off-label medication of etanercept, a kind of tumor necrosis factor-α (TNF-α) blockers with written informed consent. Among them, case1 was given the first dose doubling of TNF-α blockers for higher liver enzyme levels. There is a lack of effective and safe treatments for poison-induced liver injury. TNF-α has been proved to play an important role in the aggravation of liver injury and the start-up of inflammatory cascade reaction. Therapy with TNF-α blockers shown potential therapeutic efficacy in hepatic dysfunction by some researches. Anyway, no strong recommendation could be drawn from these small sample size studies. On the other side, TNF-α could also mediate an opposing effect for hepatocytes since the hepatic toxicity of TNF-α blockers has generated attentions. The safety for the off-label medication of TNF-α blockers in liver injury, however, still lacks strong evidences. More experimental and clinical researches are needed to focus on potential mechanisms.

[Emergence of amatoxin poisoning in the Netherlands]. / De giftige groene knolamaniet.

CASE DESCRIPTION: A 34-year-old woman from Thai origin developed acute liver failure after ingestion of a soup which contained the death cap (Amanita phalloides). BACKGROUND: In patients with poisoning due to amatoxin-containing mushrooms, gastro-intestinal complaints usually develop several hours after ingestion, followed by acute hepatic failure which occasionally leads to death. The incidence of reported mushroom poisonings in the Netherlands has increased in 2019, which is possibly associated with migration of asylum seekers who regularly pick and eat mushrooms. CONCLUSION: In the Netherlands mushroom intoxication is rare. Therefore, there is a lack of knowledge among health care personnel and foragers. The present case report highlights the importance of awareness of the poisonous death cap to prevent intoxications and optimize treatment decisions.

N-acetylcysteine as a treatment for amatoxin poisoning: a systematic review.

Introduction: Amatoxin leads to the majority of deaths by mushroom poisoning around the world. Amatoxin causes gastrointestinal disturbances and multiple organ dysfunction, including liver and renal failure. As a potential treatment for amatoxin poisoning, N-acetylcysteine (NAC) has been used for decades but its benefit is still unproven.Objectives: We undertook a systematic review to evaluate the performance and safety of N-acetylcysteine on patients suffering amatoxin intoxication.Methods: We searched Pubmed, EMBASE, CENTRAL and SinoMed databases, from inception to August 31, 2019. Articles were eligible if there were five or more patients with amatoxin poisoning and N-acetylcysteine was included in the therapeutic regimen. Mortality rate including liver transplant cases (MRLTi) was the primary outcome. Mortality rate not including liver transplant cases, liver and renal function, clinical complications, as well as any adverse reactions to intravenous NAC were secondary outcomes.Results: Thirteen studies with a total of 506 patients were included. The MRLTi of amatoxin-poisoning patients with NAC treatment was 11% (57/506), and a MRLTe of 7.9% (40/506) and a liver transplantation rate of 4.3% (22/506). Transaminase concentrations generally peaked around 3 days after ingestion, prothrombin time/International Normalized Ratio (PT/INR) generally worsened during the first 3-4 days after ingestion before returning to normal four to 7 days after ingestion, and Factor V levels normalized in about 4-5 days after ingestion in patients treated with NAC. Renal failure was reported in 3% (3/101) and acute kidney injury was reported in 19% (5/27). Gastrointestinal bleeding occurred in 21% (15/71). Anaphylactoid reactions were the principle adverse reaction to NAC treatment in amatoxin-poisoning patients with an incidence of 5% (4/73).Conclusions: NAC treatment combined with other therapies appears to be beneficial and safe in patients with amatoxin poisoning. Until further data emerge, it is reasonable to use NAC in addition to other treatments for amatoxin poisoning.

Low-cost management of mushroom poisoning in a limited-resource area: a 12-year retrospective study.

Amatoxin poisoning is the main cause of death from accidental ingestion of poisonous mushrooms and a mortality rate of 27.3% has been reported in Thailand. Symptoms of mushroom ingestion are often confused with food poisoning; thus, gastroenteritis is not recognised as the first phase of poisoning. Our study assessed the efficacy of N-acetylcysteine (NAC) as a treatment for amatoxin poisoning. We retrospectively analysed 74 medical records over 12 years. The majority (70/74) were treated successfully with NAC; death in the remaining 4 (5.4%) patients was attributed to late presentation in three and advanced alcoholic cirrhosis in one.

[The histopathological features of the severe intoxication with amatoxin (toxin contained in Amanita phalloides mushrooms)]. / Gistopatologicheskaia kartina tiazhelogo otravleniia amatoksinom (blednoi pogankoi).

Eating mushrooms known to contain amatoxin is fraught with serious complications. The analysis of the relevant literature publications revealed no article with the description of the histological picture of the internal organs in the subjects intoxicated with amatoxin. It is known, however, that such poisoning is associated with the severe irreversible injuries to all intracellular protein structures the character of which depends on time. Specifically, acute amatoxin intoxication produces the well apparent clinical picture within 6 days after intake of the poison. It is characterized by acute renal and hepatic insufficiency in the combination with the injury to the conducting system of heart and the myocrardium itself. Thereafter, the disseminated intravascular coagulation (DIC) syndrome developed accompanied by the signs of progressive tissue hypoxia that ended in death on day 9. The histological study has demonstrated necrotic foci in the liver and oedematous hepatic stroma. Kidneys underwent multiple hemorrhages, necrosis of convoluted tubules and well apparent hydropic protein dystrophy of their epithelium. The adrenal glands showed up signs of necrosis and hemorrhage. It is concluded that poisoning with mushrooms (amatoxin) should be regarded as the most probable cause of the condition requiring differential diagnostics between acute gastroenteritis and renal insufficiency.

A case study of Lepiota brunneoincarnata poisoning with endoscopic nasobiliary drainage in Shandong, China.

The most frequently reported fatal Lepiota ingestions are due to L. brunneoincarnata. We present a case of L. brunneoincarnata poisoning with endoscopic nasobiliary drainage known to be the first in China. The patient suffered gastrointestinal symptoms 9 h post ingestion of mushrooms. The patient was hospitalized 4 days after eating the mushrooms with jaundice. The peak ALT, AST, APTT, TBIL and DBIL values of the patient were as follow: ALT, 2980 U/L (day 4 post ingestion); AST, 1910 U/L (day 4 post ingestion); APTT, 92.8 seconds (day 8 post ingestion), TBIL, 136 µmol/L (day 10 post ingestion), DBIL 74 µmol/L (day 10 post ingestion). UPLC-ESI-MS/MS was used to detect the peptide toxins in the mushroom and biological samples from the patient. We calculated that the patient may have ingested a total of 29.05 mg amatoxin from 300 g mushrooms, consisting of 19.91 mg α-amanitin, 9.1 mg ß-amanitin, and 0.044 mg γ-amanitin. Amatoxins could be detected in bile even on day 6 after ingestion of L. brunneoincarnata. With rehydration, endoscopic nasobiliary drainage and intravenous infusion of Legalon SIL, the patient recovered after serious hepatotoxicity developed.

Challenges in the early diagnosis of patients with acute liver failure induced by amatoxin poisoning: Two case reports.

RATIONALE: Acute liver failure (ALF) induced by amatoxin-containing mushrooms accounts for more than 90% of deaths in patients suffering from mushroom poisoning. However, due to the fact that most hospitals cannot identify the species of mushrooms involved, or detect amatoxins, the early diagnosis of amatoxin intoxication remains a significant challenge in clinical practice. PATIENT CONCERNS: Two patients were had ingested wild mushrooms 15 hours before admission. Six hours prior to admission they experienced nausea, vomiting, weakness, abdominal pain and diarrhea. The species of mushrooms they had consumed could not be identified. DIAGNOSES: According to their delayed gastroenteritis, the two patients were clinically diagnosed with amatoxin poisoning. One week after the patients were discharged, the species of the mushrooms was identified as Amanita fuliginea and the diagnosis was confirmed. INTERVENTIONS: The two patients were treated with silibinin, penicillin G and plasma exchange. OUTCOMES: Although the two patients progressed to ALF they fully recovered and were discharged on day 10 after admission. LESSONS: Our case reports suggested that patients with unidentified wild mushroom intoxication with delayed gastroenteritis could be clinically diagnosed with amatoxin poisoning; in such cases, liver coagulation function should be frequently evaluated. Early diagnosis and treatment are crucial for survival in patients with ALF induced by amatoxin poisoning.

Amatoxin-Containing Mushroom Poisonings: Species, Toxidromes, Treatments, and Outcomes.

Amatoxins are produced primarily by 3 species of mushrooms: Amanita, Lepiota, and Galerina. Because amatoxin poisonings are increasing, the objective of this review was to identify all amatoxin-containing mushroom species, present a toxidromic approach to earlier diagnoses, and compare the efficacies and outcomes of therapies. To meet these objectives, Internet search engines were queried with keywords to select peer-reviewed scientific articles on amatoxin-containing mushroom poisoning and management. Descriptive epidemiological analyses have documented that most mushroom poisonings are caused by unknown mushrooms, and most fatal mushroom poisonings are caused by amatoxin-containing mushrooms. Amanita species cause more fatal mushroom poisonings than other amatoxin-containing species, such as Galerina and Lepiota. Amanita phalloides is responsible for most fatalities, followed by Amanita virosa and Amanita verna. The most frequently reported fatal Lepiota ingestions are due to Lepiota brunneoincarnata, and the most frequently reported fatal Galerina species ingestions are due to Galerina marginata. With the exception of liver transplantation, the current treatment strategies for amatoxin poisoning are all supportive and have not been subjected to rigorous efficacy testing in randomized controlled trials. All patients with symptoms of late-appearing gastrointestinal toxicity with or without false recovery or quiescent periods preceding acute liver insufficiency should be referred to centers providing liver transplantation. Patients with amatoxin-induced acute liver insufficiency that does not progress to liver failure will have a more favorable survival profile with supportive care than patients with amatoxin-induced acute liver failure, about half of whom will require liver transplantation.

Mushroom poisoning in Hong Kong: a ten-year review.

INTRODUCTION: Mushroom poisoning is a cause of major mortality and morbidity all over the world. Although Hong Kong people consume a lot of mushrooms, there are only a few clinical studies and reviews of local mushroom poisoning. This study aimed to review the clinical characteristics, source, and outcome of mushroom poisoning incidences in Hong Kong. METHODS: This descriptive case series review was conducted by the Hong Kong Poison Information Centre and involved all cases of mushroom poisoning reported to the Centre from 1 July 2005 to 30 June 2015. RESULTS: Overall, 67 cases of mushroom poisoning were reported. Of these, 60 (90%) cases presented with gastrointestinal symptoms of vomiting, diarrhoea, and abdominal pain. Gastrointestinal symptoms were early onset (<6 hours post-ingestion) and not severe in 53 patients and all recovered after symptomatic treatment and a short duration of hospital care. Gastrointestinal symptoms, however, were of late onset (≥6 hours post-ingestion) in seven patients; these were life-threatening cases of amatoxin poisoning. In all cases, the poisonous mushroom had been picked from the wild. Three cases were imported from other countries, and four collected and consumed the amatoxin-containing mushrooms in Hong Kong. Of the seven cases of amatoxin poisoning, six were critically ill, of whom one died and two required liver transplantation. There was one confirmed case of hallucinogenic mushroom poisoning caused by Tylopilus nigerrimus after consumption of a commercial mushroom product. A number of poisoning incidences involved the consumption of wild-harvested dried porcini purchased in the market. CONCLUSION: Most cases of mushroom poisoning in Hong Kong presented with gastrointestinal symptoms and followed a benign course. Life-threatening cases of amatoxin poisoning are occasionally seen. Doctors should consider this diagnosis in patients who present with gastrointestinal symptoms that begin 6 hours or more after mushroom consumption.

Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 1: Silibinin in suspected amatoxin-containing mushroom poisoning.

A shortcut review was carried out to establish whether silibinin is better than conservative management at reducing liver transplantation and death after poisoning with amatoxin-containing mushrooms. Thirty-eight papers were found in Medline and 86 in EMBASE using the reported searches. Of these, five presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are tabulated. It is concluded that the evidence is limited, but given the lack of alternative treatments in patients with suspected amatoxin-containing mushroom poisoning and the relatively few adverse effects, silibinin should be considered in some patients.

A Case Study: What Doses of Amanita phalloides and Amatoxins Are Lethal to Humans?

There are few data estimating the human lethal dose of amatoxins or of the toxin level present in ingested raw poisonous mushrooms. Here, we present a patient who intentionally ingested several wild collected mushrooms to assess whether they were poisonous. Nearly 1 day after ingestion, during which the patient had nausea and vomiting, he presented at the emergency department. His transaminase levels started to increase starting from hour 48 and peaking at hour 72 (alanine aminotransferase 2496 IU/L; aspartate aminotransferase 1777 IU/L). A toxin analysis was carried out on the mushrooms that the patient said he had ingested. With reversed-phase high-performance liquid chromatography analysis, an uptake of approximately 21.3 mg amatoxin from nearly 50 g mushroom was calculated; it consisted of 11.9 mg alpha amanitin, 8.4 mg beta amanitin, and 1 mg gamma amanitin. In the urine sample taken on day 4, 2.7 ng/mL alpha amanitin and 1.25 ng/mL beta amanitin were found, and there was no gamma amanitin. Our findings suggest that the patient ingested approximately 0.32 mg/kg amatoxin, and fortunately recovered after serious hepatotoxicity developed.

Amatoxin-containing mushroom (Lepiota brunneoincarnata) familial poisoning.

Serious to fatal toxicity may occur with amanitin-containing mushrooms ingestions. A Lepiota brunneoincarnata familial poisoning with hepatic toxicity is reported. In such poisonings, acute gastroenteritis may be firstly misdiagnosed leading to delay in preventing liver dysfunction by silibinin or penicillin G. Mushroom picking finally requires experience and caution.

[Management of poisoning with Amanita phalloides].

Death cap (Amanita phalloides) is commonly found and is one of the five most toxic fungi in Denmark. Toxicity is due to amatoxin, and poisoning is a serious medical condition, causing organ failure with potential fatal outcome. Acknowledgement and clarification of exposure, symptomatic and focused treatment is of primary importance. No data from randomised, controlled trials on management exists, and there is not international consensus on treatment regime. We present amatoxin-case contacts to the Danish Poison Centre from 2006-2012 and summarize current knowledge and Danish recommendations in amatoxin poisoning management.

[Toxicological analysis. Methodology, indication, and evaluation]. / Toxikologische Analytik. Methodik, Indikation und Bewertung.

Clinical toxicological analysis can significantly contribute toward the confirmation or exclusion of poisoning, especially if clinical signs and symptoms of unknown origin have to be explained. It may be of help when planning specific, but risky, poisoning therapies. Besides frequently used immunoassays for the detection of drugs of abuse, of a small number of medical drugs, and of amatoxins. Chromatographic methods with mass-selective detectors are available in specialized toxicology laboratories. The results of toxicological analyses have to be evaluated and interpreted carefully. Poison control centers can offer support for all medical aspects of poisoning including lab investigations.

Amatoxin poisoning: case reports and review of current therapies.

BACKGROUND: Diagnosis and management of Amanita mushroom poisoning is a challenging problem for physicians across the United States. With 5902 mushroom exposures and two resultant deaths directly linked to Amanita ingestion in 2009, it is difficult for physicians to determine which patients are at risk for lethal toxicity. Identification of amatoxin poisoning can prove to be difficult due to delay in onset of symptoms and difficulty with identification of mushrooms. Consequently, it is difficult for the Emergency Physician to determine proper disposition. Further, treatment options are controversial. OBJECTIVES: To review current data to help health care providers effectively identify and treat potentially deadly Amanita mushroom ingestions. CASE REPORTS: We present two cases of Amanita mushroom ingestion in the northeastern United States treated with N-acetylcysteine, high-dose penicillin, cimetidine, and silibinin, a semi-purified fraction of milk thistle-derived silymarin, as part of their treatment regimen. The mushroom species was identified by a consultant as Amanita Ocreata. CONCLUSIONS: We present the successful treatment of 2 patients who ingested what we believe to be an Amanita species never before identified in the northeastern United States.