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Treatment of Amatoxin Poisoning: 20-Year Retrospective Analysis
Abstract
Background:
Amatoxin poisoning is a medical emergency characterized by a long incubation time lag, gastrointestinal and hepatotoxic phases, coma, and death. This mushroom intoxication is ascribed to 35 amatoxin-containing species belonging to three genera: Amanita, Galerina, and Lepiota. The major amatoxins, the alpha-, beta-, and gamma-amanitins, are bicyclic octapeptide derivatives that damage the liver and kidney via irreversible binding to RNA polymerase II.
Methods:
The mycology and clinical syndrome of amatoxin poisoning are reviewed. Clinical data from 2108 hospitalized amatoxin poisoning exposures as reported in the medical literature from North America and Europe over the last 20 years were compiled. Preliminary medical care, supportive measures, specific treatments used singly or in combination, and liver transplantation were characterized. Specific treatments consisted of detoxication procedures (e.g., toxin removal from bile and urine, and extracorporeal purification) and administration of drugs. Chemotherapy included benzylpenicillin or other beta-lactam antibiotics, silymarin complex, thioctic acid, antioxidant drugs, hormones and steroids administered singly, or more usually, in combination. Supportive measures alone and 10 specific treatment regimens were analyzed relative to mortality.
Results:
Benzylpenicillin (Penicillin G) alone and in association was the mostfrequently utilized chemotherapy but showed little efficacy. No benefit was found for the use of thioctic acid or steroids. Chi-square statistical comparison of survivors and dead vs. treated individuals supported silybin, administered either as mono-chemotherapy or in drug combination and N-acetylcysteine as mono-chemotherapy as the most effective therapeutic modes. Future clinical research should focus on confirming the efficacy of silybin, N-acetylcysteine, and detoxication procedures.
... Amatoxins are heat-and frozen-stable toxic cyclic peptides (10)(11)(12). Two potent amatoxins are α-and β-amanitins (AMA). ...
... Th e toxic mechanism of AMAs is attributed to the non-covalent nuclear inhibition of RNA polymerase II in renal tubules, hepatocytes, and lymphocytes. Th e messenger RNA transcription process is suppressed, thus toxin-inhibited protein synthesis leads to cellular hepatic necrosis and apoptosis (1,4,(11)(12)(13)(14)(15).Th e hepatic centrilobular and periportal hemorrhagic hepatic necrosis brings to the rapid rise in hepatic damage biomarkers, principally serum transaminases, and coagulopathies result from defi ciencies in the synthesis of hepatic clotting factors. As the liver function fails, tubulointerstitial nephropathy follows and precipitates the hepatorenal syndrome that may be rapidly fatal if liver transplantation is not possible or available as a treatment option (22,31,35,36). ...
... Th e fi rst gastrointestinal symptoms can be seen only 6 to 12 hours aft er ingesting the mushrooms (1,(11)(12)(13)(14)(15)21). Sometimes the symptoms may appear aft er a long latency period of 40 hours, and can negatively infl uence medical intervention because cellular apoptosis and severe hepatic necrosis with fulminant hepatic failure occurs (1,4,5). ...
equal contribution Consumption of wild poison mushrooms is one of the serious poisonings which may end in death. The present case report and recent literature review describe Amanita phalloides mushroom poisoning and possible treatment for this emergency state. A 59-year-old male presented in the Emergency Unit of the Foggia University Hospital, Italy, with clinical signs of extreme dizziness , nausea, vomiting, and diarrhea, 12 h after consuming one ovule of a wild mushroom that was mistaken for an edible ovule of the Boletus edulis mushroom. The suspected poison mushrooms were collected in the forest near the city of Foggia, Italy. Urgent examination of urine showed the presence of-amanitin. After 6 days of intensive and supportive treatment with activated charcoal and N-acetyl cysteine, the patient was transferred to the internal medicine department and discharged without organ complications 10 days after mushroom ingestion. Early recognition of mushroom poisoning and immediate intensive treatment with supportive care give the patients a better chance for survival after this fatal poisoning.
... The MELD score was calculated for each of the cases using laboratory parameters. The patients were divided into three groups according to their MELD scores: mild (MELD score between 1-10), moderate (MELD score between [11][12][13][14][15][16][17][18][19][20], and severe (MELD score ≥21). The poisoning severity score (PSS) is a classification based on clinical findings developed to reveal the severity of poisoning. ...
... It has been reported that its effect is minimal when penicillin G is used as monotherapy or in combination with other treatments. Thioctic acid or steroids do not affect the treatment, and detailed studies are needed to understand the effectiveness of Silibilin and N-Acetyl Cysteine treatments (20). When the treatments were examined used in this study, It was seen that activated charcoal was administered at a rate of 67.7%, gastric lavage was performed at a rate of 42.7%, N-Acetyl Cysteine was applied at a rate of 22.1%, Penicillin G at a rate of 11.9%, and Silibilin therapy at a rate of 5.9%. ...
Aim: In this study it is aimed to investigate the general characteristics of the patients of mushroom poisoning in the emergency department and to determine the possible prognostic factors. Material and Methods: This study was conducted by retrospectively examining the records of patients who applied to the emergency department of a university hospital in Samsun, Turkey, with mushroom poisoning in 6 years. Patients were grouped using models that predict mortality and the severity of poisoning. Model for end stage liver diseases (MELD) scoring and poisoning severity score (PSS) were used for this purpose. All data obtained from this study were analyzed using the Statistical Package for Social Sciences (SPSS) for Windows 15.0 package program. Results: Liver failure developed in 16 of 471 patients who applied with mushroom poisoning. The median symptom onset time was 2 hours in 455 patients who did not develop liver failure, and the median symptom onset time was 9.5 hours in 16 patients who developed liver failure. When the patients were classified according to PSS, 91.1% of patients applied with PSS 1, while 2.1% of them applied with severe symptoms. 93.6% of the patients were with a mild MELD score. Conclusion: The most common clinical finding is nausea and vomiting. The appearance of symptoms within 2 hours is an indicator of a good prognosis. According to the MELD score, the severity of the disease increases as the BUN value increases. At the same time, high BUN and amylase levels mean a life-threatening poisoning according to PSS. ÖZ Amaç: Bu çalışmada acil servise mantar yeme sonrası gelişen zehirlenme tablosu ile başvuran hastaların genel karakteristiklerinin araştırılması ve olası prognostic faktörlerin belirlenmesi amaçlanmıştır. Gereç ve Yöntemler: Bu çalışma Samsun, Türkiye'deki bir üniversite hastanesi acil servisine 6 yıl içerisinde mantar zehirlenmesi ile başvuran 18 yaş ve üzerindeki hastaların kayıtlarının geriye dönük olarak incelenmesi ile yapıldı. Çalışmada mortalite öngördürücü ve zehirlenme ciddiyetini gösteren modeller kullanılarak hastalar gruplandırıldı. Son dönem karaciğer hastalığı için model (MELD) skorlaması ve zehirlenme şiddet skoru (PSS) bu amaçla kullanıldı. Bu çalışmaya ait elde edilen tüm veriler Statistical Package for Social Sciences (SPSS) for Windows 15.0 paket programı kullanılarak analiz edildi. Bulgular: Mantar zehirlenmesi ile acil servise başvuran 471 hastadan 16 tanesinde karaciğer yetmezliği geliştiği saptandı. Karaciğer yetmezliği gelişmeyen 455 hastada semptom başlangıç süresinin ortalama 2 saat olduğu, karaciğer yetmezliği gelişen 16 hastada ise semptom başlangıç süresinin ortalama 9,5 saat olduğu saptandı. Mantar zehirlenmeli hastalar PSS'sine göre sınıflandırıldığında, hastalarımızın %91,1'i PSS 1 olarak acil servise başvurmuş iken, %2,1'i ise şiddetli semptomlarla acil servise başvurmuştu. Mantar zehirlenmesiyle gelen hastaların %93,6'sı MELD skoru hafif olan hastalardı. Sonuç: Mantar intoksikasyonu olgularında en sık klinik bulgu bulantı ve kusmadır. Mantar intoksikasyonu hastalarında semptomların 2 saat içerisinde ortaya çıkması iyi prognoz göstergesidir. MELD skoruna göre Bun değeri yükseldikçe hastalık ciddiyeti de artmaktadır. Aynı zamanda BUN ve amilaz değeri yüksekliği PSS'ye göre hayatı tehdit edici bir
... Amatoxins are a group of highly toxic peptides produced by the fungal families Amanitaceae (genus Amanita), Agaricaceae (genus Lepiota), and Cortinariaceae (genus Galerina). More than 35 mushroom species in three genera have amatoxins as their main toxicants: Amanita [mainly, Amanita (A.) phalloides, A. virosa and A. verna], Lepiota (e.g., L. brunneoincarnata), Galerina (e.g., G. marginata) and Conocybe filaris (Fig. S1) [1,2]. Amanita species cause more fatal mushroom poisoning than other amatoxin-containing species, such as Galerina and Lepiota [1][2][3]. ...
... More than 35 mushroom species in three genera have amatoxins as their main toxicants: Amanita [mainly, Amanita (A.) phalloides, A. virosa and A. verna], Lepiota (e.g., L. brunneoincarnata), Galerina (e.g., G. marginata) and Conocybe filaris (Fig. S1) [1,2]. Amanita species cause more fatal mushroom poisoning than other amatoxin-containing species, such as Galerina and Lepiota [1][2][3]. Although Lepiota species mushrooms have lower toxin content, and have less detrimental health effects, the genus Amanita contains one of the most deadly poisonous species [1]. ...
Amatoxins are toxic bicyclic octapeptides found in certain wild mushroom species, particularly Amanita phalloides. These mushrooms contain predominantly α- and β-amanitin, which can lead to severe health risks for humans and animals if ingested. Rapid and accurate identification of these toxins in mushroom and biological samples is crucial for diagnosing and treating mushroom poisoning. Analytical methods for the determination of amatoxins are critical to ensure food safety and prompt medical treatment. This review provides a comprehensive overview of the research literature on the determination of amatoxins in clinical specimens, biological and mushroom samples. We discuss the physicochemical properties of toxins, highlighting their influence on the choice of the analytical method and the importance of sample preparation, particularly solid-phase extraction with cartridges. Chromatographic methods are emphasised with a focus on liquid chromatography coupled to mass spectrometry as one of the most relevant analytical method for the determination of amatoxins in complex matrices. Furthermore, current trends and future perspectives in amatoxin detection are also suggested.
... About 100 species of mushrooms found in India are poisonous [11]. Amatoxin and Gyromitrin, which are generated by a variety of Amanita species and some members of the Galerina, Lepiota, and Conocybe genera, are the main causes of hepatotoxicity [12][13]. Omphalotus olivascens, Mycena pura, and Chlorophyllum molybdites are frequent poisonous mushroom species found in India, although human poisonings are rare because local ethnic tribes are skilled at distinguishing between toxic and non-poisonous mushrooms [10,14]. ...
Mushroom is a fungus widely used as an edible in various parts of the world, especially in hilly regions with damp climates. Nevertheless, when picked from the wild to use as a vegetable, it has proved fatal for people ingesting it due to a lack of knowledge for distinguishing between poisonous and non-poisonous mushrooms by the people of the local community. Three cases presented as emergencies from a single household comprising a 13-year-old girl and both her grandparents following the ingestion of mushrooms picked from a nearby forest area. Luckily the parents of the girl were out for work, so they survived and helped identify the mushroom. Most cases are not reported or documented, and data are present mainly in the form of case reports.
... In antidotal therapy, various substances (silibinin, steroids, cimetidine, thioctic acid, benzylpenicillin, acetylcysteine) have been widely used in the past to treatα-amanitin poisonings. In a 20-year retrospective analysis assessed the treatments in amanitin poisonings, benzylpenicillin (penicillin G) used alone and in combination with other agents was the most frequently utilized chemotherapy, but showed little efficacy 17,18) . No benefit was found in the use of thioctic acid or steroids. ...
Purpose: Glehnia littoralis has been used to treat ischemic stroke, phlegm, cough, systemic paralysis, antipyretics and neuralgia. The pharmacological mechanisms of Glehnia littoralis include calcium channel block, coumarin derivatives, anticoagulation, anti-convulsive effect, as well as anti-oxidant and anti-inflammatory effects. Alpha-amanitin (${alpha}$-amanitin) is a major toxin from extremely poisonous Amanita fungi. Oxidative stress, which may contribute to severe hepatotoxicity was induced by ${alpha}$-amanitin. The aim of this study was to investigate whether Glehnia littoralis ethyl acetate extract (GLEA) has the protective antioxidant effects on ${alpha}$-amanitin -induced hepatotoxicity. Methods: Human hepatoma cell line HepG2 cells were pretreated in the presence or absence of GLEA (50, 100 and $200{mu}g/ml$) for 4 hours, then exposed to $60{mu}mol/L$ of${alpha}$-amanitin for an additional 4 hours. Cell viability was evaluated using the MTT method. AST, ALT, and LDH production in a culture medium and intracellular MDA, GSH, and SOD levels were determined. Results: GLEA (50, 100 and $200{mu}g/ml$) significantly increased the relative cell viability by 7.11, 9.87, and 14.39%, respectively, and reduced the level of ALT by 10.39%, 34.27%, and 52.14%, AST by 9.89%, 15.16%, and 32.84%, as well as LDH by 15.86%, 22.98%, and 24.32% in culture medium, respectively. GLEA could also remarkably decrease the level of MDA and increase the content of GSH and SOD in the HepG2 cells. Conclusion: In the in vitro model, Glehnia littoralis was effective in limiting hepatic injury after ${alpha}$-amanitin poisoning. Its antioxidant effect is attenuated by antidotal therapy.
... Bunun yanında tekrarlanan dozlarda aktif kömür, kömür hemoperfüzyonu, plazmaferez, albuminli moleküler absorban rejenerasyon sistemi (MARS), hemodiyaliz gibi uzaklaştırıcı ve destekleyici tedaviler yanında; penisilin, silibinin gibi hepatositlere toxin alınımını engelleyen antidotlar ve N-asetil sistein gibi hepatoprotektif tedaviler kullanılmaktadır (12,19). Literatürde tek başına veya birlikte silibinin, penisilin, NAS kullanımının yararlı oluşunu destekleyen çeşitli retrospektif analizler yer almaktadır (17,18,20,21). Çalışma grubumuzda hastaların %35'i yoğun bakımda izlenmiş, %30'unda tek başına penisilin infüzyonu verilirken, 3 hasta Penisilin, silibinin ve NAS tedavilerini birlikte almıştı ve hastalardan ikisi şifa ile taburcu edilmiş, biri karaciğer nakli sonrası taburcu edilmişti. ...
AMAÇ: Bu çalışma mantar tüketimi ile ilgili çocuk acil başvurularının klinik özellikleri ve sonlanımlarını değerlendirerek merkezimize ait tabloyu resmetmek, hasta yönetimi ve eğitim planlamasına yol gösterici veri üretmek amacıyla gerçekleştirildi. GEREÇ VE YÖNTEM: Geriye dönük 10 yıllık sürede mantar zehirlenmesi tanısı ile acil servise başvurmuş 18 yaş altı hastaların dosyaları incelendi ve oluşturulan bir form üzerinden hastaların demografik ve klinik özellikleri kaydedilerek değerlendirildi. BULGULAR: Değerlendirilen süre kapsamında çocuk acil servise başvurmuş toplam 689.000 hastadan 65 çocuk (%0,009) mantar zehirlenmesi tanısı almıştı. Mantar yedikten sonra semptomların başlama süresi ortalama 5,2±10,3 saatti ve hastaların %71’inde semptomlar ilk 6 saat içinde başlamıştı. Büyük çoğunluğunda gastrointestinal yakınmalar ön planda olup, kusma (%78) en sık görülen semptomdu. Hastaların tamamı hastaneye yatırıldı. Hastanede izlem süresi ortalama 3±1,5 gündü. Hasta yaşının küçük olması, başvuru fizik muayenesinde patolojik bulgu saptanması ve spesifik hepatoprotektif ve antidot tedavileri verilmiş olması hastanede yatış süresinin daha uzun olması ile ilişkili bulundu(p<0.05). Hastaların yaklaşık 1/3’ü çocuk yoğun bakım koşullarında izlenmiş olup, kaybedilen hasta olmadı. Ancak semptomları geç başlayan ve tıbbi yardıma geç başvuran sadece bir çocukta (%2) ilerleyici geri dönüşsüz karaciğer yetmezliği nedeniyle organ nakil merkezine sevk gerekti. SONUÇ: Çocuklarda mantar zehirlenmeleri çoğunlukla gastrointestinal sistem belirtilerinin ön planda olduğu iyi bir klinik seyir gösterse de özellikle semptomları geç başlayan ve tıbbi yardıma geç başvuran hastalarda karaciğer yetmezliği ile sonuçlanabilecek ağır klinik tablo açısından dikkatli yaklaşım gereklidir.
Acute liver failure (ALF) is a rare, acute, potentially reversible condition resulting in severe liver impairment and rapid clinical deterioration in patients without preexisting liver disease. Due to the rarity of this condition, published studies are limited by the use of retrospective or prospective cohorts and lack of randomized controlled trials. Current guidelines represent the suggested approach to the identification, treatment, and management of ALF and represent the official practice recommendations of the American College of Gastroenterology. The scientific evidence was reviewed using the Grading of Recommendations, Assessment, Development and Evaluation process to develop recommendations. When no robust evidence was available, expert opinions were summarized using Key Concepts. Considering the variety of clinical presentations of ALF, individualization of care should be applied in specific clinical scenarios.
Zusammenfassung
Mit über 90% der Todesfälle nach Pilzingestion gehört die Vergiftung mit Amatoxinen zu den gefährlichsten Lebensmittelintoxikationen. Trotz zahlreicher Fallberichte gibt es aufgrund fehlender randomisiert kontrollierter Studien lediglich limitierte Therapieempfehlungen.
Wir präsentieren den Fall eines 32-jährigen Patienten, der sich mit einem akuten Leberversagen nach Amanita phalloides (Grüner Knollenblätterpilz)-Ingestion vorgestellt hatte. Der Therapieerfolg wurde maßgeblich durch die Gabe von Aktivkohle, Silibinin und N-Acetylcystein sowie die beherzte Recherche eines Pilzsachverständigen ermöglicht.
In retrospektiven Studien konnte eine relevante Senkung der Letalität durch die genannten medikamentösen Maßnahmen gezeigt werden. Trotz der hohen geschätzten Ingestionsmenge konnten wir in diesem Fall die Effektivität dieser Kombinationstherapie bestätigen.
In dieser Fallübersicht soll neben der medikamentösen Therapie der Fokus insbesondere auf die außergewöhnliche Mitarbeit eines Pilzexperten gelegt werden, der durch sein investigatives Vorgehen die Verdachtsdiagnose sichern konnte und somit zum Therapieerfolg beigetragen hat. Ein zeitnaher Kontakt mit der zuständigen Giftnotrufzentrale und das Hinzuziehen eines Pilzexperten in unklaren Situationen wird daher empfohlen.
Analysis of two mushroom poisonings and their sequelae emphasizes the uncertainties often experienced in such cases, and alerts the mycological community to a new and potentially life-saving treatment, plasmapheresis.
Twenty-five carpophores were sampled and the influence of various factors on concentration and distribution of principal neutral (phalloin, phalloidin, phallisin) and acid (phallacidin and phallisacin) phallotoxins in Amanita phalloides was investigated. The nature of the organ investigated is stressed; for phallotoxins, the volva is most toxic. In addition, specimens collected from ordinary lowland countryside contained twice the toxin quantities as those from a medium altitude site; these quantities depend on a high neutral molecule content and particularly phalloidin. Substantial variations in toxin levels between two consecutive collection operations during the mushroom season were also observed whatever the collection site. This indicated a fall in these values at the end of the seasonal cycle. Although toxin levels depended on collection date, predominance of neutral or acid molecules remained constant. Phallotoxin levels also varied by various stages of carpophore development. In specimens from the plain, this resulted in a different distribution of neutral and acid toxins at maturity. Determination of toxin levels at various stages of maturation varied according to the specimens analyzed.
A 62-year-old woman and her 67-year-old husband suffered, in June 1994, from Amanita phalloides poisoning. This is an unusually early time of the year for these mushrooms to appear. The patients were successfully treated with intensive supportive therapy and with intravenous application of penicillin and silibinin (Legalon SIL). After 12 and 15 days of treatment, respectively, the patients could leave the hospital. Our investigation demonstrates the efficiency of intensive supportive and medical therapy with penicillin and silibinin. After an analysis of the existing literature, we recommend the immediate application of penicillin and silibinin if Amanita phalloides poisoning occurs. It has not yet been proved whether there are any benefits in using hemodialysis or hemoperfusion in the early stages in Amanita phalloides poisoning.
The case described is a serious parasuicide (failed suicide) by voluntary ingestion of a considerable amount of highly poisonous mushrooms (Amanita phalloides). The liver transplant performed straight afterwards enabled the patient to survive, but after a period of relative well-being in the immediate postoperative period, her pervasive suicidal ideation returned to the fore in all its dramatic ambivalence. The difficulties involved in managing the case and the decision to transplant a living organ in an individual who has just attempted suicide are discussed.
There are many species of poisonous mushrooms, but in the United States most poisoning is due to the Amanita. More than 100 deaths result each year from consumption of wild poisonous mushrooms. 90 percent being due to A. phalloides (death cap) or closely related species. Fatalities have occured after ingestion of only part of one mushroom. A. phalloides, A. virosa (destroying angel), some other Amanita species, and Galeria venenata contain heat-stable cyclopeptide cytotoxins which are rapidly bound to tissues. The principal toxin is alfa-amanitin, which binds to and inhibits specifically the mammalian RNA polymerase responsible for messenger RNA synthesis. Ingestion of these dangerous mushrooms is followed by a latent period of 6 to 20h. Manifestations of cytotoxicity then may appear suddenly and consist of severe nausea, violent abdominal pain, bloody vomiting and diarrhea, and cardiovascular collapse. Headache, mental confusion, coma, or convulsions are common. Painful and tender hepatomegaly, jaundice, hypoglycemia, dehydration, and oliguria or anuria frequently appear on the first or second day after ingestion. Ingestion of other poisonous mushrooms may cause gastrointestinal symptoms, visual disturbances, ataxia, disorientation, convulsions, coma, fever, hemolysis, and methemoglobinemia. Treatment of mushroom poisoning depends upon the species ingested. If parasympathomimetic manifestations are prominent, atropine in doses of 1 to 2 mg given intramuscularly and repeated every 30 min until symptoms are controlled. Poisoning by cytotoxic mushrooms in treated mainly symptomatically. Fluid and electrolyte balance must be carefully maintained. Hypoglycemia should be avoided; large quantities of carbohydrate may exert some protective effect on the liver. Excitement convulsions pain, hypotension, and fever may need symptomatic therapy.
Die Umsetzung von Silybin (I) mit alkalischem Wasserstoffperoxid ergibt das Dehydrierungsprodukt (II).