Mushrooms, amatoxins and the liver
2004; Elsevier BV; Volume: 42; Issue: 2 Linguagem: Inglês
10.1016/j.jhep.2004.12.003
ISSN1600-0641
Autores Tópico(s)Cholinesterase and Neurodegenerative Diseases
ResumoAcute liver failure (ALF) due to mushrooms containing amatoxins is relatively rare. In a survey of ALF in Spain, only 10 out of 267 cases (4%) were caused by amatoxins (pending publication). Amatoxin poisoning is a world wide problem: 50–100 fatal cases are reported yearly in Western Europe, being less common in the United States with fewer than 100 deaths in 5 years (1990–1994) [[1]Broussard C.N. Aggarwal A. Lacey S.R. Post A.B. Gramlich T. Henderson J.M. et al.Mushroom poisoning-from diarrhea to liver transplantation.Am J Gastroenterol. 2001; 56: 3195-3198Google Scholar]. There have been reports from Africa, Asia, Australia, as well as North, Central and South America [2Karlson-Stiber C. Persson H. Cytotoxic fungi-an overview.Toxicon. 2003; 42: 339-349Google Scholar, 3Enjalbert F. Rapior S. Nouguier-Soulé J. Guillon S. Amouroux N. Cabot C. Treatment of Amatoxin poisoning: 20-year retrospective analysis.J Toxicol Clin Toxicol. 2002; 40: 715-757Google Scholar]. Mortality by mushroom poisoning causing liver involvement varies widely, being higher in children (up to 50%) [[2]Karlson-Stiber C. Persson H. Cytotoxic fungi-an overview.Toxicon. 2003; 42: 339-349Google Scholar]. In the Hospital Clínic of Barcelona, a total of 33 adult cases have been admitted in the last 25 years, with a mortality of 11% (data kindly provided by Dr Santiago Nogué, Toxicology Dpt).Amatoxins are present in nine Amanita species (the most common being A. phalloides, but also A. virosa, and A. verna). Other Amanita species are toxic but do not cause liver diseases (i.e. A. muscarina), while many other Amanita species are edible, and one is considered to be among the most delicious mushrooms (A. cesarea). In ancient Rome, Emperor Claudius was assassinated by his wife Agrippina with a dish of A. cesarea served with the juice of A. phalloides [[4]Reuben A. The last Gasp or Caveat Cenans!.Hepatology. 2003; 38: 273-276Google Scholar]. Two other genera contain amatoxins: 24 Lepiota species (mainly L. brunneoincarnata, or L. helveolla), and nine Gallerina (the most frequently reported are G. autumnalis, and G. marginata) [[3]Enjalbert F. Rapior S. Nouguier-Soulé J. Guillon S. Amouroux N. Cabot C. Treatment of Amatoxin poisoning: 20-year retrospective analysis.J Toxicol Clin Toxicol. 2002; 40: 715-757Google Scholar]. According to other authors, of the three genera mentioned above the number of species containing amatoxins is lower [[5]Vetter J. Toxins of Amanita phalloides.Toxicon. 1998; 36: 13-24Google Scholar].Amatoxins are bicyclic octapeptides with a molecular weight around 900, formed by at least nine different compounds (alpha, beta and gamma amanitin being the main toxins) [[5]Vetter J. Toxins of Amanita phalloides.Toxicon. 1998; 36: 13-24Google Scholar]. They are not destroyed by cooking and can be present after long periods of storage (a fatal case has been reported after consuming A. phalloides frozen during 7–8 months) [[6]Himmelmann A. Mang G. Schnorf-Huber S. Lethal ingestion of stored Amanita phalloides mushrooms.Swiss Med Wkly. 2001; 131: 616-617Google Scholar]. Phallotoxins and virotoxins, much less toxic products, may also be present in the same mushrooms, the first being the cause of the initial gastrointestinal symptoms after ingestion [3Enjalbert F. Rapior S. Nouguier-Soulé J. Guillon S. Amouroux N. Cabot C. Treatment of Amatoxin poisoning: 20-year retrospective analysis.J Toxicol Clin Toxicol. 2002; 40: 715-757Google Scholar, 5Vetter J. Toxins of Amanita phalloides.Toxicon. 1998; 36: 13-24Google Scholar].The LD50 of amatoxins is very low. As little as 0.1 mg/kg body weight may be lethal in adults and this may be present in a single mushroom. The mechanism of toxicity is well known. Amatoxins interact with RNA polymerase II in the eukariotic cells, inhibiting transcription. This results in a progressive decrease in mRNA, causing deficient protein synthesis and cell death. Intestinal mucosa, hepatocytes and proximal tubules of the kidneys are the main target organs, hepatic necrosis being the most important injury. There is an enterohepatic recycling of the amatoxin that may have therapeutic implications [2Karlson-Stiber C. Persson H. Cytotoxic fungi-an overview.Toxicon. 2003; 42: 339-349Google Scholar, 5Vetter J. Toxins of Amanita phalloides.Toxicon. 1998; 36: 13-24Google Scholar].In this issue of the Journal, Ganzert et al. [[7]Ganzert M. Felgenhauer N. Zilker T. Indication of liver transplantation following amatoxin intoxication.J Hepatol. 2005; 42: 202-209Abstract Full Text Full Text PDF Scopus (106) Google Scholar] analyse the prognostic factors of amatoxin poisoning in 198 cases seen in the last 25 years in Munich and in other European hospitals. The authors consider that the data obtained may be useful in deciding whether to proceed with emergency liver transplantation (ELT) in cases developing ALF.Recently, in an Editorial in this journal, Dr Jacques Bernuau stressed the importance of early specific medical therapy, when available, in cases of ALF [[8]Bernuau J. Acute liver failure: avoidance of deleterious cofactors and early specific medical therapy for the liver are better than late intensive care for the brain.J Hepatol. 2004; 41: 152-155Google Scholar]. I fully agree with his statements. Although he did not mention amatoxin poisoning as a 'treatable liver disease' causing ALF, probably because of the weakness of the data supporting the efficacy of the different therapeutic modalities, I believe that it is very important to briefly analyse the symptoms of amatoxin poisoning and its possible therapeutic approach before discussing the role of ELT in the most severe cases.The clinical picture of amatoxin poisoning is classically divided into four phases [1Broussard C.N. Aggarwal A. Lacey S.R. Post A.B. Gramlich T. Henderson J.M. et al.Mushroom poisoning-from diarrhea to liver transplantation.Am J Gastroenterol. 2001; 56: 3195-3198Google Scholar, 2Karlson-Stiber C. Persson H. Cytotoxic fungi-an overview.Toxicon. 2003; 42: 339-349Google Scholar, 5Vetter J. Toxins of Amanita phalloides.Toxicon. 1998; 36: 13-24Google Scholar]. After a latency period greater than 6 h (usually 8–12 h) severe gastrointestinal symptoms appear (vomiting, abdominal pain and watery diarrhoea). It is important for early diagnosis to always suspect amatoxin intoxication after mushroom ingestion when a relatively prolonged latency period is present, since other toxic mushrooms that do not cause liver involvement can induce gastrointestinal symptoms much earlier, 1–2 h after ingestion. However, some exceptions can occur: after ingestion of a mixture of different hepatotoxic and non-hepatotoxic mushrooms, early gastrointestinal symptoms may be present due to the latter, and therefore, the latency period may not be present (Dr Santiago Nogué, personal communication). In the gastroenteritic phase, oliguria, electrolyte and acid–base abnormalities and renal failure can occur if not adequately treated with i.v. fluids. After a few hours, diarrhoea ceases and the patient's condition improves, if correction of the dehydration has been achieved. However, 36–48 h after ingestion signs of liver involvement may appear, ranging from an asymptomatic increase in transaminases to a full ALF syndrome, that can lead to death. Renal failure may appear in this phase (3–5 days after ingestion) due to direct toxic damage. This occurs specially in cases of massive ingestion. In patients with a favourable outcome, a rapid improvement in liver function tests occurs, followed by full recovery.Diagnosis is based on the described clinical manifestations and can be confirmed by the determination of alpha amanitin in urine. There are different methods of analysis (RIA, ELISA, HPLC) [9Butera R. Locatelli C. Coccini T. Manzo L. Diagnostic accuracy of urinary amanitin in suspected mushroom poisoning: a pilot study.J Toxicol Clin Toxicol. 2004; 42: 901-912Google Scholar, 10Defendenti C. Bonacina E. Mauroni M. Gelosa L. Validation of a high performance liquid chromatographic method for alpha amanitin determination in urine.Forensic Sci Int. 1998; 92: 59-68Google Scholar]. These techniques are highly sensitive, without false negatives if performed in the first 48 h after ingestion. The relationship between the urinary concentration of alpha amanitin and the severity of the liver damage is very weak and most authors consider that it can not be used as a prognostic tool [[2]Karlson-Stiber C. Persson H. Cytotoxic fungi-an overview.Toxicon. 2003; 42: 339-349Google Scholar].The management of amatoxin poisoning includes preliminary medical care, supportive measures, specific treatments and ELT if deemed necessary. An exhaustive analysis of the world experience in this field was published in 2002 by Enjalbert et al. [[3]Enjalbert F. Rapior S. Nouguier-Soulé J. Guillon S. Amouroux N. Cabot C. Treatment of Amatoxin poisoning: 20-year retrospective analysis.J Toxicol Clin Toxicol. 2002; 40: 715-757Google Scholar]. These authors analysed 2108 cases seen in 20 years in different centres in Europe and the USA. Another recent review of cytotoxic fungi also gives similar therapeutic recommendations [[2]Karlson-Stiber C. Persson H. Cytotoxic fungi-an overview.Toxicon. 2003; 42: 339-349Google Scholar].Gastric lavage should only be performed if the patient is seen early after ingestion. In an asymptomatic patient whole bowel irrigation could be considered. The first goal should be directed to treatment of dehydration and electrolyte disturbances caused by the gastrointestinal fluid loss. Intense forced neutral diuresis is no longer recommended, with urinary output of 100–200 ml/h for 4–5 days being sufficient to increase the renal elimination of amatoxins. Repeated activated charcoal administration is a generally recommended method to avoid reabsorption of the toxins, due to their enterohepatic circulation. The doses suggested are as high as 12.5 g/h in adults. In the Hospital Clínic, the protocol indicates 25 g of activated charcoal dissolved in 240 ml of water by mouth or nasogastric tube every 3 h and should be maintained during 3–4 days after ingestion. Nasoduodenal aspiration aimed to eliminate the toxins excreted by bile is a difficult procedure. If diarrhoea has ceased, the use of cathartics is recommended (sodium sulphate, 30 g in 240 ml of water, every 12 h).The use of extracorporeal methods for toxin removal (haemodialysis, haemoperfusion, plasma exchange) was common in the past, but continues to be used in some centres [11Jander S. Bischoff J. Plasmapheresis in the treatment of Amanita phalloides poisoning: II. A review and recommendations.Ther Apher. 2000; 4: 308-312Google Scholar, 12Splendiani G. Zazzano D. Di Pietrantonio P. Delfino L. Continuous renal replacement therapy and charcoal plasmaperfusion in treatment of amanita mushroom poisoning.Artif Organs. 2000; 24: 305-308Google Scholar]. As with other therapeutic measures, there are no convincing data about their efficacy. A recent report has indicated that haemoperfusion is futile in A. phalloides intoxication (no toxin was detected in haemodialysis or haemoperfusion circuits) [[13]Mullins M.E. Horowitz B.Z. The futility of hemoperfusion and hemodialysis in Amanita phalloides poisoning.Vet Hum Toxicol. 2000; 42: 90-91Google Scholar], and indications of plasma exchange recently made by a group of experts in the USA do not include mushroom poisoning [[14]Smith J.W. Weinstein R. Hillyer K.L. AABB Hemapheresis Committee Therapeutic apheresis: a summary of current indications categories endorsed by the AABB and the American Society for apheresis.Transfusion. 2003; 43: 820-822Google Scholar]. Therefore, taking into account the possible risk of these techniques and the lack of evidence concerning their efficacy, their use should be restricted to cases of massive ingestion, always starting early (maximum 24–36 h after ingestion) or in patients with preexisting renal insufficiency [[2]Karlson-Stiber C. Persson H. Cytotoxic fungi-an overview.Toxicon. 2003; 42: 339-349Google Scholar].Case reports or short series of patients with severe amatoxin poisoning treated with the MARS system have recently been published [15Catalina M.V. Núñez O. Ponferrada A. Menchén L. Matilla A. Clemente G. et al.Toxicidad hepática por ingesta de setas: curso clínico y nuevas perspectivas de tratamiento.Gastroenterol Hepatol. 2003; 26: 417-420Google Scholar, 16Covic A. Goldsmith D.J.A. Gusbeth-Tatomir P. Volovat C. Dimitriu A.G. Cristogel F. et al.Successful use of Molecular Absorbent Regenerating System (MARS) dialysis for the treatment of fulminant hepatic failure in children accidentally poisoned by toxic mushroom ingestion.Liver Int. 2003; 23: 21-27Google Scholar, 17Faybik P. Hetz H. Baker A. Bittermann C. Berlakovich G. Werba A. et al.Extracorporeal albumin dialysis in patients with Amanita phalloides poisoning.Liver Int. 2003; 23: 28-33Google Scholar]. Although the data seem promising, the real efficacy of this method, or that of the other liver support systems, should be analysed in appropriate trials.Along with measures directed to increase the elimination of the toxin, various 'specific' pharmacological treatments are in use in amatoxin poisoning. Silibinin, a water soluble silimarin derivative, has shown to reduce amatoxin uptake by hepatocytes [2Karlson-Stiber C. Persson H. Cytotoxic fungi-an overview.Toxicon. 2003; 42: 339-349Google Scholar, 3Enjalbert F. Rapior S. Nouguier-Soulé J. Guillon S. Amouroux N. Cabot C. Treatment of Amatoxin poisoning: 20-year retrospective analysis.J Toxicol Clin Toxicol. 2002; 40: 715-757Google Scholar]. For this reason, it is widely used in this situation and some data seem to indicate that it is useful in clinical settings [[18]Saller R. Meier R. Brignoli R. The use of silymarin in the treatment of liver diseases.Drugs. 2001; 61: 2035-2063Google Scholar]. The recommended dose is empirical (5 mg/kg i.v. in bolus followed by a continuous infusion of 20 mg/kg/h, or a total of 1400 mg/day also in perfusion). Treatment is continued during 3–4 days [[2]Karlson-Stiber C. Persson H. Cytotoxic fungi-an overview.Toxicon. 2003; 42: 339-349Google Scholar].Penicillin G has a similar effect in experimental animals (i.e. inhibition of amanitin uptake by the liver), although other studies suggest other intracellular mechanisms of hepatoprotection against amatoxin. The doses employed are very high (4 million units/i.v./2 h). Having a similar mechanism of action, is seems illogical to use both drugs together and many authors consider that silibinin alone should be used as a first option [2Karlson-Stiber C. Persson H. Cytotoxic fungi-an overview.Toxicon. 2003; 42: 339-349Google Scholar, 3Enjalbert F. Rapior S. Nouguier-Soulé J. Guillon S. Amouroux N. Cabot C. Treatment of Amatoxin poisoning: 20-year retrospective analysis.J Toxicol Clin Toxicol. 2002; 40: 715-757Google Scholar].N-acetylcysteine (NAC), used mainly in paracetamol overdose, has also been proposed as a protective agent in amatoxin poisoning because of a reduction in hepatocyte glutathione content found in animals treated with Amanita extracts. These results have not been reproduced in other studies [[2]Karlson-Stiber C. Persson H. Cytotoxic fungi-an overview.Toxicon. 2003; 42: 339-349Google Scholar]. NAC is used in many centres in cases of ALF not induced by paracetamol based on King's College Hospital (KCH) data showing an improvement of haemodynamics and oxygen transport [[19]Harrison P.M. Wendon J.A. Gimson A.E. Alexander G.J. Williams R. Improvement by acetylcysteine of hemodynamics and oxygen transport in fulminant hepatic failure.N Engl J Med. 1991; 324: 1852-1857Google Scholar]. Therefore, its use in amatoxin poisoning is recommended, independently of the possible glutathione depletion caused by amatoxins [2Karlson-Stiber C. Persson H. Cytotoxic fungi-an overview.Toxicon. 2003; 42: 339-349Google Scholar, 3Enjalbert F. Rapior S. Nouguier-Soulé J. Guillon S. Amouroux N. Cabot C. Treatment of Amatoxin poisoning: 20-year retrospective analysis.J Toxicol Clin Toxicol. 2002; 40: 715-757Google Scholar]. However, a recent review has raised doubts about the usefulness of NAC administration in patients with ALF not due to paracetamol [[20]Sklar G.E. Subramaniam M. Acetylcysteine treatment for non-acetaminophen-induced acute liver failure.Ann Pharmacother. 2004; 38: 498-500Google Scholar].As discussed by Enjalbert et al. [[3]Enjalbert F. Rapior S. Nouguier-Soulé J. Guillon S. Amouroux N. Cabot C. Treatment of Amatoxin poisoning: 20-year retrospective analysis.J Toxicol Clin Toxicol. 2002; 40: 715-757Google Scholar], many other drugs were used in the past in this setting: other beta-lactam antibiotics, antioxidants, thioctic acid, hormones and steroids. All have been abandoned. According to retrospective data, most authors indicate that silibinin and NAC are the drugs of choice [1Broussard C.N. Aggarwal A. Lacey S.R. Post A.B. Gramlich T. Henderson J.M. et al.Mushroom poisoning-from diarrhea to liver transplantation.Am J Gastroenterol. 2001; 56: 3195-3198Google Scholar, 2Karlson-Stiber C. Persson H. Cytotoxic fungi-an overview.Toxicon. 2003; 42: 339-349Google Scholar, 3Enjalbert F. Rapior S. Nouguier-Soulé J. Guillon S. Amouroux N. Cabot C. Treatment of Amatoxin poisoning: 20-year retrospective analysis.J Toxicol Clin Toxicol. 2002; 40: 715-757Google Scholar].As stated previously, in cases of severe liver insufficiency after amatoxin poisoning, ELT should be indicated [1Broussard C.N. Aggarwal A. Lacey S.R. Post A.B. Gramlich T. Henderson J.M. et al.Mushroom poisoning-from diarrhea to liver transplantation.Am J Gastroenterol. 2001; 56: 3195-3198Google Scholar, 2Karlson-Stiber C. Persson H. Cytotoxic fungi-an overview.Toxicon. 2003; 42: 339-349Google Scholar, 3Enjalbert F. Rapior S. Nouguier-Soulé J. Guillon S. Amouroux N. Cabot C. Treatment of Amatoxin poisoning: 20-year retrospective analysis.J Toxicol Clin Toxicol. 2002; 40: 715-757Google Scholar, 21Ramírez P. Parrilla P. Sánchez Bueno F. Robles R. Pons J.A. Bixquert V. et al.Fulminant hepatic failure after Lepiota mushroom poisoning.J Hepatol. 1993; 19: 51-54Google Scholar, 22Meunier B.C. Camus C.M. Houssin D.P. Messner M.J. Gerault A.M. Launois B.G. Liver transplantation after severe poisoning due to amatoxin-containing Lepiota - report of three cases.J Toxicol Clin Toxicol. 1995; 33: 165-171Google Scholar, 23Alves A. Gouveia Ferreira M. Paulo J. França A. Carvalho A. Mushroom poisoning with Amanita phalloides—a report of four cases.Eur J Intern Med. 2001; 12: 64-66Google Scholar, 24Pawlowska J. Pawlak J. Kaminski A. Jankowska P. Helveke M. Teisseyre M. et al.Liver transplantation in three family members after Amanita phalloides mushroom poisoning.Transplant Proc. 2002; 34: 3313-3314Google Scholar]. The decision to transplant such a patient is exceedingly difficult [[25]Bernuau J. Benhamou J.P. Fulminant and subfulminant liver failure.in: Bircher J. Benhamou J.P. McIntyre N. Rizzetto M. Rodés J. Oxford textbook of clinical hepatology. 2nd ed. Oxford Medical Publications, Oxford1999: 1341-1372Google Scholar]. Ganzert et al. [[7]Ganzert M. Felgenhauer N. Zilker T. Indication of liver transplantation following amatoxin intoxication.J Hepatol. 2005; 42: 202-209Abstract Full Text Full Text PDF Scopus (106) Google Scholar], retrospectively analyse the outcome of a large series of amatoxin intoxication cases and have found that predictors of death were prothrombin index in combination with serum creatinine on days 3–10 after ingestion. These parameters showed a very high specificity and sensitivity, superior to others analysed in the same paper (i.e ALAT and bilirubin values). According to the authors these results should be considered in the decision to indicate ELT.Criteria for ELT in ALF are not universally accepted. The most widely used are those described by KCH, that include different parameters for paracetamol and non-paracetamol induced ALF [[26]O'Grady J.G. Alexander G.J. Hayllar K.M. Williams R. Early indicators of prognosis in fulminant hepatic failure.Gastroenterology. 1989; 97: 439-445Crossref Scopus (1724) Google Scholar]. Using the latter criteria, only three out of five parameters could be used in ALF due to amatoxin poisoning, as stated by Ganzert et al. [[7]Ganzert M. Felgenhauer N. Zilker T. Indication of liver transplantation following amatoxin intoxication.J Hepatol. 2005; 42: 202-209Abstract Full Text Full Text PDF Scopus (106) Google Scholar]: aetiology is obviously excluded as is duration of jaundice before encephalopathy greater than 7 days, since death occurs in less than 9 days in the vast majority of cases. The prognostic power of bilirubin concentration in the study of Ganzert et al. [[7]Ganzert M. Felgenhauer N. Zilker T. Indication of liver transplantation following amatoxin intoxication.J Hepatol. 2005; 42: 202-209Abstract Full Text Full Text PDF Scopus (106) Google Scholar] is very weak, probably for the same reason (very rapid fatal outcome, without enough time to achieve high bilirubin levels). In this regard, Enjalbert et al. [[3]Enjalbert F. Rapior S. Nouguier-Soulé J. Guillon S. Amouroux N. Cabot C. Treatment of Amatoxin poisoning: 20-year retrospective analysis.J Toxicol Clin Toxicol. 2002; 40: 715-757Google Scholar] reported some clinical and biological data of ELT performed between 1985 and 2001 in amatoxin poisoning: serum bilirubin, when given, was below the threshold of 300 umol/l (parameter of KCH) in nine cases, being higher than this figure in only four. Therefore, the prognostic values of the parameters proposed by Ganzert et al. [[7]Ganzert M. Felgenhauer N. Zilker T. Indication of liver transplantation following amatoxin intoxication.J Hepatol. 2005; 42: 202-209Abstract Full Text Full Text PDF Scopus (106) Google Scholar] seem to be clearly superior to those of the KCH in amatoxin poisoning.Other criteria for ELT in ALF are based on Factor V and age (Clichy criteria) [[27]Bernuau J. Selection for emergency liver transplantation.J Hepatol. 1993; 19: 486-487Google Scholar]. Data from Enjalbert et al. [[3]Enjalbert F. Rapior S. Nouguier-Soulé J. Guillon S. Amouroux N. Cabot C. Treatment of Amatoxin poisoning: 20-year retrospective analysis.J Toxicol Clin Toxicol. 2002; 40: 715-757Google Scholar] in patients transplanted for amatoxin poisoning indicate that Factor V was below 20% in all cases except one in which this parameter was given. In clinical settings, Factor V is rarely determined (except in French centres), and therefore, I suppose this is why the possible predictive role of outcome of factor V is not discussed in the study by Ganzert et al. [[7]Ganzert M. Felgenhauer N. Zilker T. Indication of liver transplantation following amatoxin intoxication.J Hepatol. 2005; 42: 202-209Abstract Full Text Full Text PDF Scopus (106) Google Scholar].The use of specific criteria for ELT in paracetamol overdose in amatoxin poisoning seems illogical. Although Ganzert et al. [[7]Ganzert M. Felgenhauer N. Zilker T. Indication of liver transplantation following amatoxin intoxication.J Hepatol. 2005; 42: 202-209Abstract Full Text Full Text PDF Scopus (106) Google Scholar] have tried to apply these criteria in their series, the data also showed a weak prognostic power.The presence of hepatic encephalopathy in acute liver diseases is (or was?) an absolute requirement for the diagnosis of ALF. In recent years there has been confounding terminology, using sometimes ALF in cases of severe liver insufficiency without encephalopathy. As Jacques Bernuau suggests (personal communication), a consensus conference to define terminology: fulminant and subfulminant hepatic failure, fulminant hepatitis, hyperacute, acute and subacute liver failure, acute liver failure without hepatic encephalopathy,… [[28]Vaquero J. Blei A.T. Etiology and management of fulminant hepatic failure.Curr Gastroenterol Rep. 2003; 5: 39-47Google Scholar] is necessary. Surprisingly, in the paper by Ganzert et al. [[7]Ganzert M. Felgenhauer N. Zilker T. Indication of liver transplantation following amatoxin intoxication.J Hepatol. 2005; 42: 202-209Abstract Full Text Full Text PDF Scopus (106) Google Scholar] hepatic encephalopathy is not investigated, because of 'imprecise data in the patient's records'. Does this mean that a patient with amatoxin poisoning without any clinical sign of hepatic encephalopathy should be listed for ELT if the prothrombin index is less than 25% and the serum creatinine is greater that 106 umol/l day 3 after ingestion? If the answer is yes, this obviously contrasts with the fact that the presence of hepatic encephalopathy (any degree) is a necessary condition to indicate ELT in the KCH and Clichy criteria. The degree of hepatic encephalopathy and the clinical course of ALF (fulminant or subfulminant) are the main criteria for indicating ELT in my centre [[29]Mas A. Rodés J. Fulminant hepatic failure.Lancet. 1997; 349: 1081-1085Google Scholar]. Again, data given by Enjalbert et al. [[3]Enjalbert F. Rapior S. Nouguier-Soulé J. Guillon S. Amouroux N. Cabot C. Treatment of Amatoxin poisoning: 20-year retrospective analysis.J Toxicol Clin Toxicol. 2002; 40: 715-757Google Scholar] indicate that all amatoxin poisoned patients transplanted except one (in whom data was not indicated) had different degrees of hepatic encephalopathy (mostly III or IV). I obviously agree with the statement 'the liver fails before encephalopathy', and with 'encephalopathy should be considered as a late symptom of ALF' [[8]Bernuau J. Acute liver failure: avoidance of deleterious cofactors and early specific medical therapy for the liver are better than late intensive care for the brain.J Hepatol. 2004; 41: 152-155Google Scholar]. However, my personal position is to not indicate ELT in patients without encephalopathy. Of course, I fully support the suggestion to refer, as early as possible, any patient with an acute liver disease and an important coagulopathy to a centre with experienced hepatologists and an active liver transplant program [8Bernuau J. Acute liver failure: avoidance of deleterious cofactors and early specific medical therapy for the liver are better than late intensive care for the brain.J Hepatol. 2004; 41: 152-155Google Scholar, 25Bernuau J. Benhamou J.P. Fulminant and subfulminant liver failure.in: Bircher J. Benhamou J.P. McIntyre N. Rizzetto M. Rodés J. Oxford textbook of clinical hepatology. 2nd ed. Oxford Medical Publications, Oxford1999: 1341-1372Google Scholar]. This is one of the most important messages that should be given. In the case of amatoxin poisoning, I believe that even a minimal suspicion of ingestion of mushrooms containing amatoxin should be an indication for referral to such a centre, with, if possible, a potent Toxicology Department.Two final considerations. Only paracetamol overdose has specific criteria for ELT; the remaining cases, with a wide variety of aetiologies, clinical courses, and even prognosis have, until now, common criteria for ELT. The paper by Ganzert et al. [[7]Ganzert M. Felgenhauer N. Zilker T. Indication of liver transplantation following amatoxin intoxication.J Hepatol. 2005; 42: 202-209Abstract Full Text Full Text PDF Scopus (106) Google Scholar] provides specific criteria for unusual cases of ALF (amatoxin poisoning). This opens the possibility that new criteria for ELT in specific cause(s) of ALF will be described in the future.My last thought refers to the fact that studies on the efficacy of prognostic factors used as indicators of ELT in ALF are carried out in countries in which a graft is usually available within a short time. However, the waiting time on the emergency transplant list, if it exists, may be very prolonged in some parts of the world [[30]Mas A. Salmerón J.M. Tost J. Applicability of liver transplantation in fulminant hepatic failure.in: Arroyo V. Bosch J. Bruix J. Ginès P. Navasa M. Rodés J. Therapy in hepatology. Ars Medica, Barcelona2001: 159-165Google Scholar], and liver transplant may never be performed in others [[8]Bernuau J. Acute liver failure: avoidance of deleterious cofactors and early specific medical therapy for the liver are better than late intensive care for the brain.J Hepatol. 2004; 41: 152-155Google Scholar]. In these situations the use of new therapies (i.e. MARS) could be useful. Nevertheless, taking into account that many patients will not benefit from ELT, I believe that the main aims of our daily work in the field of acute liver diseases should be directed at the prevention of diseases (i.e. education regarding mushroom poisoning), early diagnosis, avoidance of further deteriorating factors and, when possible, the prompt use of specific therapeutic measures. Acute liver failure (ALF) due to mushrooms containing amatoxins is relatively rare. In a survey of ALF in Spain, only 10 out of 267 cases (4%) were caused by amatoxins (pending publication). Amatoxin poisoning is a world wide problem: 50–100 fatal cases are reported yearly in Western Europe, being less common in the United States with fewer than 100 deaths in 5 years (1990–1994) [[1]Broussard C.N. Aggarwal A. Lacey S.R. Post A.B. Gramlich T. Henderson J.M. et al.Mushroom poisoning-from diarrhea to liver transplantation.Am J Gastroenterol. 2001; 56: 3195-3198Google Scholar]. There have been reports from Africa, Asia, Australia, as well as North, Central and South America [2Karlson-Stiber C. Persson H. Cytotoxic fungi-an overview.Toxicon. 2003; 42: 339-349Google Scholar, 3Enjalbert F. Rapior S. Nouguier-Soulé J. Guillon S. Amouroux N. Cabot C. Treatment of Amatoxin poisoning: 20-year retrospective analysis.J Toxicol Clin Toxicol. 2002; 40: 715-757Google Scholar]. Mortality by mushroom poisoning causing liver involvement varies widely, being higher in children (up to 50%) [[2]Karlson-Stiber C. Persson H. Cytotoxic fungi-an overview.Toxicon. 2003; 42: 339-349Google Scholar].
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