Drug‐induced acute liver failure: Results of a U.S. multicenter, prospective study

Acute liver failure (ALF) due to drug‐induced liver injury (DILI), though uncommon, is a concern for both clinicians and patients. The Acute Liver Failure Study Group has prospectively collected cases of all forms of acute liver failure since 1998. We describe here cases of idiosyncratic DILI ALF enrolled during a 10.5‐year period. Data were collected prospectively, using detailed case report forms, from 1198 subjects enrolled at 23 sites in the United States, all of which had transplant services. A total of 133 (11.1%) ALF subjects were deemed by expert opinion to have DILI; 81.1% were considered highly likely, 15.0% probable, and 3.8% possible. Subjects were mostly women (70.7%) and there was overrepresentation of minorities for unclear reasons. Over 60 individual agents were implicated, the most common were antimicrobials (46%). Transplant‐free (3‐week) survival was poor (27.1%), but with highly successful transplantation in 42.1%, overall survival was 66.2%. Transplant‐free survival in DILI ALF is determined by the degree of liver dysfunction, specifically baseline levels of bilirubin, prothrombin time/international normalized ratio, and Model for End‐Stage Liver Disease scores. Conclusion: DILI is an uncommon cause of ALF that evolves slowly, affects a disproportionate number of women and minorities, and shows infrequent spontaneous recovery, but transplantation affords excellent survival. (HEPATOLOGY 2010)

[1]  J. Ludwig,et al.  Fulminant hepatitis: Mayo Clinic experience with 34 cases. , 1985, Mayo Clinic proceedings.

[2]  D. Larrey.  Drug-induced liver diseases. , 2000, Journal of hepatology.

[3]  W. Kim,et al.  The model for end‐stage liver disease (MELD) , 2007, Hepatology.

[4]  N. Kaplowitz,et al.  Drug-Induced Liver Disease, Second Edition , 2002 .

[5]  E. Forrest,et al.  Causes of obvious jaundice in South West Wales , 2002, Gut.

[6]  K. Tolman.  The liver and lovastatin. , 2002, The American journal of cardiology.

[7]  S. Marciano,et al.  Imatinib-induced fatal acute liver failure. , 2007, World journal of gastroenterology.

[8]  E. Björnsson,et al.  Outcome and prognostic markers in severe drug‐induced liver disease , 2005, Hepatology.

[9]  P. Hillon,et al.  Incidence of drug‐induced hepatic injuries: A French population‐based study , 2002, Hepatology.

[10]  D. Larrey.  Epidemiology and Individual Susceptibility to Adverse Drug Reactions Affecting the Liver , 2002, Seminars in liver disease.

[11]  William M. Lee,et al.  Acetaminophen‐induced acute liver failure: Results of a United States multicenter, prospective study , 2005, Hepatology.

[12]  E. Björnsson,et al.  Severe Jaundice in Sweden in the New Millennium: Causes, Investigations, Treatment and Prognosis , 2003, Scandinavian journal of gastroenterology.

[13]  S. Wolfe,et al.  Timing of new black box warnings and withdrawals for prescription medications. , 2002, JAMA.

[14]  E. Björnsson,et al.  Fulminant drug-induced hepatic failure leading to death or liver transplantation in Sweden , 2005, Scandinavian journal of gastroenterology.

[15]  Wei-xing Chen,et al.  Evaluation of prognostic markers in severe drug-induced liver disease. , 2007, World journal of gastroenterology.

[16]  M. Rawlins,et al.  Accuracy of hepatic adverse drug reaction reporting in one English health region , 1999, BMJ.

[17]  C. Lake,et al.  Disulfiram-induced fulminating hepatitis: guidelines for liver-panel monitoring. , 1988, The Journal of clinical psychiatry.

[18]  William M. Lee,et al.  Measurement of serum acetaminophen-protein adducts in patients with acute liver failure. , 2006, Gastroenterology.

[19]  M. G. Peters,et al.  Etiology and outcome for 295 patients with acute liver failure in the United States. , 1999, Liver transplantation and surgery : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[20]  M. Black,et al.  Drug induced liver disease. , 1983, Postgraduate medical journal.

[21]  William M. Lee,et al.  Results of a Prospective Study of Acute Liver Failure at 17 Tertiary Care Centers in the United States , 2002, Annals of Internal Medicine.

[22]  M. Madariaga,et al.  Drug-related hepatotoxicity. , 2006, The New England journal of medicine.

[23]  M W Whitehead,et al.  The causes of obvious jaundice in South West Wales: perceptions versus reality , 2001, Gut.

[24]  E. Björnsson,et al.  Suspected drug-induced liver fatalities reported to the WHO database. , 2006, Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver.

[25]  D. Larrey,et al.  Hepatotoxicity of herbal remedies. , 1997, Journal of hepatology.

[26]  A. Bergquist,et al.  Long-term follow-up of patients with acute liver failure of indeterminate aetiology , 2008, Scandinavian journal of gastroenterology.

[27]  R. Andrade,et al.  Assessment of drug-induced hepatotoxicity in clinical practice: a challenge for gastroenterologists. , 2007, World Journal of Gastroenterology.

[28]  William M. Lee,et al.  Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure. , 2009, Gastroenterology.

[29]  Luis Rodrigo,et al.  Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. , 2005, Gastroenterology.

[30]  Profile of General Demographic Characteristics : 2000 , 2002 .

[31]  Y. Chawla,et al.  Prognostic Evaluation of Early Indicators in Fulminant Hepatic Failure by Multivariate Analysis , 1998, Digestive Diseases and Sciences.

[32]  William M. Lee,et al.  Influence of high body mass index on outcome in acute liver failure. , 2006, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[33]  S. Evans,et al.  Monitoring for adverse drug reactions. , 2006, British journal of clinical pharmacology.

[34]  A. Bergquist,et al.  Acute liver failure in Sweden: etiology and outcome , 2007, Journal of internal medicine.

[35]  I. Sternlieb,et al.  Liver transplantation for Wilson's disease: Indications and outcome , 1994, Hepatology.

[36]  F. D. de Abajo,et al.  Acute and clinically relevant drug-induced liver injury: a population based case-control study. , 2004, British journal of clinical pharmacology.

[37]  E. Björnsson,et al.  The impact of eosinophilia and hepatic necrosis on prognosis in patients with drug‐induced liver injury , 2007, Alimentary pharmacology & therapeutics.

[38]  D. Wysowski,et al.  Adverse drug event surveillance and drug withdrawals in the United States, 1969-2002: the importance of reporting suspected reactions. , 2005, Archives of internal medicine.

[39]  H. Friis,et al.  Drug‐induced hepatic injury: an analysis of 1100 cases reported to The Danish Committee on Adverse Drug Reactions between 1978 and 1987 , 1992, Journal of internal medicine.

[40]  S. Gordon,et al.  The Burden of Acute Nonfulminant Drug-induced Hepatitis in a United States Tertiary Referral Center , 2005, Journal of clinical gastroenterology.

[41]  L. Lasagna,et al.  Drug safety discontinuations in the United Kingdom, the United States, and Spain from 1974 through 1993: A regulatory perspective , 1995, Clinical pharmacology and therapeutics.

[42]  William M. Lee,et al.  AUTOIMMUNE, CHOLESTATIC AND BILIARY DISEASE Antimitochondrial Antibodies in Acute Liver Failure: Implications for Primary Biliary Cirrhosis , 2007 .

[43]  K. Ishak,et al.  Chronic Active Hepatitis and Severe Hepatic Necrosis Associated with Nitrofurantoin , 1980, Annals of Internal Medicine.

[44]  R Williams,et al.  Early indicators of prognosis in fulminant hepatic failure. , 1989, Gastroenterology.

[45]  J. Samet,et al.  Food and Drug Administration , 2007, BMJ : British Medical Journal.

[46]  G. Folkers,et al.  Incidence of drug-induced liver injury in medical inpatients , 2005, European Journal of Clinical Pharmacology.

[47]  R. Fontana,et al.  Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. , 2008, Gastroenterology.

[48]  R. Andrade,et al.  Drug-induced hepatotoxicity , 2003, The New England journal of medicine.

[49]  P. Watkins,et al.  Liver transplantation for acute liver failure from drug induced liver injury in the United States , 2004, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[50]  J. Luyendyk,et al.  Adverse hepatic drug reactions: inflammatory episodes as consequence and contributor. , 2004, Chemico-biological interactions.

[51]  G. Farrell,et al.  Hepatotoxic slimming aids and other herbal hepatotoxins , 2008, Journal of gastroenterology and hepatology.