Causes, Clinical Features, and Outcomes From a Prospective Study of Drug-Induced Liver Injury in the United States
Background & Aims
Idiosyncratic drug-induced liver injury (DILI) is among the most common causes of acute liver failure in the United States, accounting for approximately 13% of cases. A prospective study was begun in 2003 to recruit patients with suspected DILI and create a repository of biological samples for analysis. This report summarizes the causes, clinical features, and outcomes from the first 300 patients enrolled.
Methods
Patients with suspected DILI were enrolled based on predefined criteria and followed up for at least 6 months. Patients with acetaminophen liver injury were excluded.
Results
DILI was caused by a single prescription medication in 73% of the cases, by dietary supplements in 9%, and by multiple agents in 18%. More than 100 different agents were associated with DILI; antimicrobials (45.5%) and central nervous system agents (15%) were the most common. Causality was considered to be definite in 32%, highly likely in 41%, probable in 14%, possible in 10%, and unlikely in 3%. Acute hepatitis C virus (HCV) infection was the final diagnosis in 4 of 9 unlikely cases. Six months after enrollment, 14% of patients had persistent laboratory abnormalities and 8% had died; the cause of death was liver related in 44%.
Conclusions
DILI is caused by a wide array of medications, herbal supplements, and dietary supplements. Antibiotics are the single largest class of agents that cause DILI. Acute HCV infection should be excluded in patients with suspected DILI by HCV RNA testing. The overall 6-month mortality was 8%, but the majority of deaths were not liver related.
Abbreviations used in this paper: DILI, drug-induced liver injury, DILIN, Drug-Induced Liver Injury Network, INR, international normalized ratio, RUCAM, Roussel Uclaf Causality Assessment Method, ULN, upper limit of normal
DILIN is supported by the National Institute of Diabetes and Digestive and Kidney Diseases under the following cooperative agreements: 1U01DK065201, 1U01DK065193, 1U01DK065184, 1U01DK065211, 1U01DK065238, and 1U01DK065176.
The authors disclose the following: N.C. served as a paid consultant in the preceding 12 months to Takeda Pharmaceuticals, AtheroGenics, Advanced Life Sciences, Kari Bio, Metabasis, Pfizer, and Eli Lilly. He received research grant support from Debiovision and Sanofi-Aventis. On his behalf, his institution has initiated contract negotiations with Gilead Sciences and Pfizer for conducting clinical trials unrelated to drug-induced liver injury. He served as an expert witness for a product liability litigation involving suspected drug-induced liver injury.
R.J.F. has served on the speakers' bureau or as a paid consultant during the past 12 months to Roche, Bristol-Myers Squibb, Vertex Pharmaceuticals, and Gilead Sciences.
H.L.B. served as a paid advisor to InfaCare Pharmaceuticals, Novartis Pharmaceuticals, and Ovation Pharmaceuticals. He is on the speakers' bureau of Ovation Pharmaceuticals. He receives support for research studies from the American Porphyria Foundation, Merck, Novartis, Roche, and Vertex. During the past 12 months, he has served as an expert witness for plaintiffs in litigation regarding suspected drug-induced liver injury.
P.B.W. served as a paid consultant in the preceding 12 months to the following pharmaceutical companies: Actelion, Aldus, Astellas, Bristol-Myers Squibb, Boehringer-Ingleheim, Danube, Endo, FibroGen, GlaxoSmithKline, Hoffmann-La Roche, Imtech, King, Millennium, Merck, Novartis, Nuon, Orion, Pfizer, Pharmasset, Schering Plough, TAP, Valiant, VIA, and Wyeth. He served as both a plaintiff and a defense expert in litigation involving suspected drug-induced liver injury.
T.D. served as a paid consultant to Entelos and FibroGen. He served as both a plaintiff and a defense expert in litigation involving suspected drug-induced liver injury.
J.S., H.Y., and J.R. have no potential conflicts of interest to report.
Members of DILIN include the following: Clinical Centers—Indiana University: Naga Chalasani, MD (primary investigator), Raj Vuppalanchi, MD (coinvestigator), Jean Molleston, MD (coinvestigator), Lawrence Lumeng, MD (coinvestigator), Audrey Corne (research coordinator), Angie Plummer (research coordinator); University of Connecticut: Herbert Bonkovsky, MD (primary investigator), Petr Protiva, MD (coinvestigator), James Freston, MD, PhD (coinvestigator), Robert Rosson, MD (coinvestigator), Robert A. Levine, MD (satellite site investigator), Benedict Maliakkal, MD (satellite site investigator), Paul Appleton, MD (research coordinator), Mariola Smialek, RN (research coordinator); University of Michigan: Robert J. Fontana, MD (primary investigator), Hari Conjeevaram, MD (coinvestigator), Stuart Gordon, MD (satellite site investigator), Suzanne Welch (research coordinator), Jessica Worley (research coordinator), Jordan Kridler (research coordinator); University of North Carolina: Paul Watkins, MD (primary investigator), Paul Hayashi, MD (coinvestigator), Mark Russo, MD (coinvestigator), the late Harry Guess, MD, PhD (coinvestigator), Kimberly Beaver, MD (satellite site investigator), Alastair Smith, MD (satellite site investigator), James Lewis, MD (satellite site investigator), Susan Pusek (research coordinator); University of California, San Francisco: Tim Davern, MD (primary investigator), Maurizo Bonacini, MD (coinvestigator), Kristine Partovi (research coordinator). Data Coordinating Center—Duke Clinical Research Institute: James Rochon, MD (primary investigator), John McHutchison, MD (coinvestigator), Don Rockey, MD (coinvestigator), Mary Maggio (project manager), Hongqiu Yang, PhD (biostatistician); National Institute of Diabetes and Digestive and Kidney Diseases Scientists: Jose Serrano, MD (project officer), Leonard Seeff, MD, Jay Hoofnagle, MD, Mark Avigan, MD, and John Senior, MD, employees of the US Food and Drug Administration, have participated in selected aspects of DILIN activities.
PII: S0016-5085(08)01674-0
doi:10.1053/j.gastro.2008.09.011
© 2008 AGA Institute. Published by Elsevier Inc. All rights reserved.
Refers to article:
- Do Hepatotoxicity Registries Have a Role in Health Care? , 11 November 2008
