Clinical Advances in Liver, Pancreas, and Biliary TractCauses, Clinical Features, and Outcomes From a Prospective Study of Drug-Induced Liver Injury in the United States
Section snippets
Patients and Methods
The DILIN prospective study is an ongoing multicenter observational study. The study design and procedures were approved by the institutional review board of each clinical center site, and all enrolled patients provided written, fully informed consent. The study design has been described in detail elsewhere.21 In brief, patients (2 years of age or older) were enrolled in this study if there was a strong clinical suspicion that a liver injury event was caused by a medication or an herbal agent
Presenting Features
The 300 patients included in this report were enrolled between September 2004 and December 2007. Selected demographic and clinical characteristics are shown in Table 1. Ninety-three percent were adults (≥18 years), 18% were older than 65 years, and 60% were women. Six percent of patients had known liver disease before the onset of DILI, and 3% had underlying human immunodeficiency virus infection. Sixty-nine percent had jaundice during the DILI episode, and 60% were hospitalized. The median
Discussion
This is an initial analysis of an ongoing prospective study of DILI being performed in the United States, the primary aim of which is to develop well-characterized cases of medication-related liver injury on which to conduct hypothesis-driven research aimed at developing means to diagnose, prevent, and treat DILI. Among the first 300 cases identified, more than 100 different medications, herbal supplements, and dietary supplements were implicated. Newly identified hepatotoxic drugs that had
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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.