Drug induced liver injury (DILI) is an uncommon adverse drug reaction (ADR) of increasing importance to the medical community, pharmaceutical, regulatory agencies, and the general public. DILI is the leading cause of acute liver failure in the United States and the leading reason for discontinuation of drugs in development as well as removal of approved drugs from the marketplace. The Drug Induced Liver Injury Network (DILIN) was established in 2003 to advance understanding and research into DILI. The Retrospective study has collected DNA samples from 58 subjects with liver injury attributed to amoxicillin/clavulanate, valproate, phenytoin, isoniazid for future pharmacogenetic and mechanistic studies. In addition, over 400 patients with DILI due to a multitude of medications and herbal products have been enrolled into the Prospective study wherein DNA, serum, plasma, urine, and liver tissue samples as well as extensive clinical data are collected. To build upon the growing repository of data, biological samples, and research expertise, a competing renewal with expansion of the number of DILIN clinical sites is proposed. The primary aim of this proposal is to continue to enroll bonafide DILI patients with varying disease severity recruited from the Michigan Hepatoxicity Research Network into the DILIN Prospective study at the University of Michigan. A causality assessment instrument as well as novel diagnostic and prognostic biomarkers will be developed from the collected clinical data and biological samples. The secondary aim of this proposal is to conduct pharmacogenetic analyses of DNA samples collected from the DILI cases and controls. Whole genome SNP analyses and/or targeted gene approaches are proposed to help elucidate the contribution of host pharmacogenetics in the susceptibility and outcome of DILI. A Genetic Profiling Committee with bioinformatics expertise is proposed to analyze and interpret the pharmacogenetic data and help formulate additional hypothesis driven mechanistic studies. Finally, maintaining contact with the DILI case patients for up to 20 years after enrollment will allow performance of confirmatory genotype-phenotype association and other follow-up studies in DILI patients, family members, and controls. These supplemental studies may lead to the identification and refinement of genetic biomarkers to assist in the prevention, diagnosis and management of future DILI patients.
The third aim of this proposal is to develop an authoritative and comprehensive LiverTox website in conjunction with the National Library of Medicine to help educate and assist practicing physicians, researchers, and the general public on DILI. A LiverTox website will not only improve worldwide knowledge and awareness of DILI but also potentially enhance recruitment for the DILIN Prospective study and other future initiatives.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
Special Emphasis Panel (ZDK1-GRB-8 (O1))
Program Officer
Serrano, Jose
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
Zip Code
Kleiner, David E; Chalasani, Naga P; Lee, William M et al. (2014) Hepatic histological findings in suspected drug-induced liver injury: systematic evaluation and clinical associations. Hepatology 59:661-70
Fontana, Robert J (2014) Pathogenesis of idiosyncratic drug-induced liver injury and clinical perspectives. Gastroenterology 146:914-28
Tischer, Sarah; Fontana, Robert J (2014) Drug-drug interactions with oral anti-HCV agents and idiosyncratic hepatotoxicity in the liver transplant setting. J Hepatol 60:872-84
Fontana, Robert J; Hayashi, Paul H; Gu, Jiezhun et al. (2014) Idiosyncratic drug-induced liver injury is associated with substantial morbidity and mortality within 6 months from onset. Gastroenterology 147:96-108.e4
Russo, Mark W; Hoofnagle, Jay H; Gu, Jiezhun et al. (2014) Spectrum of statin hepatotoxicity: experience of the drug-induced liver injury network. Hepatology 60:679-86
Ghabril, Marwan; Fontana, Robert; Rockey, Don et al. (2013) Drug-induced liver injury caused by intravenously administered medications: the Drug-induced Liver Injury Network experience. J Clin Gastroenterol 47:553-8
Ghabril, Marwan; Bonkovsky, Herbert L; Kum, Clarissa et al. (2013) Liver injury from tumor necrosis factor-* antagonists: analysis of thirty-four cases. Clin Gastroenterol Hepatol 11:558-564.e3
Bell, L N; Vuppalanchi, R; Watkins, P B et al. (2012) Serum proteomic profiling in patients with drug-induced liver injury. Aliment Pharmacol Ther 35:600-12
Lucena, M Isabel; Molokhia, Mariam; Shen, Yufeng et al. (2011) Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles. Gastroenterology 141:338-47
Orman, Eric S; Conjeevaram, Hari S; Vuppalanchi, Raj et al. (2011) Clinical and histopathologic features of fluoroquinolone-induced liver injury. Clin Gastroenterol Hepatol 9:517-523.e3

Showing the most recent 10 out of 24 publications