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.
|Ahmad, Jawad; Odin, Joseph A; Hayashi, Paul H et al. (2017) Identification and Characterization of Fenofibrate-Induced Liver Injury. Dig Dis Sci 62:3596-3604|
|de Boer, Ynto S; Kosinski, Andrzej S; Urban, Thomas J et al. (2017) Features of Autoimmune Hepatitis in Patients With Drug-induced Liver Injury. Clin Gastroenterol Hepatol 15:103-112.e2|
|Chalasani, Naga; Reddy, K Rajender K; Fontana, Robert J et al. (2017) Idiosyncratic Drug Induced Liver Injury in African-Americans Is Associated With Greater Morbidity and Mortality Compared to Caucasians. Am J Gastroenterol 112:1382-1388|
|Bonkovsky, Herbert L; Kleiner, David E; Gu, Jiezhun et al. (2017) Clinical presentations and outcomes of bile duct loss caused by drugs and herbal and dietary supplements. Hepatology 65:1267-1277|
|Nicoletti, Paola; Aithal, Guruprasad P; Bjornsson, Einar S et al. (2017) Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study. Gastroenterology 152:1078-1089|
|Goldring, Christopher; Antoine, Daniel J; Bonner, Frank et al. (2017) Stem cell-derived models to improve mechanistic understanding and prediction of human drug-induced liver injury. Hepatology 65:710-721|
|Spengler, Erin K; Kleiner, David E; Fontana, Robert J (2017) Vemurafenib-induced granulomatous hepatitis. Hepatology 65:745-748|
|Hayashi, Paul H; Rockey, Don C; Fontana, Robert J et al. (2017) Death and liver transplantation within 2 years of onset of drug-induced liver injury. Hepatology 66:1275-1285|
|Urban, Thomas Jacob; Nicoletti, Paola; Chalasani, Naga et al. (2017) Minocycline hepatotoxicity: Clinical characterization and identification of HLA-B?35:02 as a risk factor. J Hepatol 67:137-144|
|Navarro, Victor J; Khan, Ikhlas; Björnsson, Einar et al. (2017) Liver injury from herbal and dietary supplements. Hepatology 65:363-373|
Showing the most recent 10 out of 61 publications