Collaborative Clinical Research on Hepatotoxicity

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DESCRIPTION (provided by applicant): This application is submitted in response to RFA DK-13-003 which solicits applications from qualified investigators for the continuation of the Drug Induced Liver Injury Network (DILIN). Indiana University is one of the five founding clinical centers and has robustly participated in all DILIN operations since its inception. We propose the following specific aims to meet the goals of this RFA. Specific Aim # 1: To enroll large number of eligible adults with suspected DILI into ongoing DILIN studies. We propose to collect prospective cases of suspected DILI from multiple sources in Central Indiana, each providing distinctive epidemiological facets and research potential. Specific Aim # 2: To enroll significant number of eligible children with suspected DILI into ongoing DILIN studies. We propose to include Cincinnati Children's Hospital as a satellite site to significantly increase the number of children enrolled into ongoing DILIN studies. Specific Aim # 3: The DILI is currently a diagnosis of exclusion and it can be a challenging diagnosis to make. We propose to conduct two ancillary studies in order to develop tests that facilitate the diagnosis of DILI: (i) we will conduct a discovery proteomic study of individuals with acute liver injury due to DILI and non-DILI etiologies enrolled within two weeks of liver injury onset to identify biomarkers specific for acut liver injury due to DILI; (ii) DILI can sometime mimic autoimmune hepatitis and it is difficult to distinguish it from de novo autoimmune hepatitis. To address this clinical conundrum, we will conduct a preliminary study for autoantibody profiling using an auto-antigen array assay among individuals with (i) acute DILI with autoimmune hepatitis-like features, (ii) acute DILI without autoimmune hepatitis features, and (iii) acute autoimmune hepatitis without precedent medication exposure. Specific Aim # 4: DILI carries considerable mortality and morbidity but there is no treatment available other than withdrawing the offending agent. In order to address this unmet therapeutic need, we propose to conduct a randomized, double-blind, placebo-controlled pilot study of budesonide in individuals with well characterized hepatocellular DILI meeting predefined eligibility criteria. Our hypothesis is that oral budesonide, a steroid with hig glucocorticoid activity and substantial first pass elimination, attenuates liver injury and improve outcomes of patients with hepatocellular DILI.