Michigan Hepatotoxicity Clinical Research Network

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DESCRIPTION (provided by applicant): An increasing awareness of the importance of drug induced liver injury (DILl) has come from the large number of prescription drugs either being withdrawn or failing to gain regulatory approval due to hepatotoxicity. In addition, DILl has been identified as the leading cause of acute liver failure in the United States. However, the incidence and risk factors for drug, toxin, and complementary medication induced liver injury remain ill defined due to their unpredictable nature, varying clinical manifestations, and lack of diagnostic tests. Aberrant host immune responses, metabolic activation of the parent drug, and altered metabolite detoxification have been implicated in the pathogenesis of DILl but the molecular mechanisms involved in most cases remains unknown. The majority of DILl clinical studies have been uncontrolled, retrospective case-series involving small numbers of patients and individual agents. The primary aim of this proposal is to develop standardized instruments and methods to identify and characterize cases of drug, toxin, and complementary medication induced liver injury. Simple, reproducible causality assessment instruments will be developed and validated to provide more accurate case definitions. The secondary aim of this proposal is to develop a hepatotoxicity clinical research network that will prospectively enroll a large number of drug, toxin, and complementary medication induced liver injury cases as well as case controls that received the suspect drug but did not develop toxicity. A prospective case-control study design will help identify potential clinical, immunological, and genetic risk factors for DILl. Collection of clinical data, blood, urine, DNA, and liver tissue samples will allow for subsequent studies of the molecular pathogenesis of drug, toxin, and complementary medication induced liver injury and potentially help identify high risk individuals.