Hepatotoxicity, or drug-induced liver inury (DILI), is currently the most common cause of acute liver failure in the United States and the main indication for market withdrawal of drugs. DILI thus represents a problem of enormous medical, financial, legal and regulatory importance. Although a vast number of drugs, toxins and alternative medications have the potential to cause liver injury, severe DILI is a problem of sufficient rarity that a large group of dedicated investigators working in a cooperative and coordinated effort is required to better understand the pathogenesis of DILI and develop effective prevention and treatment strategies. This proposal brings together a unique, multi-disciplinary consortium of investigators and resources, concentrated within Northern California, with a plan for a continuing participation as a Clinical Center in the Drug-Induced Liver Injury Network (DILIN). Our research plan describes, firstly, the establishment of a large multi-component Clinical Center patient database that would contribute to the DILIN. The proposed DILI patient informational database, serum, DNA and tissue bank will comprise a prospective cohort derived from several sources, each providing distinct epidemiological facets and research potential. These include the Liver Transplant Programs at UCSF, Stanford University and California Pacific Medical Center, the liver clinics and inpatient service at the Palo Alto Veterans Administration Hospital, and the HIV Clinic at San Francisco General Hospital. At each site, we have developed strategies to identify well-defined cases of toxin-induced liver injury in a prospective manner that will permit careful collection of detailed epidemiological and clinical information, as well as serum, DNA and tissue samples for biochemical, pharmacological and genetic studies. We plan to initially identify patients with potential DILI based on proposed operational diagnostic criteria and then further evaluate cases using a validated causality assessment instrument. Patients classified as having """"""""highly probable"""""""" DILI using this instrument will be followed prospectively in order to better define the natural history of DILI. Identification of such DILI-associated polymorphisms is an essential first step in the development of a rational gene-based prevention strategy. We anticipate that our Clinical Center will recruit approximately 120 cases and well-matched controls from an ethnically and racially diverse patient population to the DILIN. We have a well-organized, multi-disciplinary group of physicians, scientists, and research nurses who are dedicated to the success of this Clinical Center and the overall DILIN effort.
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