This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Background and Rationale: Liver injury due to prescription and non-prescription medication use is a medical, scientific, and public health problem of increasing frequency and importance in the United States. Indeed, drug-induced liver injury (DILI) is the most common reason for nonapproval, withdrawal, limitation in use, and clinical monitoring by the Food and Drug Administration (FDA). However, detection of signals for liver injury frequently relies upon the reporting of cases by practitioners to health authorities in post-marketing surveillance. Underreporting of cases, lack of mandatory reporting systems, and difficulties in establishing a diagnosis make the current system sub-optimal. Moreover, with the growing use of complementary and alternative medications (CAM), there have also been increasing reports of liver toxicity due to various non-prescription herbal, dietary, and food additive supplements. Because the manufacturing, dispensing, and testing of these products is not regulated, the hepatotoxic potential of these formulations is poorly characterized or completely unknown. As a result, there is a great need to develop an improved means of detecting, defining, and studying DILI in the United States. The DILIN prospective study is a multi-center study designed to gather clinical information and biological specimens on cases of suspected liver injury due to drugs and CAM. The goals of this study include the earlier recognition of DILI, especially due to newer drugs, development of standardized instruments and terminology to help identify cases of DILI, investigating clinical and genetic risk factors that predict DILI, and performing a careful longitudinal follow-up of DILI subjects. The biological samples collected will be used in future studies of the mechanisms and genetics of DILI.
Specific Aims and Objectives: The primary objective of this study is to prospectively identify bona fide cases of liver injury due to drugs and complementary and alternative medications within 6 months of presentation. Secondary objectives include collecting clinical data and biological specimens including blood, DNA, urine, and liver tissue from affected patients and matched controls for future mechanistic and genetic studies. We will also investigate the clinical, immunological, and environmental risk factors of drug-mediated hepatotoxicity by comparing DILI cases to matched controls with a similar drug exposure history but no evidence of clinically significant liver injury. The natural history of drug- and CAM-induced DILI will be tracked for at least 6 months following enrollment, with longer follow-up for those in whom there is evidence of chronic liver injury at 6 months. We will also develop and test causality assessment instruments for drug and CAM-induced liver injury that are sensitive, specific, and reproducible. Basic Study Design: The DILIN Prospective Study is a multi-center, prospective, epidemiological study. Patients who are referred to one of the DILIN clinical sites and who, in the opinion of a gastroenterologist / hepatologist, experienced a drug-induced liver injury will be enrolled. Detailed clinical data and biological specimens will be collected. Clinical data will be reviewed by the DILIN Causality Committee, and it will make the final determination of whether the subject qualifies as a bona fide DILI case. Up to three matched controls will be individually matched to each index case. They will be matched by age, duration of exposure to the implicated medication, and from the same clinical site. DILI cases (only) will be followed for at least 6 months to derive the longitudinal profile of drug- and CAM-induced liver injury. Detailed clinical data and biological specimens will be collected at this time point. Patients who satisfy the definition of chronic DILI will be evaluated at 12 months and yearly thereafter.
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