Idiosyncratic drug induced liver injury (DILI) remains poorly understood. It is assumed that the affected individuals possess a rare combination of genetic and non genetic factors that, if identified, would greatly improve understanding of the underlying mechanisms. This single topic conference brought together basic scientists, translational investigators, and clinicians with an interest in DILI. The goal was to define high priority areas of investigation that will soon be made possible by The Drug-Induced Liver Injury Network (DILIN). Since 2004 DILIN has been collecting clinical data, genomic DNA and some tissues from patients who have experienced bone fide DILI. The presentations spanned many different areas of DILI, and included novel data concerning mechanisms of hepatotoxicity, new "omics" approaches, and the challenges of improving causation assessment. (HEPATOLOGY 2006;43: 618-631.)
D rug-induced liver injury (DILI) is a major problem for affected patients as well as for their health care providers. Not only is it the primary cause for acute liver failure in the United States, it is also a strong consideration in differential diagnosis when abnormal liver-related chemistries are identified in persons with minimal or no symptoms. There is presently no specific diagnostic test for DILI, or a means of confidently singling out an implicated drug among many being received, so that the physician must empirically decide which, if any, treatments to discontinue or substitute when DILI is suspected. DILI is also a serious problem for the pharmaceutical industry. Indeed, safety and toxicology issues are now major reasons for failure of drugs in clinical trials. Moreover, DILI is also the most common factor that compels regulatory actions due to drugs, such as failure of approval or restriction of indications of the drug, as well as the mailing of Dear Doctor letters. 1 As drugs are increasingly designed to potently interact with known molecular targets, it will become possible to genetically determine ahead of time who among a patient pop-ulation will likely respond to the drug. If likely responders can be identified, it should be possible to show efficacy in smaller and less costly clinical trials. Nevertheless, demonstration of drug safety will continue to require large clinical trials until the propensity to adverse events is eliminated from the molecule, or those susceptible to the toxicity can be identified before they are treated.
Among the several manifestations of drug toxicity, the most problematic is the idiosyncratic form. This term derives from Greek words meaning "mixture of characteristics" and in the context of drug toxicity, refers to the combination of genetic and non-genetic factors that make a rare patient susceptible to drug injury. 2 There are currently no validated animal models for studying idiosyncratic DILI. Indeed, humans as a group are not appropriate subjects for study since they are only occasionally susceptible to the toxicity. Therefore, the best models to study idiosyncratic DILI are the rare patients who have already experienced the phenomenon.
Accordingly, the Drug-Induced Liver Injury Network (DILIN) was established in 2003 with the aim of studying the problem of hepatotoxicity 3 (http://dilin.dcri.duke. edu). Supported by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institutes of Health, the goals of the network are to: (1) establish a registry of well characterized patients who have experienced clinically significant DILI and agree to be contacted and offered participation in future studies, (2) develop improved tools to aid in the diagnosis of DILI, and (3) provide to the scientific community genomic DNA, serum and immortalized lymphocytes obtained from the patients in the registry for future research purposes.