Drug‐induced liver injury: Mechanisms and test systems

Drug-induced liver injury is an unresolved problem, with an impact well beyond the number of actual cases that occur annually. It has emerged as the most frequent cause for aftermarketing withdrawal of medications, despite a rigorous preclinical and clinical review process. This points to serious limitations in current knowledge regarding mechanisms of hepatic toxicity, in methods for identifying susceptible individuals and in preclinical test systems. For compounds that cause predictable dose-related toxicity, such as acetaminophen, mechanisms are generally well understood. However, these constitute a small proportion of the total. For idiosyncratic reactions—recent examples include bromfenac and troglitazone—little is known regarding mechanism; specific kinds of individual susceptibility are involved, possibly related to environmental or genetic factors that remain to be identified. Although this type of reaction is infrequent, it can be fatal. Unfortunately, it cannot be excluded by current approaches to preclinical testing. A workshop sponsored by the National Institutes of Health entitled “New Directions in Drug-Induced Liver Injury: Mechanisms and Test Systems” brought together a group of experts in this area with the goal of reviewing the status of the field, defining areas in need of study, and proposing next steps.