Idiosyncratic drug-induced liver injury in patients: Detection, severity assessment, and regulatory implications

Idiosyncratic Drug-Induced Liver Injury (IDILI) is a rare but potentially life-threatening event that is caused by drugs that, at usual therapeutic doses, do not cause any biochemical or clinical evidence of liver injury in the majority of treated patients. The most common clinical phenotypes of IDILI are "acute hepatitis," "mixed hepatocellular-cholestatic hepatitis," and "cholestatic hepatitis" and these are distinguished by clinical, biochemical and histologic characteristics. Anti-microbials, herbals and dietary supplements are now the agents most often implicated in the US Drug-Induced Liver Injury Network registry. There are several scales that have been used to characterize the severity of IDILI events. There are no reliable means to accurately predict the course of an IDILI event at presentation. In clinical trials, the "gold standard" liver safety signal is the occurrence of "Hy's Law Cases." Making the diagnosis of IDILI, and when a patient is taking multiple drugs, identifying the most likely culprit can be challenging, but many drugs cause IDILI with characteristic clinical and biochemical presentations, or "signatures." In a clinical trial, it is sometimes possible to identify an overlooked "signature" of IDILI by characterizing more minor, asymptomatic, and transient elevations in liver chemistries. This observation can be helpful in assessing causation in rare serious liver events occurring in the clinical trial, or first recognized post-marketing.