The Art and Science of Diagnosing and Managing Drug-induced Liver Injury in 2015 and Beyond

• Published in: Clinical gastroenterology and hepatology Vol. 13; no. 12; pp. 2173 - 2189.e8
• Main Author: Lewis, James H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2015
• Subjects: Alanine Transaminase - blood; Biomarkers - blood; Case Management; Chemical and Drug Induced Liver Injury - diagnosis; Chemical and Drug Induced Liver Injury - therapy; Decision Support Techniques; DILI; Drug-induced Liver Injury; Gastroenterology and Hepatology; Hepatotoxicity; Humans; Internet; DILI; AST; FDA; INH; RUCAM; ALT; Drug-induced Liver Injury; DILIN; iDILI; DI-ALF; LAE; HDS; ULN; CLD; ALF; Hepatotoxicity; drug-induced acute liver failure; alanine aminotransferase; liver-associated enzyme; herbal compounds and dietary supplements; idiosyncratic drug-induced liver injury; chronic liver disease; Food and Drug Administration; isoniazid; aspartate aminotransferase; upper limit of normal; acute liver failure; Drug-Induced Liver Injury Network; Roussel Uclaf Causality Assessment Method
• ISSN: 1542-3565; 1542-7714; 1542-7714
• DOI: 10.1016/j.cgh.2015.06.017

Drug-induced liver injury (DILI) remains a leading reason why new compounds are dropped from further study or are the subject of product warnings and regulatory actions. Hy’s Law of drug-induced hepatocellular jaundice causing a case-fatality rate or need for transplant of 10% or higher has been validated in several large national registries, including the ongoing, prospective U.S. Drug-Induced Liver Injury Network. It serves as the basis for stopping rules in clinical trials and in clinical practice. Because DILI can mimic all known causes of acute and chronic liver disease, establishing causality can be difficult. Histopathologic findings are often nonspecific and rarely, if ever, considered pathognomonic. A daily drug dose >50–100 mg is more likely to be hepatotoxic than does <10 mg, especially if the compound is highly lipophilic or undergoes extensive hepatic metabolism. The quest for a predictive biomarker to replace alanine aminotransferase is ongoing. Markers of necrosis and apoptosis such as microRNA-122 and keratin 18 may prove useful in identifying patients at risk for severe injury when they initially present with a suspected acetaminophen overdose. Although a number of drugs causing idiosyncratic DILI have HLA associations that may allow for pre-prescription testing to prevent hepatotoxicity, the cost and relatively low frequency of injury among affected patients limit the current usefulness of such genome-wide association studies. Alanine aminotransferase monitoring is often recommended but has rarely been shown to be an effective method to prevent serious DILI. Guidelines on the diagnosis and management of DILI have recently been published, although specific therapies remain limited. The LiverTox Web site has been introduced as an interactive online virtual textbook that makes the latest information on more than 650 agents available to clinicians, regulators, and drug developers alike.