title: Drug-induced liver injury: Advances in mechanistic understanding that will inform risk management.
abstract: Drug-induced liver injury (DILI) is a major public health problem. Intrinsic (dose-dependent) DILI associated with acetaminophen overdose is the number one cause of acute liver failure in the US. However, the most problematic type of DILI impacting drug development is idiosyncratic, occurring only very rarely among treated patients and often only after several weeks or months of treatment with the offending drug. Recent advances in our understanding of the pathogenesis of DILI suggest that three mechanisms may underlie most hepatocyte effects in response to both intrinsic and idiosyncratic DILI drugs: mitochondrial dysfunction, oxidative stress, and alterations in bile acid homeostasis. However, in some cases hepatocyte stress promotes an immune response that results in clinically important idiosyncratic DILI. This review discusses recent advances in our understanding of the pathogenesis of both intrinsic and idiosyncratic DILI as well as emerging tools and techniques that will likely improve DILI risk identification and management.
authors.affiliation: Institute for Drug Safety Sciences, University of North Carolina at Chapel Hill, Research Triangle Park, North Carolina, USA; Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina, USA.
authors.forename: M
authors.initials: M
authors.lastname: Mosedale
authors.affiliation: Institute for Drug Safety Sciences, University of North Carolina at Chapel Hill, Research Triangle Park, North Carolina, USA; Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina, USA.
authors.forename: P B
authors.initials: PB
authors.lastname: Watkins
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000453:epidemiology / Q000276:immunology / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology / Q000517:prevention & control*; D006801:Humans; D012307:Risk Factors; D012308:Risk Management
chemical_list: D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen