title: The transformation in biomarker detection and management of drug-induced liver injury.
abstract: Drug-induced liver injury (DILI) is a major concern for patients, care givers and the pharmaceutical industry. Interpretation of the serum biomarkers routinely used to detect and monitor DILI, which have not changed in almost 50 years, can be improved with recently proposed models employing quantitative systems pharmacology. In addition, several newer serum biomarkers are showing great promise. Studies in rodents indicate that the ratio of the caspase cleaved fragment of cytokeratin 18 to total K18 in serum (termed the "apoptotic index") estimates the relative proportions of apoptosis vs necrosis during drug-induced liver injury. Glutamate dehydrogenase can reliably differentiate liver from muscle injury and, when serum is properly prepared, may also detect mitochondrial toxicity as a mechanism of liver injury. MicroRNA-122 is liver-specific, but recent data suggests it can be actively released from hepatocytes in the absence of overt toxicity limiting enthusiasm for it as a DILI biomarker. Finally, damage associated molecular patterns, particularly high mobility group box 1 and its various modified forms, are promising biomarkers of innate immune activation, which may be useful in distinguishing benign elevations in aminotransferases from those that portend clinically important liver injury. These new biomarkers are already being measured in early clinical trials, but broad acceptance will require widespread archiving of serum from diverse clinical trials and probably pre-competitive analysis efforts. We believe that utilization of a panel of traditional and newer biomarkers in conjunction with quantitative systems pharmacology modelling approaches will transform DILI detection and risk management.
authors.affiliation: Institute for Drug Safety Sciences, University of North Carolina at Chapel Hill, Research Triangle Park, NC, USA.|Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, NC, USA.
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Church
authors.affiliation: Institute for Drug Safety Sciences, University of North Carolina at Chapel Hill, Research Triangle Park, NC, USA.|Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, NC, USA.
authors.forename: Paul B
authors.identifier: 0000-0001-9541-8917
authors.initials: PB
authors.lastname: Watkins
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D017209:Apoptosis; D001219:Aspartate Aminotransferases / Q000097:blood; D015415:Biomarkers / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood* / Q000175:diagnosis; D024243:HMGB1 Protein / Q000097:blood*; D006801:Humans; D053538:Keratin-18 / Q000097:blood*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D035683:MicroRNAs / Q000097:blood*; D009336:Necrosis / Q000097:blood*; D012308:Risk Management
chemical_list: D015415:Biomarkers; D024243:HMGB1 Protein; D053538:Keratin-18; D035683:MicroRNAs; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase
keywords: biomarkers; drug-induced liver injury; hepatotoxicity; idiosyncratic DILI