• Open Access

Mechanistic biomarkers provide early and sensitive detection of acetaminophen-induced acute liver injury at first presentation to hospital

Authors

  • Daniel J. Antoine,

    1. MRC Centre for Drug Safety Science, Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, UK
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    • These authors contributed equally to this work.

  • James W. Dear,

    1. NPIS Edinburgh, Royal Infirmary of Edinburgh, UK
    2. University of Edinburgh/British Heart Foundation Centre for Cardiovascular Science, Edinburgh, UK
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    • These authors contributed equally to this work.

  • Philip Starkey Lewis,

    1. MRC Centre for Drug Safety Science, Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, UK
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    • These authors contributed equally to this work.

  • Vivien Platt,

    1. MRC Centre for Drug Safety Science, Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, UK
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  • Judy Coyle,

    1. Emergency Medicine Research Group, Department of Emergency Medicine, Royal Infirmary of Edinburgh, Edinburgh, UK
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  • Moyra Masson,

    1. Emergency Medicine Research Group, Department of Emergency Medicine, Royal Infirmary of Edinburgh, Edinburgh, UK
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  • Ruben H. Thanacoody,

    1. NPIS Newcastle, Regional Drugs and Therapeutics Centre, School of Clinical and Laboratory Sciences, University of Newcastle, Newcastle upon Tyne, UK
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  • Alasdair J. Gray,

    1. Emergency Medicine Research Group, Department of Emergency Medicine, Royal Infirmary of Edinburgh, Edinburgh, UK
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  • David J. Webb,

    1. NPIS Edinburgh, Royal Infirmary of Edinburgh, UK
    2. University of Edinburgh/British Heart Foundation Centre for Cardiovascular Science, Edinburgh, UK
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  • Jonathan G. Moggs,

    1. Discovery & Investigative Safety, Preclinical Safety, Novartis Institutes for Biomedical Research (NIBR), Basel, Switzerland
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  • D. Nicholas Bateman,

    1. NPIS Edinburgh, Royal Infirmary of Edinburgh, UK
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  • Christopher E. Goldring,

    1. MRC Centre for Drug Safety Science, Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, UK
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  • B. Kevin Park

    Corresponding author
    1. MRC Centre for Drug Safety Science, Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, UK
    • Address reprint requests to: Prof. B. Kevin Park, Ph.D., MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool, UK, L69 3GE. E-mail: bkpark@liv.ac.uk fax: +44 151 795 0382.

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  • Potential conflict of interest: The authors have no conflict of interest to declare. J.G.M. is a full-time employee of, consults for, and advises Novartis therapeutic targets or biomarkers were investigated in this study.

  • Supported by the Medical Research Council (via the Centre for Drug Safety Science, grant number G0700654), Chief Scientist's Office of Scotland, Mason Medical Research Foundation; D.J.A. received financial support from the Wellcome Trust; J.W.D. received a contribution from the British Heart Foundation Center of Research Excellence Award and financial support from the National Health Service (NHS) Research Scotland though NHS Lothian.

Abstract

Acetaminophen overdose is a common reason for hospital admission and the most frequent cause of hepatotoxicity in the Western world. Early identification would facilitate patient-individualized treatment strategies. We investigated the potential of a panel of novel biomarkers (with enhanced liver expression or linked to the mechanisms of toxicity) to identify patients with acetaminophen-induced acute liver injury (ALI) at first presentation to the hospital when currently used markers are within the normal range. In the first hospital presentation plasma sample from patients (n = 129), we measured microRNA-122 (miR-122; high liver specificity), high mobility group box-1 (HMGB1; marker of necrosis), full-length and caspase-cleaved keratin-18 (K18; markers of necrosis and apoptosis), and glutamate dehydrogenase (GLDH; marker of mitochondrial dysfunction). Receiver operator characteristic curve analysis and positive/negative predictive values were used to compare sensitivity to report liver injury versus alanine transaminase (ALT) and International Normalized Ratio (INR). In all patients, biomarkers at first presentation significantly correlated with peak ALT or INR. In patients presenting with normal ALT or INR, miR-122, HMGB1, and necrosis K18 identified the development of liver injury (n = 15) or not (n = 84) with a high degree of accuracy and significantly outperformed ALT, INR, and plasma acetaminophen concentration for the prediction of subsequent ALI (n = 11) compared with no ALI (n = 52) in patients presenting within 8 hours of overdose. Conclusion: Elevations in plasma miR-122, HMGB1, and necrosis K18 identified subsequent ALI development in patients on admission to the hospital, soon after acetaminophen overdose, and in patients with ALTs in the normal range. The application of such a biomarker panel could improve the speed of clinical decision-making, both in the treatment of ALI and the design/execution of patient-individualized treatment strategies. (Hepatology 2013;58:777–787)

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