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Hepatology. 2018 Jan 22. doi: 10.1002/hep.29802. [Epub ahead of print]

Candidate biomarkers for the diagnosis and prognosis of drug-induced liver injury: An international collaborative effort.

Author information

1
Institute for Drug Safety Sciences, University of North Carolina at Chapel Hill, Research Triangle Park, NC.
2
Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina Eshelman School of Pharmacy, Chapel Hill, NC.
3
Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Switzerland.
4
Mechanistic Safety, Novartis Global Drug Development, Basel, Switzerland.
5
Drug Safety R&D, Pfizer Inc, Groton, CT.
6
Wake Forest University School of Medicine, Winston-Salem, NC.
7
School of Medicine, Indiana University, Indianapolis, IN.
8
University of Michigan, Ann Arbor, MI.
9
Natural and Medical Sciences Institute, Reutlingen, Germany.
10
Pfizer Inc, New York, NY.
11
Predictive Safety Testing Consortium, Tucson, AZ.
12
Takeda Pharmaceuticals, Deerfield, IL.
13
Global Patient Safety, AstraZeneca R&D, Gothenburg, Sweden.
14
Science for Life Laboratory, Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
15
Tel Aviv Sourasky Medical Center, Tel Aviv University, Israel.
16
Discovery and Investigative Safety, Novartis Institutes for Biomedical Research, Basel, Switzerland.
17
Unidad de Gestión Clínica de Aparato Digestivo, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Málaga, Spain.
18
Section of Hepatology, Clinic of Gastroenterology and Hepatology, University Hospital Leipzig, Leipzig, Germany.
19
Department of Hepatology, Groupe Hospitalier Pitié Salpêtrière, University Pierre et Marie Curie, INSERM UMR 938, Paris, France.

Abstract

Current blood biomarkers are suboptimal in detecting drug-induced liver injury (DILI) and predicting its outcome. We sought to characterize the natural variabilty and performance characteristics of 14 promising DILI biomarker candidates. Serum or plasma from multiple cohorts of healthy volunteers (n = 192 and n = 81), subjects who safely took potentially hepatotoxic drugs without adverse effects (n = 55 and n = 92) and DILI patients (n = 98, n = 28, and n = 143) were assayed for microRNA-122 (miR-122), glutamate dehydrogenase (GLDH), total cytokeratin 18 (K18), caspase cleaved K18, glutathione S-transferase α, alpha-fetoprotein, arginase-1, osteopontin (OPN), sorbitol dehydrogenase, fatty acid binding protein, cadherin-5, macrophage colony-stimulating factor receptor (MCSFR), paraoxonase 1 (normalized to prothrombin protein), and leukocyte cell-derived chemotaxin-2. Most candidate biomarkers were significantly altered in DILI cases compared with healthy volunteers. GLDH correlated more closely with gold standard alanine aminotransferase than miR-122, and there was a surprisingly wide inter- and intra-individual variability of miR-122 levels among healthy volunteers. Serum K18, OPN, and MCSFR levels were most strongly associated with liver-related death or transplantation within 6 months of DILI onset. Prediction of prognosis among DILI patients using the Model for End-Stage Liver Disease was improved by incorporation of K18 and MCSFR levels.

CONCLUSION:

GLDH appears to be more useful than miR-122 in identifying DILI patients, and K18, OPN, and MCSFR are promising candidates for prediction of prognosis during an acute DILI event. Serial assessment of these biomarkers in large prospective studies will help further delineate their role in DILI diagnosis and management. (Hepatology 2018).

Comment in

PMID:
29357190
PMCID:
PMC6054900
[Available on 2019-07-22]
DOI:
10.1002/hep.29802

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