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

Rachel J. Church, Gerd A. Kullak-Ublick, Jiri Aubrecht, Herbert L. Bonkovsky, Naga Chalasani, Robert J. Fontana, Jens C. Goepfert, Frances Hackman, Nicholas M.P. King, Simon Kirby, Patrick Kirby, John Marcinak, Sif Ormarsdottir, Shelli J. Schomaker, Ina Schuppe-Koistinen, Francis Wolenski, Nadir Arber, Michael Merz, John Michael Sauer, Raul J. AndradeFlorian van Bömmel, Thierry Poynard, Paul B. Watkins

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)760-773
Number of pages14
JournalHepatology
Volume69
Issue number2
DOIs
StatePublished - Feb 1 2019

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Chemical and Drug Induced Liver Injury
Biomarkers
Macrophage Colony-Stimulating Factor Receptors
MicroRNAs
Glutamate Dehydrogenase
Osteopontin
Healthy Volunteers
L-Iditol 2-Dehydrogenase
Keratin-18
Aryldialkylphosphatase
Arginase
Fatty Acid-Binding Proteins
End Stage Liver Disease
Chemotactic Factors
alpha-Fetoproteins
Prothrombin
Caspases
Serum
Alanine Transaminase
Leukocytes

ASJC Scopus subject areas

  • Hepatology

Cite this

Church, R. J., Kullak-Ublick, G. A., Aubrecht, J., Bonkovsky, H. L., Chalasani, N., Fontana, R. J., ... Watkins, P. B. (2019). Candidate biomarkers for the diagnosis and prognosis of drug-induced liver injury: An international collaborative effort. Hepatology, 69(2), 760-773. https://doi.org/10.1002/hep.29802

Candidate biomarkers for the diagnosis and prognosis of drug-induced liver injury : An international collaborative effort. / Church, Rachel J.; Kullak-Ublick, Gerd A.; Aubrecht, Jiri; Bonkovsky, Herbert L.; Chalasani, Naga; Fontana, Robert J.; Goepfert, Jens C.; Hackman, Frances; King, Nicholas M.P.; Kirby, Simon; Kirby, Patrick; Marcinak, John; Ormarsdottir, Sif; Schomaker, Shelli J.; Schuppe-Koistinen, Ina; Wolenski, Francis; Arber, Nadir; Merz, Michael; Sauer, John Michael; Andrade, Raul J.; van Bömmel, Florian; Poynard, Thierry; Watkins, Paul B.

In: Hepatology, Vol. 69, No. 2, 01.02.2019, p. 760-773.

Research output: Contribution to journalArticle

Church, RJ, Kullak-Ublick, GA, Aubrecht, J, Bonkovsky, HL, Chalasani, N, Fontana, RJ, Goepfert, JC, Hackman, F, King, NMP, Kirby, S, Kirby, P, Marcinak, J, Ormarsdottir, S, Schomaker, SJ, Schuppe-Koistinen, I, Wolenski, F, Arber, N, Merz, M, Sauer, JM, Andrade, RJ, van Bömmel, F, Poynard, T & Watkins, PB 2019, 'Candidate biomarkers for the diagnosis and prognosis of drug-induced liver injury: An international collaborative effort', Hepatology, vol. 69, no. 2, pp. 760-773. https://doi.org/10.1002/hep.29802
Church, Rachel J. ; Kullak-Ublick, Gerd A. ; Aubrecht, Jiri ; Bonkovsky, Herbert L. ; Chalasani, Naga ; Fontana, Robert J. ; Goepfert, Jens C. ; Hackman, Frances ; King, Nicholas M.P. ; Kirby, Simon ; Kirby, Patrick ; Marcinak, John ; Ormarsdottir, Sif ; Schomaker, Shelli J. ; Schuppe-Koistinen, Ina ; Wolenski, Francis ; Arber, Nadir ; Merz, Michael ; Sauer, John Michael ; Andrade, Raul J. ; van Bömmel, Florian ; Poynard, Thierry ; Watkins, Paul B. / Candidate biomarkers for the diagnosis and prognosis of drug-induced liver injury : An international collaborative effort. In: Hepatology. 2019 ; Vol. 69, No. 2. pp. 760-773.
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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.",
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T1 - Candidate biomarkers for the diagnosis and prognosis of drug-induced liver injury

T2 - An international collaborative effort

AU - Church, Rachel J.

AU - Kullak-Ublick, Gerd A.

AU - Aubrecht, Jiri

AU - Bonkovsky, Herbert L.

AU - Chalasani, Naga

AU - Fontana, Robert J.

AU - Goepfert, Jens C.

AU - Hackman, Frances

AU - King, Nicholas M.P.

AU - Kirby, Simon

AU - Kirby, Patrick

AU - Marcinak, John

AU - Ormarsdottir, Sif

AU - Schomaker, Shelli J.

AU - Schuppe-Koistinen, Ina

AU - Wolenski, Francis

AU - Arber, Nadir

AU - Merz, Michael

AU - Sauer, John Michael

AU - Andrade, Raul J.

AU - van Bömmel, Florian

AU - Poynard, Thierry

AU - Watkins, Paul B.

PY - 2019/2/1

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N2 - 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.

AB - 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.

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