Journal
LIVER INTERNATIONAL
Volume 34, Issue 3, Pages 367-378Publisher
WILEY
DOI: 10.1111/liv.12322
Keywords
acetaminophen; biomarkers; drug development; hepatotoxicity; HIV; liver; plasma; safety; toxicology; tuberculosis
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Funding
- European and Developing Countries Clinical Trial Partnership [CG_TA.05.40204_005, CT.2005.32030.001]
- Swedish Research Council [348-2011-7383]
- National Center for Advancing Translational Sciences, National Institutes of Health [UL1TR000083]
- Medical Research Council through the Centre for Drug Safety Science [G0700654]
- Wellcome Trust Research Fellowship
- MRC [G0700654, MR/L006758/1] Funding Source: UKRI
- Medical Research Council [MR/L006758/1, G0700654] Funding Source: researchfish
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Background & AimsThere is a demand for more sensitive, specific and predictive biomarkers for drug-induced liver injury (DILI) than the gold standard used today, alanine aminotransferase (ALT). The aim of this study was to qualify novel DILI biomarkers (keratin-18 markers M65/M30, microRNA-122, glutamate dehydrogenase and alpha-foetoprotein) in human DILI. MethodsLevels of the novel biomarkers were measured by enzyme-linked immunosorbent assay or real-time quantitative reverse-transcription PCR (qRT-PCR) in two human DILI cohorts: a human volunteer study with acetaminophen and a human immunodeficiency virus (HIV)/tuberculosis (TB) study. ResultsIn the acetaminophen study, serum M65 and microRNA-122 levels were significantly increased at an earlier time point than ALT. Furthermore, the maximal elevation of M65 and microRNA-122 exceeded the increase in ALT. In the HIV/TB study, all the analysed novel biomarkers increased after 1 week of treatment. In contrast to ALT, the novel biomarkers remained stable in a human cohort with exercise-induced muscular injury. ConclusionsM65 and microRNA-122 are potential biomarkers of DILI superior to ALT with respect to sensitivity and specificity.
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