Keratin-18 and microRNA-122 complement alanine aminotransferase as novel safety biomarkers for drug-induced liver injury in two human cohorts

Petra Thulin, Gunnar Nordahl, Marcus Gry, Getnet Yimer, Eleni Aklillu, Eyasu Makonnen, Getachew Aderaye, Lars Lindquist, C. Mikael Mattsson, Bjorn Ekblom, Daniel J. Antoine, B. Kevin Park, Stig Linder, Alison H. Harrill, Paul B. Watkins, Bjorn Glinghammar, Ina Schuppe-Koistinen*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)367-378
Number of pages12
JournalLiver International
Volume34
Issue number3
DOIs
Publication statusPublished - Mar 2014

Keywords

  • acetaminophen
  • biomarkers
  • drug development
  • hepatotoxicity
  • HIV
  • liver
  • plasma
  • safety
  • toxicology
  • tuberculosis
  • CIRCULATING MICRORNAS
  • ALPHA-FETOPROTEIN
  • CELL-DEATH
  • ACETAMINOPHEN HEPATOTOXICITY
  • HEPATOCELLULAR-CARCINOMA
  • TRANSAMINASE ACTIVITY
  • SERUM BIOMARKERS
  • FUNCTION TESTS
  • MARKERS
  • PROGNOSIS

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