Reference intervals for putative biomarkers of drug-induced liver injury
and liver regeneration in healthy human volunteers
Abstract
Background & Aims: The potential of mechanistic biomarkers to improve
prediction of drug-induced liver injury (DILI) and hepatic regeneration
is widely acknowledged. We sought to determine reference intervals for
new biomarkers of DILI and regeneration, as well as to characterize
their natural variability and impact of diurnal variation. Methods:
Serum samples from 227 healthy volunteers were recruited as part of a
cross-sectional study; of these, 25 subjects had weekly serial sampling
over 3 weeks, while 23 had intensive blood sampling over a 24h period.
Alanine aminotransferase (ALT), MicroRNA-122 (miR-122), High Mobility
Group Box-1 (HMGB1), total Keratin-18 (K18), caspase-cleaved Keratin-18
(ccK18), Glutamate Dehydrogenase (GLDH) and Macrophage
Colony-Stimulating Factor-1 (CSF-1) were assayed. Results: Reference
intervals were established for each biomarker based on the 97.5%
quantile (90% CI) following the assessment of fixed effects in
univariate and multivariable models. Intra-individual variability was
found to be non-significant, and there was no significant impact of
diurnal variation. Conclusions: Reference intervals for novel DILI
biomarkers have been described. An upper limit of a reference range
might represent the most appropriate mechanism to utilize these data.
These data can now be used to interpret data from exploratory clinical
DILI studies and to assist their further qualification as required by
regulatory authorities.