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

Abstract

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).

Serum biomarkers of drug‐induced liver injury: Current status and future directions

“…One cohort of healthy volunteers (Cohort 1) had three serial serum collections taken over 3 weeks, thus allowing for the calculation of intra‐individual variability. In agreement with previously reported data, the reference interval for GLDH was found to be ~1 to 10 U/L . The percentage coefficient of variation (%CV) is a measure of variability in the data.…”

“…In agreement, various studies have demonstrated that patients with an acetaminophen overdose experience significant GLDH elevations . Similar to miR‐122, in acetaminophen overdoses GLDH appears to be more sensitive to liver injury than ALT and GLDH elevations also occur in idiosyncratic DILI …”

“…This has been addressed recently in a large collaboration between the Predictive Safety Testing Consortium, SAFE‐T and the Drug‐Induced Liver Injury Network (DILIN) . Biomarkers were quantified in two cohorts of healthy volunteers in addition to patients with DILI . One cohort of healthy volunteers (Cohort 1) had three serial serum collections taken over 3 weeks, thus allowing for the calculation of intra‐individual variability.…”

“…The intra‐individual variability of miR‐122 was also greater than that of GLDH with a %CV of 93.56%. Interestingly, it seemed that the patient's race may influence the intra‐subject variability observed …”

Improving Interpretation of New and Old Serum Biomarkers of Drug‐Induced Liver Injury Through Mechanistic Modeling

“…Novel biomarkers, including HMBG1, have been proposed to be danger signals that can be measured in serum, and various cytokines, microRNAs, and acetylated HMGB1 have been proposed as serum biomarkers of immune cell activation . Identification of new and mechanistic biomarkers of drug‐induced liver injury has been a major focus of international research efforts, including a major new effort to start in 2019 . Mechanistic modeling incorporating production and release kinetics of these new biomarkers could make it possible to identify serious liver safety liability of new drug candidates early in clinical trials and with minimum subject risk and thus reducing the current need for large clinical trials to define liver safety.…”