Biomarkers of drug-induced liver injury: progress and utility in research, medicine, and regulation

ABSTRACT

Introduction: The difficulty of understanding and diagnosing drug-induced liver injury (DILI) has led to proliferation of serum and genetic biomarkers. Many applications of these biomarkers have been proposed, including investigation of mechanisms, prediction of DILI during early trials or before initiation of therapy in patients, and diagnosis of DILI during therapy.

Areas covered: We review the definition and categories of DILI, describe recent developments in DILI biomarker development, and provide guidance for future directions in DILI biomarker research.

Expert commentary: There are major obstacles to DILI biomarker development and implementation, including the low prevalence of idiosyncratic DILI (IDILI), weak associations of IDILI with genetic variants, and lack of specificity of many biomarkers for the liver. Certain serum biomarkers, like miR-122, may have clinical utility in early-presenting patients with either intrinsic or idiosyncratic DILI in the future, while others likely will not find use. Future research should focus on implementation of biomarkers to predict later injury and outcome in early presenters with intrinsic DILI, and on development of biomarkers of adaptation and repair in the liver that can be used to determine if a liver test abnormality is likely to be clinically significant in IDILI.

KEYWORDS:

• Hepatotoxicity
• adverse drug reactions
• idiosyncratic drug toxicity
• acetaminophen

Declaration of interest

MRM received a pinnacle research award from the AASLD. HJ was funded by the National Institutes of Health grant R01 DK102142, and grants from National Institute of General Medical Sciences (P20 GM103549 and P30 GM118247) of the National Institutes of Health. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded in part by National Institutes of Health (US) and funded in part by a grant from the American Association for the Study of Liver Disease (AASLD).