Abstract
Despite being relatively rare, drug-induced liver injury (DILI) is a serious condition, both for the individual patient due to the risk of acute liver failure, and for the drug development industry and regulatory agencies due to associations with drug development attritions, black box warnings, and postmarketing withdrawals. A major limitation in DILI diagnosis and prediction is the current lack of specific biomarkers. Despite refined usage of traditional liver biomarkers in DILI, reliable disease outcome predictions are still difficult to make. These limitations have driven the growing interest in developing new more sensitive and specific DILI biomarkers, which can improve early DILI prediction, diagnosis, and course of action. Several promising DILI biomarker candidates have been discovered to date, including mechanistic-based biomarker candidates such as glutamate dehydrogenase, high-mobility group box 1 protein and keratin-18, which can also provide information on the injury mechanism of different causative agents. Furthermore, microRNAs have received much attention lately as potential non-invasive DILI biomarker candidates, in particular miR-122. Advances in “omics” technologies offer a new approach for biomarker exploration studies. The ability to screen a large number of molecules (e.g., metabolites, proteins, or DNA) simultaneously enables the identification of ‘toxicity signatures,’ which may be used to enhance preclinical safety assessments and disease diagnostics. Omics-based studies can also provide information on the underlying mechanisms of distinct forms of DILI that may further facilitate the identification of early diagnostic biomarkers and safer implementation of personalized medicine. In this review, we summarize recent advances in the area of DILI biomarker studies.
Highlights
Drug-induced liver injury (DILI) is one of many forms of adverse drug reactions that appear in a small proportion of patients
Impact on patient health due to its potential to cause acute liver failure, most idiosyncratic drug-induced liver injury (DILI) cases have a favorable outcome with full recovery after withdrawal of the culprit drug
Drug-induced liver injury is generally classified into three patterns of liver injury, based originally on histological features
Summary
Drug-induced liver injury (DILI) is one of many forms of adverse drug reactions that appear in a small proportion of patients. DILI is generally classified as intrinsic if predictable based on dose and pharmacological properties [for example acetaminophen (APAP) overdose] or idiosyncratic when unpredictable by the same features The latter is believed to be a consequence of interactions between drug properties, host factors, and environmental conditions in a susceptible individual. The lack of DILI specific biomarkers affects the drug development process and can result in early termination of drug candidates with assumed idiosyncratic hepatotoxicity potential. This can have considerable economic consequences and can prevent a large targeted recipient group from benefitting from a drug that may only be harmful to a small proportion of patients. New more specific and sensitive DILI biomarkers could enable better monitoring of patients receiving new drugs and minimize liver injury through early detection and subsequent cessation of dosing
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