Novel biomarkers for drug-induced liver injury.

Liver toxicity due to medicines (drug-induced liver injury) is a challenge for clinicians and drug developers. There are well-established biomarkers of drug-induced liver injury, which are widely used and validated by decades of clinical experience. These include alanine aminotransferase and bilirubin. Limitations of the current biomarkers are well described, and this has resulted in global efforts to identify and develop new candidates. This process has been aided by regulatory pathways being established for biomarker qualification. This article aims to provide a broad overview of the mechanisms of liver toxicity and discuss emerging novel biomarkers. There is a focus on the recent advances in the identification and validation of novel biomarkers, their potential applications in drug development and clinical practice, and the challenges and opportunities in translating these biomarkers into routine clinical use. Alanine and aspartate aminotransferase activities perform well in diagnosing established drug-induced liver injury but may lack specificity and are not prognostic. The amount of evidence required for a new biomarker will depend on its context-of-use, specifically on the impact on patient outcome of a false negative or false positive result. Cytokeratin-18, glutamate dehydrogenase, microRNA-122, high-mobility group box 1 proteins, osteopontin, and macrophage colony-stimulating factor receptor 1 are examples of lead candidates. The early detection of drug-induced liver injury, interpretation of an alanine aminotransferase activity increase, and decisions about dose escalation in clinical trials may all be informed by new biomarkers. There have been numerous exploratory studies describing differences in biomarkers and their potential value in risk-stratifying populations or identifying specific patients who may be failed by current assessment protocols. Additionally, the use of exploratory biomarkers to guide clinical trial decision-making is becoming routine. The challenge is now clinically validating leading candidate biomarkers in the assessment of patients presenting with conditions such as paracetamol overdose, which place them at risk of acute liver injury. This will require robust clinical trials. If the use of these biomarkers is to be widely adopted, they will need to unequivocally demonstrate benefit in overall cost, morbidity or mortality.