Abstract
Drug-induced liver injury (DILI) is one among the common adverse drug reactions and the leading causes of drug development attritions, black box warnings, and post-marketing withdrawals. Despite having relatively low clinical incidence, its potentially severe adverse events should be considered in the individual patients due to the high risk of acute liver failure. Although traditional liver parameters have been applied to the diagnosis of DILI, the lack of specific and sensitive biomarkers poses a major limitation, and thus accurate prediction of the subsequent clinical course remains a significant challenge. These drawbacks prompt the investigation and discovery of more effective biomarkers, which could lead to early detection of DILI, and improve its diagnosis and prognosis. Novel promising biomarkers include glutamate dehydrogenase, keratin 18, sorbitol dehydrogenase, glutathione S-transferase, bile acids, cytochrome P450, osteopontin, high mobility group box-1 protein, fatty acid binding protein 1, cadherin 5, miR-122, genetic testing, and omics technologies, among others. Furthermore, several clinical scoring systems have gradually emerged for the diagnosis of DILI including the Roussel Uclaf Causality Assessment Method (RUCAM), Clinical Diagnostic Scale (CDS), and Digestive Disease Week Japan (DDW-J) systems. However, currently their predictive value is limited with certain inherent deficiencies. Thus, perhaps the greatest benefit would be achieved by simultaneously combining the scoring systems and those biomarkers. Herein, we summarized the recent research progress on molecular biomarkers for DILI to improved approaches for its diagnosis and clinical management.
Highlights
Drug-induced liver injury (DILI) remains one of the most challenging diseases to treat by physicians and can be caused by many types of prescription or over-the-counter drugs, biological agents, natural medicines, herbs, dietary supplements, health care products, and their metabolic products or accessories
The mechanism underlying DILI has not been fully elucidated, and recent studies suggested that the reactive metabolites of drugs in the liver could generate a variety of biochemical consequences, including covalent binding, stress kinase activation, mitochondria stress, and endoplasmic reticulum stress, which either lead to necrosis or apoptosis or elicit an adaptive immune response to drug-adducts in susceptible individuals
Levels of Glutamate Dehydrogenase (GLDH) were stable between healthy and liver-injured subjects regardless of gender or age (Schomaker et al, 2013). It remains controversial whether GLDH can accurately predict hepatocyte necrosis, as necrosis may not result in mitochondrial toxicity, and it is a specific biomarker for mitochondrial dysfunction
Summary
Drug-induced liver injury (DILI) remains one of the most challenging diseases to treat by physicians and can be caused by many types of prescription or over-the-counter drugs, biological agents, natural medicines, herbs, dietary supplements, health care products, and their metabolic products or accessories DILI is one of the main causes of chronic liver diseases It is generally classified as intrinsic (or direct) or idiosyncratic; indirect injury is becoming a third type (Hoofnagle and Bjornsson, 2019). Indirect DILI is a new and not yet fully accepted category of hepatotoxicity, which results from the action of the drug rather than from its inherent hepatotoxic effects or immunogenicity It can manifest as a new liver disease or as the deterioration of preexisting conditions (Hoofnagle and Bjornsson, 2019). This review summarizes the current molecular biomarkers with the potential to provide more precise and accurate diagnosis and treatment of DILI (Figure 1)
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