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, 18 (9), 797-807

Biomarkers of Drug-Induced Liver Injury: Progress and Utility in Research, Medicine, and Regulation


Biomarkers of Drug-Induced Liver Injury: Progress and Utility in Research, Medicine, and Regulation

Mitchell R McGill et al. Expert Rev Mol Diagn.


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; acetaminophen; adverse drug reactions; idiosyncratic drug toxicity.


Figure 1.
Figure 1.. Serum biomarkers of DILI.
Promising biomarkers of DILI include mechanistic biomarkers (necrosis: HMGB1, K18, miR-122; Inflammation: acHMGB1; mitochondrial damage: GLDH, mtDNA, acylcarnitines; apoptosis: caspase cleaved K18), markers for early prediction of acute injury, and markers of repair and survival/death.
Figure 2:
Figure 2:. Plot of predictive values vs. prevalence.
Solid lines show positive predictive values and dashed lines show negative predictive values over a range of prevalence at set values of sensitivity and specificity. Each line represents a specific combination of equal sensitivity and specificity from 0.8 to 0.95, as shown in the figure legend. For example, the line with the darkest circles shows predictive values vs. prevalence when sensitivity and specificity both equal 0.95 (or 95%). (A) Full range of prevalence. (B) Zoomed in on the range of prevalence relevant to drug-induced liver injury. Darkened area shows the commonly cited prevalence of idiosyncratic DILI (1 in 10,000 or 0.01%).

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