Biomarkers of drug-induced liver injury

Abstract

Drug-induced liver injury (DILI) is a major clinical and regulatory challenge. As a result, interest in DILI biomarkers is growing. So far, considerable progress has been made in identification of biomarkers for diagnosis (acetaminophen-cysteine protein adducts), prediction (genetic biomarkers), and prognosis (microRNA-122, high mobility group box 1 protein, keratin-18, glutamate dehydrogenase, mitochondrial DNA). Many of those biomarkers also provide mechanistic insight. The purpose of this chapter is to review major advances in DILI biomarker research over the last decade, and to highlight some of the challenges involved in implementation. Although much work has been done, more liver-specific biomarkers, more DILI-specific biomarkers, and better prognostic biomarkers for survival are all still needed. Furthermore, more work is needed to define reference intervals and medical decision limits.

Keywords: Acetaminophen; Diagnosis; Drug regulation; Hepatotoxicity; Idiosyncratic drug-induced liver injury; Predictive value; Prognosis.

Figure 1.. Relationship between prevalence and predictive values.

Positive post-test probability (left upper portion), a surrogate of PPV when pre-test probability or prevalence is estimated, increases with increasing prevalence, while negative post-test probability (right lower portion), a surrogate for negative predictive value (NPV), decreases. Blue-shaded areas show different levels sensitivity and specificity. For the different levels, both sensitivity and specificity were set at either 70%, 80%, 90%, or 95%. Vertical, grey-shaded areas show the approximate ranges of prevalence for idiosyncratic drug-induced liver injury (IDILI) among users of a given IDILI-associated drug, for acute liver injury (ALI) among early-presenting acetaminophen (APAP) overdose patients, and for mortality among acute liver failure (ALF) patients.