Challenges and Future of Drug-Induced Liver Injury Research—Laboratory Tests

Abstract

Drug-induced liver injury (DILI) is a rare but potentially severe adverse drug event, which is also a major cause of study cessation and market withdrawal during drug development. Since no acknowledged diagnostic tests are available, DILI diagnosis poses a major challenge both in clinical practice as well as in pharmacovigilance. Differentiation from other liver diseases and the identification of the causative agent in the case of polymedication are the main issues that clinicians and drug developers face in this regard. Thus, efforts have been made to establish diagnostic testing methods and biomarkers in order to safely diagnose DILI and ensure a distinguishment from alternative liver pathologies. This review provides an overview of the diagnostic methods used in differential diagnosis, especially with regards to autoimmune hepatitis (AIH) and drug-induced autoimmune hepatitis (DI-AIH), in vitro causality methods using individual blood samples, biomarkers for diagnosis and severity prediction, as well as experimental predictive models utilized in pre-clinical settings during drug development regimes.

Establishment of an <i>in vitro</i> cholestasis risk assessment system using two-dimensional cultured HepaRG cells and 12 bile acids

“…Recent studies on DILI have proposed various biomarkers (apolipoprotein E, miR-122(-5p), miR-129, miR-382-5p, miR-4463, pre-miR-4270, glutamate dehydrogenase (GLDH), γ-Glu-citrulline, genome-wide association studies (GWAS) for genetic susceptibility, high-mobility group box 1 (HMGB 1), interleukin (IL)-9, IL-17, integrin subunit beta 3 (ITGB 3), keratin 18 (K18), metabolomic classification model (P-cresol sulfate vs. phenylalanine and inosine vs. bilirubin), platelet-derived growth factor (PDGF)-bb, regulated on activation, normal T expressed and secreted (RANTES) serum metabolites (BAs)), which are expected to reduce not only DIC but also DILI risk (Weber and Gerbes, 2022). In the future, it is expected that these biomarkers will be taken into account in DILI risk assessment.…”

Computational models for predicting liver toxicity in the deep learning era

“…Drug-induced liver injury (DILI) is a substantial safety concern, with a reported potential for more than 1,000 drugs or supplements to induce liver damage (Alempijevic et al, 2017;Zhu et al, 2018). DILI presents a significant challenge for healthcare professionals, pharmaceutical developers, and regulatory authorities (George et al, 2018), and frequently results in the discontinuation of drug candidates during their development (Weber and Gerbes, 2022). It also is a primary reason for the withdrawal of over 50 medications from the market (Devarbhavi, 2012;Wu et al, 2022) and ranks as a leading cause of acute liver failure in both the United States and Europe (Andrade et al, 2019).…”

Ethyl gallate concurrent administration protects against acetaminophen‐induced acute liver injury in mice: An in vivo and in silico approach

“…According to recent reports, DILI is a significant cause of global health burden and it is increasingly recognized as one of the causes of acute hepatitis and acute liver failure (Asrani et al, 2019; Ledgerwood et al, 2022). DILI is one of the common reasons for drug withdrawal from the market and cessation of study during drug development (Björnsson & Björnsson, 2022; Weber & Gerbes, 2022). DILI are two types, that is, intrinsic DILI and idiosyncratic DILI.…”