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.

Keywords: adverse drug events; biomarkers; drug development; drug-induced liver injury; hepatotoxicity.

Figure 1

Example of an MH cell test result. The spiderweb graph shows the toxicity results in a patient with suspected DILI. Methylprednisolone as the likely cause of DILI in this case (causality assessment: highly likely with a positive rechallenge) induces toxicity of 60% at 2 × C_max, of 66% at 5 × C_max and 87% at 10 × C_max. No toxicity of the comedication with ibuprofen, acyclovir, pantoprazole, hyperforin (a herbal remedy), ceftriaxone or prednisolone, which was used to treat the DILI episode, was observed in MH cell testing in this patient. APAP is a standard part of the test for demonstrating dose-dependent drug-induced liver injury. Lysis with 1% TWEEN^®20 (polyethylene glycol sorbitan monolaurate) is used as a positive control. Abbreviations: Acic: Acyclovir; APAP: Acetaminophen; con: Negative control; CTX: Ceftriaxone; Ibu: Ibuprofen; Hyper: Hyperforin; Ibu: Ibuprofen; Methylpred: Methylprednisolone; Panto: Pantoprazole.