Mechanisms of drug-induced liver injury and novel biomarkers for its assessment

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Drug-induced liver injury (DILI) accounts for <1% of cases of acute liver injury seen by gastroenterologists, but is the most common cause for acute liver failure in the United States and Europe. Marketed drugs that commonly cause DILI include acetaminophen (paracetamol), amoxicillin/clavulanate, isoniazid and NSAIDS. Of note, herbals and dietary supplements are increasingly being recognized as potential causes of liver injury.

DILI is a diagnosis of exclusion that physicians have to consider in patients with an unexplained increase of liver enzymes. Assessment of DILI depends on expert opinion that is based on patient data and the typical “signatures” associated with certain drugs. Causality scores such as RUCAM are useful to confirm or exclude the suspicion of DILI. Immunoallergic hepatotoxicity is caused by neoantigens that result from the interaction of drugs or their metabolites with host proteins. These drug-protein adducts are presented by major histocompatibility complex (MHC) class II, thereby triggering an immune reaction. Current management of DILI would benefit greatly from novel biomarkers that separate patients with a likelihood of recovering spontaneously from those who are at risk of worsening to a state of advanced liver injury. A biomarker that could predict the clinical course of a patient in whom a drug-induced elevation of alanine transaminase (ALT) has been observed could help to scale the risk of subsequent deterioration, which would also impact on the overall clinical management.

The IMI SAFE-T Consortium (Safer And Faster Evidence-based Translation) was initiated to qualify new biomarkers for drug-induced kidney injury (DIKI), drug-induced liver injury (DILI) and drug-induced vascular injury (DIVI) for human applications. A panel of potential biomarkers for DIKI, DILI, and DIVI was assessed in clinical studies in healthy volunteers and patients with drug- and non-drug induced kidney, liver and vascular injuries and common systemic diseases. Investigations on biologic/mechanistic understanding for DIKI, DILI, and DIVI biomarkers was undertaken to support the clinical scientific qualification strategy of the candidate biomarkers. Results from the SAFE-T consortium on novel DILI biomarkers were submitted to the regulatory agencies FDA and EMA in 2016 and both issued Letters of Support that explicitly encourage the exploratory use of DILI biomarkers by sponsors in the context of drug registration trials. DILI biomarkers that show promise include high mobility group box 1 (HMGB1), cytokeratin 18 (CK-18), macrophage colony-stimulating factor receptor 1 (MCSFR1) and microRNA-122. 

When: 16th November at 2pm GMT 

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Gerd Kullak-Ublick Chairman The Investigative Liver Expert Team, Novartis Pharma, Basel, Switzerland

As well as standing as Head of the Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Gerd also acts as Chairman of the Novartis Liver Expert Team in Basel. 

Over the last four years Gerd has been the work package leader of the work package “Drug-induced liver injury” in the IMI SAFE-T consortium (evaluation of novel biomarkers in drug-induced liver injury), in close collaboration with the Predictive Safety Testing Consortium (PSTC) and the US Drug-Induced Liver Injury Network (DILIN). 

His research achievements include cloning the first human OATP transporter in 1995 (now called OATP1A2).