Drug- and herb-induced liver injury: Progress, current challenges and emerging signals of post-marketing risk

Abstract

Drug-induced liver injury (DILI) and herb-induced liver injury is a hot topic for clinicians, academia, drug companies and regulators, as shown by the steadily increasing number of publications in the past 15 years. This review will first provide clues for clinicians to suspect idiosyncratic (unpredictable) DILI and succeed in diagnosis. Causality assessment remains challenging and requires careful medical history as well as awareness of multifaceted aspects, especially for herbs. Drug discontinuation and therapy reconciliation remain the mainstay in patent’s management to minimize occurrence of acute liver failure. The second section will address novel agents associated with liver injury in 2014 (referred to as “signals”), especially in terms of clinical, research and drug development implications. Insights will be provided into recent trends by highlighting the contribution of different post-marketing data, especially registries and spontaneous reporting systems. This literature scrutiny suggests: (1) the importance of post-marketing databases as tools of clinical evidence to detect signals of DILI risk; and (2) the need for joining efforts in improving predictivity of pre-clinical assays, continuing post-marketing surveillance and design ad hoc post-authorization safety studies. In this context, ongoing European/United States research consortia and novel pharmaco-epidemiological tools (e.g., specialist prescription event monitoring) will support innovation in this field. Direct oral anticoagulants and herbal/dietary supplements appear as key research priorities.

Keywords: Hepatotoxicity, Liver damage, Herb, Signal, Safety, Predictivity

Core tip: Drug- and herb-induced liver injury remains a clinical challenge, attracting multidisciplinary interest for its translational aspects (from bench to bedside approach and vice versa). When considering differential diagnosis in patients with liver damage, clinicians should always keep in mind drugs and herbs as possible liver offenders, especially in subjects with comorbidities requiring long-term multiple therapies (likelihood of drug interactions). Drug withdrawal and therapy reconciliation represent key issues in patient’ management to minimize the risk of acute liver failure. Notwithstanding the progress in the tools for early detection of hepatotoxicity, there is growing literature on drugs and herbs possibly associated with liver injury in the post-marketing phase: often undetected during drug development, signals of liver toxicity emerge from spontaneous reporting systems and registries. This calls for a joint, multidisciplinary action to improve predictivity of pre-clinical assays, continuing post-marketing surveillance and designing ad hoc population-based studies.