Abstract
Early identification of individuals susceptible to idiosyncratic drug-induced liver injury (IDILI) is a challenging unmet demand. Diclofenac, one of the most widely available over-the-counter drugs for pain management worldwide, may induce liver dysfunction, acute liver failure, and death. Herein, we report that diclofenac-related hepatobiliary adverse reactions occurred more frequently in cases with immune activation. Furthermore, experiments with rats demonstrated divergent hepatotoxicity responses in individuals exposed to diclofenac, and modest inflammation potentiated diclofenac-induced liver injury. Susceptible rats had unique plasma metabolomic characteristics, and as such, the metabolomic approach could be used to distinguish susceptible individuals. The 23 identified susceptibility-related metabolites were enriched by several metabolic pathways related to acute-phase reactions of immunocytes and inflammatory responses, including sphingolipid, tyrosine, phenylalanine, tryptophan, and lipid metabolism pathways. This finding implies a mechanistic role of metabolic and immune disturbances affects susceptibility to diclofenac-IDILI. Further nine metabolite biomarkers with potent diagnostic capabilities were identified using receiver operating characteristic curves. These findings elucidated the potential utility of metabolomic biomarkers to identify individuals susceptible to drug hepatotoxicity and the underlying mechanism of metabolic and immune disturbances occurring in IDILI.
Highlights
Drug-induced hepatotoxicity is a major cause of severe internal damage, exhibiting divergent responses between individuals
Dicl-hepatobiliary adverse drug reaction (ADR) often occurred in cases with immune abnormalities (Figure 1B), such as with gout, rheumatoid arthritis, and joint pain, which suggested that abnormal immune activation in the hosts might be a factor increasing susceptibility to Dicl-idiosyncratic drug-induced liver injury (IDILI)
Due to the great variation in toxic responses and the unpredictable nature of IDILI, early identification of susceptible individuals is critically important in clinical practice
Summary
Drug-induced hepatotoxicity is a major cause of severe internal damage, exhibiting divergent responses between individuals. Idiosyncratic drug-induced liver injury (IDILI) is the primary type of hepatotoxicity, causing liver dysfunction, acute liver failure, and death (Björnsson, 2016; Andrade et al, 2019). The idiosyncratic nature of IDILI presents a vital challenge to its management due to the difficulty in predicting its incidence and the dosage of the causative pharmacotherapies (Roth and Lee, 2017; Uetrecht, 2019). In this regard, screening susceptible individuals using novel predictive biomarkers is of great value in the clinical prevention and management of this unique medicinal concern
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call