Idiosyncratic drug-induced liver injury (IDILI) remains a substantial concern for patients as well as drug development. The idiosyncratic nature of IDILI makes mechanistic studies challenging, and little is known about its pathogenesis.

Circumstantial evidence suggests that mostly IDILI is caused by reactive metabolites of drugs that are bioactivated by cytochromes P450 and other enzymes in the liver. Also, there is strong evidence that most IDILI is mediated by the adaptive immune system; one such example is the association of IDILI caused by specific drugs with specific human leukocyte antigen (HLA) haplotypes, and this may partly describe the idiosyncratic nature of these reactions. The T cell receptor repertoire probably also donates to the idiosyncratic nature. Although most liver injury is presumably mediated by the adaptive immune system, specifically cytotoxic CD8+ T cells, adaptive immune activation initially requires an innate immune response to activate antigen-presenting cells and produce cytokines required for T cell proliferation. This innate response is assumably generated by either a reactive metabolite or some form of cell stress that is clinically silent but not idiosyncratic. If this is true it would make it feasible to study the early steps in the immune response that in some patients can lead to IDILI. Other hypotheses have been proposed, like mitochondrial injury, inhibition of the bile salt export pump, unfolded protein response, and oxidative stress although, in most scenarios, they may be also implicated in the initiation of an immune response rather than depicting a completely separate mechanism. 

SOURCE- Jee A, Sernoskie SC, Uetrecht J. Idiosyncratic Drug-Induced Liver Injury: Mechanistic and Clinical Challenges. Int J Mol Sci. 2021;22(6):2954. Published 2021 Mar 14. doi:10.3390/ijms22062954