# Insights into the Biochemical and Immune Mechanisms in Drug-Induced Liver Injury Pathogenesis

## TL;DR

This paper reviews how drugs can cause liver injury through biochemical and immune mechanisms, focusing on how individual differences and immune responses contribute to this condition.

## Contribution

The paper provides a synthesis of current understanding of immune-mediated mechanisms in drug-induced liver injury (DILI) and highlights risk factors for individual susceptibility.

## Key findings

- Immune-mediated DILI is linked to drug-protein adducts and neoantigen formation.
- HLA alleles and T-cell responses influence susceptibility to DILI.
- Liver-resident immune cells like natural killer T-cells enhance drug-specific immune responses.

## Abstract

DILI is the leading
cause of drug failure in clinical trials and
withdrawal from the market. Certain intrinsic mechanisms of injury
have been characterized such as the direct cytotoxicity exerted by
NAPQI, a reactive metabolite of acetaminophen. However, presentation
of DILI is highly heterogeneous with several idiosyncratic presentations
being observed in patients. Such manifestations are often linked to
aberrant immune activation although the biochemical mechanisms directing
such responses currently evade complete understanding. This review
consolidates current literature findings into potential mechanisms
of immune-mediated DILI as well as risk factors which may polarize
both the liver itself and certain individuals toward a drug-reactive
phenotype. Current theories implicate neoantigen formation as a result
of the generation of drug–protein adducts by both parent drugs
and reactive metabolites. Responses to such adducts can be restricted
to the presence of certain HLA alleles though these associations are
identified through epidemiological means rather than mechanistic investigations.
Further, susceptibility to DILI can be linked to nuance in the T-cell
responses to HLA displayed antigens where basal levels of effector
molecules and inflammation as well as the presence of liver resident
immune cells, such as natural killer T-cells, can augment drug-specific
immune responses.