Human Leukocyte Antigen (HLA) Signatures and Idiosyncratic Drug-Induced Liver Injury

Sep 30, 2026

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Drug-induced liver injury (DILI) remains among the most challenging adverse drug reactions, especially idiosyncratic DILI, which is not dose-dependent and is driven by host-specific immune and genetic determinants. Genomic studies link particular human leukocyte antigen (HLA) alleles to susceptibility, supporting an immunogenetic mechanism in which drug or metabolite–protein adducts form neoantigens and trigger aberrant T-cell activation and hepatocellular damage. This review compiles evidence for HLA polymorphisms in idiosyncratic DILI pathogenesis, emphasizing allele-specific risk patterns and ethnic variability. Integrating genetic and immunological insights, HLA signatures enable precision medicine approaches for earlier risk identification and prevention of severe hepatotoxicity.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages15

Reading Time38 min

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Abstract

Introduction

Review Human Leukocyte Antigen (HLA) Signatures and Idiosyncratic Drug-Induced Liver Injury Alexia Onaciu 1, Alina Grama 2,3,*, S, tefan Agos, ton 1, Alexandra Mititelu 2,3, Bianca Mari¸s 2,3, Horia ¸Stefănescu 4,5 and Tudor Lucian Pop 2,3 1 Faculty of Medicine,“Iuliu Hat, ieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania 2 2nd Pediatric Discipline, Department of Mother and Child, Faculty of Medicine,“Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania 3 2nd Pediatric Clinic, Emergency Clinical Hospital for Children, 400370 Cluj-Napoca, Romania 4 “Prof. Dr. Octavian Fodor” Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania 5 Department of Internal Medicine,“Iuliu Haieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania * Correspondence: [gramaalina16@elearn.umfcluj.ro](gramaalina16@elearn.umfcluj.ro) Abstract Drug-induced liver injury (DILI) remains one of the most challenging adverse drug reactions in clinical practice, particularly in its idiosyncratic form, which is not dose-dependent and is largely driven by host-specific immune and genetic factors. Recent genomic studies have revealed strong associations between certain human leukocyte antigen (HLA) alleles and susceptibility to DILI, supporting an immunogenetic mechanism in which drug or metabolite–protein adducts act as neoantigens, triggering aberrant T-cell activation and hepatocellular injury. This review summarizes current evidence on the contribution of HLA polymorphisms to the pathogenesis of idiosyncratic DILI, highlighting allele-specific risk patterns, such as HLA-B*57:01 associated with flucloxacillin, HLA-DRB1*15:01–DQB1*06:02 in amoxicillin–clavulanate, and HLA-B*35:02 in minocycline-induced liver injury. Furthermore, ethnic variability and allele-haplotype interactions are discussed as potential modulators of susceptibility and clinical phenotype. By integrating genetic and immunological insights, the identification of HLA signatures offers promising tools for precision medicine, enabling earlier identification of at-risk individuals and improved prevention of severe hepatotoxic reactions. Keywords: drug-induced liver injury; HLA polymorphisms; adaptive immune response; idiosyncratic drug reactions Academic Editor: Sharon DeMorrow Received: 23 November 2025 Revised: 28 December 2025 Accepted: 1 January 2026 Published: 2 January 2026 Copyright: © 2026 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. 1. Introduction Drug-Induced Liver Injury (DILI) is an acute or chronic liver injury secondary to exposure to certain xenobiotics, mainly pharmaceutical drugs. Depending on the typeof toxic agent, hepatotoxic reactions can be classified as either intrinsic or idiosyncratic. Intrinsic hepatotoxicity is a dose-dependent toxicity that appears shortly after exposure, due to exceeding the liver detoxification capacity by administering overdoses. Histological findings are characterized by hepatic necrosis or steatosis, which may result from the direct action of the chemical substance or its metabolites (direct hepatotoxicity) or from disruption of intracellular metabolic processes (indirect toxicity) . Acetaminophen is the prototype agent of direct hepatotoxicity, whereas the toxicity of Amanita phalloides is often indirect, by inhibiting RNA polymerase II and impairing protein synthesis [1,2] . The liver functions as the primary organ of biotransformation, converting lipophilic xenobiotics into hydrophilic metabolites mainly through cytochrome P450–mediated oxidative pathways, thereby facilitating their excretion via renal or biliary routes [3] . Mechanisms of hepatotoxicity predominantly involve the hepatic biotransformation of drugs into reactive metabolites, which may exceed the liver’s

FAQs

Why is idiosyncratic drug-induced liver injury considered difficult to predict or prevent?

It is not dose-dependent and is largely driven by host-specific immune and genetic factors, making susceptibility complex and variable across individuals.

How do HLA alleles contribute to the pathogenesis of idiosyncratic DILI?

Certain HLA alleles are associated with susceptibility, supporting an immunogenetic mechanism where drug or metabolite–protein adducts act as neoantigens that trigger aberrant T-cell activation and hepatocellular injury.

What is the clinical relevance of identifying HLA signatures?

HLA signatures can support precision medicine by enabling earlier identification of at-risk individuals and improved prevention of severe hepatotoxic reactions.

Sep 30, 2026

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