Advances in immunogenetic mechanisms of drug-induced liver injury

doi:10.12092/j.issn.1009-2501.2025.08.016

Abstract

Abstract: Drug-induced liver injury (DILI) is one of the major challenges in drug development and clinical practice, and effective prevention and control measures remain lacking. Research has shown that DILI is primarily mediated by immune responses. Human leukocyte antigen (HLA) alleles are currently the strongest genetic factors reported to be associated with DILI. Due to the low positive predictive value of HLA alleles, preemptive HLA genetic screening has limited clinical utility in preventing DILI. However, its high negative predictive value makes it valuable for DILI diagnosis and causality assessment. In recent years, polymorphisms in immune-related genes-such as those involved in antigen processing and presentation pathways, T-cell receptors, immunostimulatory molecules, and cytokines-have been found to be associated with DILI. Future studies combining these genes with HLA analysis may provide deeper mechanistic insights into DILI and facilitate their translational application in clinical practice, ultimately improving drug safety.

Key words: drug-induced liver injury, human leukocyte antigen, immunogenetics, pharmacogenomics

CLC Number:

R968

ZENG Xiangchang^{1, 2, 3, 4, 5, 7}, RAO Tai^{1, 3, 4, 5}, CHEN Lulu², LI Chaopeng², ZENG Guirong⁶, CHEN Jun⁷, OUYANG Dongsheng^{1, 2, 3, 4, 5}. Advances in immunogenetic mechanisms of drug-induced liver injury[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2025, 30(8): 1133-1146.

References

[1] Hoofnagle JH, Bjornsson ES.Drug-induced liver injury-types and phenotypes[J]. N Engl J Med, 2019, 381(3): 264-273.
[2] Stravitz RT, Lee WM.Acute liver failure[J]. Lancet, 2019, 394(10201): 869-881.
[3] Wang Y, Zou C, Wee A, et al.Comparison of the prognostic models for mortality in idiosyncratic drug-induced liver injury[J]. Hepatol Int, 2023, 17(2): 488-498.
[4] Uetrecht J.Mechanistic studies of idiosyncratic DILI: Clinical Implications[J]. Front Pharmacol, 2019, 10: 837.
[5] Daly AK, Donaldson PT, Bhatnagar P, et al.HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin[J]. Nat Genet, 2009, 41(7): 816-819.
[6] Nicoletti P, Aithal GP, Chamberlain TC, et al.Drug-induced liver injury due to flucloxacillin: Relevance of multiple human leukocyte antigen alleles[J]. Clin Pharmacol Ther, 2019, 106(1): 245-253.
[7] Clare KE, Miller MH, Dillon JF.Genetic factors influencing drug-induced liver injury: Do they have a role in prevention and diagnosis ?[J]. Curr Hepatol Rep, 2017, 16(3): 258-264.
[8] Donaldson PT, Daly AK, Henderson J, et al.Human leucocyte antigen class II genotype in susceptibility and resistance to co-amoxiclav-induced liver injury[J]. J Hepatol, 2010,53(6): 1049-1053.
[9] Lucena MI, Molokhia M, Shen Y, et al.Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles[J]. Gastroenterology, 2011, 141(1): 338-347.
[10] Nicoletti P, Dellinger A, Li YJ, et al.Identification of reduced ERAP2 expression and a novel HLA allele as components of a risk score for susceptibility to liver injury due to amoxicillin-clavulanate[J]. Gastroenterology, 2023, 164(3): 454-466.
[11] Singer JB, Lewitzky S, Leroy E, et al.A genome-wide study identifies HLA alleles associated with lumiracoxib-related liver injury[J]. Nat Genet, 2010, 42(8): 711-714.
[12] Kindmark A, Jawaid A, Harbron CG, et al.Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis[J]. Pharmacogenomics J, 2008, 8(3): 186-195.
[13] Bessone F, Bjornsson ES.Drug-induced liver injury due to biologics and immune check point inhibitors[J]. Med Clin North Am, 2023, 107(3): 623-640.
[14] Fontana RJ, Bjornsson ES, Reddy R, et al.The evolving profile of idiosyncratic drug-induced liver injury[J]. Clin Gastroenterol Hepatol, 2023, 21(8): 2088-2099.
[15] Bjornsson ES, Gunnarsson BI, Grondal G, et al.Risk of drug-induced liver injury from tumor necrosis factor antagonists[J]. Clin Gastroenterol Hepatol, 2015, 13(3): 602-608.
[16] Bruno CD, Fremd B, Church RJ, et al.HLA associations with infliximab-induced liver injury[J]. Pharmacogenomics J, 2020, 20(5): 681-686.
[17] Bjornsson HK, Gudbjornsson B, Bjornsson ES.Infliximab-induced liver injury: Clinical phenotypes, autoimmunity and the role of corticosteroid treatment[J]. J Hepatol, 2022, 76(1): 86-92.
[18] de Joode K, Heersche N, Basak EA, et al. Review-The impact of pharmacogenetics on the outcome of immune checkpoint inhibitors[J]. Cancer Treat Rev, 2024, 122: 102662.
[19] Sung C, An J, Lee S, et al.Integrative analysis of risk factors for immune-related adverse events of checkpoint blockade therapy in cancer[J]. Nat Cancer, 2023, 4(6): 844-859.
[20] Navarro VJ, Barnhart H, Bonkovsky HL, et al.Liver injury from herbals and dietary supplements in the U.S. Drug-Induced Liver Injury Network[J]. Hepatology, 2014, 60(4): 1399-1408.
[21] Li C, Rao T, Chen X, et al.HLA-B*35:01 Allele is a potential biomarker for predicting polygonum multiflorum-induced liver injury in humans[J]. Hepatology, 2019, 70(1): 346-357.
[22] Yang WN, Pang LL, Zhou JY, et al.Single-nucleotide polymorphisms of HLA and Polygonum multiflorum-induced liver injury in the Han Chinese population[J]. World J Gastroenterol, 2020, 26(12): 1329-1339.
[23] Hoofnagle JH, Bonkovsky HL, Phillips EJ, et al.HLA-B*35:01 and green tea-induced liver injury[J]. Hepatology, 2021,73(6): 2484-2493.
[24] Line J, Ali SE, Grice S, et al.Investigating the immune basis of green tea extract induced liver injury in healthy donors expressing HLA-B*35:01[J]. Chem Res Toxicol, 2023, 36(12): 1872-1875.
[25] Halegoua-demarzio D, Navarro V, Ahmad J, et al. Liver injury associated with turmeric-a growing problem: Ten cases from the drug-induced liver injury network [DILIN][J]. Am J Med, 2023, 136(2): 200-206.
[26] Vuppalanchi R, Bonkovsky HL, Ahmad J, et al.Garcinia cambogia, either alone or in combination with green tea, causes moderate to severe liver injury[J]. Clin Gastroenterol Hepatol, 2022, 20(6): e1416-e1425.
[27] Nakamura R, Arakawa N, Tanaka Y, et al.Significant association between HLA-B*35:01 and onset of drug-induced liver injury caused by Kampo medicines in Japanese patients[J]. Hepatol Res, 2023, 53(5): 440-449.
[28] Mosedale M, Watkins PB.Understanding idiosyncratic toxicity: lessons learned from drug-induced liver injury[J]. J Med Chem, 2020, 63(12): 6436-6461.
[29] Kim SH, Saide K, Farrell J, et al.Characterization of amoxicillin- and clavulanic acid-specific T cells in patients with amoxicillin-clavulanate-induced liver injury[J]. Hepatology, 2015, 62(3): 887-899.
[30] Monshi MM, Faulkner L, Gibson A, et al.Human leukocyte antigen (HLA)-B*57:01-restricted activation of drug-specific T cells provides the immunological basis for flucloxacillin-induced liver injury[J]. Hepatology, 2013, 57(2): 727-739.
[31] Wuillemin N, Adam J, Fontana S, et al.HLA haplotype determines hapten or p-i T cell reactivity to flucloxacillin[J]. J Immunol, 2013, 190(10): 4956-4964.
[32] Illing PT, Vivian JP, Dudek NL, et al.Immune self-reactivity triggered by drug-modified HLA-peptide repertoire[J]. Nature, 2012, 486(7404): 554-558.
[33] Ahmad J, Dellinger A, Nicoletti P, et al.Clinical and HLA associations of fluoroquinolone induced liver injury: results from the Drug-Induced Liver Injury Network[J]. Am J Gastroenterol, 2025, doi: 10.14309/ ajg.0000000000003457.
[34] Conlon C, Li YJ, Ahmad J, et al.Clinical characteristics and HLA associations of azithromycin-induced liver injury[J]. Aliment Pharmacol Ther, 2024, 60(6): 787-795.
[35] Bonkovsky HL, Ghabril M, Nicoletti P, et al.Drug-induced liver injury (DILI) ascribed to non-steroidal anti-inflammatory drugs (NSAIDs) in the USA-Update with genetic correlations[J]. Liver Int, 2024, 44(6): 1409-1421.
[36] Asif BA, Koh C, Phillips EJ, et al.Vancomycin-induced liver injury, DRESS, and HLA-A *32:01[J]. J Allergy Clin Immunol Pract, 2024, 12(1): 168-174.
[37] Nicoletti P, Dellinger A, Li YJ, et al.HLA-B*53:01 is a significant risk factor of liver injury due to phenytoin and other antiepileptic drugs in African Americans[J]. Am J Gastroenterol, 2024, 119(1): 200-202.
[38] Chalasani N, Li YJ, Dellinger A, et al.Clinical features, outcomes, and HLA risk factors associated with nitrofurantoin-induced liver injury[J]. J Hepatol, 2023, 78(2): 293-300.
[39] Devarbhavi H, Patil M, Menon M.Association of human leukocyte antigen-B*13:01 with dapsone-induced liver injury[J]. Br J Clin Pharmacol, 2022, 88(3): 1369-1372.
[40] Fontana RJ, Li YJ, Phillips E, et al.Allopurinol hepatotoxicity is associated with human leukocyte antigen Class I alleles[J]. Liver Int, 2021, 41(8): 1884-1893.
[41] Nicoletti P, Devarbhavi H, Goel A, et al.Genetic risk factors in drug-induced liver injury due to isoniazid-containing antituberculosis drug regimens[J]. Clin Pharmacol Ther, 2021, 109(4): 1125-1135.
[42] Li YJ, Phillips EJ, Dellinger A, et al.Human leukocyte antigen B*14:01 and B*35:01 are associated with trimethoprim-sulfamethoxazole induced liver injury[J]. Hepatology, 2021, 73(1): 268-281.
[43] Li X, Jin S, Fan Y, et al.Association of HLA-C*03:02 with methimazole-induced liver injury in Graves' disease patients[J]. Biomed Pharmacother, 2019, 117: 109095.
[44] Fontana RJ, Cirulli ET, Gu J, et al.The role of HLA-A*33:01 in patients with cholestatic hepatitis attributed to terbinafine[J]. J Hepatol, 2018, 69(6): 1317-1325.
[45] Nicoletti P, Aithal GP, Bjornsson ES, et al.Association of liver injury from specific drugs, or groups of drugs, with polymorphisms in hla and other genes in a genome-wide association study[J]. Gastroenterology, 2017, 152(5): 1078-1089.
[46] Urban T J, Nicoletti P, Chalasani N, et al.Minocycline hepatotoxicity: Clinical characterization and identification of HLA-B *35:02 as a risk factor[J]. J Hepatol, 2017, 67(1): 137-144.
[47] Nicoletti P, Werk AN, Sawle A, et al.HLA-DRB1*16: 01-DQB1*05: 02 is a novel genetic risk factor for flupirtine-induced liver injury[J]. Pharmacogenet Genomics, 2016, 26(5): 218-224.
[48] Xu CF, Johnson T, Wang X, et al.HLA-B*57:01 confers susceptibility to pazopanib-associated liver injury in patients with cancer[J]. Clin Cancer Res, 2016, 22(6): 1371-1377.
[49] Schaid DJ, Spraggs CF, Mcdonnell SK, et al.Prospective validation of HLA-DRB1*07:01 allele carriage as a predictive risk factor for lapatinib-induced liver injury[J]. J Clin Oncol, 2014, 32(22): 2296-2303.
[50] O'donohue J, Oien KA, Donaldson P, et al. Co-amoxiclav jaundice: clinical and histological features and HLA class II association[J]. Gut, 2000, 47(5): 717-720.
[51] Hirata K, Takagi H, Yamamoto M, et al.Ticlopidine-induced hepatotoxicity is associated with specific human leukocyte antigen genomic subtypes in Japanese patients: a preliminary case-control study[J]. Pharmacogenomics J, 2008, 8(1): 29-33.
[52] Dawes P, Moulder C.Perhexiline hepatitis and HLA-B8[J]. Lancet, 1982, 2(8289): 109.
[53] Carr DF, Bourgeois S, Chaponda M, et al.Genome-wide association study of nevirapine hypersensitivity in a sub-Saharan African HIV-infected population[J]. J Antimicrob Chemother, 2017, 72(4): 1152-1162.
[54] Pavlos R, Deshpande P, Chopra A, et al.New genetic predictors for abacavir tolerance in HLA-B*57:01 positive individuals[J]. Hum Immunol, 2020, 81(6): 300-304.
[55] Fontana RJ, Li YJ, Vuppalanchi R, et al.ERAP-1 and ERAP-2 variants in liver injury following COVID-19 mRNA vaccination: A US multicenter study[J]. Am J Gastroenterol, 2024, 119(8): 1496-1505.
[56] Urrutia-maldonado E, Ales-palmer M, Munoz DRP, et al. The relation between activator and inhibitor killer-cell immunoglobulin-like receptors and hepatotoxicity in oncological treatment[J]. Minerva Pediatr (Torino), 2023, 75(5): 668-673.
[57] Puig M, Ananthula S, Venna R, et al.Alterations in the HLA-B*57:01 Immunopeptidome by Flucloxacillin and Immunogenicity of Drug-Haptenated Peptides[J]. Front Immunol, 2020, 11: 629399.
[58] Thomson P, Hammond S, Naisbitt DJ.Pathology of drug hypersensitivity reactions and mechanisms of immune tolerance[J]. Clin Exp Allergy, 2022, 52(12): 1379-1390.
[59] Tai Y, Wang Q, Korner H, et al.Molecular mechanisms of T cells activation by dendritic cells in autoimmune diseases[J]. Front Pharmacol, 2018, 9: 642.
[60] Gibson A, Faulkner L, Lichtenfels M, et al.The effect of inhibitory signals on the priming of drug hapten-specific T cells that express distinct vbeta receptors[J]. J Immunol, 2017, 199(4): 1223-1237.
[61] Cardone M, Garcia K, Tilahun ME, et al.A transgenic mouse model for HLA-B*57:01-linked abacavir drug tolerance and reactivity[J]. J Clin Invest, 2018, 128(7): 2819-2832.
[62] Susukida T, Kuwahara S, Song B, et al.Regulation of the immune tolerance system determines the susceptibility to HLA-mediated abacavir-induced skin toxicity[J]. Commun Biol, 2021, 4(1): 1137.
[63] Song B, Aoki S, Liu C, et al.The PD1 inhibitory pathway and mature dendritic cells contribute to abacavir hypersensitivity in human leukocyte antigen transgenic PD1 knockout mice[J]. Toxicology, 2021, 463: 152971.
[64] Ananthula S, Krishnaveni SK, Cardone M, et al.Development of mouse models with restricted HLA-B *57:01 presentation for the study of flucloxacillin-driven T-cell activation and tolerance in liver injury[J]. J Allergy Clin Immunol, 2023, 152(2): 486-499.
[65] Guo Y, Fan Y, Qiu J, et al.Polymorphisms in CTLA4 influence incidence of drug-induced liver injury after renal transplantation in Chinese recipients[J]. PLoS One, 2012, 7(12): e51723.
[66] Aithal GP, Ramsay L, Daly AK, et al.Hepatic adducts, circulating antibodies, and cytokine polymorphisms in patients with diclofenac hepatotoxicity[J]. Hepatology, 2004, 39(5): 1430-1440.
[67] Pachkoria K, Lucena MI, Crespo E, et al.Analysis of IL-10, IL-4 and TNF-alpha polymorphisms in drug-induced liver injury (DILI) and its outcome[J]. J Hepatol, 2008, 49(1): 107-114.
[68] Li Y, Tang H, Qi H, et al.rs1800796 of the IL6 gene is associated with increased risk for anti-tuberculosis drug-induced hepatotoxicity in Chinese Han children[J]. Tuberculosis (Edinb), 2018, 111: 71-77.
[69] Carr DF, Alfirevic A, Tugwood JD, et al.Molecular and genetic association of interleukin-6 in tacrine-induced hepatotoxicity[J]. Pharmacogenet Genomics, 2007, 17(11): 961-972.
[70] Kim SH, Kim SH, Yoon HJ, et al.TNF-alpha genetic polymorphism -308G/A and antituberculosis drug-induced hepatitis[J]. Liver Int, 2012, 32(5): 809-814.
[71] Liang X, Zhang J, Zhu Y, et al.Specific genetic polymorphisms of IL10-592 AA and IL10-819 TT genotypes lead to the key role for inducing docetaxel-induced liver injury in breast cancer patients[J]. Clin Transl Oncol, 2013, 15(4): 331-334.
[72] Mallal S, Phillips E, Carosi G, et al.HLA-B*5701 screening for hypersensitivity to abacavir[J]. N Engl J Med, 2008, 358(6): 568-579.
[73] Alfirevic A, Pirmohamed M.Predictive genetic testing for drug-induced liver injury: considerations of clinical utility[J]. Clin Pharmacol Ther, 2012, 92(3): 376-380.
[74] Aithal GP.Pharmacogenetic testing in idiosyncratic drug-induced liver injury: current role in clinical practice[J]. Liver Int, 2015, 35(7): 1801-1808.
[75] Swen JJ, van der Wouden CH, Manson LE, et al. A 12-gene pharmacogenetic panel to prevent adverse drug reactions: an open-label, multicentre, controlled, cluster-randomised crossover implementation study[J]. Lancet, 2023, 401(10374): 347-356.
[76] Stephens C, Andrade RJ.Genetic predisposition to drug-induced liver injury[J]. Clin Liver Dis, 2020, 24(1): 11-23.
[77] Stephens C, Lucena MI, Andrade RJ.Genetic risk factors in the development of idiosyncratic drug-induced liver injury[J]. Expert Opin Drug Metab Toxicol, 2021, 17(2): 153-169.
[78] Kullak-ublick GA, Andrade RJ, Merz M, et al. Drug-induced liver injury: recent advances in diagnosis and risk assessment[J]. Gut, 2017, 66(6): 1154-1164.
[79] Ariyoshi N, Iga Y, Hirata K, et al.Enhanced susceptibility of HLA-mediated ticlopidine-induced idiosyncratic hepatotoxicity by CYP2B6 polymorphism in Japanese[J]. Drug Metab Pharmacokinet, 2010, 25(3): 298-306.
[80] Su SC, Chen CB, Chang WC, et al.HLA Alleles and CYP2C9*3 as Predictors of Phenytoin Hypersensitivity in East Asians[J]. Clin Pharmacol Ther, 2019, 105(2): 476-485.
[81] Chanhom N, Jittikoon J, Wattanapokayakit S, et al.The association of HLA-B*35 and GSTT1 genotypes and hepatotoxicity in Thai people living with HIV[J]. J Pers Med, 2022, 12(6): 940.