Susceptibility to Amoxicillin-Clavulanate-Induced Liver Injury Is Influenced by Multiple HLA Class I and II Alleles

doi:10.1053/j.gastro.2011.04.001

Gastroenterology

Volume 141, Issue 1, July 2011, Pages 338-347

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https://doi.org/10.1053/j.gastro.2011.04.001 Get rights and content

Background & Aims

Drug-induced liver injury (DILI), especially from antimicrobial agents, is an important cause of serious liver disease. Amoxicillin-clavulanate (AC) is a leading cause of idiosyncratic DILI, but little is understood about genetic susceptibility to this adverse reaction.

Methods

We performed a genome-wide association study using 822,927 single nucleotide polymorphism (SNP) markers from 201 White European and US cases of DILI following AC administration (AC-DILI) and 532 population controls, matched for genetic background.

Results

AC-DILI was associated with many loci in the major histocompatibility complex. The strongest effect was with an HLA class II SNP (rs9274407, P = 4.8 × 10⁻¹⁴), which correlated with rs3135388, a tag SNP of HLA-DRB1*1501-DQB1*0602 that was previously associated with AC-DILI. Conditioned on rs3135388, rs9274407 is still significant (P = 1.1 × 10⁻⁴). An independent association was observed in the class I region (rs2523822, P = 1.8 × 10⁻¹⁰), related to HLA-A*0201. The most significant class I and II SNPs showed statistical interaction (P = .0015). High-resolution HLA genotyping (177 cases and 219 controls) confirmed associations of HLA-A*0201 (P = 2 × 10⁻⁶) and HLA-DQB1*0602 (P = 5 × 10⁻¹⁰) and their interaction (P = .005). Additional, population-dependent effects were observed in HLA alleles with nominal significance. In an analysis of autoimmune-related genes, rs2476601 in the gene PTPN22 was associated (P = 1.3 × 10⁻⁴).

Conclusions

Class I and II HLA genotypes affect susceptibility to AC-DILI, indicating the importance of the adaptive immune response in pathogenesis. The HLA genotypes identified will be useful in studies of the pathogenesis of AC-DILI but have limited utility as predictive or diagnostic biomarkers because of the low positive predictive values.

Section snippets

Case Recruitment

Cases (n = 211) were recruited in 4 separate studies (DILIGEN,¹⁶ Spanish DILI Registry,⁶ Drug-induced liver injury network [DILIN],⁷ and EUDRAGENE¹⁷) that used similar inclusion criteria. All participants provided written informed consent, and each study had been approved by the appropriate ethical review boards.

Clinical Characteristics of the Cases

Clinical details of the 201 cases included in this study are summarized in Table 1. As in previous studies of AC-DILI, there were more male than female cases. The average age at onset was 61 ± 14 years. Four cases underwent liver transplantation. Most cases (70%) were characterized as cholestatic or mixed at presentation, and 88% had bilirubin levels >2.4 mg/dL. Most causality scores (93%) suggested that DILI was either probably or highly likely because of AC. There were some significant

Discussion

This study was accomplished through an international cooperation to assemble a considerably larger and more diverse AC-DILI patient collection than previous published studies on the subject.11, 12, 13 This resulted in the most powerful and comprehensive investigation into genetic risk factors for AC-DILI and the largest GWA for any rare serious adverse event conducted to date. We confirmed the previous associations of HLA-DRB1*1501 and DQB1*0602 with DILI susceptibility, and our larger sample

Acknowledgments

Contributors to sample collection via Spanish DILI network, EUDRAGENE, DILIN, and DILIGEN are listed in the Appendix.

Drs Lucena, Molokhia, Shen, and Daly contributed equally to this manuscript.

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Seventy-eight individuals with definite, highly likely, or probable NTF-DILI were enrolled into DILIN studies between 2004–2020. HLA alleles were compared between NTF-DILI and three control groups: population (n = 14,001), idiopathic autoimmune hepatitis (n = 231), and non-NTF DILI (n = 661).
Liver injury was hepatocellular in 69% and icteric in 55%. AST > ALT was more common in the 44 long-exposure (≥1 year) NTF-DILI cases than in the 18 short (≤7 days) and 16 intermediate (>7 to <365 days) exposure cases (73% vs. 33% vs. 50%, respectively, p = 0.018), as was ANA or SMA positivity (91% vs. 44% vs. 50%, respectively, p <0.001), and corticosteroid use (61% vs. 27% vs. 44%, respectively, p = 0.06). In long-term NTF-DILI, bridging fibrosis, nodularity or cirrhosis, or clinical and imaging evidence for cirrhosis were present in 38%, with massive or sub-massive necrosis in 20%. No one in the short-term exposure group died or underwent transplantation, whereas 7 (12%) patients from the other groups died or underwent transplantation. After covariate adjustments, HLA-DRB1∗11:04 was significantly more frequent in NTF-DILI compared to population controls (odds ratio [OR] 4.29, p = 1.15 × 10⁻⁴), idiopathic autoimmune hepatitis (OR 11.77, p = 7.76 × 10⁻⁵), and non-NTF DILI (OR 3.34, p = 0.003).
NTF-DILI can result in parenchymal necrosis, bridging fibrosis, cirrhosis, and death or liver transplantation, especially with long-term exposure, and is associated with HLA-DRB1∗11:04. To mitigate against serious liver injury associated with NTF, regulators should revise the prescribing information and consider other mitigation strategies.
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Drug-induced liver injury (DILI) is a potentially serious clinical condition that remains a major problem for patients, physicians and those involved in the development of new drugs. Population and hospital-based studies have reported incidences of DILI varying from 1.4 to 19.1/100.000. Overall, females have a 1.5- to 1.7-fold greater risk of developing adverse drug reactions and the female/male ratio increases after the age of 49 years, suggesting a clear susceptibility of DILI after menopause. Sex differences in pharmacokinetics and pharmacodynamic, sex-specific hormonal effects or interaction with signalling molecules that can influence drug efficacy and safety and differences in abnormal immune response following drug exposure are the main probable causes of the higher vulnerability observed among female patients. A novel phenotype of autoimmune-mediated DILI following the use of check-point inhibitors in oncology and haematology has been recently described. Finally, there have been increasing reports of DILI associated with use of herbal and dietary supplements that is more frequently reported in women.
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: Conflicts of interest The authors disclose the following: Dr Fontana acted as a consultant to GlaxoSmithKline. Dr Nelson is an employee of GlaxoSmith Kline. The remaining authors disclose no conflicts.

: Funding The genome-wide association study and HLA genotyping was funded by the International Serious Adverse Events Consortium with support from Abbott, Daiichi-Sankyo, GlaxoSmithKline, Johnson & Johnson, Novartis, Pfizer, Roche, Sanofi-Aventis, Takeda, Wellcome Trust, and Wyeth. The DILIGEN sample collection was partly funded by the UK Department of Health (ref. PHGX10A) and by UK NIHR funding to the Nottingham Digestive Diseases Centre. The DILIN network is structured as a U01 cooperative agreement with funds provided by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) under grants 2U01-DK065176-06 (Duke), 2U01-DK065201-06 (UNC), 2U01-DK065184-06 (Michigan), 2U01-DK065211-06 (Indiana), 5U01DK065193-04 (UConn), 5U01-DK065238-08 (UCSF/CPMC). Additional funding is provided by CTSA grants UL1 RR025761 (Indiana), UL1 RR025747 (UNC), and UL1 UL1 RR024986 (UMich). The EUDRAGENE collaboration has received support from the EC 5th Framework program (QLRI-CT-2002-02757) and the SAEC. The UK NIHR postdoctoral award funded Mariam Molokhia. The Spanish DILI Registry is partly funded by the Spanish Medicine Agency and has received support from SAEC and Boehringer-Ingelheim, Barcelona, Spain. CIBERehd and RETIC are funded by Instituto de Salud Carlos III. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Original ResearchBasic and Translational-LiverSusceptibility to Amoxicillin-Clavulanate-Induced Liver Injury Is Influenced by Multiple HLA Class I and II Alleles

Background & Aims

Methods

Results

Conclusions

Section snippets

Case Recruitment

Clinical Characteristics of the Cases

Discussion

Acknowledgments

Hepatology

Gastroenterology

Gastroenterology

J Hepatol

J Clin Epidemiol

Am J Hum Genet

Am J Hum Genet

Am J Hum Genet

Am J Hum Genet

Trends Immunol

Lancet

Idiosyncratic drug hepatotoxicity

Nat Rev Drug Discov

Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States

Ann Intern Med

Cholestatic hepatitis due to antibacterial combination of amoxicillin and clavulanic acid (augmentin)

Dig Dis Sci

Acute and clinically relevant drug-induced liver injury: a population based case-control study

Br J Clin Pharmacol

Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States

Gastroenterology

Outcome of acute idiosyncratic drug-induced liver injury: long-term follow-up in a hepatotoxicity registry

Hepatology

Risk of acute liver injury associated with the combination of amoxicillin and clavulanic acid

Arch Intern Med

Acute liver failure due to amoxicillin and amoxicillin/clavulanate

Dig Dis Sci

Original Research
Basic and Translational-Liver
Susceptibility to Amoxicillin-Clavulanate-Induced Liver Injury Is Influenced by Multiple HLA Class I and II Alleles