Advertisement

Drug-induced liver injury due to nitrofurantoin: similar clinical features, but different HLA risk alleles in an independent cohort

  • Ann K. Daly
    Correspondence
    Corresponding author.
    Affiliations
    Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
    Search for articles by this author
  • Einar S. Bjornsson
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine, The National University Hospital of Iceland, Reykjavik, Iceland
    Search for articles by this author
  • M. Isabel Lucena
    Affiliations
    UGC Digestivo y Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga (IBIMA_Plataforma Bionand), Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain and

    Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
    Search for articles by this author
  • Raul J. Andrade
    Affiliations
    UGC Digestivo y Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga (IBIMA_Plataforma Bionand), Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain and

    Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
    Search for articles by this author
  • Guruprasad P. Aithal
    Affiliations
    NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, UK
    Search for articles by this author
Published:November 29, 2022DOI:https://doi.org/10.1016/j.jhep.2022.11.022

      Linked Article

      We read with great interest the recent article on the subject of nitrofurantoin-related drug-induced liver injury (DILI) in the DILIN cohort from Chalasani and colleagues.
      • Chalasani N.
      • Li Y.J.
      • Dellinger A.
      • Navarro V.
      • Bonkovsky H.
      • Fontana R.J.
      • et al.
      Clinical features, outcomes, and HLA risk factors associated with nitrofurantoin-induced liver injury.
      Independently of the DILIN project, projects entitled DILIGEN and iDILIC, involving both retrospective and prospective recruitment of DILI cases outside the USA for study of genetic susceptibility, took place from 2004 to 2014. A total of 26 nitrofurantoin DILI cases from these studies passed expert adjudication and were classified as possible, probable or highly probable based on Roussel Uclaf Causality Assessment Method (RUCAM) causality scores of 3 or higher. These cases were included in a recent genome-wide association study (GWAS) on DILI.
      • Nicoletti P.
      • Aithal G.P.
      • Bjornsson E.S.
      • Andrade R.J.
      • Sawle A.
      • Arrese M.
      • 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.
      The DILIGEN/iDILIC cases were recruited from the United Kingdom (n=21), Netherlands (n=3), Australia (n=1) and South America (n=1). All had white European ethnicity. Interestingly, the clinical features of this cohort were very similar to those described in the recent report
      • Chalasani N.
      • Li Y.J.
      • Dellinger A.
      • Navarro V.
      • Bonkovsky H.
      • Fontana R.J.
      • et al.
      Clinical features, outcomes, and HLA risk factors associated with nitrofurantoin-induced liver injury.
      with 85% of cases female, a mean age of 62 years and the majority of cases showing hepatocellular injury (73%). For RUCAM, 70% had a score of 6 or above which represents probable or highly probable causality. When we divided the cohort on the basis of nitrofurantoin exposure time, 31% had received the drug for <7 days, 31% for 8 to 365 days and 38% for >365 days. This longer exposure group is smaller in our cohort than in the recent DILIN report.
      • Chalasani N.
      • Li Y.J.
      • Dellinger A.
      • Navarro V.
      • Bonkovsky H.
      • Fontana R.J.
      • et al.
      Clinical features, outcomes, and HLA risk factors associated with nitrofurantoin-induced liver injury.
      As previously described in detail, HLA genotype can be imputed from GWAS data with a high level of reliability.
      • Zheng X.
      • Shen J.
      • Cox C.
      • Wakefield J.C.
      • Ehm M.G.
      • Nelson M.R.
      • et al.
      HIBAG--HLA genotype imputation with attribute bagging.
      Imputed HLA genotypes had already been obtained using this approach for all 26 nitrofurantoin cases as part of the larger GWAS.
      • Nicoletti P.
      • Aithal G.P.
      • Bjornsson E.S.
      • Andrade R.J.
      • Sawle A.
      • Arrese M.
      • 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.
      As summarised in Table 1, which shows HLA alleles showing differences between cases and controls with uncorrected p values <0.05, certain HLA alleles were more common among the nitrofurantoin DILI cases compared with population controls. The strongest association was with HLA-A*33:01, which we reported previously to be a risk factor for DILI due to several drugs, particularly terbinafine.
      • Nicoletti P.
      • Aithal G.P.
      • Bjornsson E.S.
      • Andrade R.J.
      • Sawle A.
      • Arrese M.
      • 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.
      The haplotype HLA-DRB1*07:01–HLA-DQA1*02:01–HLA-DQB1*02:02, previously reported by others to be a risk factor for some forms of DILI (e.g. due to lapatinib and asparaginase),
      • Spraggs C.F.
      • Budde L.R.
      • Briley L.P.
      • Bing N.
      • Cox C.J.
      • King K.S.
      • et al.
      HLA-DQA1*02:01 Is a Major Risk Factor for Lapatinib-Induced Hepatotoxicity in Women With Advanced Breast Cancer.
      ,
      • Fernandez C.A.
      • Smith C.
      • Yang W.
      • Daté M.
      • Bashford D.
      • Larsen E.
      • et al.
      HLA-DRB1*07:01 is associated with a higher risk of asparaginase allergies.
      also appears more common in our cohort but none of our nitrofurantoin DILI cases had exposure to other drugs for which this haplotype association had been reported. None of the cases in our cohort were positive for DRB1*11:04, in contrast with the findings of Chalasani et al..
      • Chalasani N.
      • Li Y.J.
      • Dellinger A.
      • Navarro V.
      • Bonkovsky H.
      • Fontana R.J.
      • et al.
      Clinical features, outcomes, and HLA risk factors associated with nitrofurantoin-induced liver injury.
      It is possible that we did not detect this association in our cohort due to a lower incidence of cases with DILI after prolonged nitrofurantoin exposure. However, we did not see a significant increase in frequency of HLA-A*01:01 in our cohort either (OR 1.29 (95% CI 0.66-2.54), p= 0.45), even though this was detected more commonly in patients with short nitrofurantoin exposure in the DILIN cohort.
      • Chalasani N.
      • Li Y.J.
      • Dellinger A.
      • Navarro V.
      • Bonkovsky H.
      • Fontana R.J.
      • et al.
      Clinical features, outcomes, and HLA risk factors associated with nitrofurantoin-induced liver injury.
      Table 1Comparison of imputed HLA allele frequencies in nitrofurantoin DILI cases (n=26) compared with controls.
      AlleleOdds Ratio95% Confidence intervalP value
      HLA-A*33:0110.932.447-48.840.0017
      HLA-DQB1*02:022.4831.231-5.010.0111
      HLA-A*30:025.5631.274-24.290.0225
      HLA-DQA1*02:012.1581.106-4.2080.0240
      HLA-DRB1*07:012.1411.099-4.1710.0253
      HLA-DPB1*16:014.8361.099-21.270.0370
      HLA-C*06:022.2021.047-4.630.0373
      Frequencies in cases were compared with those in 10588 European ancestry controls as described previously.2 Only alleles where the difference between cases and controls shows a p value <0.05 are listed.
      Despite the fact that it is possible to obtain interesting data on genetic risk factors for DILI, especially HLA, using small case cohorts, we believe some caution is needed. In particular, use of replication cohorts is generally recommended in genetic studies.
      • Aslibekyan S.
      • Claas S.A.
      • Arnett D.K.
      To replicate or not to replicate: the case of pharmacogenetic studies: Establishing validity of pharmacogenomic findings: from replication to triangulation.
      Assembly of a larger cohort of nitrofurantoin DILI cases would be useful both in resolving the issue of at risk HLA genotypes and in identifying non-HLA genetic risk factors for this serious and relatively common form of DILI.

      Financial support

      This study is part of the COST Action "CA17112 - Prospective European Drug-Induced Liver Injury Network" supported by COST (European Cooperation in Science and Technology)(www.cost.eu). The genome-wide association study and iDILIC case enrolment and sample collection was funded by the International Serious Adverse Events Consortium. The University of Nottingham sample collection was funded by the National Institute for Health Research (NIHR) Nottingham Digestive Diseases Biomedical Research Unit at the Nottingham University Hospitals NHS Trust and University of Nottingham. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. GPA is the gastrointestinal and liver disorder theme lead for the NIHR Nottingham BRC (Reference no: BRC-1215-20003). The Spanish DILI Registry is partly funded by the Spanish Medicine Agency, Fondo Europeo de Desarrollo Regional - FEDER (FIS PI19_00883, PI 21_01248). CIBERehd is funded by Instituto de Salud Carlos III.

      Authors' contributions

      All authors developed and performed the original study. Ann Daly and Guruprasad Aithal wrote the manuscript in consultation with the other authors with all authors editing and approving the final version.

      Conflicts of interest

      Ann K. Daly, Einar S. Bjornsson, M. Isabel Lucena, Raul J Andrade and Guruprasad P. Aithal do not have any conflicts of interest.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      References

        • Chalasani N.
        • Li Y.J.
        • Dellinger A.
        • Navarro V.
        • Bonkovsky H.
        • Fontana R.J.
        • et al.
        Clinical features, outcomes, and HLA risk factors associated with nitrofurantoin-induced liver injury.
        J Hepatol. 2022; (Sep 21)
        • Nicoletti P.
        • Aithal G.P.
        • Bjornsson E.S.
        • Andrade R.J.
        • Sawle A.
        • Arrese M.
        • 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.
        Gastroenterology. 2017; 152: 1078-1089
        • Zheng X.
        • Shen J.
        • Cox C.
        • Wakefield J.C.
        • Ehm M.G.
        • Nelson M.R.
        • et al.
        HIBAG--HLA genotype imputation with attribute bagging.
        Pharmacogenomics J. 2014; 14: 192-200
        • Spraggs C.F.
        • Budde L.R.
        • Briley L.P.
        • Bing N.
        • Cox C.J.
        • King K.S.
        • et al.
        HLA-DQA1*02:01 Is a Major Risk Factor for Lapatinib-Induced Hepatotoxicity in Women With Advanced Breast Cancer.
        J Clin Oncol. 2011; 29: 667-673
        • Fernandez C.A.
        • Smith C.
        • Yang W.
        • Daté M.
        • Bashford D.
        • Larsen E.
        • et al.
        HLA-DRB1*07:01 is associated with a higher risk of asparaginase allergies.
        Blood. 2014; 124: 1266-1276
        • Aslibekyan S.
        • Claas S.A.
        • Arnett D.K.
        To replicate or not to replicate: the case of pharmacogenetic studies: Establishing validity of pharmacogenomic findings: from replication to triangulation.
        Circ Cardiovasc Genet. 2013; 6: 409-412