Advertisement

Clinical features, outcomes, and HLA risk factors associated with nitrofurantoin-induced liver injury

Published:September 21, 2022DOI:https://doi.org/10.1016/j.jhep.2022.09.010

      Highlights

      • We identified 78 high-confidence cases of NTF-DILI in US DILIN studies from 2004-2020.
      • Liver injury could occur following, short, intermediate and long drug exposures.
      • Long-exposure NTF-DILI cases had greater frequency of AST > ALT, ANA or SMA positivity, and corticosteroid use.
      • No one in the short-exposure group died or underwent transplantation compared to 12% from the other groups combined.
      • There was a significant association between NTF-DILI and HLA-DRB1∗11:04

      Background & Aims

      Nitrofurantoin (NTF) is widely used for the treatment (short-term) and prevention (long-term) of urinary tract infections. We aimed to describe the clinical characteristics, outcomes, and HLA risk factors for NTF-induced liver injury (NTF-DILI) among individuals enrolled in the Drug Induced Liver Injury Network (DILIN).

      Methods

      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).

      Results

      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).

      Conclusion

      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.

      Impact and implications

      Nitrofurantoin is a recognized cause of drug-induced liver injury (DILI). In this study consisting of a large cohort of well-phenotyped individuals with nitrofurantoin-induced liver injury, two distinct patterns of liver injury were identified: liver injury associated with short-term exposure, which is generally self-limiting, and liver injury associated with long-term exposure, which can lead to advanced fibrosis, cirrhosis and liver failure. HLA DRB1∗11:04 is a risk factor for liver injury due to long-term nitrofurantoin exposure. Our findings are important for regulators as well as physicians prescribing and pharmacists dispensing nitrofurantoin.

      Graphical abstract

      Keywords

      Linked Article

      • Drug-induced liver injury due to nitrofurantoin: similar clinical features, but different HLA risk alleles in an independent cohort
        Journal of Hepatology
        • Preview
          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.1 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.
        • Full-Text
        • PDF
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of Hepatology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Nitrofurantoin
        LiverTox: clinical and research information on drug-induced liver injury.
        ([Internet]) National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda (MD)2012 (Nitrofurantoin. [Updated 2020 May 1]. Available from:)
      1. Kane SP. Nitrofurantoin, ClinCalc DrugStats Database, Version 2021.10. ClinCalc: https://clincalc.com/DrugStats/Drugs/Nitrofurantoin. Updated September 15, 2021. Accessed December 27, 2021.

        • Chalasani N.
        • Bonkovsky H.L.
        • Fontana R.J.
        • Lee W.
        • Stolz A.
        • Talwalkar J.
        • et al.
        Features and outcomes of 899 patients with drug-induced liver injury: the DILIN prospective study.
        Gastroenterology. 2015 Jun; 148: 1340-1352
        • Reuben A.
        • Koch D.G.
        • Lee W.M.
        • The Acute Liver Failure Study Group
        Drug induced acute liver failure: results of a U.S. multicenter prospective study.
        Hepatology. 2010; 52: 2065-2076
        • Ghabril M.
        • Ma J.
        • Patidar K.R.
        • Nephew L.
        • Desai A.P.
        • Orman E.
        • et al.
        Trends in liver transplant waitlisting and outcomes for drug-induced liver injury in the United States.
        Liver Transplant. 2022; 28: 169-179
        • Stricker B.H.
        • Blok A.P.
        • Claas F.H.
        • Van Parys G.E.
        • Desmet V.J.
        Hepatic injury associated with use of nitrofurans: a clinicopathological study of 52 reported cases.
        Hepatology. 1988; 8: 599-606
        • Holmberg L.
        • Boman G.
        • Böttiger L.E.
        • Eriksson B.
        • Spross R.
        • Wessling A.
        Adverse reactions to nitrofurantoin. Analysis of 921 reports.
        Am J Med. 1980; 69: 733-738
        • Friis H.
        • Andreasen P.B.
        Drug-induced hepatic injury: an analysis of 1100 cases reported to the Danish Committee on Adverse Drug Reactions between 1978 and 1987.
        J Intern Med. 1992; 232: 133-138
        • Pillans P.I.
        Drug associated hepatic reactions in New Zealand: 21 years’ experience.
        N Z Med J. 1996; 109: 315-319
        • Dam-Larsen S.
        • Kromann-Andersen H.
        Hepatic toxicity of nitrofurantoin. Cases reported to the center for monitoring adverse drug reactions 1968-1998. Danish.
        Ugeskr Laeger. 1999; 161: 6650-6652
        • Daly A.K.
        • Donaldson P.T.
        • Bhatnagar P.
        • Shen Y.
        • Pe’er I.
        • Floratos A.
        • et al.
        HLA-B-∗5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin.
        Nat Genet. 2009; 41: 816-819
        • Lucena M.I.
        • Molokhia M.
        • Shen Y.
        • Urban T.J.
        • Aithal G.P.
        • Andrade A.J.
        • et al.
        Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles.
        Gastroenterology. 2011; 141: 338-347
        • Fontana R.J.
        • Cirulli E.T.
        • Gu J.
        • Kleiner D.
        • Ostrov D.
        • Phillips E.
        • et al.
        The role of HLA-A∗33:01 in patients with cholestatic hepatitis attributed to terbinafine.
        J Hepatol. 2018; 69: 1317-1325
        • Li Y.J.
        • Phillips E.J.
        • Dellinger A.
        • Nicoletti P.
        • Schutte R.
        • Li D.
        • et al.
        Human leukocyte antigen B∗14:01 and B∗35:01 are associated with trimethoprim-sulfamethoxazole induced liver injury.
        Hepatology. 2021; 73: 268-281
        • Hatoff D.E.
        • Cohen M.
        • Schweigert B.F.
        • Talbert W.M.
        Nitrofurantoin: another cause of drug-induced chronic active hepatitis? A report of a patient with HLA-B8 antigen.
        Am J Med. 1979; 67: 117-121
        • De Boer Y.S.
        • Kosinski A.S.
        • Urban T.J.
        • Zhao Z.
        • Long N.
        • Chalasani N.
        • et al.
        Features of autoimmune hepatitis in patients with drug-induced liver injury.
        Clin Gastroenterol Hepatol. 2017; 15: 103-112
        • Fontana R.J.
        • Watkins P.B.
        • Bonkovsky H.L.
        • et al.
        Drug-Induced Liver Injury Network (DILIN) prospective study: rationale, design and conduct.
        Drug Saf. 2009; 32: 55-68
        • Chalasani N.
        • Fontana R.J.
        • Bonkovsky H.L.
        • Chalasani N.
        • Davern T.
        • Serrano J.
        • et al.
        Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States.
        Gastroenterology. 2008; 135 (1934 e1-4): 1924-1934
        • Cirulli E.T.
        • Nicoletti P.
        • Abramson K.
        • Andrade R.J.
        • Bjornsson E.S.
        • Chalasani N.
        • et al.
        A missense variant in PTPN22 is a risk factor for drug-induced liver injury.
        Gastroenterology. 2019; 156: 1707-17016 e2
        • 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 (PMCID: PMC3772955): 192-200
        • Price A.L.
        • Patterson N.J.
        • Plenge R.M.
        • Weinblatt M.E.
        • Shadick N.A.
        • Reich D.
        Principal components analysis corrects for stratification in genome-wide association studies.
        Nat Genet. 2006; 38: 904-909
        • Nicoletti P.
        • Innocenti F.
        • Etheridge A.
        • Chalasani N.P.
        • Fontana R.J.
        • Li Y.-J.
        • et al.
        Discovery of ERAP2 gene expression as a risk factor for drug-induced liver injury due to amoxicillin-clavulanic acid.
        Hepatology. 2019; 70 (Abstract): 137A-138A
        • Storey J.D.
        • Bass A.J.
        • Dabney A.
        • Robinson D.
        qvalue: Q-value estimation for false discovery rate control.
        (R package version 2.28.0)2022
        • Hayashi P.H.
        • Rockey D.
        • Fontana R.J.
        • Tillmann H.L.
        • Kaplowitz N.
        • Barnhart H.
        • et al.
        Death and liver transplantation within two years of onset of drug-induced liver injury.
        Hepatology. 2017; 66: 1275-1285
        • Hoofnagle J.H.
        • Bonkovsky H.L.
        • Phillips E.J.
        • Li Y.J.
        • Ahmad J.
        • Barnhart H.
        • et al.
        HLA-B∗35:01 and green tea induced liver injury.
        Hepatology. 2021; 73: 2484-2493
      2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020064s019lbl.pdf (Accessed on May/8/2022).

      3. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/016620s068lbl.pdf (Accessed on May/8/2022).

      4. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/009175s037lbl.pdf (Accessed on May/8/2022).

        • Pedala R.L.
        • Shihadeh K.C.
        • Knepper B.C.
        • Haas M.K.
        • Burman W.J.
        • Jenkins T.C.
        Preferential use of nitrofurantoin over fluoroquinolones for acute uncomplicated cystitis and outpatient Escherichia coli resistance in an integrated health care system.
        Infect Control Hosp Epidemiol. 2017; 38: 461-468
        • Bjornsson E.S.
        • Medina-Caliz I.
        • Andrade R.J.
        • Lucena M.I.
        Setting up criteria for drug-induced autoimmune-like hepatitis through a systematic analysis of published reports.
        Hepatol Commun. 2022; 6 (8): 1895-1909