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Research Article| Volume 78, ISSUE 2, P293-300, February 2023

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

      Figure thumbnail ga1
      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
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          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.
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      Article info

      Publication history

      Published online: September 21, 2022
      Accepted: September 13, 2022
      Received in revised form: September 8, 2022
      Received: July 21, 2022

      Footnotes

      Author names in bold designate shared co-first authorship

      Identification

      DOI: https://doi.org/10.1016/j.jhep.2022.09.010

      Copyright

      © 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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