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

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

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.

Informations de copyright

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

Déclaration de conflit d'intérêts

Conflict of interest Dr. Chalasani has ongoing paid consulting activities (or had in preceding 12 months) with AbbVie, Madrigal, Foresite labs, Galectin, Zydus, Boehringer-Ingelheim, Lilly and Altimmune. He has grant support from Exact Sciences and DSM. These activities are not directly or significantly related to this paper. Dr. Robert Fontana reports ongoing research support from Abbvie and Gilead but not related to current study. Dr. Herbert L Bonkovsky reports recent (in preceding 12 months) or ongoing paid consulting activities with Alnylam Pharma, Disc Medicine, Protagonist Pharma, Recordati Rare Chemicals. He serves as PI for sponsored clinical research awarded to Wake Forest Baptist Medical Center from Alnylam, Gilead Sciences, Genkyotex SA, Mitsubishi-Tanabe, NA. These activities are not directly or significantly related to this paper. Dr. Nicoletti is an employee of Sema 4. She also reports ongoing piad consulting activities with Chieso Farmaceutici S.p.A and Audentes Therapeutics, but these activities are not directly or significantly related to this paper. Drs. Barnhart, Navarro, Kleiner, Hoofnagle, Phillips, Dellinger, Gu, Tae-Hwi Schwantes-An, and Lammert have no conflicts of interests to disclose. Please refer to the accompanying ICMJE disclosure forms for further details.