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.

中文翻译：

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呋喃妥因所致肝损伤相关的临床特征、结果和 HLA 危险因素

背景与目标

呋喃妥因 (NTF) 广泛用于治疗（短期）和预防（长期）尿路感染。我们的目的是描述加入药物性肝损伤网络 (DILIN) 的个体中 NTF 性肝损伤 (NTF-DILI) 的临床特征、结果和 HLA 危险因素。

方法

2004 年至 2020 年间，78 名患有明确、极有可能或可能患有 NTF-DILI 的个体被纳入 DILIN 研究。对 NTF-DILI 和三个对照组之间的 HLA 等位基因进行比较：人群（n = 14,001）、特发性自身免疫性肝炎（n = 231）和非 NTF DILI（n = 661）。

结果

肝损伤 69% 为肝细胞性损伤，55% 为黄疸。AST > ALT 在 44 例长期暴露（≥1 年）NTF-DILI 病例中比 18 例短时间（≤7 天）和 16 例中度（>7 至 <365 天）暴露病例更常见（73% vs. 33 %） % vs. 50%，分别为p  = 0.018），ANA 或 SMA 阳性率（分别为 91% vs. 44% vs. 50%，p <0.001）以及皮质类固醇的使用（61% vs. 27% vs.分别为 44%，p = 0.06）。在长期 NTF-DILI 中，38% 存在桥接纤维化、结节或肝硬化，或肝硬化的临床和影像学证据，20% 存在大块或次大块坏死。短期暴露组中没有人死亡或接受移植，而其他组中有 7 名患者（12%）死亡或接受移植。协变量调整后，与人群对照相比，NTF-DILI 中HLA-DRB1*11:04的出现频率显着更高（比值比 [OR] 4.29，p = 1.15 × 10 ^-4）、特发性自身免疫性肝炎（OR 11.77，p = 7.76） × 10 ⁻⁵）和非 NTF DILI（OR 3.34，p = 0.003）。

结论

NTF-DILI 可导致实质坏死、桥接纤维化、肝硬化和死亡或肝移植，尤其是长期暴露，并且与HLA-DRB1*11:04相关。为了减轻与 NTF 相关的严重肝损伤，监管机构应修改处方信息并考虑其他缓解策略。

影响和影响

呋喃妥因是药物性肝损伤 (DILI) 的公认原因。在这项由一大群表型良好的呋喃妥因诱导肝损伤个体组成的研究中，确定了两种不同的肝损伤模式：与短期暴露相关的肝损伤，通常是自限性的，以及与呋喃妥因诱导的肝损伤相关的肝损伤。长期接触，可导致晚期纤维化、肝硬化和肝衰竭。HLA DRB1*11:04是长期接触呋喃妥因导致肝损伤的危险因素。我们的研究结果对于监管机构以及开具处方的呋喃妥因的医生和配药呋喃妥因的药剂师都很重要。