Unidad de Gestión Clínica del Aparato Digestivo, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, CIBERehd, Málaga, Spain.
Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, Arkansas, USA.
Liver Int. 2019 Feb;39(2):401-410. doi: 10.1111/liv.13952. Epub 2018 Sep 29.
BACKGROUND & AIMS: Most patients with drug-induced liver injury (DILI) manifest clinical symptoms while on therapy, while some patients manifest days or weeks after drug cessation (delayed onset). This challenges DILI causality assessment and diagnosis. Factors contributing to the delayed onset phenotype are currently unknown. We explored factors contributing to delayed onset of DILI by analysing culprit drug properties, host factors and their interactions in a large patient population from the Spanish DILI Registry.
Clinical information from 388 patients (69 presented delayed onset) and drug properties of 43 causative drugs (45 active ingredients) were analysed. A two-tier regression-based model was used to assess host/drug interactions affecting the probability of delayed onset.
Antibacterial and anti-inflammatory drugs accounted for the delayed onset cases. Drug property of <50% hepatic metabolism (odds ratio [OR] 11.06, 95% confidence interval [95% CI]: 4.4-32.2, P = 0.0003), daily dose ≥1000 mg (OR: 2.77, 95% CI: 1.3-6.1, P = 0.0063) and the absence of pre-existing conditions in a patient (OR: 2.55, 95% CI: 1.3-4.9, P = 0.0043) were independently associated with delayed onset. The findings were consistent when externally validated using Latin American DILI Network cases (N = 131). Likewise, drug properties of mitochondrial liability and Pauling electronegativity were associated with delayed onset, but dependent on specific host factors such as age, sex and pre-existing cardiac diseases.
This study demonstrated that delayed onset, a specific DILI phenotype, is explained by complex interactions among drug properties and host factors and provided mechanistic hypotheses for future studies. These findings can help improve the diagnostic capability and causality assessment.
大多数药物性肝损伤（DILI）患者在治疗过程中出现临床症状，而有些患者在停药后数天或数周（迟发性）出现症状。这对 DILI 因果关系评估和诊断提出了挑战。目前尚不清楚导致迟发性发病表型的因素。我们通过分析西班牙 DILI 注册中心的大量患者人群中的致病药物特性、宿主因素及其相互作用，探讨了导致 DILI 迟发性发病的因素。
分析了 388 名患者（69 名患者出现迟发性）的临床信息和 43 种致病药物（45 种活性成分）的药物特性。采用基于两阶段回归的模型评估影响迟发性发病概率的宿主/药物相互作用。
抗菌和抗炎药物导致了迟发性发病病例。药物<50%肝脏代谢（比值比 [OR] 11.06，95%置信区间 [95%CI]：4.4-32.2，P=0.0003）、每日剂量≥1000mg（OR：2.77，95%CI：1.3-6.1，P=0.0063）和患者无预先存在的疾病（OR：2.55，95%CI：1.3-4.9，P=0.0043）与迟发性发病独立相关。使用拉丁美洲 DILI 网络病例（N=131）进行外部验证时，结果一致。同样，线粒体易感性和鲍林电负性的药物特性与迟发性发病相关，但取决于年龄、性别和预先存在的心脏病等特定宿主因素。
本研究表明，一种特定的 DILI 表型——迟发性发病，是由药物特性和宿主因素之间的复杂相互作用解释的，并为未来的研究提供了机制假说。这些发现有助于提高诊断能力和因果关系评估。
