目的:程序性细胞死亡受体(配体)-1抑制剂(PD-(L)1),作为首选的免疫疗法,已经在中国大陆广泛使用,并且已经报道了药物性肝损伤(DILI)。该研究旨在探讨免疫治疗相关DILI的临床特征或危险因素。
方法:对2020年1月至2021年7月接受PD-(L)1抑制剂治疗的患者进行回顾性分析。DILI的可能性由Roussel-Uclaf因果关系评估判定。
结果:本研究共纳入1175例患者,89例患者(7.6%)发展为DILI,其中12例(13.5%)进展为急性肝功能衰竭(ALF),3例(3.4%)死亡。在DILI人口中,与肝细胞和混合模式相比,56(62.9%)具有胆汁淤积模式,并表现出延长的治疗过程和持续时间。肝细胞癌(HCC),乙型肝炎病毒(HBV)和碱性磷酸酶(ALP)异常基线的DILI风险增加2.1倍(95%置信区间[CI],1.231-3.621),1.9倍[95%CI,1.123-3.325]和2.1倍[95%CI,1.317-3.508],分别。终末期肝病(MELD)评分模型的c统计量为0.894(95%CI,0.778-1.000),敏感性为67%,不良结果的特异性为95%。COX分析显示MELD≥18是免疫治疗相关ALF或死亡的预测因素。
结论:PD-(L)1抑制剂相关的肝损伤主要表现为胆汁淤积型,与肝细胞和混合模式相比,皮质类固醇治疗效果最小。在免疫检查点抑制剂(ICI)相关的DILI中,肝损伤时的MELD评分≥18在预测ALF或死亡方面表现最佳。
OBJECTIVE: Programmed cell death receptor (ligand)-1 inhibitors (PD-(L)1), as the preferred immunotherapy, have been widely used in the Chinese mainland and drug-induced liver injury (DILI) has been reported. The
study aimed to investigate the clinical features or risk factors for immunotherapy-related DILI.
METHODS: Patients who received PD-(L)1 inhibitors from January 2020 to July 2021 were retrospectively reviewed. The likelihood of DILI was adjudicated by the Roussel-Uclaf causality assessment.
RESULTS: A total of 1175 patients were included in the
study and 89 patients (7.6%) developed DILI, of which 12 (13.5%) progressed to acute liver failure (ALF) and three (3.4%) died. Among the DILI population, 56 (62.9%) had a cholestatic pattern and exhibited a prolonged treatment course and duration for resolution compared to the hepatocellular and mixed patterns. Hepatocellular carcinoma (HCC), hepatitis B virus (HBV) and abnormal baseline of alkaline phosphatase (ALP) had increased risks of DILI by 2.1-fold (95% confidence interval [CI], 1.231-3.621), 1.9-fold [95% CI, 1.123-3.325] and 2.1-fold [95% CI, 1.317-3.508], respectively. The model for end-stage liver disease (MELD) score had a c-statistic of 0.894 (95% CI, 0.778-1.000) with a sensitivity of 67% and a specificity of 95% for poor outcomes. COX analysis showed that the MELD ≥ 18 was predictive of immunotherapy-related ALF or death.
CONCLUSIONS: PD-(L)1 inhibitor-related liver injury manifests primarily as a cholestatic pattern, on which corticosteroid treatment has minimal effect compared to hepatocellular and mixed patterns. MELD score ≥ 18 at the time of liver injury performed best in the prediction of ALF or death in immune checkpoint inhibitor (ICI)-related DILI.