免疫检查点抑制剂致肝损伤的临床病例分析

Clinical case analysis of liver injury induced by immune checkpoint inhibitors

目的探讨使用免疫检查点抑制剂(ICI)导致肿瘤患者肝损伤的发生情况及其临床特征。方法收集2017年1月至2022年12月在北京友谊医院住院期间使用ICI且用药前肝功能正常的肿瘤患者病例资料,从中筛选出ICI相关肝损伤病例。提取ICI相关肝损伤患者基本信息、ICI种类及用法用量、合并用药、用药前后的肝功能、干预措施及其转归等信息,对ICI相关肝损伤的临床特征进行描述性分析。结果在设定时段内共有155例实体肿瘤患者使用ICI治疗,其中15例(9.7%)被诊断为ICI相关肝损伤。15例患者中,男性6例,女性9例,中位年龄59(41,76)岁。可疑致肝损伤药物中卡瑞利珠单抗5例,舒格利单抗、斯鲁利单抗、特瑞普利单抗、信迪利单抗各2例,派安普利单抗、卡度尼利单抗各1例。15例患者均联合应用了传统化疗药物、受体酪氨酸激酶抑制剂和/或其他ICI。15例患者用药至发生肝损伤的中位时间为22(4~64)d,其中9例患者发生在ICI治疗的第1个周期后。丙氨酸转氨酶中位峰值为157(15~508)U/L,天冬氨酸转氨酶中位峰值为131(77~696)U/L;3例患者总胆红素大于参考值上限2倍。临床分型为肝细胞型者6例,胆汁淤积型5例,混合型3例,因缺少数据未分型1例。15例患者中肝损伤严重程度为2级者8例,3级者7例;9例在肝损伤发生后停用了可疑药物,6例未停药。停药和未停药者中分别有7和5例在1~4个月后肝功能恢复或基本恢复正常;3例随访2~9个月,肝功能未恢复正常。结论ICI相关肝损伤多发生在ICI治疗第1个周期后(1~2个月内),严重程度多为2级或3级,药物性肝损伤的3种临床类型(肝细胞型、胆汁淤积型和混合型)均可见,发生肝损伤后及时停药和/或治疗,多数预后良好。

Objective To explore the occurrence and clinical characteristics of liver injury caused by immune checkpoint inhibitors(ICI)in cancer patients.Methods Medical records of cancer patients with normal liver function who used ICI during hospitalization in Beijing Friendship Hospital from January 2017 to December 2022 were collected,and those with liver injury related to ICI were screened out.The basic information of patients with ICI‑related liver injury,treatment regime of ICI,concomitant medication,liver function before and after medication,intervention measures and outcomes were extracted,and the clinical characteristics of ICI‑related liver injury were analyzed descriptively.Results A total of 155 patients with solid tumors were treated with ICI within the set time,of which 15(9.7%)were diagnosed with ICI‑related liver injury.Among the 15 patients,there were 6 males and 9 females,with a median age of 59(41,76)years.The suspected drug causing liver injury was camrelizumab in 5 patients,sugemalimab in 2 patients,serplulimab in 2 patients,toripalimab in 2 patients,sintilimab in 2 patients,penpulimab in 1 patient,and cadonilimab in 1 patient.All 15 patients received combined medication,such as traditional chemotherapy drugs,receptor tyrosine kinases inhibitors,and/or other ICIs.The median time from suspected ICI administration to liver injury in 15 patients was 22(4‑64)days,and the liver injury occurred after the first cycle of ICI treatment in 9 patients.The medians of peak value of alanine aminotransferase and aspar‑tate aminotransferase were 157(15‑508)U/L and 131(77‑696)U/L,respectively;the total bilirubin was more than 2 times of the upper limit of normal in 3 patients.The liver injury was classified as hepatocellular type in 6 patients,cholestasis type in 5 patients,and mixed type in 3 patients;the type was unable to be determined due to lack of data in 1 patient.Among the 15 patients,8 had liver injury of grade 2 and 7 had liver injury of grade 3;the suspected medication were discontinued after liver injury occurrence in 9 patients and did not discontinue in 6 patients.Seven and 5 patients recovered or basically had normal liver function after 1‑4 months,respectively among those who stopped and did not stop ICI;the liver function did not return to normal in the other 3 patients at 2 to 9 months of follow‑up.Conclusions ICI‑related liver injury usually occurs after the first cycle of ICI treatment(within 1‑2 months of medication),and the severity is mostly grade 2 or 3.The 3 clinical types of drug‑induced liver injury(hepatocellular type,cholestatic type,and mixed type)are clinically visible.After the occurrence of liver injury,most patients have a good prognosis through timely discontinuation and/or treatments.