免疫检查点抑制剂相关肝损伤临床特征的回顾性分析

Retrospective analysis of clinical characteristics of liver injury related to immune checkpoint inhibitors

目的探讨免疫检查点抑制剂(ICI)导致免疫相关肝损伤(IMLI)患者的临床表现、治疗和转归。方法收集2018年1月至2022年11月青岛大学附属医院肿瘤内科住院的ICI导致IMLI患者,对其基本情况、肿瘤治疗情况、IMLI临床表现、治疗及转归进行描述性统计分析。结果共29例患者纳入分析,男性17例(58.6%),女性12例(41.4%),中位年龄65岁;从使用ICI至发生肝损伤的中位治疗周期为3个,中位时间为78 d。48.3%(14/29)的IMLI患者无明显症状,51.7%(15/29)的有食欲下降、恶心、腹胀、乏力、发热和黄疸等症状,13例(44.8%)同时伴有其他系统免疫相关不良事件。29例IMLI的临床分型为肝细胞型18例(62.1%),胆汁淤积型4例(13.8%),混合型7例(24.1%)。按美国国立癌症研究所通用不良事件术语标准(CTCAE)分级,严重(≥3级)病例占86.2%(25/29);按我国《药物性肝损伤诊治指南》(DILI指南)分级,严重(≥2级)病例占34.5%(10/29)。29例患者在发生IMLI后均暂停ICI治疗,28例使用了糖皮质激素,其中7例联合吗替麦考酚酯和/或人免疫球蛋白、人工肝治疗;22例(75.9%)好转,7例(24.1%)未愈(包括自动出院4例,死亡2例,无法判断1例)。3例患者肝功能好转后重新启用ICI治疗,IMLI均未复发。结论IMLI多发生于ICI治疗后2~3个月,临床类型以肝细胞型最常见,临床症状轻重不一,停用ICI并给予糖皮质激素治疗后大多数患者预后良好。部分患者经权衡利弊在严密监测下可以重启ICI治疗。

Objective To explore the clinical manifestation,treatments,and outcomes of immune checkpoint inhibitor(ICI)‑induced immune‑mediated liver injury(IMLI).Methods The patients with ICI‑related IMLI and hospitalized in the Department of Oncology,the Affiliated Hospital of Qingdao University from January 2018 to November 2022 were collected.The basic information,tumor treatments,clinical mani‑festation,treatments and outcomes of the patients with IMLI were retrospectively analyzed.Results A total of 29 patients were included in the study,including 17 males(58.6%)and 12 females(41.4%),with a median age of 65 years.The median treatment cycle from the use of ICI to the occurrence of liver injury was 3 cycles,and the median time was 78 days.In patients with IMLI,48.3%(14/29)had no obvious symptoms and 51.7%(15/29)had symptoms such as decreased appetite,nausea,abdominal distension,fatigue,fever and jaundice;44.8%(13/29)were accompanied by other immune‑related adverse events.The clinical clas‑sification of IMLI was hepatocellular type in 18 patients(62.1%),cholestasis type in 4 patients(13.8%),and mixed type in 7 patients(24.1%).According to the Common Terminology Criteria for Adverse Events(CTCAE)classification,severe liver injury(≥grade 3)accounted for 86.2%(25/29),while according to the Chinese Diagnosis and Treatment Guideline on Drug‑Induced Liver Injury(DILI guidelines)classification,severe liver injury(≥grade 2)accounted for 34.5%(10/29).All 29 patients discontinued the treatment of ICIs after occurrence of IMLI,and 28 patients were treated with glucocorticoids,7 of which were combined with mycophenolate mofetil and/or human immunoglobulin and artificial liver;22 patients(75.9%)were improved.In the other 7 patients that did not recover,4 discharged automatically,2 died,and 1 could not be judged.ICI was rechallenged in 3 patients after liver function improvement,and IMLI did not recur.Conclusions The IMLIs often occur 2 to 3 months after the start of ICI treatment,the most common clinical type is hepatocyte type,and the severity of clinical symptoms in patients vary from mild to severe.After discontinuing ICIs and receiving glucocorticoid treatments,most patients may have a good prognosis.