Immunotherapy for metastatic cancer can be complicated by the onset of hepatic immune-related adverse events (IRAEs). This study compared hepatic IRAEs associated with anti-programmed cell death protein 1 (PD-1)/PD ligand 1 (PD-L1) and anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) monoclonal antibodies (mAbs). Among 536 patients treated with anti-PD-1/PD-L1 or CTLA-4 immunotherapies, 19 (3.5%) were referred to the liver unit for grade ≥3 hepatitis. Of these patients, nine had received anti-PD-1/PD-L1 and seven had received anti-CTLA-4 mAbs, in monotherapy or in combination with anti-PD-1. Liver investigations were undertaken in these 16 patients, including viral assays, autoimmune tests and liver biopsy, histological review, and immunostaining of liver specimens. In the 16 patients included in this study, median age was 63 (range 33-84) years, and nine (56%) were female. Time between therapy initiation and hepatitis was five (range, 1–49) weeks and median number of immunotherapy injections was two (range, 1–36). No patients developed hepatic failure. Histology related to anti-CTLA-4 mAbs demonstrated granulomatous hepatitis including fibrin ring granulomas and central vein endotheliitis. Histology related to anti-PD-1/PD-L1 mAbs was characterised by lobular hepatitis. The management of hepatic IRAEs was tailored according to the severity of both the biology and histology of liver injury: six patients improved spontaneously; seven received oral corticosteroids at 0.5–1 mg/kg/day; two were maintained on 0.2 mg/kg/day corticosteroids; and one patient required pulses and 2.5 mg/kg/day of corticosteroids, and the addition of a second immunosuppressive drug. In three patients, immunotherapy was reintroduced without recurrence of liver dysfunction. Acute hepatitis resulting from immunotherapy for metastatic cancer is rare (3.5%) and, in most cases, not severe. Histological assessment can distinguish between anti-PD-1/PD-L1 and anti-CTLA-4 mAb toxicity. The severity of liver injury is helpful for tailoring patient management, which does not require systematic corticosteroid administration. Immunotherapy for metastatic cancer can be complicated by immune-related adverse events in the liver. In patients receiving immunotherapy for metastatic cancer who develop immune-mediated hepatitis, liver biopsy is helpful for the diagnosis and evaluation of the severity of liver injury. This study demonstrates the need for patient-oriented management, which could eventually avoid unnecessary systemic corticosteroid treatment.

中文翻译：

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使用免疫检查点抑制剂的癌症免疫治疗引起的肝损伤的特征

转移性癌症的免疫治疗可能因肝脏免疫相关不良事件 (IRAE) 的发生而变得复杂。本研究比较了与抗程序性细胞死亡蛋白 1 (PD-1)/PD 配体 1 (PD-L1) 和抗细胞毒性 T 淋巴细胞抗原 4 (CTLA-4) 单克隆抗体 (mAb) 相关的肝脏 IRAE。在 536 名接受抗 PD-1/PD-L1 或 CTLA-4 免疫疗法治疗的患者中，19 名 (3.5%) 因 ≥3 级肝炎转诊至肝脏病房。在这些患者中，9 名接受了抗 PD-1/PD-L1 治疗，7 名接受了抗 CTLA-4 mAb 单一疗法或与抗 PD-1 联合治疗。对这 16 名患者进行了肝脏检查，包括病毒检测、自身免疫检测和肝活检、组织学检查以及肝脏标本的免疫染色。在本研究纳入的 16 名患者中，中位年龄为 63 岁（范围 33-84），其中 9 名患者（56%）为女性。开始治疗和肝炎之间的时间为五周（范围，1-49）周，免疫治疗注射的中位数为两次（范围，1-36）。没有患者出现肝衰竭。与抗 CTLA-4 mAb 相关的组织学显示肉芽肿性肝炎，包括纤维蛋白环肉芽肿和中央静脉内皮炎。与抗 PD-1/PD-L1 mAb 相关的组织学特征为小叶性肝炎。肝IRAE的治疗根据肝损伤的生物学和组织学严重程度进行定制：6名患者自发改善； 7 名患者接受口服皮质类固醇，剂量为 0.5–1 毫克/公斤/天；两人维持0.2毫克/公斤/天的皮质类固醇；一名患者需要脉冲和 2.5 毫克/公斤/天的皮质类固醇，并添加第二种免疫抑制药物。三名患者重新接受免疫治疗，肝功能障碍未复发。转移性癌症免疫治疗引起的急性肝炎很少见（3.5%），而且在大多数情况下并不严重。组织学评估可以区分抗 PD-1/PD-L1 和抗 CTLA-4 mAb 毒性。肝损伤的严重程度有助于调整患者管理，不需要系统性皮质类固醇给药。转移性癌症的免疫治疗可能因肝脏中免疫相关的不良事件而变得复杂。对于接受转移性癌症免疫治疗并出现免疫介导性肝炎的患者，肝活检有助于诊断和评估肝损伤的严重程度。这项研究表明需要以患者为中心的管理，这最终可以避免不必要的全身性皮质类固醇治疗。