Ipilimumab-associated Hepatitis Clinicopathologic Characterization in a Series of 11 Cases
Ipilimumab-associated Hepatitis Clinicopathologic Characterization in a Series of 11 Cases
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DOI：
10.1097/pas.0000000000000453
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发表时间：
2015-08-01
影响因子：
5.6
通讯作者：
Doyle, Leona A.
中科院分区：
文献类型：
--
作者：
Johncilla, Melanie;Misdraji, Joseph;Doyle, Leona A.
Ipilimumab是一种单克隆抗体，可抑制细胞毒性T淋巴细胞上的CTLA 4受体，导致免疫介导的肿瘤细胞死亡。伊匹单抗最常用于治疗转移性黑色素瘤，很少发生需要停止治疗的肝毒性。本研究的目的是描述伊匹单抗相关性肝炎的组织学特征和临床病程。在6年的时间内，确定了11例因接受治疗时肝功能检查（LFT）异常而临床疑似易普利姆单抗诱导肝炎的患者，并进行了肝活检。10例患者为男性和1例女性（中位年龄58岁），均接受1 - 4剂伊匹单抗。没有人知道先前存在的肝脏疾病。两名患者肥胖，另一名有酗酒史。除1例ANA滴度轻度升高外，所有患者的病毒和自身免疫血清学均为阴性。9例活组织检查显示活动性肝炎有2种不同的组织学类型：6例全小叶性肝炎和3例3区肝炎。两种模式的炎性浸润成分相似，主要由CD 8（+）T淋巴细胞、混合的组织细胞、散在的浆细胞和嗜酸性粒细胞组成。7例可见明显的组织细胞窦浸润，经常形成松散的组织细胞聚集体。中心静脉内皮细胞增生8例。该组患者的ALT、AST和总胆红素倾向于显著升高。2例不符合上述2种组织学类型：1例表现为门静脉炎症伴胆管炎，另1例表现为与非酒精性脂肪性肝炎难以鉴别的形态学特征。停用易普利姆玛和给予免疫抑制剂导致所有患者在发病后3个月内LFT消退或显著改善。伊匹单抗可能潜在地揭示先前的亚临床肝病，例如脂肪肝，并且伊匹单抗诱导的肝损伤的诊断可能仅在停药导致LFT正常化之后才能确定地被识别。总体而言，伊匹单抗相关肝炎最常表现为类似于自身免疫性肝炎的全小叶活动性肝炎。显著的肝窦组织细胞浸润和中央静脉损伤伴内皮细胞增生可能是诊断伊匹单抗相关性肝炎的有用组织学线索。
Ipilimumab is a monoclonal antibody that inhibits the CTLA4 receptor on cytotoxic T lymphocytes, resulting in immune-mediated tumor cell death. Ipilimumab is most often used in the treatment of metastatic melanoma, and rarely liver toxicity necessitating cessation of treatment occurs. The aim of this study was to characterize the histologic features and clinical course of ipilimumab-associated hepatitis. Eleven patients with clinical suspicion of ipilimumab-induced hepatitis, due to the development of abnormal liver function tests (LFTs) while receiving treatment, and who underwent liver biopsy, were identified over a 6-year period. Ten patients were male and 1 female (median age 58 y), and all received 1 to 4 doses of ipilimumab. None had known preexisting liver disease. Two patients were obese, and another had a history of alcohol abuse. Viral and autoimmune serologies were negative in all patients except 1 who had a mildly elevated ANA titer. Nine biopsies showed active hepatitis with 2 distinct histologic patterns: panlobular hepatitis in 6 cases and zone 3 hepatitis in 3. The inflammatory infiltrate was similar in composition in both patterns, composed predominantly of CD8(+) T lymphocytes, admixed histiocytes, scattered plasma cells, and eosinophils. Prominent histiocytic sinusoidal infiltrates were present in 7 cases and frequently formed loose histiocytic aggregates. Central vein endothelialitis was present in 8 cases. Patients in this group tended to have markedly elevated ALT, AST, and total bilirubin. Two cases did not fit into the above 2 histologic groups: 1 showed portal inflammation with cholangitis, and the other showed morphologic features indistinguishable from nonalcoholic steatohepatitis. Discontinuation of ipilimumab and administration of immunosuppressives resulted in resolution or marked improvement of LFTs in all patients within 3 months of presentation. Ipilimumab may potentially unmask previously subclinical liver disease, for example, fatty liver disease, and the diagnosis of ipilimumab-induced liver injury may only be recognized with certainty after cessation of the drug leads to normalization of LFTs. Overall, ipilimumab-associated hepatitis most often presents with a panlobular active hepatitis that resembles autoimmune hepatitis. Prominent sinusoidal histiocytic infiltrates and central vein damage with endothelialitis may be helpful histologic clues to the diagnosis of ipilimumab-associated hepatitis.