Hepatotoxicity of immune checkpoint inhibitors: a histology study of seven cases in comparison with autoimmune hepatitis and idiosyncratic drug-induced liver injury
Hepatotoxicity of immune checkpoint inhibitors: a histology study of seven cases in comparison with autoimmune hepatitis and idiosyncratic drug-induced liver injury
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DOI：
10.1038/s41379-018-0013-y
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发表时间：
2018-06-01
期刊：
影响因子：
7.5
通讯作者：
Yeh, Matthew M.
中科院分区：
文献类型：
--
作者：
Zen, Yoh;Yeh, Matthew M.
免疫检查点抑制剂在不同器官中的不良影响可能归因于自我耐受被破坏而触发的免疫介导过程；然而，它们是否与经典的器官特异性自身免疫性疾病相似或不同尚不清楚。本研究旨在比较检查点抑制剂诱导的肝损伤和急性表现的自身免疫性肝炎或特殊药物诱导的肝损伤的临床病理特征。7名接受nivolumab(n=5)或ipilimumab(n=2)治疗的患者在免疫治疗开始后出现肝功能障碍，中位数为41天(范围21-120天)。所有患者都有肝酶升高，而高胆红素血症较少见。所有患者均未出现抗核抗体或免疫球蛋白升高。在所有接受治疗的患者中，停止免疫治疗和使用皮质类固醇的额外免疫抑制使肝酶恢复正常或降低。组织学上，所有活检均显示以小叶性肝炎为主，伴有较轻微的门脉炎症。单个病例可观察到小叶中心性融合坏死和浆细胞增多症，与自身免疫性肝炎相比明显较少见且程度较轻(p=0.017和p<；0.001)。胆管损伤、微小脓肿和髓外造血各1例。免疫组织化学染色显示，与自身免疫性肝炎和药物性肝损伤相比，检查点抑制剂诱导的肝损伤中CD3+和CD8+淋巴细胞大量存在，而CD20+B细胞和CD4+T细胞较少。综上所述，癌症免疫治疗所致的肝损伤与自身免疫性肝炎的肝损伤有一定的相似之处，但也有明显的不同。检查点抑制剂诱导的肝损伤可能是一种免疫介导的、区域选择性较低的肝细胞坏死，不需要辅助性T细胞的强烈激活和免疫球蛋白的产生。
The adverse effects of immune checkpoint inhibitors in various organs may be attributed to immune-mediated processes triggered by disrupted self-tolerance; however, it remains unclear whether they are similar or dissimilar to classic organ-specific autoimmune diseases. The present study aimed to compare clinicopathologic features between checkpoint inhibitor-induced liver injury and acutely presenting autoimmune hepatitis or idiosyncratic drug-induced liver injury. Seven patients treated with nivolumab (n = 5) or ipilimumab (n = 2) presented with liver dysfunction a median of 41 days (range 21-120) after the initiation of immunotherapy. All patients had elevated liver enzymes, whereas hyper-bilirubinemia was less common. None of the patients had antinuclear antibodies or IgG elevations. Stopping the immunotherapy and additional immunosuppression with corticosteroids normalized or decreased liver enzymes in all patients treated. Histologically, all biopsies showed predominantly lobular hepatitis with milder portal inflammation. Centrilobular confluent necrosis and plasmacytosis were observed in a single case, and were markedly less common and milder than those in autoimmune hepatitis (p = 0.017 and p < 0.001, respectively). Bile duct injury, micro-abscesses, and extramedullary hematopoiesis were also found in one case each. Immunostaining revealed the presence of large numbers of CD3+ and CD8+ lymphocytes, whereas CD20+ B cells and CD4+ T cells were fewer in checkpoint inhibitor-induced liver injury than in autoimmune hepatitis or drug-induced liver injury. In conclusion, liver injury caused by cancer immunotherapy shares some features with injury of autoimmune hepatitis; however, there are obvious differences between the two conditions. Checkpoint inhibitor-induced liver injury may represent an immune-mediated, less zone-selective hepatocyte necrosis not requiring the strong activation of helper T cells and immunoglobulin production.