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免疫治疗相关肝毒性的诊断与管理

华雨薇 赵林

华雨薇, 赵林. 免疫治疗相关肝毒性的诊断与管理[J]. 协和医学杂志, 2021, 12(5): 798-806. doi: 10.12290/xhyxzz.2021-0138
引用本文: 华雨薇, 赵林. 免疫治疗相关肝毒性的诊断与管理[J]. 协和医学杂志, 2021, 12(5): 798-806. doi: 10.12290/xhyxzz.2021-0138
HUA Yuwei, ZHAO Lin. Diagnosis and Management of Immunotherapy-related Liver Toxicity[J]. Medical Journal of Peking Union Medical College Hospital, 2021, 12(5): 798-806. doi: 10.12290/xhyxzz.2021-0138
Citation: HUA Yuwei, ZHAO Lin. Diagnosis and Management of Immunotherapy-related Liver Toxicity[J]. Medical Journal of Peking Union Medical College Hospital, 2021, 12(5): 798-806. doi: 10.12290/xhyxzz.2021-0138

免疫治疗相关肝毒性的诊断与管理

doi: 10.12290/xhyxzz.2021-0138
详细信息
    通讯作者:

    赵林  电话: 010-88068315, E-mail: wz20010727@aliyun.com

  • 中图分类号: R730.51;R575.1

Diagnosis and Management of Immunotherapy-related Liver Toxicity

More Information
  • 摘要: 免疫检查点抑制剂开启了肿瘤治疗的新时代,但随着临床应用的增加,免疫治疗相关不良反应亦不断被报道并逐渐引发关注。肝毒性是其中较常发生且具有一定致死性的严重不良反应,及早识别、诊断并对其进行恰当管理非常重要。目前国内外临床指南均对免疫治疗相关肝毒性的管理发布了指导性建议,但在肝毒性分级、激素使用剂量、激素治疗无效的后线治疗以及免疫治疗再挑战方面,仍存有较多争议和商榷空间。此外,早期识别肝毒性的发生、发现兼具灵敏度和特异度的预测指标具有重要意义。
    作者贡献:华雨薇负责文章撰写;赵林负责文章修订。
    利益冲突:
  • 表  1  免疫治疗相关肝毒性的严重程度分级[24]

    1级 2级 3级 4级
    胆红素 1~1.5倍ULN 1.5~3倍ULN 3~10倍ULN >10倍ULN
    转氨酶(AST/ALT) 1~3倍ULN 3~5倍ULN 5~20倍ULN >20倍ULN
    ULN:正常值上限;AST:天冬氨酸转氨酶;ALT:丙氨酸转氨酶
    下载: 导出CSV

    表  2  免疫治疗相关肝毒性的管理建议[4, 20, 22, 24-25]

    分级 项目 SITC ASCO NCCN ESMO CSCO
    1级 免疫治疗 继续 继续 继续 继续 继续
    肝功能监测频率 每周1次 每周1~2次 每周1~2次 每周1次 每周1次
    2级 免疫治疗 暂停免疫治疗,肝功能恢复至1级且激素减量至10 mg泼尼松当量时可重新启用
    肝功能监测频率 每周1~2次 每周1~2次 每周1~2次 每周1~2次 每周1~2次
    激素干预 泼尼松0.5~1 mg/kg 症状明显且肝功能异常持续3~5 d,开始泼尼松0.5~1 mg/kg 泼尼松0.5~ 1 mg/kg 肝功能异常持续3~ 5 d,开始泼尼松龙1 mg/kg口服 泼尼松0.5~1 mg/kg口服
    肝脏活检 可选择肝脏活检 可选择肝脏活检
    3级 免疫治疗 永久停用 永久停用 永久停用 永久停用 暂停免疫治疗,肝功恢复至1级且激素减量至10 mg泼尼松当量时可重新启用
    肝功能监测频率 1~2 d监测1次 1~2 d监测1次 1~2 d监测1次 每天1次 1~2 d监测1次
    激素干预 泼尼松1~2 mg/kg 甲基泼尼松龙1~ 2 mg/kg 泼尼松1~ 2 mg/kg AST或ALT<400,且胆红素/凝血/白蛋白无异常,开始泼尼松龙1 mg/kg口服;AST或ALT>400,或胆红素升高/凝血异常/白蛋白低,开始甲泼尼龙/泼尼松龙2 mg/kg静脉输注,肝功能恢复至2级等效改为泼尼松口服 甲基泼尼松龙1~2 mg/kg静脉输注,肝功恢复至2级后可换口服
    后线治疗 激素治疗3 d无改善,考虑MMF 激素无效或治疗3 d无改善,考虑MMF或AZA(剂量未提及) 激素无效或治疗3 d无改善,考虑MMF 激素治疗2~3 d无改善,可加用MMF 1000 mg,2次/d 激素治疗3 d无改善,考虑加用MMF 500~1000 mg,2次/d; MMF治疗效果不佳可加用他克莫司(剂量未提及)
    肝脏活检 建议肝脏活检 激素治疗无效或患者同时使用其他抗肿瘤药物,建议肝病专家会诊 肝病专家会诊 激素和MMF治疗效果不佳,可肝病专家会诊+肝脏活检 肝病专家会诊+肝脏活检, 建议肝脏CT或超声检查
    4级 免疫治疗 永久停用 永久停用 永久停用 永久停用 永久停用
    肝功能监测频率 1~2 d监测1次 每天1次 每天1次 每天1次 1~2 d监测1次
    激素干预 泼尼松1~2 mg/kg 甲基泼尼松龙2 mg/kg 甲基泼尼松龙/泼尼松2 mg/kg 甲基泼尼松龙/泼尼松龙2 mg/kg静脉输注 甲基泼尼松龙1~2 mg/kg静脉输注,肝功能恢复至2级后可改为口服
    后线治疗 激素治疗3 d无改善,考虑MMF 激素无效或治疗3 d无改善,考虑MMF 激素无效或治疗3 d无改善,考虑MMF 激素治疗2~3 d无改善,可加用MMF 1000 mg,2次/d 激素治疗3 d无改善,考虑加用MMF 500~1000 mg,2次/d;MMF治疗效果不佳可加用他克莫司(剂量未提及)
    肝脏活检 建议肝脏活检 激素无效建议肝病专家会诊 肝病专家会诊+肝脏活检 激素和MMF疗效不佳,可肝病专家会诊+肝脏活检 肝病专家会诊+肝脏活检, 建议肝脏CT或超声检查
    表格中未出现使用途径(如口服、静脉等)均为原指南未提及; SITC:癌症免疫治疗学会;ASCO:美国临床肿瘤学会;NCCN:美国国家综合癌症网;ESMO:欧洲肿瘤内科学会;CSCO:中国临床肿瘤学会;AST、ALT:同表 1;MMF:吗替麦考酚酯;AZA:硫唑嘌呤
    下载: 导出CSV
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出版历程
  • 收稿日期:  2021-01-31
  • 录用日期:  2021-03-12
  • 网络出版日期:  2021-08-03
  • 刊出日期:  2021-10-12

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