中草药相关肝损伤的研究进展与挑战

刘成海

doi:10.12449/JCH240801

中草药相关肝损伤的研究进展与挑战

DOI: 10.12449/JCH240801

刘成海^{1, 2, 3, , ,}

1.
上海中医药大学附属曙光医院肝病研究所，上海 201203
2.
上海市中医临床重点实验室，上海 201203
3.
肝肾疾病病证教育部重点实验室，上海 201203

基金项目:

上海市中医药事业发展三年行动计划 (ZY（2018-2020）-CCCX-5001);

上海市科学技术委员会科技创新行动计划医学创新研究专项 (20Z21900100);

上海市临床重点专科建设项目 (shslczdzk01201)

利益冲突声明：本文不存在任何利益冲突。

详细信息

通信作者:
刘成海， chenghailiu@hotmail.com （ORCID： 0000-0002-1696-6008）

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出版历程
- 收稿日期: 2024-06-26
- 录用日期: 2024-07-10
- 出版日期: 2024-08-25

Research advances and challenges in herb-induced liver injury

Chenghai LIU^{1, 2, 3
, ,
,}

1.
Institute of Liver Diseases，Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine，Shanghai 201203，China
2.
Shanghai Key Laboratory of Traditional Chinese Clinical Medicine，Shanghai 201203，China
3.
Key Laboratory of Liver and Kidney Diseases，Ministry of Education，Shanghai 201203，China

Research funding:

Shanghai TCM Development Three-Year Action Plan Project (ZY（2018-2020）-CCCX-5001);

Shanghai Science and Technology Innovation Action Plan Medical Innovation Research Special Project (20Z21900100);

Shanghai Key Specialty of Traditional Chinese Clinical Medicine (shslczdzk01201)

More Information

Corresponding author: LIU Chenghai， chenghailiu@hotmail.com （ORCID： 0000-0002-1696-6008）

摘要

摘要: 中草药相关肝损伤发生众多，对中药临床安全用药与产业健康发展等有重要影响，近年来中草药肝损伤研究受到广泛重视并取得显著进展，我国与国际学术组织均制订并更新了相关临床诊疗指南。本文比较分析了近期有关中草药相关肝损伤诊疗指南的特点，继而从毒性机制、临床诊断与病情评估、风险因素与临床防治等方面简述主要进展，提出部分尚未满足的需求、需要重视的研究难点与可能的防治措施。
- 中草药 /
- 化学性与药物性肝损伤 /
- 毒理机制 /
- 诊断 /
- 危险因素 /
- 治疗学
Abstract: Herb-induced liver injury （HILI） shows a high incidence rate and has great impacts on the clinical medication safety of traditional Chinese medicine and the healthy development of the industry. In recent years， the research on HILI has attracted wide attention and made remarkable progress， and related clinical diagnosis and treatment guidelines have been formulated and updated by the academic organizations in China and globally. This article compares the recent guidelines on HILI formulated by different organizations and elaborates on the main achievements in terms of mechanism of toxicity， clinical diagnosis and disease assessment， risk factors， and clinical prevention and treatment， and it also proposes the unmet needs， the research difficulties that need to be taken seriously， and possible prevention and treatment strategies.
- Drugs， Chinese Herbal /
- Chemical and Drug Induced Liver Injury /
- Toxic Mechanism /
- Diagnosis /
- Risk Factors /
- Therapeutics

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表 1 国内外新近主要DILI诊疗指南关于HILI的比较

Table 1. Comparison of Chinese herbal medicine liver injury in the main DILI diagnosis and treatment guidelines

项目	中华医学会肝病学分会 DILI指南（2023）^［6］	美国肝病学会 DILI指南（2023）^［7］	亚太肝病学会 DILI指南（2021）^［8］	CIOMS DILI共识（2020）^［9］	欧洲肝病学会 DILI指南（2019）^［10］
TCM/HDS的定义范围	中药及含有中药组分的保健食品，其中中药包括中药材、中药饮片、中药提取物、中药配方颗粒、中成药，民间用药材	HDS	TCM、HDS	HDS	HDS
占比	美国20%，欧洲和拉丁美洲8%～16%，中国20%～30%，韩国27.5%，日本6%～9%	HDS：20%	美国20%；中国20%～30%；西班牙13%		HDS：美国20%，冰岛16%
诊断	TCM/HDS肝毒性的诊断策略与DILI相同，根据TCM/HDS使用史、临床表现、体格检查、实验室检查、影像学或肝组织学检查等综合信息，排除其他肝损伤病因，最后诊断
评估量表	RUCAM评分，专家意见程序，证据链方法	RUCAM评分， RECAM评分， CDS/DDW-J/SEOP，专家意见程序	RUCAM评分，专家意见程序，证据链方法	RUCAM评分，证据链方法	RUCAM评分， CDS/SEOP，专家意见程序，证据链方法
治疗	TCM/HDS肝损伤的治疗方案与DILI基本相同，包括停药、药物治疗等，进展至肝衰竭或肝功能失代偿可考虑人工肝支持，必要时行肝移植治疗
注：TCM，中医药。

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表 2 常见的导致肝损伤的中草药毒性成分和毒理机制

Table 2. The toxic components and mechanisms of common Chinese herbal medicine with liver toxicity

药物	毒性成分	作用机制
雷公藤	雷公藤甲素	①脂质过氧化反应；②免疫性损伤；③P450酶系代谢异常；④肠道菌群
黄药子	薯蓣皂苷及毒皂苷、呋喃去甲基二萜类化合物	①肝细胞的氧化损伤直接毒性；②与胆汁淤积、胆盐刺激有关
菊三七（土三七）	吡咯烷类生物碱（千里光宁、千里光非灵和全缘千里光碱）	代谢形成吡咯，与组织中的核酸与蛋白质等结合，或与还原型谷胱甘肽等形成加合物
何首乌	蒽醌类	①药物本身及代谢产物对肝细胞的直接毒性；②免疫性损伤
千里光	吡咯里西啶类生物碱	代谢形成吡咯，与核酸或蛋白质等结合形成加合物，直接损伤肝窦内皮细胞，并导致肝窦阻塞
苍耳子	苍术苷、毒蛋白	脂质过氧化反应
薄荷	长叶薄荷酮、薄荷呋喃、异薄荷酮	炎症反应
苍术	苍术苷、羧基或去磺基苍术苷	脂质过氧化反应、影响肝细胞能量代谢
柴胡	柴胡总皂苷、柴胡皂苷D	氧化损伤
淫羊藿	黄酮类（2″-鼠李糖基淫羊藿次苷Ⅱ、淫羊藿次苷宝藿苷Ⅱ、淫羊藿素）	①氧化应激与细胞凋亡；②调控NLRP3炎症小体活性引起特异质性肝损伤；③抑制法尼醇X受体通路引起胆汁酸蓄积
蓖麻子	蓖麻毒蛋白	与膜受体作用形成通道并内吞，催化失活核糖体的60S亚基，抑制蛋白质合成
川楝子	呋喃三萜类化合物（川楝素）	降低线粒体膜电位，诱导肝细胞死亡
大黄	大黄素、大黄蒽醌	肝细胞脂肪变性
栀子	栀子苷	①抑制CYP3A2活性，使毒性成分蓄积；②肝细胞脂质过氧化
秋水仙	秋水仙碱	胆汁淤积
麻黄	麻黄碱	脂质过氧化损伤
山豆根	苦参碱	①过氧化损伤；②脂质代谢紊乱；③炎症反应
艾叶	艾叶挥发油	①氧化应激；②线粒体结构与功能障碍
补骨脂	补骨脂二氢黄酮甲醚	①细胞凋亡与坏死；②脂质氧化应激损伤；③胆汁酸代谢与转运异常；④代谢酶活性抑制

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