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）

计量
- 文章访问数: 540
- HTML全文浏览量: 487
- PDF下载量: 162
- 被引次数: 0
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

HTML全文

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。

下载: 导出CSV

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

下载: 导出CSV

参考文献(41)

[1]	SHEN T, LIU YX, SHANG J, et al. Incidence and etiology of drug-induced liver injury in mainland China[J]. Gastroenterology, 2019, 156( 8): 2230- 2241. e 11. DOI: 10.1053/j.gastro. 2019. 02.002.
[2]	ZHENG E, SANDHU N, NAVARRO V. Drug-induced liver injury secondary to herbal and dietary supplements[J]. Clin Liver Dis, 2020, 24( 1): 141- 155. DOI: 10.1016/j.cld.2019.09.009.
[3]	NAVARRO VJ, BARNHART H, BONKOVSKY HL, et al. Liver injury from herbals and dietary supplements in the U.S. Drug-Induced Liver Injury Network[J]. Hepatology, 2014, 60( 4): 1399- 1408. DOI: 10.1002/hep.27317.
[4]	VUPPALANCHI R, BONKOVSKY HL, AHMAD J, et al. Garcinia cambogia, either alone or in combination with green tea, causes moderate to severe liver injury[J]. Clin Gastroenterol Hepatol, 2022, 20( 6): e1416- e1425. DOI: 10.1016/j.cgh.2021.08.015.
[5]	JING J, WANG RL, ZHAO XY, et al. Association between the concurrence of pre-existing chronic liver disease and worse prognosis in patients with an herb-Polygonum multiflorum thunb. induced liver injury: A case-control study from a specialised liver disease center in China[J]. BMJ Open, 2019, 9( 1): e023567. DOI: 10.1136/bmjopen-2018-023567.
[6]	Committee on DILI Prevention and Management, Chinese Medical Biotechnology Association; Study Group of Drug-Induced Liver Disease, Chinese Medical Association for the Study of Liver Diseases. Chinese guideline for diagnosis and management of drug-induced liver injury(2023 version)[J].[J]. Chin J Gastroenterol, 2023, 28( 7): 397- 431. DOI: 10.3760/cma.j.cn501113-20230419-00176. 中国医药生物技术协会药物性肝损伤防治技术专业委员会, 中华医学会肝病学分会药物性肝病学组. 中国药物性肝损伤诊治指南(2023年版)[J]. 胃肠病学, 2023, 28( 7): 397- 431. DOI: 10.3760/cma.j.cn501113-20230419-00176.
[7]	FONTANA RJ, LIOU I, REUBEN A, et al. AASLD practice guidance on drug, herbal, and dietary supplement-induced liver injury[J]. Hepatology, 2023, 77( 3): 1036- 1065. DOI: 10.1002/hep.32689.
[8]	DEVARBHAVI H, AITHAL G, TREEPRASERTSUK S, et al. Drug-induced liver injury: Asia Pacific Association of Study of Liver consensus guidelines[J]. Hepatol Int, 2021, 15( 2): 258- 282. DOI: 10.1007/s12072-021-10144-3.
[9]	Council for International Organizations of Medical Sciences. Drug-induced liver injury(DILI): Current status and future directions for drug development and the post-market setting[M]. Geneva, 2020.
[10]	European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Drug-induced liver injury[J]. J Hepatol, 2019, 70( 6): 1222- 1261. DOI: 10.1016/j.jhep. 2019. 02.014.
[11]	State Drug Administration. Technical guidelines for clinical evaluation of liver injury induced by traditional Chinese medicine[J]. J Clin Hepatol, 2018, 34( 7): 1403- 1409. DOI: 10.3969/j.issn.1001-5256.2018.07.008. 国家药品监督管理局. 中药药源性肝损伤临床评价技术指导原则[J]. 临床肝胆病杂志, 2018, 34( 7): 1403- 1409. DOI: 10.3969/j.issn.1001-5256.2018.07.008.
[12]	World Health Organization. General guidelines for methodologies on research and evaluation of traditional medicine[M]. Geneva: World Health Organization, 2000.
[13]	YU YC, FAN Y, CHEN CW. Research status and prospect of liver injury related to herbs and dietary supplements[J]. Chin Hepatol, 2017, 22( 4): 296- 300. DOI: 10.14000/j.cnki.issn.1008-1704.2017.04.003. 于乐成, 范晔, 陈成伟. 草药和膳食补充剂相关肝损伤的研究现状及展望[J]. 肝脏, 2017, 22( 4): 296- 300. DOI: 10.14000/j.cnki.issn.1008-1704.2017.04.003.
[14]	JING J, WANG RL, BAI ZF, et al. Interpretation on consensus on drug-induced liver injury by CIOMS Working Group: liver injury attributed to herbal and dietary supplements[J]. China J Chin Mater Med, 2023, 48( 9): 2552- 2556. DOI: 10.19540/j.cnki.cjcmm.20230123.501. 景婧, 王睿林, 柏兆方, 等. CIOMS《药物性肝损伤国际共识》解读——草药和膳食补充剂(HDS)致肝损伤[J]. 中国中药杂志, 2023, 48( 9): 2552- 2556. DOI: 10.19540/j.cnki.cjcmm.20230123.501.
[15]	LIN N, JIANG Q, LIU W, et al. Editorial explanation for clinical practice guideline for Tripterygium Glycosides/Tripterygium wilfordii tablets in treatment of rheumatoid arthritis[J]. China J Chin Mater Med, 2020, 6( 17): 4154- 4157. 林娜, 姜泉, 刘维, 等.《雷公藤多苷/雷公藤片治疗类风湿关节炎用药指南》编制说明[J]. 中国中药杂志, 2020, 6( 17): 4154- 4157.
[16]	GABBI C, BERTOLOTTI M. Drug-induced liver injury-types and phenotypes[J]. N Engl J Med, 2019, 381( 14): 1395- 1396. DOI: 10.1056/NEJMc1911063.
[17]	LI M, LI RR, LIU CH. Clinic diagnosis and treatment of herb-induced liver injury[J]. Chin J Pharmacovigil, 2023, 20( 2): 127- 131. DOI: 10.19803/j.1672-8629.20220661. 李盟, 李容容, 刘成海. 中草药引起肝损伤的临床诊治与用药[J]. 中国药物警戒, 2023, 20( 2): 127- 131. DOI: 10.19803/j.1672-8629.20220661.
[18]	ARLT VM, STIBOROVA M, SCHMEISER HH. Aristolochic acid as a probable human cancer hazard in herbal remedies: A review[J]. Mutagenesis, 2002, 17( 4): 265- 277. DOI: 10.1093/mutage/17.4.265.
[19]	STIBOROVÁ M, FREI E, BREUER A, et al. Aristolactam I a metabolite of aristolochic acid I upon activation forms an adduct found in DNA of patients with Chinese herbs nephropathy[J]. Exp Toxicol Pathol, 1999, 51( 4-5): 421- 427. DOI: 10.1016/S0940-2993(99)80033-5.
[20]	JIANG HY, BAO YN, LIN FM, et al. Triptolide regulates oxidative stress and inflammation leading to hepatotoxicity via inducing CYP2E1[J]. Hum Exp Toxicol, 2021, 40( 12_suppl): S775- S787. DOI: 10.1177/09603271211056330.
[21]	LI J, SHEN FH, GUAN CW, et al. Activation of Nrf2 protects against triptolide-induced hepatotoxicity[J]. PLoS One, 2014, 9( 7): e100685. DOI: 10.1371/journal.pone.0100685.
[22]	LI CP, RAO T, CHEN XP, et al. HLA-B*35:01 allele is a potential biomarker for predicting Polygonum multiflorum-induced liver injury in humans[J]. Hepatology, 2019, 70( 1): 346- 357. DOI: 10.1002/hep.30660.
[23]	REMASH D, PRINCE DS, MCKENZIE C, et al. Immune checkpoint inhibitor-related hepatotoxicity: A review[J]. World J Gastroenterol, 2021, 27( 32): 5376- 5391. DOI: 10.3748/wjg.v27.i32.5376.
[24]	LI M, LUO Q, CHEN X, et al. Screening of major hepatotoxic components of Tripterygium wilfordii based on hepatotoxic injury patterns[J]. BMC Complement Med Ther, 2023, 23( 1): 9. DOI: 10.1186/s12906-023-03836-w.
[25]	MU GD, NIU M, GAO YJ, et al. Construction and application of liver injury risk prediction model of Chinese medicinals based on indirect toxicity[J]. J Tradit Chin Med, 2023, 64( 17): 1763- 1770. DOI: 10.13288/j.11-2166/r.2023.17.008. 母光頔, 牛明, 高云娟, 等. 基于间接毒性认知的中药肝损伤风险预测模式的构建及应用[J]. 中医杂志, 2023, 64( 17): 1763- 1770. DOI: 10.13288/j.11-2166/r.2023.17.008.
[26]	WANG XY, LI WX, ZHANG H, et al. The mechanism of Psoralea fructus induced idiosyncratic liver injury based on metabolomics[J]. Chin J Pharmacovigil, 2021, 18( 11): 1014- 1019. DOI: 10.19803/j.1672-8629.2021.11.04. 王晓艳, 李伟霞, 张辉, 等. 基于代谢组学的补骨脂致特异质肝损伤机制研究[J]. 中国药物警戒, 2021, 18( 11): 1014- 1019. DOI: 10.19803/j.1672-8629.2021.11.04.
[27]	MA J, XIA QS, FU PP, et al. Pyrrole-protein adducts-A biomarker of pyrrolizidine alkaloid-induced hepatotoxicity[J]. J Food Drug Anal, 2018, 26( 3): 965- 972. DOI: 10.1016/j.jfda.2018.05.005.
[28]	XU ZN, ZHAO YQ, CHEN SY, et al. Advantage and risk analysis on combination of traditional Chinese medicines and Western medicines[J]. Chin Tradit Herb Drugs, 2023, 54( 2): 408- 415. DOI: 10.7501/j.issn.0253-2670.2023.02.007. 徐振娜, 赵逸卿, 陈思宇, 等. 中西药联合用药的优势及风险分析[J]. 中草药, 2023, 54( 2): 408- 415. DOI: 10.7501/j.issn.0253-2670.2023.02.007.
[29]	DING ZH, ZHANG YQ, LIN N. Component-effect/toxicity-target correlations of Tripterygium wilfordii in terms of lipid metabolism[J]. Chin J Pharmacovigil, 2023, 20( 5): 489- 495. DOI: 10.19803/j.1672-8629.20220734. 丁子禾, 张彦琼, 林娜. 从脂质代谢途径探讨中药雷公藤“物-效/毒-靶”关联性的研究现状与展望[J]. 中国药物警戒, 2023, 20( 5): 489- 495. DOI: 10.19803/j.1672-8629. 20220734.
[30]	HUANG JF, ZHAO Q, DAI MY, et al. Gut microbiota protects from triptolide-induced hepatotoxicity: Key role of propionate and its downstream signalling events[J]. Pharmacol Res, 2020, 155: 104752. DOI: 10.1016/j.phrs.2020.104752.
[31]	BAI ZF, ZHAN XY, YAO Q, et al. Theoretical innovation and technological breakthroughs in the safety evaluation of traditional Chinese medicine: Disease-syndrome-based toxicology[J]. Chin J Pharmacovigil, 2024, 21( 1): 6- 14. DOI: 10.19803/j.1672-8629.20230787. 柏兆方, 湛小燕, 姚清, 等. 中药安全性评价理论创新与技术突破:病证毒理学[J]. 中国药物警戒, 2024, 21( 1): 6- 14. DOI: 10.19803/j.1672-8629.20230787.
[32]	HE TT, GONG M, BAI YF, et al. Clinical analysis of two diagnosis methods for herb-induced liver injury[J]. China J Chin Mater Med, 2016, 41( 16): 3096- 3099. DOI: 10.4268/cjcmm20161626. 何婷婷, 宫嫚, 白云峰, 等. 2种药物性肝损伤诊断指南的应用分析[J]. 中国中药杂志, 2016, 41( 16): 3096- 3099. DOI: 10.4268/cjcmm20161626.
[33]	MENG Y, ZHANG MM, ZHAO XY. Evolution of causality evaluation of drug-induced liver injury: From RUCAM to RECAM[J]. Chin Hepatol, 2023, 28( 6): 631- 633. DOI: 10.14000/j.cnki.issn.1008-1704.2023.06.001. 孟尧, 张萌萌, 赵新颜. 药物性肝损伤因果关系评估演变:从RUCAM到RECAM[J]. 肝脏, 2023, 28( 6): 631- 633. DOI: 10.14000/j.cnki.issn.1008-1704.2023.06.001.
[34]	AHMAD J, BARNHART HX, BONACINI M, et al. Value of liver biopsy in the diagnosis of drug-induced liver injury[J]. J Hepatol. 2022, 76( 5): 1070- 1078. DOI: 10.1016/j.jhep.2021.12.043.
[35]	LUO Q, ZHU GR, GU HT, et al. Liver histopathological features of patients with drug-induced liver injury due to Chinese herbal medicine or Western medicine: A comparative analysis of 50 cases[J]. J Clin Hepatol, 2020, 36( 3): 596- 601. DOI: 10.3969/j.issn.1001-5256.2020.03.025. 罗琼, 朱哿瑞, 顾宏图, 等. 50例中草药与西药致药物性肝损伤患者的肝组织病理学特点比较[J]. 临床肝胆病杂志, 2020, 36( 3): 596- 601. DOI: 10.3969/j.issn.1001- 5256. 2020. 03.025.
[36]	Cooperative Group for Hepatic and Gall Diseases, Chinese Society of Gastroenterology, Chinese Medical Association. Expert consensus on diagnosis and treatment of pyrrolidine alkaloids-related sinusoidal obstruction syndrome(2017, Nanjing)[J]. J Clin Hepatol, 2017, 3( 9): 1627- 1637. DOI: 10.3969/j.issn.1001-5256.2017.09.003. 中华医学会消化病学分会肝胆疾病协作组. 吡咯生物碱相关肝窦阻塞综合征诊断和治疗专家共识意见(2017年, 南京)[J]. 临床肝胆病杂志, 2017, 33( 9): 1627- 1637. DOI: 10.3969/j.issn.1001-5256.2017.09.003.
[37]	LIU CH, ZHU CW. Epidemic features, major causes, and diagnostic evaluation of herb-induced liver injury[J]. J Clin Hepatol, 2017, 33( 5): 829- 832. DOI: 10.3969/j.issn.1001-5256.2017.05.007. 刘成海, 朱春雾. 中草药相关药物性肝损伤的流行特点、主要原因与诊断评估[J]. 临床肝胆病杂志, 2017, 33( 5): 829- 832. DOI: 10.3969/j.issn.1001-5256.2017.05.007.
[38]	World Health Organization. Key technical issues of herbal medicines with reference to interaction with other medicines[M]. Geneva: World Health Organization, 2021.
[39]	WANG LX, WANG MM, LI YY, et al. Pharmacovigilance Guidelines for proprietary Chinese medicines[J/OL]. Chin J Chin Mat Med, 2024: 1- 7.[ 2024-07-10]. https://doi.org/10.19540/j.cnki.cjcmm.20240623.501. DOI: 10.19540/j.cnki.cjcmm.20240623.501 王连心, 王萌萌, 黎元元, 等. 中成药药物警戒指南[J/OL]. 中国中药杂志, 2024: 1- 7.[ 2024-07-10]. https://doi.org/10.19540/j.cnki.cjcmm.20240623.501. DOI: 10.19540/j.cnki.cjcmm.20240623.501
[40]	SONG HB, HAN L. Epidemiologic characteristics, risk factors and safety evaluation of traditional Chinese medicine induced liver injury[J]. Chin J Pharmacol Toxicol, 2016, 30( 4): 291- 305. DOI: 10.3867/j.issn.1000-3002.2016.04.001. 宋海波, 韩玲. 中药肝损伤的流行特点、风险因素及评价[J]. 中国药理学与毒理学杂志, 2016, 30( 4): 291- 305. DOI: 10.3867/j.issn.1000-3002.2016.04.001.
[41]	HOOFNAGLE JH, BONKOVSKY HL, PHILLIPS EJ, et al. HLA-B*35:01 and green tea-induced liver injury[J]. Hepatology, 2021, 73( 6): 2484- 2493. DOI: 10.1002/hep.31538.