补肾健脾利湿法治疗慢性乙型肝炎临床效果及相关机制研究

朱晓骏; 张景豪; 孙学华; 张鑫; 高月求

doi:10.3969/j.issn.1001-5256.2023.06.003

补肾健脾利湿法治疗慢性乙型肝炎临床效果及相关机制研究

DOI: 10.3969/j.issn.1001-5256.2023.06.003

1.
上海中医药大学附属曙光医院肝病科，上海 201203
2.
上海中医药大学附属曙光医院细胞免疫实验室，上海 201203

基金项目:

国家“艾滋病和病毒性肝炎等重大传染病防治”科技重大专项 (2018ZX10725504);

国家自然科学基金 (82274467);

国家自然科学基金 (81774256);

上海市进一步加快中医药传承创新发展三年行动计划(2021年-2023年)(华东片区及市级中医专科专病联盟建设-长三角中医肝病专科联盟建设) (ZY(2021-2023)-0302);

上海市浦东新区卫健委浦东名中医培养项目 (PWRzm2020-02);

高月求上海市名老中医学术经验研究工作室 (SHGZS-202246)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：朱晓骏、张景豪参与文章内容的撰写；张鑫参与相关研究结果的整理；孙学华对文章撰写思路提供建议；高月求对文章的撰写思路提供关键贡献。

详细信息

通信作者:
高月求，gaoyueqiu@hotmail.com (ORCID: 0000-0001-7276-9810)

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出版历程
- 收稿日期: 2023-03-29
- 录用日期: 2023-04-30
- 出版日期: 2023-06-20

Clinical efficacy and mechanism of action of kidney-tonifying, spleen-strengthening, and diuresis-promoting therapy in treatment of chronic hepatitis B

1.
Department of Hepatopathy, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
2.
Laboratory of Cellular Immunity, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China

Research funding:

National Science and Technology Key Project for the Prevention and Treatment of Major Infectious Diseases such as AIDS and Viral Hepatitis (2018ZX10725504);

National Natural Science Foundation of China (82274467);

National Natural Science Foundation of China (81774256);

Shanghai Three-year Action Plan to Further Accelerate TCM Inheritance and Innovation Development (2021-2023) (Construction of TCM specialty disease Alliance in East China Region and Municipal Level-Construction of TCM Liver Disease Specialty Alliance in Yangtze River Delta) (ZY(2021-2023)-0302);

Pudong Famous Traditional Chinese Medicine Training Project of Shanghai Pudong New Area Health Commission (PWRzm2020-02);

Shanghai Famous Old Chinese Medicine Academic Experience Research Studio for Yueqiu Gao (SHGZS-202246)

More Information

Corresponding author: GAO Yueqiu, gaoyueqiu@hotmail.com (ORCID: 0000-0001-7276-9810)

摘要

摘要: 慢性乙型肝炎是世界范围内的公共健康问题，核苷酸类似物和干扰素治疗可以有效抑制HBV复制，但存在无法实现对HBV cccDN进行彻底清除、HBsAg阴转率低等不足。“补肾法治疗慢性乙型肝炎”的学术观点的提出为乙型肝炎的治疗提供了新的思路和方法；曙光医院肝病科在长期的临床实践中明确“脾肾亏虚、兼湿热未尽”是慢性乙型肝炎持续进展的关键病机，并确立了补肾健脾利湿为基本治法的慢性乙型肝炎论治方案，历经“十一五”至“十三五”的国家科技重大专项的临床研究验证了该方案确切的临床疗效，明确了补肾健脾利湿法治疗慢性乙型肝炎的主要作用机制在于调节机体免疫功能。
- 乙型肝炎, 慢性 /
- 补肾 /
- 健脾 /
- 清化湿浊
Abstract: Chronic hepatitis B is a public health issue worldwide. Nucleotide analogues and interferon therapy can effectively inhibit HBV replication, but they still have the shortcomings such as inability to achieve the clearance of HBV cccDNA and low HBsAg clearance rate. The academic viewpoint of "kidney-tonifying therapy for chronic hepatitis B" provides new ideas and methods for the treatment of hepatitis B. During long-term clinical practice, Department of Hepatology in Shuguang Hospital has identified that "deficiency of spleen and kidney with damp heat remaining" is the key pathogenesis of the continuous progression of chronic hepatitis B and has established the treatment regimen for chronic hepatitis B with the basic treatment method of tonifying the kidney, strengthening the spleen, and promoting diuresis. The clinical research of National Science and Technology Major Project from The 11th Five Year Plan to The 13th Five Year Plan has validated the clinical efficacy of this regimen and clarified that regulating the immune function of the body is the main mechanism of the kidney-tonifying, spleen-strengthening, and diuresis-promoting therapy in the treatment of chronic hepatitis B.
- Hepatitis B, Chronic /
- Reinforcing Kidney /
- Strengthening Spleen /
- Removing Dampness and Turbid

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参考文献(28)

[1]	World Health Organization. Global progress report on HIV, viral hepatitis and sexually transmitted infections, 2021. Accountability for the global health sector strategies 2016-2021: actions for impact[EB/OL]. https://apps.who.int/iris/bitstream/handle/10665/342808/9789240030985-eng.pdf.
[2]	LIU J, LIANG W, JING W, et al. Countdown to 2030: eliminating hepatitis B disease, China[J]. Bull World Health Organ, 2019, 97(3): 230-238. DOI: 10.2471/BLT.18.219469.
[3]	LIAW YF, KAO JH, PIRATVISUTH T, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2012 update[J]. Hepatol Int, 2012, 6(3): 531-561. DOI: 10.1007/s12072-012-9365-4.
[4]	LOK AS. Hepatitis: Long-term therapy of chronic hepatitis B reverses cirrhosis[J]. Nat Rev Gastroenterol Hepatol, 2013, 10(4): 199-200. DOI: 10.1038/nrgastro.2013.13.
[5]	MARCELLIN P, GANE E, BUTI M, et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study[J]. Lancet, 2013, 381(9865): 468-475. DOI: 10.1016/S0140-6736(12)61425-1.
[6]	Chinese Society of Hepatology, Chinese Medical Association; Chinese Society of Infectious Diseases, Chinese Medical Association. Guidelines for the prevention and treatment of chronic hepatitis B (2022 version)[J]. Chin J Infect Dis, 2023, 41(1): 3-28. DOI: 10.3760/cma.j.cn311365-20230220-00050. 中华医学会肝病分会, 中华医学会感染病分会. 慢性乙型肝炎防治指南(2022年版)[J]. 中华传染病杂志, 2023, 41(1): 3-28. DOI: 10.3760/cma.j.cn311365-20230220-00050.
[7]	GAO YQ. Regulation of immunity by traditional Chinese medicine is the dominant link in the treatment of chronic hepatitis B[J]. Chin J Integr Tradit West Med Liver Dis, 2010, 20(3): 129-130. DOI: 10.3969/j.issn.1005-0264.2010.03.001. 高月求. 中医药调控免疫是治疗慢性乙型肝炎优势环节[J]. 中西医结合肝病杂志, 2010, 20(3): 129-130. DOI: 10.3969/j.issn.1005-0264.2010.03.001.
[8]	GAO YQ, ZHANG X, LI M, et al. Immunological mechanism of traditional Chinese medicine in treatment of chronic hepatitis B[J]. World Chin J Dig, 2016, 19: 2943-2949. DOI: 10.11569/wcjd.v24.i19.2943. 高月求, 张鑫, 李曼, 等. 中医药治疗慢性乙型肝炎的免疫学机制研究进展[J]. 世界华人消化杂志, 2016, 19: 2943-2949. DOI: 10.11569/wcjd.v24.i19.2943.
[9]	Hepatobiliary Specialized Committee of China Association of Chinese Medicine, Liver Diseases Specialized Committee of China Medical Association of Minorities. The clinical guidelines of diagnosis and treatment of chronic hepatitis B with traditional Chinese medicine(2018)[J]. J Clin Hepatol, 2018, 34(12): 2520-2525. DOI: 10.3969/j.issn.1001-5256.2018.12.007. 中华中医药学会肝胆病专业委员会, 中国民族医药学会肝病专业委员会. 慢性乙型肝炎中医诊疗指南(2018年版)[J]. 临床肝胆病杂志, 2018, 34(12): 2520-2525. DOI: 10.3969/j.issn.1001-5256.2018.12.007.
[10]	ZHANG MY, LIANG HQ, WU CC, et al. Discussion on the etiology and pathogenesis of liver stagnation and spleen deficiency syndrome of chronic hepatitis B based on the theory of liver and spleen[J]. Lishizhen Med Mater Med Res, 2020, 10: 2444-2446. DOI: 10.3969/j.issn.1008-0805.2020.10.041. 张满英, 梁惠卿, 吴春城, 等. 基于肝脾理论的慢乙肝肝郁脾虚证证候漂变的病因病机探讨[J]. 时珍国医国药, 2020, 10: 2444-2446. DOI: 10.3969/j.issn.1008-0805.2020.10.041.
[11]	ZHANG CT, HU XY, ZHOU DJ, et al. Randomized, controlled clinical study about treaing HBeAg positive chronic asymptomatic hepatitis B virus carriers based on 'Kidney Deficiency Fuxie' theory[J]. Chin J Exp Med Formul, 2014, 20(3): 175-179. DOI: 10.11653/syfj2014030175. 张传涛, 扈晓宇, 周道杰, 等. 基于"肾虚伏邪"理论论治HBeAg阳性慢性无症状乙型肝炎病毒携带者的临床观察[J]. 中国实验方剂学杂志, 2014, 20(3): 175-179. DOI: 10.11653/syfj2014030175.
[12]	HAN L, ZHENG XR. Discussion on treating chronic hepatitis B from kidney theory[J]. J Shaanxi Univ Chin Med, 2019, 42(1): 44-46. DOI: 10.13424/j.cnki.jsctcm.2019.01.015. 韩乐, 郑旭锐. 慢性乙型肝炎从肾论治理论探讨[J]. 陕西中医药大学学报, 2019, 42(1): 44-46. DOI: 10.13424/j.cnki.jsctcm.2019.01.015.
[13]	GAO YQ, WANG LT. Discussion and study on Chinese medicine syndrome types of chronic hepatitis B[J]. Chin J Basic Med Tradit Chin Med, 2003, 9(9): 40-41. DOI: 10.3969/j.issn.1006-3250.2003.08.016. 高月求, 王灵台. 慢性乙型肝炎中医证型研究探讨[J]. 中国中医基础医学杂志, 2003, 9(9): 40-41. DOI: 10.3969/j.issn.1006-3250.2003.08.016.
[14]	ZHU LL, MENG H, JIANG J, et al. Study on TCM syndrome typing of chronic hepatitis B[J]. Chin J Integr Trad West Med, 2008, 28(1): 20-23. DOI: 10.3321/j.issn:1003-5370.2008.01.007. 朱蕾蕾, 孟虹, 蒋健, 等. 慢性乙型肝炎中医证型分类的研究[J]. 中国中西医结合杂志, 2008, 28(1): 20-23. DOI: 10.3321/j.issn:1003-5370.2008.01.007.
[15]	ZHU XJ, SUN XH, ZHOU ZH, et al. Lingmao formula combined with entecavir for HBeAg-positive chronic hepatitis B patients with mildly elevated alanine aminotransferase: A multicenter, randomized, double-blind, placebo-controlled trial[J]. Evid Based Complement Alternat Med, 2013, 2013: 620230. DOI: 10.1155/2013/620230.
[16]	ZHANG JH, ZHANG X, ZHOU ZH, et al. Bushen Jianpi Formula combined with Entecavir for the treatment of HBeAg-negative chronic hepatitis B: A multicenter, randomized, double-blind, placebo-controlled trial[J]. Evid Based Complement Alternat Med, 2022, 2022: 6097221. DOI: 10.1155/2022/6097221.
[17]	LI M, ZHOU ZH, SUN XH, et al. The dynamic changes of circulating invariant natural killer T cells during chronic hepatitis B virus infection[J]. Hepatol Int, 2016, 10(4): 594-601. DOI: 10.1007/s12072-015-9650-0.
[18]	LI M, ZHOU ZH, SUN XH, et al. Hepatitis B core antigen upregulates B7-H1 on dendritic cells by activating the AKT/ERK/P38 pathway: a possible mechanism of hepatitis B virus persistence[J]. Lab Invest, 2016, 96(11): 1156-1164. DOI: 10.1038/labinvest.2016.96.
[19]	WU SF, WANG WJ, GAO YQ. Natural killer cells in hepatitis B virus infection[J]. Braz J Infect Dis, 2015, 19(4): 417-425. DOI: 10.1016/j.bjid.2015.05.006.
[20]	LI M, SUN XH, ZHU XJ, et al. HBcAg induces PD-1 upregulation on CD4⁺T cells through activation of JNK, ERK and PI3K/AKT pathways in chronic hepatitis-B-infected patients[J]. Lab Invest, 2012, 92(2): 295-304. DOI: 10.1038/labinvest.2011.157.
[21]	JI LS, GAO QT, GUO RW, et al. Immunomodulatory effects of combination therapy with bushen formula plus entecavir for chronic hepatitis B patients[J]. J Immunol Res, 2019, 2019: 8983903. DOI: 10.1155/2019/8983903.
[22]	LI M, ZHOU ZH, BAO T, et al. Beneficial effects of bushen formula combined with enticavir on chronic hepatitis B patients with suboptimal response to enticavir by regulating B-cell differentiation[J]. Cell Physiol Biochem, 2018, 48(2): 633-643. DOI: 10.1159/000491891.
[23]	ZHOU ZH, SUN XH, LI M, et al. Effect of kidney-tonifying and spleen-strengthening prescription on PD-1 and PD-L1 expression in HBeAg-positive chronic hepatitis B patients with slightly increased ALT levels[J]. J Clin Hepatol, 2015, 31(1): 58-62. DOI: 10.3969/j.issn.1001-5256.2015.01.013. 周振华, 孙学华, 李曼, 等. 补肾健脾方对ALT轻度升高的HBeAg阳性慢性乙型肝炎患者程序性死亡受体1/程序性死亡配体1表达的影响[J]. 临床肝胆病杂志, 2015, 31(1): 58-62. DOI: 10.3969/j.issn.1001-5256.2015.01.013.
[24]	LE F, ZHANG X, ZHU XJ, et al. Effects of Bushen Jianpi Recipe on NKT cell function in positive HBeAg chronic hepatitis B patients after entecavir treatment[J]. Acta Univ Tradit Med Sin Pharmacol Shanghai, 2018, 32(3): 22-27. DOI: 10.16306/j.1008-861x.2018.03.005. 乐凡, 张鑫, 朱晓骏, 等. 补肾健脾方对恩替卡韦经治HBeAg阳性慢性乙型肝炎患者NKT细胞功能的影响[J]. 上海中医药大学学报, 2018, 32(3): 22-27. DOI: 10.16306/j.1008-861x.2018.03.005.
[25]	ZHANG JH, ZHENG C, ZHU XJ, et al. Anti-inflammation antiviral effects and mechanisms of Bushen recipe based on MAVS mediated signal pathway[J]. Chin J Integr Tradit West Med Liver Dis, 2019, 29(2): 155-158, Back insert 7. DOI: 10.3969/j.issn.1005-0264.2019.02.019. 张景豪, 郑超, 朱晓骏, 等. 基于MAVS介导信号通路的补肾方抗炎抗HBV作用及机制研究[J]. 中西医结合肝病杂志, 2019, 29(2): 155-158, 后插7. DOI: 10.3969/j.issn.1005-0264.2019.02.019.
[26]	NIE H, MEI Z, WANG R, et al. Bushen recipe and its disassembled prescriptions inhibit inflammation of liver injury associated with concanavalin A through Toll-like receptor 3/9 signaling pathway[J]. Mol Med Rep, 2018, 18(2): 1682-1691. DOI: 10.3892/mmr.2018.9082.
[27]	LI M, SUN XH, ZHOU ZH, et al. Beneficial therapeutic effect of Chinese herbal Bushen formula on CHB patients with mildly elevated alanine aminotransferase by down-regulating CD4⁺CD25⁺T cells[J]. J Ethnopharmacol, 2013, 146(2): 614-622. DOI: 10.1016/j.jep.2013.01.038.
[28]	REVILL PA, CHISARI FV, BLOCK JM, et al. A global scientific strategy to cure hepatitis B[J]. Lancet Gastroenterol Hepatol, 2019, 4(7): 545-558. DOI: 10.1016/S2468-1253(19)30119-0.