The “Traditional Chinese medicine regulating liver regeneration” treatment plan for reducing mortality of patients with hepatitis B-related liver failure based on real-world clinical data

Abstract

On the basis of real-world clinical data, the study aimed to explore the effect and mechanisms of the treatment plan of “traditional Chinese medicine (TCM) regulating liver regeneration.” A total of 457 patients with HBV-related liver failure were retrospectively collected. The patients were divided into three groups: the modern medicine control group (MMC group), patients treated with routine medical treatment; the control group combining traditional Chinese and Western medicine (CTW), patients treated with routine medical treatment plus the common TCM formula; and the treatment group of “TCM regulating liver regeneration” (RLR), patients treated with both routine medical treatment and the special TCM formula of RLR. After 8 weeks of treatment, the mortality of patients in the RLR group (12.31%) was significantly lower than those in the MMC (50%) and CTW (29.11%) groups. Total bilirubin level significantly decreased and albumin increased in the RLR group when compared with the MMC and CTW groups (P<0.05). In addition, there were significant differences in the expression of several cytokines related to liver regeneration in the RLR group compared with the MMC group. RLR treatment can decrease jaundice, improve liver function, and significantly reduce the mortality in patients with HBV-related liver failure. The mechanism may be related to the role of RLR treatment in influencing cytokines related to liver regeneration.

Keywords

hepatitis B virus-related liver failure / traditional Chinese medicine / liver regeneration / liver regeneration microenvironment / cytokines

References

[1] Ma Z, Wu Y. Current status of liver failure treatment. J Clinic Hepatol (Lin Chuang Gan Dan Bing Za Zhi) 2016; 32: 1668–1672 (in Chinese)

[2] Zhao ZG, Han T, Gao YT, Gao YY, Zhang Y, Wu ZP. Causes and clinical outcomes of acute-on-chronic liver failure in patients with hepatitis B virus infection: an analysis of 289 cases. World Chin J Dig (Shi Jie Hua Ren Xiao Hua Za Zhi) 2009; 17(31): 3269–3272 (in Chinese)

[3] Organization Committee of 13th Asia-Pacific Congress of Clinical Microbiology and Infection. 13th Asia-Pacific Congress of Clinical Microbiology and Infection Consensus Guidelines for diagnosis and treatment of liver failure. Hepatobiliary Pancreat Dis Int 2013; 12(4): 346–354

[4] Ning Q, Zhu L, Yan WM. Prewarning of severe acute aggravation of chronic hepatitis B. Chin J Hepatol (Zhonghua Gan Zang Bing Za Zhi) 2010; 18(11): 805–807 (in Chinese)

[5] Tan XM, Ning Q. The progress in molecular mechanism of severe hepatitis. Int J Epidemiol Infect Dis (Guo Ji Liu Xing Bing Xue Chuan Ran Bing Xue Za Zhi) 2004; 31: 150–157 (in Chinese)

[6] Li HM. Basic and clinical research of traditional Chinese medicine regulating and controlling liver regeneration. Chin Arch Tradit Chin Med (Zhonghua Zhong Yi Yao Xue Kan) 2017; 35: 1927–1931 (in Chinese)

[7] Liver Failure and Artificial Liver Group, Chinese Society of Infectious Diseases, Chinese Medical Association. Diagnostic and treatment guidelines for liver failure (2012 version). Chin J Hepatol (Zhonghua Gan Zang Bing Za Zhi) 2013; 21(3): 177–183 (in Chinese)

[8] Zhou SN, Zhang N, Wang LF, Li J. Clinical research of hepatitis B-related liver failure by TCM and WM combination therapy. Chin Hepatol (Gan Zang) 2012; 17: 36–38 (in Chinese)

[9] Li HM. Progress and prospect of regulation of liver regeneration by traditional Chinese medicine. World Chin J Dig (Shi Jie Hua Ren Xiao Hua Za Zhi) 2017; 25(15): 1338 (in Chinese)

[10] Wang LF, Li J, Li FY. Analysis the curative efficacy of combination of Chinese and Western medicine treatment the hepatitis B virus associated hepatic failure. Chin J Integr Tradit West Med Liver Dis (Zhong Xi Yi Jie He Gan Bing Za Zhi) 2018; 28: 70–74 (in Chinese)

[11] Gong M, Zhou C, Zhang N. Clinical effect of integrated traditional Chinese and Western medicine therapy in patients with hepatitis B virus-related acute-on-chronic liver failure complicated by hepatic encephalopathy. J Clinic Hepatol (Lin Chuang Gan Dan Bing Za Zhi) 2018; 34: 795–800 (in Chinese)

[12] Li HM, Ye ZH, Zhang J, Gao X, Chen YM, Yao X, Gu JX, Zhan L, Ji Y, Xu JL, Zeng YH, Yang F, Xiao L, Sheng GG, Xin W, Long Q, Zhu QJ, Shi ZH, Ruan LG, Yang JY, Li CC, Wu HB, Chen SD, Luo XL. Clinical trial with traditional Chinese medicine intervention “tonifying the kidney to promote liver regeneration and repair by affecting stem cells and their microenvironment” for chronic hepatitis B-associated liver failure. World J Gastroenterol 2014; 20(48): 18458–18465

[13] Li HM. Discussion on the treatment principle of “tonifying the kidney to regulate stem cells transforming the liver”. Chin Arch Tradit Chin Med (Zhonghua Zhong Yi Yao Xue Kan) 2012; 30: 937–940 (in Chinese)

[14] Li HM. Regulation of liver regeneration: research progress and prospect. World Chin J Dig (Shi Jie Hua Ren Xiao Hua Za Zhi) 2015; 23(21): 3337–3343 (in Chinese)

[15] Li HM. The unbalance of EMT/MET and “marrow cells cannot differentiate into liver cells”. Chin J Integr Tradit West Med Liver Dis (Zhong Xi Yi Jie He Gan Bing Za Zhi) 2012; 21: 385–389 (in Chinese)

[16] Li HM. Evolution rule of jaundice syndromes in chronic sever hepatitis. Chin J Integr Tradit West Med Liver Dis (Zhong Xi Yi Jie He Gan Bing Za Zhi) 2009; 19: 148–150 (in Chinese)

[17] Li HM. Comprehensive and systematic in-depth study on traditional Chinese medicine for regulating liver regeneration. Chin J Integr Tradit West Med Liver Dis (Zhong Xi Yi Jie He Gan Bing Za Zhi) 2007; 17: 129–132 (in Chinese)

[18] Li HM, Gao X, Yan XS, Ming AP, Peng YQ. Study on molecular mechanism of Zuoguiwan in promoting bone marrow cells to form hepatic cells. J Tradit Chin Med (Zhong Yi Za Zhi) 2006; 47: 778–780 (in Chinese)

[19] Song HL, Li HM, Lin LS, Gao X, Zhao BB, Zhang J, Wu Y, Yan XS, Xiao L. Effects of Diwuyanggan capsule on liver regeneration of rat with deficiency of kidney essence and liver blood. Chin J Integr Tradit West Med Liver Dis (Zhong Xi Yi Jie He Gan Bing Za Zhi) 2013; 23: 90–92 (in Chinese)

[20] Li HM. Basic and clinical research of “tonifying the kidney to regulate stem cells transforming the liver” for liver diseases. World Sci Technol/Modernization Tradit Chin Med Mater Med (Shi Jie Ke Xue Ji Shu—Zhong Yi Yao Xian Dai Hua) 2013; 15: 1425–1428 (in Chinese)

[21] Gao X, Ye ZH, Dai L, Li HM. Molecular mechanism research of Zuogui Pill about “tonifying kidney to promote liver regeneration and repair by effecting stem cells and their microenvironment” by using the network pharmacology method. Chin J Integr Tradit West Med Liver Dis (Zhong Xi Yi Jie He Gan Bing Za Zhi) 2018; 28: 96–99 (in Chinese)

[22] Li HM, Gao X, Yan XS, Ming AP, Peng YQ, Li JJ. Promotion effect of Zuoguiwan on bone marrow cells’ forming into liver cells in mice. World Chin J Dig (Shi Jie Hua Ren Xiao Hua Za Zhi) 2005; 13: 2818–2822 (in Chinese)

[23] Li HM, Xiang G, Yan XS. Studies of Zuogui Wan medicated serum pharmacology based on the co-culture system of bone marrow stem cells and hepatocytes. J Clin Rehabil Tissue Eng Res (Zhongguo Zu Zhi Gong Cheng Yan Jiu Yu Lin Chuang Kang Fu) 2010; 14: 3527–3532 (in Chinese)

[24] Li HM, Yan XS, Luo JJ, Li JJ, Gao X, Ming AP, Peng YQ. Effect of Zuogui Wan drug serum on the differentiation of bone marrow mesenchymal stem cells into hepatocytes. J Clin Rehabil Tissue Eng Res (Zhongguo Zu Zhi Gong Cheng Yan Jiu Yu Lin Chuang Kang Fu) 2007; 11: 5465–5468 (in Chinese)

[25] Li HM, Yan XS, Ming AP, Peng YQ, Luo JJ, Lan SB, Gao X. The differentiation of marrow stromal cells into hepatocyte by conditioned medium of liver cells in vitro. Chin J Integr Tradit West Med Liver Dis (Zhong Xi Yi Jie He Gan Bing Za Zhi) 2005; 15: 28–30, 67 (in Chinese)

[26] Li HM, Gui WJ, Li JJ, Gao X, Yan XS, Cheng Y. Effects of Zuoguiwan on the liver regeneration related gene signaling pathway in female mice with male mice bone marrow transplant. J Clin Rehabil Tissue Eng Res (Zhongguo Zu Zhi Gong Cheng Yan Jiu Yu Lin Chuang Kang Fu) 2008; 12: 6069–6073 (in Chinese)

[27] Li HM, Gao X, Yan XS, Ming AP, Peng YQ. Analysis of gene expression profile of bone marrow cells forming liver cells. Chin J Integr Tradit West Med Liver Dis (Zhong Xi Yi Jie He Gan Bing Za Zhi) 2006; 16: 212–214, 217 (in Chinese)

[28] Li HM, Gao X, Zhou MS. Effects of Zuogui Pill on gene expression profile of regenerate hepatic tissue in MSG-liver regeneration-rat. China J Tradit Chin Med Pharm (Zhonghua Zhong Yi Yao Za Zhi) 2006; 21: 104–106 (in Chinese)

[29] Li HM, Gao X, Zhou MS. Zuogui Pill regulating gene expression profile in liver of MSG-induced liver regeneration in rats. Chin J Basic Med Tradit Chin Med (Zhongguo Zhong Yi Ji Chu Yi Xue Za Zhi) 2005; 11: 595–598 (in Chinese)

[30] Li HM, Yang ML, Mei JJ, Zhang LT, Qiu XF. The effects of Zuogui Pill on expression of TGF-α,β and it’s receptor in ARN and regenerative liver of the MSG-regeneration-rat. Chin J Hepatol (Zhonghua Gan Zang Bing Za Zhi) 2004; 12(5): 307–308 (in Chinese)

[31] Li HM, Gao X, Yang ML, Mei JJ, Zhang LT, Qiu XF. Effects of Zuogui Wan on neurocyte apoptosis and down-regulation of TGF-β1 expression in nuclei of arcuate hypothalamus of monosodium glutamate-liver regeneration rats. World J Gastroenterol 2004; 10(19): 2823–2826

[32] Li HM, Yang ML, Mei JJ, Zhang LT, Qiu XF. Apoptosis of hypothalamic neural cell and genetic expression of TGF-β1 in MSG-liver regeneration-rats. Chin J Appl Physiol (Zhongguo Ying Yong Sheng Li Xue Za Zhi) 2003; 19: 46–47, 93 (in Chinese)

[33] Xu CL, Hao YH, Lu YP, Tang ZS, Yang XC, Wu J, Zheng X, Wang BJ, Liu J, Yang DL. Upregulation of Toll-like receptor 4 on T cells in PBMCs is associated with disease aggravation of HBV-related acute-on-chronic liver failure. J Huazhong Univ Sci Technolog Med Sci 2015; 35(6): 910–915

[34] Zhao ZH, Fan YC, Zhao Q, Dou CY, Ji XF, Zhao J, Gao S, Li XY, Wang K. Promoter methylation status and expression of PPAR-g gene are associated with prognosis of acute-on-chronic hepatitis B liver failure. Clin Epigenetics 2015; 7(1): 115

[35] Fujiwara K, Yasui S, Yokosuka O. Corticosteroid and nucleoside analogue for hepatitis B virus-related acute liver failure. World J Gastroenterol 2015; 21(36): 10485–10486

[36] Cao Z, Li F, Xiang X, Liu K, Liu Y, Tang W, Lin L, Guo Q, Bao S, Xie Q, Wang H. Circulating cell death biomarker: good candidates of prognostic indicator for patients with hepatitis B virus related acute-on-chronic liver failure. Sci Rep 2015; 5(1): 14240

[37] Wang J, Yu Y, Yang Y, Wu SS, Zhu HH, Liu YN, Liu WX, Hu Y, Wu W, Xia CX, Chen Z. Expression of serum sCD163 in patients with liver diseases and inflammatory disorders. Int J Clin Exp Pathol 2015; 8(7): 8419–8425

[38] Porowski D, Wirkowska A, Hryniewiecka E, Wyzgał J, Pacholczyk M, Pączek L. Liver failure impairs the intrahepatic elimination of interleukin-6, tumor necrosis factor-α, hepatocyte growth factor, and transforming growth factor-β. BioMed Res Int 2015; 2015: 934065

[39] Zeng W, Xiao J, Zheng G, Xing F, Tipoe GL, Wang X, He C, Chen ZY, Liu Y. Antioxidant treatment enhances human mesenchymal stem cell anti-stress ability and therapeutic efficacy in an acute liver failure model. Sci Rep 2015; 5(1): 11100

[40] Manzini BM, da Silva Santos Duarte A, Sankaramanivel S, Ramos AL, Latuf-Filho P, Escanhoela C, Kharmandayan P, Olalla Saad ST, Boin I, Malheiros Luzo AC. Useful properties of undifferentiated mesenchymal stromal cells and adipose tissue as the source in liver-regenerative therapy studied in an animal model of severe acute fulminant hepatitis. Cytotherapy 2015; 17(8): 1052–1065

[41] Ma HC, Shi XL, Ren HZ, Yuan XW, Ding YT. Targeted migration of mesenchymal stem cells modified with CXCR4 to acute failing liver improves liver regeneration. World J Gastroenterol 2014; 20(40): 14884–14894

[42] Chiang CH, Wu WW, Li HY, Chien Y, Sun CC, Peng CH, Lin AT, Huang CS, Lai YH, Chiou SH, Hung SI, Chang YL, Lan YT, Liu DM, Chien CS, Huo TI, Lee SD, Wang CY. Enhanced antioxidant capacity of dental pulp-derived iPSC-differentiated hepatocytes and liver regeneration by injectable HGF-releasing hydrogel in fulminant hepatic failure. Cell Transplant 2015; 24(3): 541–559

[43] Cienfuegos JA, Rotellar F, Baixauli J, Martínez-Regueira F, Pardo F, Hernández-Lizoáin JL. Liver regeneration—the best kept secret. A model of tissue injury response. Rev Esp Enferm Dig 2014; 106(3): 171–194

[44] Xiao JQ, Shi XL, Tan JJ, Zhang L, Xu Q, Ding YT. A novel treatment regimen for acute liver failure based on a combination of mesenchymal stem cells transplantation and IL-lRa-loaded chitosan nanoparticles. Chin J Hepatol (Zhonghua Gan Zang Bing Za Zhi) 2013; 21(4): 308–314 (in Chinese)

[45] Xiao JQ, Shi XL, Ma HC, Tan JJ, zhang L, Xu Q, Ding YT. Administration of IL-1Ra chitosan nanoparticles enhances the therapeutic efficacy of mesenchymal stem cell transplantation in acute liver failure. Arch Med Res 2013; 44(5): 370–379

[46] Yoon M, Kim MY. The anti-angiogenic herbal composition Ob-X from Morus alba, Melissa officinalis, and Artemisia capillaris regulates obesity in genetically obese ob/ob mice. Pharm Biol 2011; 49(6): 614–619

[47] Zhang T, Chen D. Anticomplementary principles of a Chinese multiherb remedy for the treatment and prevention of SARS. J Ethnopharmacol 2008; 117(2): 351–361

[48] Ríos JL. Chemical constituents and pharmacological properties of Poria cocos. Planta Med 2011; 77(7): 681–691

[49] Lee HY, Kim SW, Lee GH, Choi MK, Chung HW, Lee YC, Kim HR, Kwon HJ, Chae HJ. Curcumin and Curcuma longa L. extract ameliorate lipid accumulation through the regulation of the endoplasmic reticulum redox and ER stress. Sci Rep 2017; 7(1): 6513

[50] Uchio R, Higashi Y, Kohama Y, Kawasaki K, Hirao T, Muroyama K, Murosaki S. A hot water extract of turmeric (Curcuma longa) suppresses acute ethanol-induced liver injury in mice by inhibiting hepatic oxidative stress and inflammatory cytokine production. J Nutr Sci 2017; 6: e3

[51] Liang B, Guo XL, Jin J, Ma YC, Feng ZQ. Glycyrrhizic acid inhibits apoptosis and fibrosis in carbon-tetrachloride-induced rat liver injury. World J Gastroenterol 2015; 21(17): 5271–5280

[52] Isaza JH, Ito H, Yoshida T. A flavonol glycoside-lignan ester and accompanying acylated glucosides from Monochaetum multiflorum. Phytochemistry 2001; 58(2): 321–327

[53] Wang CM, Yuan RS, Zhuang WY, Sun JH, Wu JY, Li H, Chen JG. Schisandra polysaccharide inhibits hepatic lipid accumulation by downregulating expression of SREBPs in NAFLD mice. Lipids Health Dis 2016; 15(1): 195

[54] Liao WY, Tsai TH, Ho TY, Lin YW, Cheng CY, Hsieh CL. Neuroprotective effect of paeonol mediates anti-inflammation via suppressing Toll-like receptor 2 and Toll-like receptor 4 signaling pathways in cerebral ischemia-reperfusion injured rats. Evid Based Complement Alternat Med 2016; 2016: 3704647

[55] Liu PJ, Miao MS, Gao JL. Effect of gross polysaccharide of Radix Rehmanniae Preparata on levels of whole blood cells and serum macrophage colony stimulating factor in mice with both qi and blood deficiency. J Clin Rehabil Tissue Eng Res 2008; 12: 7543–7546

[56] Li FS, Xu HG, Li MY, Liu H. Stndy on immunological properties of polysaccharide extracted from rehmanniae preparata. Chin J Publ Health 2008; 24: 1109–1110

[57] Sherman RE, Anderson SA, Dal Pan GJ, Gray GW, Gross T, Hunter NL, LaVange L, Marinac-Dabic D, Marks PW, Robb MA, Shuren J, Temple R, Woodcock J, Yue LQ, Califf RM. Real-world evidence—what is it and what can it tell us? N Engl J Med 2016; 375(23): 2293–2297

Acknowledgements

The present study was financially supported by the National Natural Science Foundation of China (Nos. 81973669, 81703912, and 81603484), the financial support of the Research Project for Practice Development of National TCM Clinical Research Bases (JDZX2015172), and Program of Hanmin Li Famous and Old TCM master’ Inheritance Studio.

Compliance with ethics guidelines

Ling Dai, Xiang Gao, Zhihua Ye, Hanmin Li, Xin Yao, Dingbo Lu, and Na Wu declare that they have no conflict of interest. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. The Ethics Committee of Hubei Province Hospital of Traditional Chinese Medicine reviewed and approved the protocol and patient consent form prior to initiation of the study (approval number, 2006001). Informed consent was obtained from all patients who provided blood samples.

RIGHTS & PERMISSIONS

2020 Higher Education Press