Traditional Chinese medicine syndromes of chronic hepatitis B with precore mutant

ABM: This study aims at exploring the distribution of TCM syndromes in CHB patients with HBV pre-core mutation (1896) and the relationship between pre-core mutation and T lymphocytes subgroup, through which to provide objective data on clinical syndrome differentiation of TCM, and further to suggest the therapeutic principle and guide clinical treatment. METHODS: One hundred and forty CHB patients were evenly divided into two study groups, HBV pre-core mutant group and HBV pre-core wild-type group. Besides, 30 healthy blood donors were selected as a healthy control group. HBV-labeled compound, T lymphocytes subgroup, and HBV-DNA pre-core mutant were tested in the study groups. T lymphocytes subgroup were also tested in the control group. All the patients were both diagnosed by syndrome differentiation of TCM and western medicine. RESULTS: The most common syndrome in mutant group was damp-heat combined with blood stasis, and the most common syndrome in the wild-type group was damp-heat stasis in the middle-jiao. There were more cases of medium and severe hepatitis in mutant group than that in wild-type group. The content of CD4+ lymphocytes and CD4+/CD8+ ratio were decreased gradually (healthy control group>wild-type group>mutant group). In the wild-type group, severe and medium CHB patients had considerably lower level of them than mild CHB patients. However, in the mutant group, the opposite result appeared. Meanwhile, the content of HBV-DNA in mutant group was higher than that in wild-type group. CONCLUSION: Damp, heat, toxin and blood stasis were the basic pathogens of CHB, whether pre-core mutant or not. CHB with precore mutant may lead to more severe hepatitis. The decreased content of CD4+ lymphocytes and ratio of CD4+/CD8+ may be taken as one of the indices in confirming the deficiency syndrome of CHB patients with pre-core mutation.

Traditional Chinese herbal medicine plus triple therapy in treating Helicobacter pylori-induced chronic atrophic gastritis: a meta-analysis and cumulative meta-analysis

Objectives:To evaluate the benefits of traditional Chinese herbal medicine(TCHM)plus triple therapy(TT)in the management of Helicobacter pylori(H.pylori)-induced chronic atrophic gastritis(CAG).Methods:A comprehensive access and electronic database search were carried out from inception to June 2020.Prospective randomized trials(TCHM plus TT vs.TT)were selected to assess the eradication rate of H.pylori(ER of H.pylori),clinical symptom relief rate(SRR),treatment-related adverse reactions(TRAR)and 95%confidence intervals(CI)in the meta-analysis and cumulative meta-analysis(CMA).Meta-regression analysis was used to analyze heterogeneity between studies and publication bias.Results:33 studies contained 3,226 participants were included.Compared with the TT group,TCHM plus TT group showed a significantly higher ER of H.pylori(OR=4.14,95%CI:3.21-5.35;P=0.000)and SRR(OR=4.50,95%CI:3.59-5.64).Meanwhile,the TRAR of TCHM plus TT remedy was significantly lower than TT monopoly(RR=0.43,95%CI:0.29-0.64;P=0.000).The results of the CMA,sorted by publication year,duration of treatment,and sample size,confirmed that combined treatment remedy was superior to TT monopoly in respect of ER of H.pylori and SRR.Conclusions:The present study obtained reliable and convincing evidence suggesting that TCHM plus TT remedy was efficacious and safe in treating H.pylori-induced CAG.

Beneficial Effects of Traditional Chinese Medicine Fuzheng Huayu on the Occurrence of Hepatocellular Carcinoma in Patients with Compensated Chronic Hepatitis B Cirrhosis Receiving Entecavir:A Multicenter Retrospective Cohort Study

Background and Aims:The application of antifibrotic drugs to treat patients with chronic liver diseases who are receiving antiviral therapies for hepatocellular carcinoma(HCC)has not been established.Here,we aimed to assess the impact of the Traditional Chinese Medicine Fuzheng Huayu(FZHY)on the occurrence of HCC in patients with hepatitis B virus-related compensated cirrhosis receiving the antiviral drug entecavir(ETV).Methods:A multicenter retrospective cohort study was performed.Compensated liver cirrhosis patients were divided into the ETV+FZHY group or the ETV group according to treatment.The cumulative incidence of HCC was analyzed using Kaplan-Meier and log-rank tests.Propensity score matching was used for confounding factors.Stratified analysis and Cox regression were used to determine the effects of FZHY on the occurrence of HCC and liver function decompensation.Results:Out of 910 chronic hepatitis B patients,458 were in the ETV+FZHY group and 452 were in the ETV group.After propensity score matching,the 5-year cumulative incidence of HCC was 9.8%in the ETV+FZHY group and 21.8%in the ETV group(p<0.01).The adjusted hazard ratio for HCC was 0.216(0.108,0.432)when FZHY treatment was>36 months.Age,diabetes,alanine aminotransferase,-glutamyl transpeptidase,albumin,hepatitis B e-antigen,and fibrosis 4 score were associated with the occurrence of HCC.FZHY decreased the risk of HCC in patients aged>45 years with a hepatitis B virus DNA level of2,000 IU/l.Conclusion:Adjunctive FZHY treatment reduced HCC occurrence in patients with hepatitis B virus cirrhosis who were treated with ETV,possibly due to the antifibrotic properties of FZHY.

Antiviral effect of Chinese medicine jiaweisinisan in hepatitis B virus transgenic mice

AIM： To study the antiviral effect of Chinese medicine jiaweisinisan （JWSNS） on hepatitis B virus （HBV） infection in transgenic mice （TGM）. METHODS： Twenty two 6-8 wk old HBV TGM in the third generation were divided into TGM control group and TGM treated group randomly. The normal control group included ten normal BC 57L/6 mice at the same age. The mice in treated group were administrated with JWSNS at the concentration of 4 g/mL and the dosage of 50 g/kg per d for 30 d, while the mice in TGM control group and normal control group were administrated with normal saline at the same dosage and the same time. Polymerase chain reaction （PCR） was used to assess the contents of HBV DNA in serum of HBV TGM before and after treatments, whereas blot hybridization was utilized to measure the contents of HBV DNA in the liver of both HBV TGM and normal BC 57L/6 mice. RESULTS： The levels of serum HBV DNA in TGM treated group were remarkably decreased after the treatment of JWSNS （7.662±0.78 vs 5.22±3.14, P〈0.05）, while there was no obvious change after administration of normal saline in TGM control group （7.125±4.26 vs 8.932 ± 5.12, P〉 0.05）. The OD values of HBV DNA in the livers of the mice in TGM treated group were significantly lower than those of TGM control group （0.274±0.096 vs 0.432 ± 0.119, P 〈 0.01）. CONCLUSION： JWSNS exerts suppressive effects on HBV DNA in the serum and liver of TGM.

Chinese Consensus on Combination Therapy of Chronic Hepatitis B

In May 2011,editorial boards of Chinese Journal of Experimental and Clinical Infectious Diseases (Electronic Edition),Chinese Journal of Liver Diseases (Electronic Edition) and Infection International (Electronic Edition) organized an expert committee to form an expert consensus on antiviral combination therapy of chronic hepatitis B (CHB).The consensus publication promoted and standardized the combination therapy concept of chronic hepatitis B.Clinical evidence of combination therapy for CHB is incomplete.The concept of combination therapy is gradually extended,from combination of antiviral drugs plus antiviral drugs,to antiviral drugs plus hepatoprotective drugs,and antiviral drugs plus immunomodulatory drugs.Therefore,editorial boards once again asked experts to analyze the new clinical evidence,and form the expert consensus on combination therapy of chronic hepatitis B.The formulation of this consensus is according to the principles of evidence-based medicine.Large number of clinical studies of combination therapy is still in progress.This consensus can not fully answer all the problems encountered in the combination therapy of CHB.With the progress of clinical practice of antiviral therapy,and the accumulation of evidence in combination therapy,the expert committee will update the consensus timely.

Five-year Treatment with Tenofovir Alafenamide Achieves High Rates of Viral Suppression,Alanine Aminotransferase Normalization,and Favorable Bone and Renal Safety in Chinese Chronic Hepatitis B Patients

Background and Aims:After 3-years(144 week)of double-blind treatment in Chinese chronic hepatitis B patients in two ongoing phase 3 studies,tenofovir alafenamide(TAF)showed similar efficacy to tenofovir disoproxil fumarate(TDF),with improved renal and bone safety.In this study,we aimed to report the 5-year results from 2 years into the open-label TAF treatment phase.Methods:All participants completing the 144-week double-blind treatment were eligible to receive open-label TAF 25 mg once daily up to week 384.Serial analysis of viral suppression(hepatitis B virus DNA<29 IU/mL),alanine aminotransferase normalization,serological responses,and safety outcomes at year 5(week 240)was performed.Results:The openlabel phase included 93%(311/334)of the enrolled participants,which included 212 who switched from double-blind TAF to open-label TAF(TAF-TAF)and 99 who switched from double-blind TDF to open-label TAF(TDF-TAF).Baseline characteristics were comparable.Week 240 viral suppression rates were similar between groups[93.4%vs.93.9%;difference:-1.5%,(95%CI:-6.4 to-3.5),p=0.857].Alanine aminotransferase normalization and serological response rates were higher in the TAF-TAF group than in the TDF-TAF group.The frequencies of adverse events and laboratory abnormalities were low and similar between groups.Both groups had similar small numerical declines from baseline in estimated glomerular filtration rate at year 5(week 240,-2.85 mL/min vs.-3.29 mL/min,p=0.910).The greater declines in renal and bone parameters in the TDF-TAF group through week 144 improved after switching to TAF.Conclusions:The 5-year TAF treatment efficacy was high and similar to that of 3-year TDF followed by 2-year TAF in Chinese chronic hepatitis B patients.Favorable effects on bone and renal parameters were sustained with TAF treatment alone and were observed following the switch from TDF to TAF.

Distribution of Traditional Chinese Medicine patterns in 324 cases with hepatitis B-related acute-on-chronic liver failure:a prospective,cross-sectional survey

OBJECTIVE： To determine the distribution of Tradi- tional Chinese Medicine （TCM） patterns in hepatitis B-related acute-on-chronic liver failure （HB-ACLF） in different stages for guiding clinical prescriptions and treatments. METHODS： A prospective, cross-sectional survey method was used in this study. A total of 324 cases with HB-ACLF in China were involved. RESULTS： The general frequency of TCM patterns in HB-ACLF were as follows： Heat Toxin Stagnation Pattern （134/324, 41.36%）, Damp-heat Obstruction Pattern （66/324, 20.37% ）, Yong Qi Deficiency Pat- tern （52/324, 16.05%）, and Liver and Kidney Yin De- ficiency Pattern （26/324, 8.02%）. In the early stage of HB-ACLE there was a remarkably higher percent- age of excessive patterns than those in the middle and late stage. The incidence of Heat Toxin Stagna- tion reached 58.57% （82/140） in the early stage, while it was 33.96% （36/106） in the middle stage and 20.51% （16/78） in the late stage. In the early stage of HB-ACLF, excessive patterns, such as the Heat Toxin Stagnation Pattern, were more preva- lent than those in the middle and late stages （P〈a＇= 0.003）. However, in the late stage of HB-ACLE defi- cient patterns, such as the Yang Qi Deficiency Pat- tern, were more prevalent than those in the early and middle stages. The Yang Qi Deficiency Pattern had a higher rate of 41.03% （32/78） in the late stage compared with that of 20.75% （22/106） in the middle stage and 8.57% （12/140, P〈a＇ =0.003） in the early stage. The distribution of the other pat- terns was not significant between the three stages （P〉0.003）. CONCLUSIONS： There are four major patterns of HI3-ACLF, including the Heat Toxin Stagnation Pat- tern, the Damp-heat Obstruction Pattern, the Yang Qi Deficiency Pattern, and the Liver and Kidney Yin Deficiency Pattern. The Heat Toxin Stagnation and Yang Qi Deficiency Patterns are the representative patterns in the early and late stages of HB-ACLF. In the middle stage of HB-ACLF, the TCM patterns vary in a complicated manner, with no significant differ- ence among the patterns. Treatment for HB-ACLF should vary with the different representative pat- terns in the early and late stages.

A Systematic Review of RCTs and quasi-RCTs on Traditional Chinese Patent Medicines for Treatment of Chronic Hepatitis B

Traditional Chinese patent medicines (TCPMs) are widely used for treatment of chronic hepatitis B (CHB) in China. To estimate the overall effectiveness of TCPMs for CHB, we performed a systematic review of clinical reports designed as randomized controlled trials (RCTs). One hundred and thirty-eight available RCTs and quasi-RCTs on 62 TCPMs, involving 16,393 patients, were included. The methodological quality of these trials was generally "poor". Few trials (6.52%) reported the methods of randomization correctly. Another common problem was the lack of allocation concealment, proper blinding, and the reporting of lost cases and dropouts. Forty-two trials (30.43%) on 27 TCPMs reported some anti-viral effect of TCPMs. Others reported beneficial aspects, including improvements of liver function (79.71% of the studies), liver fibrosis (29.99%), and CHB symptoms (92.75%). Forty-one articles (29.71%) reported mild adverse events with TCPMs but these occurred infrequently. In summary, the outcome of the report on currently registered TCPMs may be biased due to poor methodology. The data from these trials, therefore, is too weak to use in forming a recommendation for treatment of CHB. Nevertheless, five drugs (Dan Shen agents, Da Huang Zhe Chong pill/capsule, Shuang Hu Qing Gan granule, Fu Zheng Hua Yu granule and Cao Xian Yi Gan capsule) appear to be more effective than the other TCPMs.

Clinical efficacy and safety of TCM prescriptions combined with nucleoside(acid)analogues in treating chronic hepatitis B:a meta-analysis

Objective There are many clinical reports on traditional Chinese medicine(TCM)combined with nucleoside(acid)analogues(NAs)for the treatment of chronic hepatitis B(CHB),but its efficacy and safety are not completely clear.This meta-analysis aims to evaluate the clinical efficacy and safety thus providing evidence for clinical applications.Methods We searched Chinese databases the China National Knowledge Infrastructure(CNKI),Wanfang Data,and China Science and Technology Journal Database(VIP),as well as English databases Pub Med and Cochrane Library,from time of establishment to April 14,2021.Literature quality was evaluated according to the bias risk assessment criteria of Cochrane Collaboration network.Rev Man 5.3 and Stata 12.0 software were used to perform this research.Results A total of 23 articles,3282 patients,and 25 TCM prescriptions were included in this study.NAs plus TCM remarkably improved the clinical total effective rate[Odds ratio(OR)=3.92,P<0.00001],TCM syndrome score(Mean difference=-3.73,P<0.00001),hepatitis B virus(HBV)DNA negative conversion rate(OR=1.49,P=0.0001),hepatitis Be antigen(HBe Ag)negative conversion rate(OR=2.03,P<0.00001),alanine aminotransferase levels[Std mean difference(SMD)=-0.95,P<0.00001],and aspartate aminotransferase levels(SMD=-0.70,P=0.0004).Adverse reaction rates did not increase in the combined treatment group(OR=0.97,P=0.84).A comprehensive analysis of the 25 TCM prescriptions suggested that the combination of spleen-strengthening prescriptions with NAs showed better effects than other prescriptions.Conclusion TCM in combination with NAs,demonstrated better clinical efficacy against CHB than NAs alone.In addition,the combination of spleen-strengthening prescriptions and NAs was identified as the best therapeutic strategy.However,more randomized controlled trials of high quality are needed to provide more reliable clinical basis for the application of TCM.

Qingre Lishi Tuihuang therapy for acute icteric hepatitis B: A systematic review

Objective:To assess the efficacy of Qingre Lishi Tuihuang therapy (QLTT) for acute icteric hepatitis B infection.Methods:Eight electronic databases were searched from inception to December 2016 with no language restrictions for reports of randomized controlled trials evaluating the effect of QLTT treating acute icteric hepatitis B.Two researchers independently extracted detailed data and assessed methodological quality.ReviewManager 5.3.0 software was used to analyze the data.Results:A total of 13 randomized controlled trials involving 2238 participants were included in this review.The methodological quality was generally poor.The results indicated that supplemented Yinchenhao decoction combined with non-specific treatments was more effective in improving the cure rate (risk ratio =1.80;95% CI 1.21-2.68) and reducing the serum levels of total bilirubin (mean difference =-29.74;95% CI-31.91 to-27.57) and aspartate aminotransferase.Other self-made prescriptions conforming to QLTT plus non-specific treatments had beneficial effect for acute icteric hepatitis B in curing this disease (risk ratio =1.48;95% CI 1.27-1.73),as well as for negative seroconversion of HBeAg (risk ratio =1.39;95% CI 1.11-1.74).Supplemented Yinchenhao decoction plus non-specific treatments was more effective than other self-made prescriptions conforming to QLTT in reducing serum total bilirubin level.Conclusion:Qingre Lishi Tuihuang therapy appears to improve effect based on non-specific treatments for the treatment of acute icteric hepatitis B.However,it is premature to draw confirmative conclusions,owing to the poor methodological quality and high clinical heterogeneity of the included trials.Further well-designed clinical randomized controlled trials with large sample sizes should be undertaken.

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

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.

Correlation between Traditional Chinese Medicine symptom patterns and serum concentration of zinc,iron,copper and magnesium in patients with hepatitis B and associated liver cirrhosis

OBJECTIVE:To investigate the correlation between the patterns of Traditional Chinese Medicine(TCM)syndromes and the serum concentration of zinc,iron,copper and magnesium of patients with chronic hepatitis B(CHB) and hepatitis B virus(HBV)-induced liver cirrhosis.METHODS:A total of 86 patients were included in the study between March 1,2009 and January 1,2010.All were diagnosed with CHB or HBV-induced liver cirrhosis according to the diagnosis standard of the Chinese Medical Association.Fasting serum concentrations of zinc,iron,copper and magnesium were measured.Patients were classified into different patterns of TCM symptoms according to TCM theory and clinical experience.RESULTS:In the HBV-induced liver cirrhosis group,the mean zinc concentration in patients with the TCM pattern of stagnation of fluid-Dampness was lower than that in patients with obstruction of collaterals by Blood stasis(P < 0.034).In the CHB group,the mean magnesium concentration in patients with toxic Heat flourishing was significantly lower than that in those with Damp-Heat in the Liver and Gallbladder,and those with Liver depression and Spleen deficiency(P < 0.021).The concentrations of iron and copper showed little difference among the different TCM symptom patterns.CONCLUSION:The serum zinc and magnesium concentrations correlated with certain TCM patterns of symptoms in patients with HBV-induced liver cirrhosis and CHB.It may be helpful to interpret the pathogenic change in the TCM symptom patterns in liver cirrhosis and CHB,and also to conduct clinical treatment of the diseases based on identified TCM patterns.

Guidelines for diagnosis and treatment of hepatic fibrosis with integrated traditional Chinese and Western medicine(2019 edition)

In 2006, the Hepatology Committee of Chinese Association of Integrative Medicine issued the "Guidelines for the Prevention and Treatment of Liver Fibrosis with Integrated Traditional Chinese and Western Medicine." In recent years, the fields of Chinese medicine, Western medicine, and integrative medicine have made rapid advances in basic and clinical research into chronic liver disease, and accumulated new evidence for the prevention and treatment of hepatic fibrosis. Therefore, in order to meet clinical needs, liver disease experts of integrated traditional Chinese and Western medicine were united to revise the previous guidelines in order to help physicians make correct and reasonable decisions in the diagnosis and treatment of hepatic fibrosis.

Chinese Herbal Medicine Combined with Entecavir for HBeAg Positive Chronic Hepatitis B:Study Protocol for a Multi-Center,Double-Blind Randomized-Controlled Trial

Background： The domestic prevalence of chronic hepatitis B （CHB） in China is 7.18% in 2006, imposing great societal healthcare burdens. Nucleot（s）ide analogues （NUCs） anti-hepatitis B virus （HBV） therapies are widely applied despite the relatively low rate of seroconversion and high risk of drug-resistant mutation. More effective treatments for CHB deserve further explorations. Combined therapy of NUCs plus Chinese herbal medicine （CHM） is widely accepted in China, which is recognized as a prospective alternative approach. The study was primarily designed to confirm the hypothesis that Tiaogan-Yipi Granule （调肝益脾颗粒, TGYP） or Tiaogan-Jianpi-Jiedu Granule （调肝健脾解毒颗粒, TGJPJD） plus entecavir tablet （ETV） was superior over ETV monotherapy in enhancing HBeAg loss rate. Methods： The study was a nationwide, large-scale, multi-center, double-blind, randomized, placebo-controlled trial with a designed duration of 108 weeks. A total of 16 hospitals and 596 eligible Chinese HBeAg positive CHB patients were enrolled from November 2012 to September 2013 and randomly allocated into 2 groups in 1：1 ratio via central randomization system： experimental group （EG） and control group （CG）. Subjects in EG received CM formulae （TGYP or TGJPJD, 50 g per dose, twice daily） plus ETV tablet （or ETV placebo） 0.5 mg per day in the first 24 weeks （stage 1）, and CHM granule plus ETV tablet （0.5 mg per day） from week 25 to 108 （stage 2）. Subjects in CG received CHM Granule placebo plus E＇IV tablet （0.5 mg per day） for 108 weeks throughout the trial. The assessments of primary outcomes （HBV serum markers and HBV-DNA） were conducted by a third-party College of American Pathologists （CAP） qualified laboratory. Adverse effects were observed in the hospitals of recruitment. Discussion： The study was designed to compare the curative effect of CM plus E＇IV and ETV monotherapy in respect of HBeAg loss, which is recognized by the European Association for the Study of the Liver as ＂a valuable endpoint＂. We believe this trial could provide a reliable status for patients＇ ＂joumey＂ towards durable responses after treatment discontinuation. The trial was registered before recruitment on Chinese Clinical trial registry （No. ChiCTR-TRC-12002784, Version 1.0, 2015/12/23）.

茯苓甘草合剂辅助西药对慢性阻塞性肺疾病合并肌肉衰减患者NF-κB信号通路的影响

目的探讨茯苓甘草合剂辅助西药对慢性阻塞性肺疾病(COPD)合并肌肉衰减NF-κB信号通路的影响及分子机制。方法选取2020年8月至2022年8月COPD合并肌肉衰减患者104例,作为研究对象随机数字表法分为对照组和观察组,每组52例。对照组给予西药治疗,观察组给予西药+茯苓甘草合剂治疗。统计2组中医疗效、不良反应及治疗前后中医证候积分、NF-κB mRNA、蛋白及因子[白细胞介素-8(IL-8)、白细胞介素-1(IL-1)、肿瘤坏死因子-α(TNF-α)]、营养状况指标[转铁蛋白(Tf)、血红蛋白(Hb)、白蛋白(ALB)]、肌肉衰减相关指标[握力试验、起立-行走计时测试(TUGT)、5次坐立试验(FTSST)、肌少症筛查问卷(SARC-F)]。结果观察组中医治疗总有效率[86.54%(45/52)]高于对照组[67.31%(35/52)](P<0.05);治疗1个月、3个月后观察组中医证候积分低于对照组(P<0.05);治疗1个月、3个月后观察组NF-κB mRNA、NF-κB蛋白、IL-8、IL-1、TNF-α低于对照组(P<0.05);治疗3个月后观察组握力高于对照组,FTSST、TUGT、SARC-F评分低于对照组(P<0.05);治疗期间,2组均未出现明显不良反应。结论茯苓甘草合剂辅助西药治疗COPD合并肌肉衰减效果确切,可通过抑制NF-κB信号通路,减轻炎性反应,改善患者营养状态,有效改善临床症状,且安全性高。

Key Symptoms Selection for Two Major SyndromesDiagnosis of Chinese Medicine in Chronic Hepatitis B

To identify key symptoms of two major syndromes in chronic hepatitis B (CHB), which can be the clinical evidence for Chinese medicine (CM) doctors to make decisions. Standardization scales on diagnosis for CHB in CM were designed including physical symptoms, tongue and pulse appearance. The total of 695 CHB cases with dampness-heat (DH) syndrome or Pi (Spleen) deficiency (SD) syndrome were collected for feature selection and modeling, another 275 CHB patients were collected in different locations for validation. Key symptoms were selected based on modified information gain (IG), and 5 classifiers were applied to assist with models training and validation. Classification accuracy and area under receiver operating characteristic curves (AUC) were evaluated. (1) Thirteen DH syndrome key symptoms and 13 SD syndrome key symptoms were selected from original 125 symptoms; (2) The key symptoms could achieve similar or better diagnostic accuracy than the original total symptoms; (3) In the validation phase, the key symptoms could identify syndromes effectively, especially in DH syndrome, which average prediction accuracy on 5 classifiers could achieve 0.864 with the average AUC 0.772. The selected key symptoms could be simple DH and SD syndromes diagnostic elements applied in clinical directly. (Registration N0.: ChiCTR-DCC-10000759).

白介素⁃15基因多态性与中西医结合治疗HBeAg阴性慢性乙型肝炎患者疗效的关联性分析

目的分析白介素-15(IL-15)基因多态性与中西医结合治疗乙型肝炎病毒e抗原(HBeAg)阴性慢性乙型肝炎(CHB)患者疗效的关联性。方法将312例HBeAg阴性CHB患者随机分为治疗组、对照组,每组156例,两组均给予西医抗病毒治疗,在此基础上,治疗组加用补肾健脾利湿颗粒,对照组加用补肾健脾利湿颗粒安慰剂,疗程为1年。比较两组的治疗应答率,观察血清IL-15水平的变化情况;挑选IL-15基因的标签单核苷酸多态性(SNPs),并进行基因分型,分析IL-15基因多态性与治疗应答的关联性。结果①最终完成试验者306例,其中治疗组155例、对照组151例。②两组治疗应答率比较,差异无统计学意义(P>0.05)。③治疗前后组内比较,治疗组血清HBsAg水平降低、IL-15水平升高(P<0.05),对照组血清HBsAg水平降低(P<0.05);组间治疗后比较,血清HBsAg、IL-15水平差异有统计学意义(P<0.05)。④治疗后,两组治疗应答患者血清IL-15水平升高、无应答患者血清IL-15水平降低(P<0.05),治疗组应答患者血清IL-15水平高于治疗组无应答患者(P<0.05)。⑤关联分析结果显示,有5个SNPs与治疗应答有显著性关联证据,分别为rs6819823、rs2857261、rs10519612、rs10519613、rs1057972(P<0.05)。⑥治疗前,治疗组应答患者rs6819823 TT基因型血清IL-15水平低于GG基因型、rs2857261 AA基因型血清IL-15水平低于GG基因型、rs1057972 AA基因型患者血清IL-15水平低于TT基因型(P<0.05);治疗后,携带rs6819823、rs2857261、rs10519612、rs10519613、rs1057972最小等位基因的纯合子和杂合子患者血清中IL-15水平上升(P<0.05)。结论IL-15基因遗传变异及IL-15表达水平变化与中西医结合治疗HBeAg阴性CHB的临床疗效存在关联。

Chinese Medicine for Treatment of Chronic Hepatitis B

Contemporary Western medicines approved by the U.S. Food and Drug Administration （FDA） for the treatment of chronic hepatitis B （CHB）, although available in China, have high costs, or major side effects and limited effectiveness. Research efforts have focused on looking for natural products as alternative medicines with low cost and good safety for CHB treatment. Chinese medicine （CM） has ancient, time-honored theories about methods of diagnosis and treatment for liver diseases. In recent decades, a large number of clinical trials and pre-clinical studies, which were performed in China and other countries, indicated that CM has potential benefit in several aspects of the treatment of CHB, e.g., anti-inflammatory, anticancer, antioxidant, immunomodulating, antifibrosis, and antiviral. However, there are many concerns regarding the study design and the quality of clinical trials. Further larger, stringently designed, double-blind, placebo control, randomized clinical trials and long-term follow-up are needed to provide conclusive evidence of their efficacy and safety. Components of CM deserve further study in pre-clinical models of HBV infection and in clinical trials world-wide.

DNA Methylation and Transcription of HLA-F and Serum Cytokines Relate to Chinese Medicine Syndrome Classification in Patients with Chronic Hepatitis B

Objective:To explore the molecular bases of Chinese medicine(CM) syndrome classification in chronic hepatitis B(CHB) patients in terms of DNA methylation,transcription and cytokines.Methods:Genome-wide DNA methylation and 48 serum cytokines were detected in CHB patients(DNA methylation:15 cases;serum cytokines:62 cases) with different CM syndromes,including dampness and heat of Gan(Liver) and gallbladder(CHB1,DNA methylation:5 cases,serum cytokines:15 cases),Gan stagnation and Pi(Spleen) deficiency(CHB2,DNA methylation:5 cases,serum cytokines:15 cases),Gan and Shen(Kidney) yin deficiency(CHB3,DNA methylation:5 cases,serum cytokines:16 cases),CHB with hidden symptoms(HS,serum cytokines:16 cases) and healthy controls(DNA methylation:6 cases).DNA methylation of a critical gene was further validated and its mRNA expression was detected on enlarged samples.Genome-wide DNA methylation was detected using Human Methylation 450 K Assay and further verified using pyrosequencing.Cytokines and mRNA expression of gene were evaluated using multiplex biometric enzyme-linked immunosorbent assay(ELISA)-based immunoassay and reverse transcription-quantitative polymerase chain reaction(RT-qPCR),respectively.Results:Totally 28,667 loci,covering 18,403 genes were differently methylated among CHB1,CHB2 and CHB3(P<0.05 and|△β value|> 0.17).Further validation showed that compared with HS,the hg19 CHR6:29691140 and its closely surrounded 2 CpG loci were demethylated and its mRNA expressions were significantly up-regulated in CHB1(P<0.05).However,they remained unaltered in CHB2(P>0.05).Levels of Interleukin(IL)-12 were higher in CHB3 and HS than that in CHB1 and CHB2 groups(P<0.05).Levels of macrophage inflammatory protein(MIP)-1αand MIP-1β were higher in CHB3 than other groups and leukemia inhibrtory factor level was higher in CHB1 and HS than CHB2 and CHB3 groups(P<0.05).IL-12,MIP-1α and MIP-1β concentrations were positively correlated with human leukocyte antigen F(HLA-F)mRNA expression(R;=0.238,P<0.05;R;=0.224,P<0.05;R;=0.447,P<0.01;respectively).Furthermore,combination of HLA-F mRNA and differential cytokines greatly improved the differentiating accuracy among CHB1,CHB2 and HS.Conclusions:Demethylation of CpG loci in 5’ UTR of HLA-F may up-regulate its mRNA expression and HLA-F expression was associated with IL-12,MIP-1α and MIP-1β levels,indicating that HLA-F and the differential cytokines might jointly involve in the classification of CM syndromes in CHB.(Registration No.ChiCTR-RCS-13004001)

中医三联疗法对脾肾两虚型多囊卵巢综合征不孕症患者卵泡发育、血清INHB水平及妊娠情况的影响

目的探究中医三联疗法对脾肾两虚型多囊卵巢综合征(PCOS)不孕症患者卵泡发育、血清抑制素B(INHB)水平及妊娠情况的影响。方法采用随机数字表法将选取的72例2022年6月至2023年1月于河北生殖妇产医院进行治疗的脾肾两虚型PCOS不孕症患者分为观察组(n=36)和对照组(n=36)。对照组采用克罗米芬进行治疗,观察组在对照组基础上给予中医三联疗法,比较两组患者的卵泡发育情况、激素水平和血清INHB水平、妊娠率。结果两组治疗6个月后的成熟卵泡数均比治疗3个月后有显著提升,且观察组治疗3个月、6个月后的成熟卵泡数均高于对照组(P<0.05);两组治疗3个月、6个月后的黄体生成素(LH)水平均较治疗前有所降低,卵泡刺激素(FSH)和血清INHB水平较治疗前有所提升,且观察组LH水平降低幅度、FSH和血清INHB水平升高幅度均较对照组显著(P<0.05);治疗3个月和6个月后,观察组妊娠率高于对照组,差异具有统计学意义(P<0.05)。结论中医三联疗法能够显著改善脾肾两虚型PCOS不孕症患者的卵泡发育情况,提高其血清INHB水平及妊娠率。