| Objective:This study aimed to systematically evaluate the related data and methodological quality of clinical randomized and controlled trials of traditional Chinese medicine(TCM)treatment on PBC,so as to provide evidence-based medical evidence for TCM prevention and treatment.And observing the effects of Tongdan Decoction on liver enzymes and TAM molecular family levels of PBC patients and model mice,to further discuss the effects of Tongdan Decoction.Methods:1.The part of system evaluation:Use the search term(English search term "Primary biliary cirrhosis" OR "Primary biliary cholangitis" OR "PBC" AND "Chinese medicine" OR "Herb medicine" AND"Randomized controlled trial(RCT)";Chinese search term(Chinese medicine.syndrome differentiation,traditional Chinese medicine,agent,prescription,soup)AND(primary biliary cirrhosis OR primary biliary cholangitis OR PBC)AND(random))to search PubMed database.Cochrane Library,Embase,China National Knowledge Internet(CNKI),Weipu Journal Resource Integration Service Platform(VIP),Wan Fang data,Chinese biomedical database(CBM).The literatures of clinical randomized and controlled trials.of the treatment on PBC with traditional Chinese medicine were collected,and the quality evaluation and data extraction of the literature were strictly followed by evidence-based medicine.The data was analyzed using Review Manager 5.3.The publication bias was analyzed using a funnel plot.2.The part of clinical research:PBC patients who were admitted to Department of Hepatology and Gastroenterology of our hospital from January 2016 to January 2019 were enrolled.According to the inclusion criteria and exclusion criteria,100 patients were finally enrolled,80 patients were randomly selected by SPSS and randomly divided into control group and treatment group.General information such as age,gender,and combined autoimmune diseases were collected when patients were enrolled.Liver enzyme indicators(ALP,GGT,AST,ALT,TB),Firbscan values,TAM family molecules(Axl,Mertk,Tyro-3,Gas6,Protein S)before and after treatment were tested.The patient's tongue,pulse,symptoms and signs were collected to differentiate patients.Patients in the control group were treated with UDCA alone,and patients in the treatment group were treated with UDCA and Tongdan Decoction(according to syndrome type addition and subtraction).Both groups were treated for 48 weeks.Student's t test,Fisher ?2(exact probability method)were used to compare the general data of patients,and the efficacy of intra-group and between groups before and after treatment.Pearson correlation analysis,ROC curve and COX regression model were used to explore the main enzymes of TAM family and PBC.Kaplan-Meier compared the cumulative incidence of early response in the two groups,and the COX regression model analyzed the factors associated with early response in patients.3.The part of animal experiment research:Thirty-six C57BL/6 mice were divided into 4 groups,A:control group,six C57BL/6 mice,no modeling,only given equal amount of distilled wate;B:model group,ten modeled PBC C57BL/6 mice were given equal volume of distilled water;C:positive group,ten modeled PBC C57BL/6 mice,given ursodeoxycholic acid capsule 0.1g/(kg·d);D:chinese medicine group,ten modeled PBC C57BL/6 mice,ursodeoxycholic acid capsule 0.1g/(kg·d)gavage.and administered at a dose of 1ml/100g·d Tongdan Decoction of a concentration of 2.1g/ml.The experimental animal model was constructed by intraperitoneal injection of polyl:C(polyinosinic acid)5 mg/kg.Mice intervention program was carried out at the 12th week of model establishment,with a total of 12 weeks of intervention.At the end of the intervention,the liver enzymes(ALP,GGT,AST,ALT,TB),appearance and weight,liver morphology,liver index,liver pathological specimens(HE staining and Sirus red staining),TAM receptor family molecular protein(Axl,Mer,Tyro3,Gas6,Protein S)were collected.Counting data using Kruskal-Wallis ?2 to undertake overall comparison,and then Mann-Whitney U to compare every two groups.The ANOVO test was used to compare the mouse measurement data,and the LSD/Dunnett T3 was used to compare every two groups.Results:1.The part of system evaluation:(1)A total of 15 articles were included in the systematic review.The baseline data of theexperimental and control groups of the 15 studies were comparable(P>0.05),the sample size ranged from 40 to 178,and the total number of patients in the 15 studies was 1213.The control interventions in the 15 studies were treated by oral ursodeoxycholic acid plus and liver protection program,and the experimental group was treated with oral compound Chinese medicine or proprietary Chinese medicine based on the treatment of the control group.(2)Of the 15 studies,8 studies described random assignment methods,7 studies were random but did not describe random assignment methods;15 cases of allocation concealment methods and blind methods were unclear;14 studies had complete outcome reports,1 study did not have incomplete outcome;the plan reports for 15 studies were not available.(3)In terms of clinical response rate,11 of the 15 studies observed the clinical response rate of patients.Compared with Western medicine alone,it suggested that the combination of Traditional Chinese Medicine(TCM)and Western medicine(test group)can effectively improve the clinical response rate of patients((Z=6.19,P<0.00001),OR=0.27(0.18,0.41)).The funnel plot suggests poor symmetry and publication bias.(4)Among the 15 studies,10 studies observed ALT,AST,TB,and ALP.The results showed that the combination of TCM and Western medicine was more effective in improving ALT level((Z=15.21,P<0.00001),MD=-13.82(-15.60,-12.04)),AST level((Z=11.74,P<0.00001),MD=-12.33(-14.39,-10.27)),TB level((Z=16.17,P<0.00001),MD=-10.06(-11.27,-8.44)),ALP level((Z=6.55,P<0.00001),MD=-49.42(-64.21,-34.62)).Funnel plot analysis suggests that there is a risk of publication bias.(5)11 studies observed GGT,and the results showed that the combination of TCM and Western medicine treatment(test group)was more effective in improving GGT level((Z=5.02,P<0.00001)?MD=-28.15(-39.15,-17.15)).Funnel plot analysis suggests that there is a risk of publication bias.(6)Six studies have observed IgM levels,and the results show that the combination of TCM and Western medicine treatment(test group)was more effective in improving IgM levels((Z=7.77,P<0.00001),MD=-0.98(-1.23,-0.73)).Funnel plot analysis suggests that there is a risk of publication bias.(7)Five studies have observed IgG levels,and the results show that the combination of TCM and Western medicine treatment(test group)was more effective in improving IgG levels((Z=4.86,P<0.00001),MD=-2.46(-3.45,-1.47)).Funnel plot analysis suggests that there is a risk of publication bias.(8)Four studies have observed IgA levels,and the results show that the combination of TCM and Western medicine(test group)was more effective and can better improve IgA levels((Z=3.21,P=0.001),MD=-0.52(-0.84,-0.20)).Funnel plot analysis suggests that there is a risk of publication bias.(9)A subgroup analysis of GGT was performed according to the course of treatment.Two studies were included in the subgroup of 6 weeks of treatment,and there was no significant difference between the two groups.One study was included in the subgroup of 18 weeks treatment,and it underwented descriptive analysis.Six and three studies were included in the subgroups of 24weeks and 48 weeks.The results showed that the treatment group were more effective((Z=3.68,P=0.0002,MD=-42.72(-65.49,-19.95);(Z=8.36,P=0.00001);MD=-13.72(-16.93,-10.05)).(10)A subgroup analysis of ALP was performed according to the course of treatment.The subgroups with 6 weeks,24 weeks and 48 weeks of treatment included two,seven and three studies.There were no significant differences between the two groups in the 6-week course((Z=1.42,P-0.16),MD=-52.54(-125.19,20.11)).But subgroup results of 24 weeks and 48 weeks showed that the treatment group was more effective((Z=8.81,P<0.00001),MD=-53.13(-64.95,41.32);(Z=6.22,P<0.00001),MD=-29.31(-38.54,-20.07)).(11)Few studies mentioned adverse reactions and events,and no meta-analysis was performed because of the large clinical heterogeneity and insufficient data.According to the research records,the main events of adverse reactions were nausea and vomiting,abdominal pain,diarrhea,urticaria,elevated total bile acid,and palpitations.Sensitivity analysis suggested that the meta-analysis results were stable and reliable.(12)Sensitivity analysis indicated that the meta-analysis results were stable and the results were reliable.2.The part of clinical research:(1)There were no significant differences in the baseline of age,sex ratio,and the proportion of other autoimmune diseases,AMA-M2,AMA-M4,AMA-M9 and ANA antibody-positive ratio and TCM syndrome type between the two groups(P>0.05).There were no significant differences in baseline liver enzymes ALP,GGT,ALT,AST,TB and TAM family(Axl,Mertk,Tyro-3,Gas6,Protein S)and Firbscan between the two groups(P>0.05).(2)The levels of ALP,GGT,ALT,AST,TB and Firbscan after treatment in the two groups were significantly lower than those before treatment(P<0.05).The improvement of ALP level and Firbscan level before and after treatment in the treatment group were significantly better than the control group(P<0.05).(3)The levels of Axl,Mertk,Gas6 and Protein S were significantly improved in the control group after treatment(P<0.05).The levels of Axl,Mertk,Gas6,Tyro-3 and Protein S in the treatment group were significantly improved after treatment(P<0,05).The improvement of Axl,Mertk,Gas6 and Protein S before and after treatment in the treatment group were significantly better than the control group(P<0.05).(4)The cumulative rate of early response in the treatment group was higher than control group(P<0.05),and the average response time of the treatment group was shorter than control group(P<0.05).(5)ALP was significantly correlated with Axl,Mertk,Tyro-3,Gas6(r=0.366,0.919,0.939,0.432,P=0.001,0.000,0.000,0.000<0.01);GGT was significantly correlated with Axl,Mertk,Tyro-3,Gas6(r=0.260,0.835,0.776,0.350,P=0.025,0.000,0.000,0.002<0.05);Firbscan was significantly correlated with Axl,Mertk,Tyro-3,Gas6(r=0.267,0.805,0.838,0.310,P=0.017,0.000,0.000,0.007<0.05).(6)The ROC curve showed that AUC Gas6=0.704(0.528-0.879),AUCMertk=0.944(0.891-0.997),AUC Tyro-3=0.942(0.884-0.999)(P<0.05)for the early response evaluation of Gas6,Mertk,and Tyro-3.Gas6 had a sensitivity of 0.833 and a specificity of 0.629 at 20.15.Mertk had a sensitivity of 1 at 22.73 and a specificity of 0.758.Tyro-3 had a sensitivity of 1.69 at 8.69 and a specificity of 0.790.(7)One-way COX regression analysis showed treatment group was positively correlated with early response(RR=38.885>1,P<0.05).TB,ALT,and AST were negatively correlated with patient response(RR=0.095,0.014,0.985<1,P<0.05).Axl,Mertk,and Tyro-3 were negatively correlated with patient response(RR=0.479,0.403,0.244<1,P<0.05).Protein S was positively correlated with whether the patient responded(RR=1.068>1,P<0.05).Multivariate COX regression analysis showed that the group(treatment group)was positively correlated with whether the patient responded(RR=5.265>1,P=0.000<0.05).(8)All patients had no adverse reactions directly related to treatment.3.The part of animal experiment research:(1)After the intervention,there was no significant difference in the appearance of the mice in the control group and model group.And the liver of the two groups had a clear outline.a normal structure,a smooth surface,and no significant difference in appearance color.In the model group,the liver of the mice was slightly larger and the texture was slightly tough.There was no significant difference in body weight between the two groups at 24 weeks(P>0.05).The liver index of the model group was significantly higher than that of the control group(P<0.05).(2)Compared with the control group,the positive rate of AMA-M2 in the model group was significantly increased(P<0.05).Compared with the model group,there was no significant difference in the positive rate of AMA-M2 in the positive group and the TCM group(P>0.05).(3)Compared with the control group,the ALP,GGT,ALT,AST,and TB levels in the model group were significantly higher(P<0.05).Compared with the model group,the ALP,GGT,ALT,AST,and TB levels in the positive group and the TCM group were significantly lower(P<0.05).Compared with the positive group,the ALP and TB levels in the TCM group were significantly lower(P<0.05).(4)The liver pathological pictures of the mice in the control group were almost normal.The liver pathological pictures of the mice in the model group showed changes in bile duct injury and granuloma structure in the portal area.The liver pathological pictures of the mice in positive group showed bile duct inflammation,and the degree of injury was less than that of the model group.The liver pathological picture of the mice in the traditional Chinese medicine group showed that a small amount of inflammatory cells infiltrated around the bile duct,and the portal area was slightly expanded.(5)Western Blot results showed that compared with the control group,the expression of Axl,Mertk,Tyro-3 and Gas6 protein in the model group were significantly increased,and the expression of Protein S protein was significantly decreased(P<0.05).Compared with the model group,the expression of Axl,Mertk and Tyro-3 protein in the positive group were significantly decreased.The expression of Axl,Mertk and Gas6 protein in the Chinese medicine group were significantly decreased,the expression of Protein S protein in the TCM group was significant increased(P<0.05).Compared with the positive group,the expression of Axl and Gas6 protein in the TCM group were significantly decreased,and the expression of Protein S protein was significantly increased(P<0.05).(6)qPCR results showed that compared with the control group,the expression of Axl,Mertk,Tyro-3 and Gas6 protein in the model group were significantly increased,and the expression of Protein S protein was significantly decreased(P<0.05).Compared with the model group,the expression of Axl,Mertk and Tyro-3 protein in the positive group were significantly decreased.The expression of Axl,Mertk and Gas6 protein in the Chinese medicine group were significantly decreased,and the expression of Protein S protein in the C hinese medicine group was significant increased(P<0.05).Compared with the positive group,the expression of Axl protein in the TCM group was significantly decreased,and the expression of Protein S protein was significantly increased(P<0.05).Conclusion:1.The systematic evaluation suggests that the clinical efficacy of TCM combined with UDCA is more significant.However,due to the low quality of the included studies,less mention and observation of adverse reactions,the results of this part should be cautious.2.Clinical studies shows that ursodeoxycholic acid combined with TCM is more efficient in treating PBC patients,and can be better improving the patient's TAM family molecular level.Further analysis reveals that the molecular level of the TAM family is closely related to the main enzymatic indicators and early responses of PBC.3.Animal experiment suggests that ursodeoxycholic acid combined with TCM can significantly improve the liver pathology of mice,reduce the liver enzymes and the levels of Axl and Gas6 of the mice. |
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