| BackgroundChronic hepatitis B(CHB)is one of the world’s three major chronic diseases,with the global hepatitis B carriers of about 100 million people.For patients with HBeAg-positive CHB,the fibrosis staging is higher than that of patients with HBeAg-negative CHB,so the former are more likely to develop cirrhosis and have more opportunities for clinical decompensation and hepatocellular carcinoma(HCC).Early and accurate diagnosis of early liver fibrosis is critical to the control and treatment of the disease in the vesting period.At present,the "gold standard" of liver fibrosis diagnosis is still liver biopsy,but because of the many defects of liver biopsy,the clinic medicine has been looking for a better noninvasive means of detection.With the vigorous development of glycomics,in terms of the pathogenesis of liver disease,early diagnosis and treatment,the application of glycomics has made some progress and provided a new way of thinking for the diagnostic study of liver disease.In the case of liver disease,especially liver fibrosis,N-glycomics detection is expected to become the basis for early noninvasive diagnosis of liver disease and may provide effective means for clinically early diagnosis.The results of the previous study showed that HBeAg-negative CHB could not only improve the TCM syndrome,but also prevent liver injury,andpromote the recovery of liver function as well as inhibit HBV replication and prevent or delay the disease progression of HBeAg-negative CHB patients.Therefore,it is necessary to combine the clinical efficacy and detection indicators,by analyzing the changes in the level of related cytokines before and after intervention,to reveal the therapeutic mechanism of the invigorating kidney and eliminate pathogenic method.Objectives1.To identify the biomarkers associated with HBeAg-negative CHB liver fibrosis by the used of glycomics,and to find early noninvasive diagnosis of liver diseases.2.To discuss the theory of "homogeny of liver and kidney" and the possible mechanism of the invigorating kidney and eliminate pathogenic method.Methods1.Based on the analysis of N-glycoside,this study evaluated the value of multi-index combined diagnostic model related to N-carbohydrate chain and N-carbohydrate chain in the differential diagnosis and follow-up visit of liver fibrosis.The study adopted the method of DSA-FACE to detect the serum N-glycoside map of 174 subjects(144 patients with HBeAg-negative CHB liver fibrosis and 30 normal people as the control group),and compared the characteristic changes of liver fibrosis of different degrees,and analyzed the differences between the peaks.A multi-parameter combined diagnosis model based on N-glycoside biomarkers was established by logistics regression method.The diagnostic efficacy of each index was evaluated by ROC curve.2.A random,controlled and double-blind study was conducted on 120 patients with HBeAg-negative CHB.The patients were divided into two groups which were the control group and and experimental group.The subjects from experimental group took “Diwu Yanggan Anagraph” orally,apacket/time,2 times/day(taking after mixing it with warm water in the morning and evening);at the same time,they took orally entecavir,0.5mg/time,a time/day(with an empty stomach).30 healthy people in the same period were chosen as the control group.The course of treatment was 36 weeks.HBsAg,HBV DNA,Ⅳ-C,PCⅢ,LN,HA,TNF-β1,PDGF-BB,CTGF and VEGF in serum were observed and measured before and after treatment through CLDQ and SF-36 scale.The paired t test or independent-samples t test was used to analyze it.Results1.The two structure of N-carbohydrate chain(peak4 and Peak 8)can be used as the specific diagnostic biomarkers for distinguishing the degree of HBeAg-negative CHB liver fibrosis.Lg(p4 / p8)was of certain diagnostic efficacy in the identification of early and late liver fibrosis.The N-glycan combined model Ftest A and the combined diagnostic model of N-glycan and HA were established.ROC curve analysis showed that the area under the receiver operating curve(AUC)was 0.879(0.809-0.948)in the Ftest A model to determine the significant hepatic fibrosis(S>2)in HBeAg-negative CHB patients.The sensitivity,negative predictive value and accuracy were 90.0%,91.8% and 72.9%,respectively,taking 1.75 as the dividing value of the significant hepatic fibrosis;the specificity,positive predictive value and accuracy were 91.5%,82.4% and 83.8%,respectively,taking 5.05 as the dividing value of the diagnosing significant hepatic fibrosis.If liver biopsy was not carried out on patients with FtestB<5.01 and FtestB>7.54,then 70.3%(116/165)of the patients could avoid liver puncture,with the accuracy of 85.3%(99/116).At the same time,the area under the receiver operating curve(AUC)was0.879(0.809-0.948)in the Ftest B model to determine the significant hepatic fibrosis(S>2)in HBeAg-negative CHB patients.The sensitivity,negativepredictive value and accuracy were 90.5%,90.7% and 7 0.0%,respectively,taking 2.26 as the dividing value of the significant hepatic fibrosis;the specificity,positive predictive value and accuracy were 89.7%,75.0% and 74.6%,respectively,taking 5.82 as the dividing value of the diagnosing significant hepatic fibrosis.If liver biopsy was not carried out on patients with FtestB<5.01 and FtestB>7.54,then 70.3%(116/165)of the patients could avoid liver puncture,with the accuracy of 85.3%(99/116).The above diagnostic model was applied to each validation group.There was no significant difference in AUC between the validation group and the model group.The diagnostic value of the model was similar in the two groups.2.The baseline characteristics of the two groups of patients with chronic hepatitis B were well comparable.After intervened with the invigorating kidney and eliminate pathogenic method,(1)HBV DNA negative conversion:there was no significant difference between the HBV DNA negative conversion of the experiment group and that of the control group(P> 0.05);(2)liver function and coagulation function: after the treatment,the ALT and AST levels of two group were both significantly higher than those before the treatment(P <0.01),and the ALT and AST levels of the experiment group after the treatment were significantly lower than those of the control group after the treatment(P <0.01).PT of the two groups after the treatment was lower than that before the treatment,but the difference was not statistically significant(P> 0.05);(3)liver fibrosis index: the levels of Ⅳ-C,PCⅢ,LN and HA in the two groups after the treatment were significantly lower than those before the treatment(P <0.01),and the the levels of IV-C,PC Ⅲ,LN and HA of the experiment group after the treatment were lower than those of the control group after the treatment(P <0.01);(4)liver fibrosis related cytokines : the levels of TGF-β1,PDGF-BB,CTGF and VEGF of the two groups were significantly lower than those before the treatment(P <0.01);the levels ofTGF-β1,PDGF-BB,CTGF and VEGF of the experiment group after the treatment were significantly lower than those of the control group after the treatment(P <0.05);(5)quality of life: CLDQ and the SF-36 scores of the patients from the experiment group were significantly higher than those in the control group(P <0.05),and the SF-36 scores of the patients from the control group also significantly increased(P <0.05).Conclusion1.N-carbohydrate chain lg(p4 / p8)is expected to be a specific diagnostic biomarker to identify the degree of HBeAg-negative CHB liver fibrosis;the diagnostic efficacy of the N-glycan biomaker and HA combined diagnostic model can be significantly improved and they can be used for the dynamic monitoring and efficacy evaluation of the progression.2.The invigorating kidney and eliminate pathogenic method can effectively treat HBeAg-negative CHB.On the basis of reducing the replication of virus and improving the liver function,it can also significantly improve the clinical symptoms and the quality of life of the HBeAg-negative chronic hepatitis B patients as well as delay the progression of disease;one of the possible mechanisms of action of the invigorating kidney and eliminate pathogenic method for treating HBeAg-negative CHB is to achieve anti-hepatic fibrosis through regulating the expression of hepatic fibrosis-related cytokines(TGF-β1,PDGF-BB,CTGF and VEGF)in patients with anti-hepatic fibrosis. |
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