| Objective:1. To establish noninvasive diagnostic models of liver fibrosis and inflammation in patients with chronic HBV infection in the immune tolerant phase and in the immune clearance phase and to testify its applicational value, and to provide an important basis for formulating clinical anti-virus and anti-liver fibrosis treatment program and for evaluating the efficacy.2. To observe the clinical effect of the Integration of disease and syndrome therapy of Anti-Fibrosis treated liver fibrosis in chronic hepatitis B.Methods:1. Four hundred and sixty patients with chronic HBV infection in the immune tolerant phase (n=184) and in the immune clearance phase (n=276) respective who had undergone liver biopsy in the Capital Medical University Affiliated Beijing Ditan Hospital were stratified randomly divided into two groups:one for estimation group and one for validation group. Twenty common clinical and serum markers involved in the study were analyzed initially in the estimation group by logistic regression analysis to derive predictive models to discriminate the stages of fibrosis and inflammation. Cut-off value and Diagnostic accuracies were assessed by the receiver operating characteristic (ROC) curve analysis. It was also applied to the validation group to test its overall accuracy.2. Fifty-four patients with chronic hepatitis B were separated into Integration of disease and syndrome therapy group (n=36) and Western medicine therapy group (n=18) with prospective cohort study. The patients in both group were received the Anti-Viral treatment with adefovir dipivoxil (ADV) pills10mg/q.d for of six months, and the integration of disease and syndrome therapy group was also treated with syndrome differentiation of TCM of Anti-Fibrosis. The damp-heat syndrome received qin lian wen dan Decoction, and the liver depression and spleen deficiency received xiao yao powder and er chen Decoction, and the deficiency of both qi and yin received si jun zi Decoction and er zhi pill.500ml a day. The parameters including the TCM symptoms, blood, liver function, HBV-DNA as well as marks of liver fibrosis, such as hyaluronic acid (HA), PrecollagenⅢ(PC-Ⅲ), Type Ⅳ Collagen (IV-C), and Laminin (LN), and the noninvasive diagnostic Wang Ⅲ model were determined before and after treatment.Results:1. Wang Ⅰ、Wang Ⅱ、WangⅢ、Wang Ⅳmodels were established from the independent prediction factors of the different endpoints of the study were identified to predict the stage of liver fibrosis (S) and to predict the stage of liver inflammation (G) respectively. In the receiver operating characteristic (ROC) curve analysis, the area under the receiver operating characteristic curve (AUROC) for identifying the patients with chronic HBV infection in the immune tolerant phase of the significant fibrosis (S≥2) was0.879(0.809～0.948). Using a cut-off vale of Wang Ⅰ≤1.75, significant fibrosis could be excluded in45patients of the total patient population, and the sensitivity, negative predictive value and accuracy were90.0%,91.8%, and72.9%respectively. Similarly, applying a cut-off vale of Wang I>5.05, significant fibrosis could be identified correctly in28patients of the total patient population, and the specificity, positive predictive value and accuracy were91.5%,82.4%, and83.8%respectively. Restricting biopsy to patients with intermediate scores (Wang Ⅰ>5.05and Wang Ⅰ≤1.75) may prevent liver biopsies in74.8%of the patients while maintaining88.0%accuracy.AUROC for identifying the patients with chronic HBV infection in the immune tolerant phase of the significant inflammation (G>2) was0.835(0.760～0.910). Using a cut-off vale of Wang Ⅱ≤2.26, significant inflammation could be excluded in39patients of the total patient population, and the sensitivity, negative predictive value and accuracy were90.5%,90.7%, and70.0%respectively. Similarly, applying a cut-off vale of Wang Ⅱ>5.82, significant inflammation could be identified correctly in21patients of the total patient population, and the specificity, positive predictive value and accuracy were89.7%,75.0%, and74.6%respectively. Restricting biopsy to patients with intermediate scores (Wang Ⅱ>5.82and Wang Ⅱ≤2.26) may prevent liver biopsies in64.5%of the patients while maintaining84.5%accuracy.AUROC for identifying the patients with chronic HBV infection in the immune clearance phase of the significant fibrosis (S≥2) was0.820(0.757～0.883). Using a cut-off vale of WangⅢ≤1.89, significant fibrosis could be excluded in33patients of the total patient population, and the sensitivity, negative predictive value and accuracy were91.0%,78.6%, and74.7%respectively. Similarly, applying a cut-off vale of Wang Ⅲ>5.19, significant fibrosis could be identified correctly in56patients of the total patient population, and the specificity, positive predictive value and accuracy were90.9%,90.3%, and69.8%respectively. Restricting biopsy to patients with intermediate scores (WangⅢ>5.19and WangⅢ≤1.89) may prevent liver biopsies in62.7%of the patients while maintaining85.6%accuracy.AUROC for identifying the patients with chronic HBV infection in the immune tolerant phase of the significant inflammation (G≥2) was0.836(0.775～0.897). Using a cut-off vale of Wang Ⅳ≤5.01, significant inflammation could be excluded in23patients of the total patient population, and the sensitivity, negative predictive value and accuracy were89.6%,65.7%, and76.3%respectively. Similarly, applying a cut-off vale of Wang Ⅳ>7.54, significant inflammation could be identified correctly in76patients of the total patient population, and the specificity, positive predictive value and accuracy were90.0%,93.8%, and73.4%respectively. Restricting biopsy to patients with intermediate scores (WangIV>7.54and WangⅣ≤5.01) may prevent liver biopsies in70.3%of the patients while maintaining85.3%accuracy. There were no statistically significant differences in AUROC between the training groups and the validation groups (P<0.05).2. The two group patients of chronic hepatitis B is comparable in the baseline characteristics. The patients’symptoms of anorexia and hypodynamia are remarkable improved in Integration of disease and syndrome therapy group(P<0.05). Two groups can be significantly reduced HBV-DNA level. Integration of disease and syndrome therapy group can reduce the serum levels of AST and elevate ALB, and it shows marked effect on the basis of multiply serum marks of fibrosis in improving the abnormally increased of HA、 IV-C and LN, and it also can lower the Wang Ⅲ index significantly. Integration of disease and syndrome therapy group can enhance the overall efficiency of16.7%in anti-liver fibrosis than the Western medicine therapy group.Conclusion:1. There are better accuracy and reproducible with the noninvasive diagnostic Wang models in evaluating the significant fibrosis and the significant inflammation of patients with chronic HBV infection in the immune tolerant phase as well as patients with chronic HBV infection in the immune clearance phase. It has good diagnostic value and practical significance, and may partially replace the liver biopsy.2. Integration of disease and syndrome therapy could improve clinical symptoms, liver function better, and could reduce marks of the serum fibrosis indexes and WangⅢ index efficiently. |
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