The Natural Outcome Of Patients With Chronic Hepatitis B Virus Infection In The Immune Tolerant Phase

Objective:Combined with longitudinal follow-up and cross-sectional study of patients with chronic hepatitis B virus infection in the immune tolerant phase to explore the clinical characteristics of the patients, analysis the different outcome predictors, and further improve the natural history of chronic HBV infection.Methods:This study combined a dynamics retrospective cohort study and cross-sectional prevalence survey.Collecting regular,comprehensive,clinical monitoring case data of patients with chronic hepatitis B virus infection in the immune tolerant phase previously diagnosed and Newly diagnosed patients during the period from 2013 January to 2015 March in Affiliated Hospital of Yan’an University of a total of 218 cases.The main follow-up included the basic information of the patients with chronic hepatitis B virus infection in the immune tolerant phase and hepatitis B virus marker,hepatits B virus deoxyribonucleic acid, blood biochemical examination of liver function,liver stiffness measurement values in the whole process.The clinical end point was made from different clinical outcome. Using SPSS19.0 software carry out statistical analysis, comparing multiple groups of sample mean by analysis of variance,comparing rates by the chi square test, comparing two samples mean by paired samples T test, the difference was statistically significant( P<0.05),correlation analysis by Pearson correlation analysis, determining the quantitative relationship between variables by regression analysis,wielding survival analysis by the Kaplan-Meier method to analyze different clinical outcome and drawing out the survival curve graphics,Log-rank test was performed on the graphics,multivariate analysis applied COX proportional hazard regression model.Results:1.Clinical followed-up time was 1 to 10 years, average and median follow-up time was 5 years. Untill the end of follow-up,there were 63 cases(28.90%) removing from immune tolerance state to the state of immune clearance, 3 cases(1.38%)of spontaneous HBs Ag lost and produced anti-HBs, 2 cases(0.92%) directly developed to liver cirrhosis without the phase immune clearance.2. cross-sectional study2.1Different age groups of CHB immune tolerance state of patients with family aggregation had significant difference; there was significant difference in gender distribution(χ2= 16.25 P=0.000); there was significant difference in ALT(F= 6.91 P=0.001); there was no significant difference in albumin(F= 1.81 P=0.168);there was no significant difference in globulin(F= 1.65 P=0.196); there was no significant difference in the HBs Ag(F= 1.45 P=0.239); there was significant difference in HBe Ag(F=5.19 P=0.007);HBVDNA(log10) had no significant difference(F=0.39 P=0.678).2.2 There was a positive correlation between the age and ALT、 BMI of patients with CHB infection in the immune tolerant phasel(r=0.252P=0.002),(r=0.222, P=0.005) and a negative correlation between the age and HBV DNA(log10), HBe Ag(r=-0.16, P=0.047)(r=-0.180 P=0.025); there was a negative correlation between albumin and globulin(r=-0.257 P=0.001); ALT and BMI had a positive correlation(r=0.2, P=0.013),ALT was negatively correlated with HBs Ag, HBe Ag(r=-0.228 P=0.004)(r=-0.185, P=0.021); HBs Ag and HBe Ag were positive correlation(r=0.376, P=0.000), HBs Ag had a negative correlation with BMI(r=-0.264 P=0.001).2.3There was a linear regression relation of CHB patients with immune tolerance of globulin and albumin, age, sex(b=-0.302, t=-3.248, P=0.001)(b=0.075, t=2.221, P=0.028)(b=1.924, t=2.434; P=0.016);there was a linear regression relation of albumin and age、sex、drinking(b=-0.270, t=-3.193,P=0.002),(b=-2.159,t=-3.193,P=0.002),(b=2.362,t=2.104, P=0.037); HBs Ag, HBe Ag, BMI and ALT had linear regression relation(b=-430.393, t=-2.96, P=0.004(b=0.012,t=4.518,P=0.000),(b=-2384.063, t=-3.36 P=0.001).3. longitudinal study3.1 At the end of follow-up the patients were divided into group of immune tolerance and immune clearance group according to the different natural history stage, there was a significant difference between two groups of age, family aggregation, drinking,gender,(t = 4.89, P = 0.000),(χ2=20.44 P= 0.000)(χ2=16.88 P=0.000),(χ2=5.942 P= 0.015), there was no significant difference between two groups of overworking(χ2=0.064 P = 0.800). there was no significant difference between the the starting point and the end point of immune tolerance group of globulin(t=0.937 P=0.352), ALT(t=0.6 P=0.55), HBs Ag(t=1.139 P=0.257), HBe Ag(t=0.6 P=0.55), HBVDNA(log10),(t=0.788 P=0.433); there was statistically significant difference between the the starting point and the end point of immune clearance group of globulin ALT(t=6.764, P=0.000), HBs Ag(t=3.66 P=0.001), HBe Ag(t=26.31 P=0.000), HBVDNA(log10)(t=18.07, P=0.000).3.2 At the end of follow-up, respectively, grouping with age, the level of HBVDNA, HBs Ag, HBe Ag levels at baseline, family aggregation, drinking, overworking, gender, age, the survival analysis showed, the older,lower baseline HBVDNA levels,drinking,no family aggregation,male were promoting the occurrence of immune clearance(χ2= 15.668, P = 0.000),( χ2 = 126.106, P =0.000),(χ2= 18.21, P = 0.000),(χ2 = 24.061, P = 0.000),(χ2= 5.618, P = 0.018);the baseline level of HBs Ag,HBe Ag and overworking had no Predictive value(χ2 = 2.444, P = 0.118),(χ2 = 0.485, P = 0.486),(χ2= 0.002, P = 0.964).3.3 Cox regression indicated that age,dinking were independent predictors of the occurrence of immune clearance,the relative risk ratios were 0.361(95%CI, 0.211-0.620, P=0.000) 1.327(95%CI, 0.303-0.909, P=0.021). Family aggregation was the protection factor of the tolerance state 3.027(95%CI 1.754-5.225, P=0.000).4. The hepatic pathology of the patients with chronic hepatitis B virus infection in the immune tolerant phase and the value of Fibroscan in diagnosis of these patients.Undergoing the liver biopsy and transient elastography for 67 patients transient,the result showed that the liver stiffness measurement value were mainly in F1, F2 stage, METAVIR stage were mainly in G2S1 phase, comparing the correlation between the liver biopsy and transient elastography with ROC receiver operating characteristic curve, the area under the ROC curve was 0.673, indicated that the liver stiffness measurement was of diagnostic significance for the patients of immune tolerance phase, but the accuracy was not very high.Conclusion:1.The patients with chronic HBV infection in immune tolerant phase should be followed up regularly, and monitor the biochemical, virus, liver fibrosis index, if necessary, liver biopsy is the antiviral treatment indications.2.In the immune tolerant phase, there was a positive correlation between the age and ALT、 BMI of patients, and a negative correlation between the age and HBV DNA(log10), HBe Ag ALT was negatively correlated with HBs Ag, HBe Ag; HBs Ag and HBe Ag are positive correlation.3. In the immune tolerant phase,the titer of HBs Ag and HBe Ag was stable up to 5log10IU/ml, 4log10IU/ml, respectively.4. In the transition from the immune tolerance to the immune clearance ALT was significantly increased and HBs Ag, HBe Ag,HBVDNA(log10)were decreased significantly.5. The occurrence of immune clearance influenced by genetic by age, gender, family aggregation, drinking, baseline HBVDNA,and age, drinking were independent predictive factors in patients with immune clearance, family aggregation was the protective factor for in a steady state of immune tolerance.6. The diagnostic value of liver stiffness measurement of Fibroscan had a significance for the patients in the immune tolerant phase but the diagnostic accuracy was not very high.May be related to insufficient sample size.