Retrospective Study Of Liver Pathological Changes,na(?)ve Antiviral Efficacy And Predictive Factors In Chronic Hepatitis B Patients With Normal Or Mildly Elevated Alanine Aminotransferase

Objective:1.To study the liver histological changes in chronic hepatitis B（CHB）patients with normal or mildly elevated alanine aminotransferase（ALT）and analyze the relevant factors;2.To investigate the predictive factors of significant liver histological changes in chronic hepatitis B patients with normal or mildly elevated ALT;3.Clinical efficacy analysis of antiviral therapy guided by liver biopsy in chronic hepatitis B patients with normal or mildly elevated ALT;4.To investigate the effects of different liver histological changes on the antivirus efficacy by analyzing the virological and serological responses;5.To compare the antiviral efficacy of different nucleoside（acid）analogues guided by liver biopsy.Methods:It was a retrospective study of 1210 chronic hepatitis B patients who had underwent liver biopsy from 2011 to 2018 in sichuan provincial people’s hospital,which included 958 chronic hepatitis B patients with complete baseline case data.A total of404 patients who had antiviral indications and complete antiviral data were analyzed.Results:1.958 chronic hepatitis B patients were divided into three groups according to different ALT levels:489 cases in the ALT<1×ULN（upper limit of normal）group,414cases in the 1×ULN≤ALT<2×ULN group,and 55 cases in the ALT≥2×ULN group.The ratios of significant liver inflammation activity（G≥2）in ALT<1×ULN group,1×ULN≤ALT<2×ULN group,ALT≥2×ULN group were 91.2%,93.0%and100.0%,respectively.The degree of inflammation and necrosis of liver tissue was gradually aggravated,and the total difference between the three groups was statistically significant（χ²=36.358,P<0.05）.The ratios of significant liver fibrosis（S≥2）in ALT<1×ULN group,1×ULN≤ALT<2×ULN group and ALT≥2×ULN group were 12.7%,23.4%and 36.4%,respectively.The degree of liver fibrosis was gradually aggravated,and the total difference between the three groups was statistically significant（χ²=29.058,P<0.05）.2.With the decrease level of serum HBV DNA in chronic hepatitis B patients,liver inflammation activity and fibrosis degree were aggravated,and the difference was statistically significant（χ²=22.880、32.815,P<0.05）.With the increase of age in chronic hepatitis B patients,liver inflammation activity and fibrosis degree were aggravated,and the difference was statistically significant（χ²=77.352、63.634,P<0.05）.3.Among the 958 chronic hepatitis B patients,532 were HBeAg-positive and 426were HBeAg-negative.The liver inflammatory activity grade and fibrosis stage of the HBeAg-negative patients were higher than those of the HBeAg-positive patients,the difference was statistically significant（χ²=35.696、29.211,P<0.05）.4.The expression intensity of HBcAg in liver tissue was negatively correlated with the degree of liver inflammation and fibrosis（r=-0.121、-0.165,P<0.05）.There was no correlation between the expression intensity of HBsAg in liver tissue and the degree of inflammatory activity or fibrosis（r=-0.041、-0.003,P>0.05）.5.Age was an independent predictor of significant liver inflammatory activity in chronic hepatitis B patients with ALT<2×ULN.Age,ALT and HBV DNA were independent predictors of significant liver fibrosis in chronic hepatitis B patients with ALT<2×ULN.6.The proportion of significant liver inflammation and necrosis in HBeAg-positive and HBeAg-negative patients with age≥30 years and 1.5×ULN≤ALT<2×ULN were 100%（40/40）and 97.8%（45/46）,respectively.7.The virological response rate was 82.9%in 404 chronic hepatitis B patients with normal or mildly elevated ALT who had been treated of antiviral after 48 weeks.The virological response rate was 74.3%in 214 HBeAg-positive patients and 92.6%in 190HBeAg-negative patients.The virological response rate of HBeAg-negative patients was higher than that of HBeAg-positive patients after 48 weeks of treatment,and the difference was statistically significant（χ²=23.884、P<0.05）.The virological response rate of chronic hepatitis B patients after 48 weeks of antiviral therapy was positively correlated with age,ALT and AST baseline level,and negatively correlated with serum HBV DNA baseline level,and the difference was statistically significant（P<0.05）.8.The serological response rate of 214 HBeAg-positive chronic hepatitis B patients after 48 weeks of antiviral therapy was 16.3%.The serological response rate of chronic hepatitis B patients after 48 weeks of antiviral therapy was positively correlated with age,and negatively correlated with serum HBV DNA level,and the difference was statistically significant（P<0.05）.9.The HBV DNA in serum was an independent predictor of virological response and serological response in chronic hepatitis B patients with ALT<2×ULN after 48weeks of antiviral therapy,and the optimal cutoff values were 7.40 log₁₀IU/mL and 7.38log₁₀IU/mL,respectively.10.With the aggravation of inflammatory activity and fibrosis degree in chronic hepatitis B patients,the serological response rate of antiviral therapy after 48 weeks was increased,and the difference was statistically significant（P<0.05）.Liver fibrosis was an independent predictor of serological response after 48 weeks of antiviral therapy in chronic hepatitis B patients with ALT<2×ULN.11.With the increase of HBcAg expression level in liver tissue,the virological response rate and serological response rate of chronic hepatitis B patients decreased after 48 weeks,the difference was statistically significant（P<0.05）.With the increase level of HBsAg expression in liver tissue,the virological response rate and serological response rate of antiviral therapy decreased after 48 weeks,but the difference was not statistically significant（P>0.05）.12.The virological response rates of chronic hepatitis B patients with different nucleoisde（acid）analogues after 48 weeks were significantly different（P<0.05）.Conclusion:1.About 92.0%of chronic hepatitis B patients with normal or mildly elevated ALT had significant liver histologic changes.2.In chronic hepatitis B patients with normal or mildly elevated ALT,ALT levels in serum may reflect changes in liver tissue inflammation to some extent,but they are not completely accurate.3.Age was an independent predictor of significant liver histologic changes.The proportion of significant liver inflammation and necrosis in HBeAg-positive and HBeAg-negative patients with age≥30 years and 1.5×ULN≤ALT<2×ULN were100%and 97.8%,respectively.They have strong indications of antiviral therapy.4.The heavier the degree of liver histologic changes,the higher the 48-week virological response rate and serological response rate of antiviral therapy.Significant liver fibrosis was an independent predictor of serological response to antiviral therapy after 48 weeks.5.The intensity of HBcAg expression in liver tissue was negatively correlated with the severity of liver histological lesions.The higher the expression level of HBcAg in liver tissue,the worse the antiviral efficacy.6.HBeAg-negative patients had more severe liver pathological changes and higher virological response rate than those with HBeAg-positive patients.7.Under the guidance of liver biopsy,the selection of different nucleoside（acid）analogues could affect the virological response of antiviral therapy.The efficacy of first-line antiviral drugs was higher than that of non-first-line antiviral drugs.