儿童慢性乙型肝炎肝组织HBsAg、HBcAg的表达与抗病毒疗效的关系

目的探索性研究慢性乙型肝炎(CHB)儿童肝组织HBsAg和HBcAg不同表达与抗病毒疗效的关系。方法收集2014年1月—2017年12月在解放军总医院第五医学中心青少年肝病科住院并明确诊断为CHB的276例6月~16岁儿童患者的病例资料,比较肝组织HBsAg和HBcAg免疫组化染色阳性和阴性组(HBsAg阳性组249例,HBsAg阴性组27例;HBcAg阳性组163例,HBcAg阴性组113例)患者的临床特点,以及肝组织HBsAg和HBcAg不同表达模式下抗病毒疗效的差异。计量资料组间比较采用Mann-Whitney U检验;计数资料组间比较采用χ2检验或Fisher精确检验。以肝组织HBsAg和HBcAg染色阳性和阴性为应变量,以可能影响其表达强度有意义的相关因素为自变量,进行logistic回归分析。结果276例患者年龄0.5~16岁,男性占60.51%(167例)。HBeAg阴性14例(5.07%)。肝脏炎症程度分级(G):2级52.54%,2~3级6.88%,3级7.61%。肝纤维化分期(S):3期7.25%,3~4期1.45%,4期3.62%。肝组织HBsAg阳性组儿童年龄及血清HBsAg定量高于阴性组(Z值分别为1.854、2.447,P值均<0.05)。肝组织HBcAg阳性组HBeAg阳性率高于阴性组(χ^2=2.650),ALT(Z=2.473)、AST(Z=1.813)、肝组织纤维化分期S≥3期的比例(χ^2=2.086)均低于阴性组(P值均<0.05)。logistic回归分析显示,影响肝组织HBsAg染色阳性的因素为血清HBsAg定量(P<0.05),影响肝组织HBcAg染色阳性的因素为HBeAg阴性或阳性(P<0.05)。276患者中186例完成IFNα或单用拉米夫定抗病毒治疗停药后6个月的随访,155例(83.33%)获得HBeAg血清学转换,其中76例(40.86%)HBsAg阴转。肝组织的HBsAg阳性表达强度越高,血清HBsAg阴转率越低。肝组织的HBcAg阳性表达强度越高,HBeAg血清学转换率越低。肝组织HBsAg及HBcAg均阴性表达模式的儿童HBsAg阴转率最高(100%),HBsAg阳性及HBcAg阴性的儿童HBsAg阴转率(32.31%)最低。结论肝组织HBsAg及HBcAg阴性的CHB儿童抗病毒治疗HBsAg阴转率最高。

Association of the expression of HBsAg and HBcAg in liver tissue with antiviral response in children with chronic hepatitis B

Objective To investigate the association of the expression of HBsAg and HBcAg in liver tissue with antiviral response in children with chronic hepatitis B(CHB).Methods Clinical data were collected from 276 children,aged 6 months to 16 years,who were hospitalized and diagnosed with CHB in Department of Adolescent Liver Diseases in The Fifth Medical Center of Chinese PLA General Hospital from January 2014 to December 2017,and based on the results of immunohistochemical staining for HBsAg and HBcAg,there were 249 children in the positive HBsAg group,27 in the negative HBsAg group,163 in the positive HBcAg group,and 113 in the negative HBcAg group.Clinical features were compared between groups,as well as the difference in antiviral response between the children with different expression patterns of HBsAg and HBcAg in liver tissue.The Mann-Whitney U test was used for comparison of continuous data between groups,and the chi-square test or the Fisher’s exact test was used for comparison of categorical data between groups.A logistic regression analysis was performed with positive or negative staining of HBsAg and HBcAg in liver tissue as dependent variables and related significant factors affecting their expression intensity as independent variables.Results The age of 276 children ranged from 0.5 to 16 years,and there were 167 boys,accounting for 60.51%.Of all children,14(5.07%)had negative HBeAg.As for liver inflammation grade(G),52.54%had G2 inflammation,6.88%had G2-3 inflammation,and 7.61%had G3 inflammation;as for liver fibrosis stage(S),7.25%had S3 fibrosis,1.45%had S3-4 fibrosis,and 3.62%had S4 fibrosis.The positive HBsAg group had significantly higher age and serum HBsAg quantification than the negative HBsAg group(Z=1.854,Z=2.447,both P<0.05).Compared with the negative HBcAg group,the positive HBcAg group had a significantly higher positive rate of HBeAg(χ^2=2.650,P<0.05)and significantly lower ALT(Z=2.473,P<0.05),AST(Z=1.813,P<0.05),and proportion of children with S≥3 liver fibrosis(χ^2=2.086,P<0.05).The logistic regression analysis showed that serum HBsAg quantification was an influencing factor for positive HBsAg staining in liver tissue(P<0.05)and negative or positive HBeAg was an influencing factor for positive HBcAg staining in liver tissue(P<0.05).Among the 276 children,186 completed the 6-month follow-up after antiviral therapy with IFNαor lamivudine alone,and 155(83.33%)achieved HBeAg seroconversion,among whom 76(40.86%)had HBsAg seroconversion.The higher the expression intensity of HBsAg in liver tissue,the lower the seroconversion rate of serum HBsAg;the higher the expression intensity of HBcAg in liver tissue,the lower the seroconversion rate of serum HBeAg.The children with negative expression of HBsAg and HBcAg in liver tissue had the highest HBsAg seroconversion rate of 100%,and the children with positive HBsAg and negative HBcAg in liver tissue had the lowest HBsAg seroconversion rate of 32.31%.Conclusion CHB children with negative HBsAg and HBcAg in liver tissue had the highest HBsAg seroconversion rate after antiviral therapy.