慢性HBV感染者病毒DNA水平与患者肝组织炎症损伤程度的相关性研究

Association between HBV viral load and severity of liver inflammation in patients with chronic hepatitis B virus infection

目的探讨慢性乙型肝炎病毒(HBV)感染者疾病自然进程中病毒学标志物与宿主抗HBV免疫所致肝脏病理损伤的关系及动态变化。方法回顾性选取2016年1月到2022年6月于浙江省台州医院接受肝穿刺活检的238例成人慢性HBV感染者。收集患者的年龄、性别、血小板、丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)、白蛋白、HBV DNA、qHBsAg、HBeAg等一般临床资料,以及患者的肝组织炎症活动度和纤维化分级等肝脏病理诊断指标。按HBeAg状态对患者进行分组,并分别按不同肝脏炎症活动度、不同HBV DNA载量对患者行亚组分组,统计学分析比较各组的HBV病毒学标志物水平的组间差异,及其与患者肝脏炎症损伤指标如ALT、AST及肝组织炎症活动度间的相关性。结果HBeAg阳性患者中有中度及以上肝脏炎症活动度(G≥2)患者的病毒学标志物水平均显著低于轻(无)炎症活动度(G<2)者(HBV DNA:t=3.102,P=0.002;qHBsAg:Z=-4.859,P<0.001;HBeAg:Z=-4.386,P<0.001);而在HBeAg阴性患者中则呈现相反的趋势,G≥2亚组的HBV DNA水平、qHBsAg显著高于G<2亚组(HBV DNA:t=-5.269,P<0.001;qHBsAg:Z=-2.951,P=0.003)。对应地,HBV DNA水平、qHBsAg在HBeAg阳性患者中与肝脏炎症活动度及肝脏炎症损伤指标AST呈弱到中等强度的负相关(HBV DNA与炎症活动度:r=-0.300,P=0.001;qHBsAg与炎症活动度:r=-0.432,P<0.001;qHBsAg与AST:r=-0.233,P=0.008);而在HBeAg阴性患者中则与肝脏炎症活动度及ALT、AST呈弱到中等强度的正相关(HBV DNA与炎症活动度:r=0.439,P<0.001;HBV DNA与ALT:r=0.502,P<0.001;HBV DNA与AST:r=0.582,P<0.001),其中qHBsAg仅与患者的肝脏炎症活动度呈弱的正相关(r=0.285,P=0.003)。进一步对HBeAg阳性患者按HBV DNA是否>2×106 IU/ml进行亚组分析发现,HBV DNA>2×106 IU/ml亚组的患者其HBV病毒学标志物与肝脏炎症活动度及ALT、AST间呈弱到中等强度的负相关(HBV DNA与炎症活动度:r=-0.276,P=0.009;HBV DNA与AST:r=-0.262,P=0.014;qHBsAg与炎症活动度:r=-0.448,P<0.001;qHBsAg与ALT:r=-0.223,P=0.037;qHBsAg与AST:r=-0.455,P<0.001;HBeAg与炎症活动度:r=-0.433,P<0.001;HBeAg与ALT:r=-0.257,P=0.016;HBeAg与AST:r=-0.369,P<0.001);但上述"负相关"在HBeAg仍为阳性且HBV DNA≤2×106 IU/ml的患者中消失。不仅如此,HBV DNA与ALT、HBeAg与AST更分别呈中等强度的正相关(HBV DNA与ALT:r=0.305,P=0.0497;HBeAg与AST:r=0.321,P=0.038)。结论在慢性HBV感染的疾病进程中,在HBeAg阳性且HBV DNA>2×106 IU/ml时,患者的抗HBV免疫应答可通过清除感染肝细胞来有效地抑制HBV的复制,而当HBV DNA载量低于该界值时,患者的抗HBV免疫性应答更多地造成了肝组织炎症损伤。

Objective To explore the relationship and dynamic changes between virological markers and hepatic pathological damage due to host anti-hepatitis B virus(HBV)immunity in the natural course of disease in chronic HBV infected patients.Methods Two hundred and thirty-eight adult chronic HBV-infected patients who underwent liver biopsy from January 2016 to June 2022 in Taizhou Hospital,Zhejiang Province,were retrospectively selected.General clinical data such as age,gender,platelets,ALT,AST,albumin,HBV DNA,qHBsAg,HBeAg,and liver pathology diagnostic indexes such as the grade of liver necroinflammation and liver fibrotic stages of the patients were collected.The patients were grouped according to HBeAg status,and subgrouped according to different grades of liver necroinflammation and different HBV DNA loads.Statistical analyses were performed to compare the differences in HBV virologic marker levels between the groups,and the correlation between them and the indicators of hepatic inflammatory injury,such as ALT,AST,and the grade of liver necroinflammation in the patients.Results The levels of HBV virological markers in HBeAg-positive patients with moderate or higher liver necroinflammatory grade(G≥2)were significantly lower than those with mild(no)liver necroinflammatory grade(G<2)(P<0.01);whereas the opposite trend was observed in HBeAg-negative patients,with the levels of HBV DNA,and qHBsAg in the G≥2 subgroup being significantly higher than those in the G<2 subgroup(P<0.01).Correspondingly,HBV DNA level and qHBsAg showed weak to moderately strong negative correlation with liver necroinflammatory grade and AST which was an indicator of hepatic inflammatory injury in HBeAg-positive patients(P<0.05);whereas in HBeAg-negative patients,they showed weak to moderately strong positive correlation with hepatic inflammatory activity and ALT,AST(P<0.001),in which qHBsAg showed only a weak positive correlation with patients'liver necroinflammatory grade(P=0.003).Further subgroup analyses of HBeAg-positive patients according to whether the HBV DNA level was>2×106 IU/ml showed weak to moderate negative correlations between HBV virological markers and liver necroinflammatory grade as well as ALT and AST in the subgroup of patients with HBV DNA>2×106 IU/ml(P<0.05);however,the negative correlation disappeared in patients who were still HBeAg positive and had HBV DNA≤2×106 IU/ml.Moreover,HBV DNA and ALT,HBeAg and AST showed moderate positive correlation(P<0.05).Conclusion We speculate that the activation of host anti-HBV immunity can efficiently inhibit HBV replication by targeting the infected hepatocytes,but only in the early phase of disease progression in HBeAg positive patients with HBV DNA high(>2×106 IU/ml).