乙肝病毒C基因启动子和前C/C基因变异与慢性乙肝发作及病情严重性的关系

Clinical significance of mutation in the core promoter and the precore/core gene of hepatitis B virus in patients with chronic hepatitis B

目的 研究乙型肝炎病毒 (HBV)C基因启动子 (CP)和前C/C基因变异与无症状慢性HBV携带者 (ASC)的肝炎发作及慢性乙肝病情严重性的关系。方法 通过PCR及其产物直接测序 ,检测 4例ASC、2 7例慢性乙肝和 3例慢性重型乙肝病人血清的HBVCP和前C/C基因序列 ,并定量检测HBVDNA。结果 (1)CP主要变异为nt172 6 1730聚集变异 (172 6A→C、172 7A→T、1730C→G)和nt176 2 176 4双变异 (176 2A→T和 176 4G→A)。前C区主要变异为 1896G→A。C基因变异常使C蛋白aa5、13、2 7、6 0、87、97及 130发生置换。 (2 )CP聚集变异与ASC首次肝炎急性发作有关 ,11例中 ,8例出现CP聚集变异。 (3)CP聚集变异合并CP双变异的乙肝病人 ,临床上或表现为重型肝炎或迅速进展为活动性肝硬化、HBVDNA高水平、HBeAg/抗HBe转换。 结论 同前C/C基因比较 。

Objective To study the effects of mutations in the core promoter (CP) and the precore/core gene of hepatitis B virus (HBV) on acute clinical exacerbation in chronic asymptomatic HBV carriers (ASC) and the severity of patients with chronic hepatitis B.Methods CP and precore/core gene were sequenced directly from sera of four ASCs,twenty-seven patients with chronic hepatitis B and three patients with chronic severe hepatitis B after amplication by the polymerase chain reaction.Results Clusters of mutations in CP region,an A-to-C mutation at nucleotide (nt) 1726,an A-to-T mutation at nt 1727 and a C-to-G mutation at nt 1730 were observed in eight of eleven ASCs developing acute exacerbation,none of five ASCs with no or obscure signs and gentle rise in ALT,or none of four ASCs without abnormal ALT.Moreover,the clustering mutations were found negative in the state of ASC and positive after acute exacerbation in a subject.Five patients with both the clustering mutations and the double mutations (an A-to-T mutation at nt 1762 and a G-to-A mutation at nt 1764)manifested severe hepatitis or active cirrhosis with high level of serum HBV DNA,HBV DNA positive by dot blot,HBeAg negative and Anti-HBe positive in serum.Conclusion The clustering mutations are associated with acute exacerbation in HBV ASCs,and co-existence in the clustering mutations and the double mutations is related to the severity of chronic hepatitis B.