The Second Liver Cirrhosis Diagnosis and Treatment Center, Beijing 302 Hospital, 100 Middle Street of 4th Ring Road, Beijing, 100039, China.
Institute of Infectious Diseases/Research Center for Clinical and Translational Medicine, Beijing 302 Hospital, 100 Middle Street of 4th Ring Road, Beijing, 100039, China.
Hepatol Int. 2018 Mar;12(2):107-117. doi: 10.1007/s12072-018-9858-x. Epub 2018 Apr 12.
Limited data are available regarding the association of hepatitis B virus (HBV) mutations with liver fibrosis in HBV infection. The study aimed to clarify whether HBV preS deletion mutation is associated with liver fibrosis progression.
A total of 469 patients were enrolled, including 324 with chronic hepatitis B (CHB), 28 with HBV-related compensated liver cirrhosis (LC), and 117 with HBV-related decompensated LC. All CHB and compensated LC patients received liver biopsy. Fibrosis grade was assessed using METAVIR score. HBV preS deletion was determined by direct sequencing and verified by clonal sequencing.
Overall preS deletion was detected in 12.6% (59/469) patients, specifically, in 7.51% (13/173), 10.60% (16/151), and 20.69% (30/145) of patients with no-to-mild liver fibrosis (F0-1), moderate-to-severe liver fibrosis (F2-3), and cirrhosis (F4), respectively (p < 0.01). Patients with preS-deleted HBV had lower serum HBV DNA and albumin levels compared to patients with wild-type HBV. The median length of preS deletion was 39-base pairs (bp) (3-204 bp) and the deletion most frequently emerged in preS2 initial region. Multivariate analysis identified the preS2 deletion rather than preS1 deletion to be an independent risk factor of significant fibrosis, i.e., METAVIR F ≥ 2 (p = 0.007). In addition, preS-deleted viral sequences were detected in the pool of intrahepatic HBV covalently closed circular DNA.
HBV preS deletion is positively associated with liver fibrosis progression in chronic HBV-infected patients. HBV preS2 deletion may serve as a warning indicator for liver fibrosis progression.
关于乙型肝炎病毒（HBV）突变与乙型肝炎病毒感染所致肝纤维化之间的关联，目前仅有有限的数据。本研究旨在阐明 HBV 前 S 缺失突变是否与肝纤维化进展相关。
共纳入 469 例患者，包括 324 例慢性乙型肝炎（CHB）患者、28 例乙型肝炎相关代偿性肝硬化（LC）患者和 117 例乙型肝炎相关失代偿性 LC 患者。所有 CHB 和代偿性 LC 患者均接受了肝活检。采用 METAVIR 评分评估纤维化程度。通过直接测序确定 HBV 前 S 缺失，并通过克隆测序进行验证。
总体而言，在 469 例患者中检测到 12.6%（59/469）存在前 S 缺失，分别为无至轻度肝纤维化（F0-1）患者中 7.51%（13/173）、中度至重度肝纤维化（F2-3）患者中 10.60%（16/151）和肝硬化（F4）患者中 20.69%（30/145）（p<0.01）。与野生型 HBV 患者相比，携带前 S 缺失 HBV 的患者血清 HBV DNA 和白蛋白水平较低。前 S 缺失的中位数长度为 39 个碱基对（bp）（3-204 bp），缺失最常出现在前 S2 起始区。多因素分析确定前 S2 缺失而非前 S1 缺失是显著纤维化的独立危险因素，即 METAVIR F≥2（p=0.007）。此外，在肝内 HBV 共价闭合环状 DNA 的病毒序列中也检测到前 S 缺失序列。
HBV 前 S 缺失与慢性乙型肝炎病毒感染患者的肝纤维化进展呈正相关。HBV 前 S2 缺失可能是肝纤维化进展的预警指标。
