Relationship between serum HBV-RNA levels and intrahepatic viral as well as histologic activity markers in entecavir-treated patients
Relationship between serum HBV-RNA levels and intrahepatic viral as well as histologic activity markers in entecavir-treated patients
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恩替卡韦治疗患者血清 HBV-RNA 水平与肝内病毒及组织学活性标志物之间的关系。
DOI：
10.1016/j.jhep.2017.08.021
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发表时间：
2018-01-01
影响因子：
25.7
通讯作者：
Zhang, Wenhong
中科院分区：
文献类型：
--
作者：
Wang, Jing;Yu, Yiqi;Zhang, Wenhong
背景和目的：在诊断中，当循环中的 HBV-DNA 负荷被核苷类似物 (NUC) 治疗有效抑制时，血清乙型肝炎病毒 (HBV)-RNA 水平很有价值。本研究旨在确定血清 HBV-RNA 中反映的肝内病毒复制活性，以及 HBV-RNA 是否会导致接受 NUC 治疗的患者的肝脏组织学变化。方法：从接受恩替卡韦治疗的患者中获得一组横断面的血清和肝活检样本，这些患者的血清 HBV-DNA 水平未检测到。分析了血清 HBV-RNA 浓度与外周和肝内病毒复制形式水平以及组织学评分之间的相关性。通过深度测序检查血清 HBV-RNA 准种和肝内病毒复制形式。通过原位杂交观察 HBV-RNA 阳性肝细胞。结果：47 名患者中有 35 名检测到血清 HBV-RNA（74.47%，2.33-4.80 log(10) 拷贝/ml）。这些水平不仅与肝内 HBV-RNA 水平以及肝内 HBV-RNA 与共价闭合环状 DNA (cccDNA) 的比率相关，而且与分级和分期的组织学评分相关。关于准种，血清 HBV-RNA 是动态的，并且与同时采样的肝内 HBV-RNA 相比，与 cccDNA 库相比，其遗传同质性更高。原位组织学显示，HBV-RNA 阳性肝细胞聚集在病灶内，零星分布在小叶中，并与乙型肝炎表面抗原共定位。结论：血清 HBV-RNA 水平反映了肝内病毒转录活性，并与接受 NUC 治疗的患者的肝脏组织病理学相关。我们的研究揭示了 HBV-RNA 在慢性 HBV 感染发病机制中的性质，并对 NUC 治疗期间慢性乙型肝炎的治疗具有重要意义。总结：血清 HBV-RNA 水平指示共价闭合环状 DNA 的肝内转录活性，并且与接受核苷类似物的慢性乙型肝炎患者的肝脏组织学变化相关 治疗。 (C) 2017 年欧洲肝脏研究协会。由 Elsevier B.V. 出版。保留所有权利。
Background & Aims: In diagnostics, serum hepatitis B virus (HBV)-RNA levels are valuable when the HBV-DNA load in circulation is effectively suppressed by nucleos(t) ide analogue (NUC) therapy. This study aimed to determine the intrahepatic viral replication activity reflected in serum HBV-RNA and whether HBV-RNA contributes to liver histological changes in patients treated with NUC.Methods: A cross-sectional set of serum and liver biopsy samples was obtained from patients treated with entecavir, who had undetectable levels of serum HBV-DNA. The correlations between serum HBV-RNA concentration and levels of peripheral and intrahepatic viral replicative forms, as well as histological scores, were analyzed. Quasispecies of serum HBV-RNA and intrahepatic viral replicative forms were examined by deep sequencing. HBV-RNA-positive hepatocytes were visualized by in situ hybridization.Results: Serum HBV-RNA was detected in 35 of 47 patients (74.47%, 2.33-4.80 log(10) copies/ml). These levels correlated not only with the intrahepatic HBV-RNA level and the ratio of intrahepatic HBV-RNA to covalently closed circular DNA (cccDNA), but also with the histological scores for grading and staging. Regarding quasispecies, serum HBV-RNA was dynamic and more genetically homogenous to simultaneously sampled intrahepatic HBV-RNA than to the cccDNA pool. In situ histology revealed that HBV-RNA-positive hepatocytes were clustered in foci, sporadically distributed across the lobules, and colocalized with hepatitis B surface antigen.Conclusion: Serum HBV-RNA levels reflect intrahepatic viral transcriptional activity and are associated with liver histopathology in patients receiving NUC therapy. Our study sheds light on the nature of HBV-RNA in the pathogenesis of chronic HBV infection and has implications for the management of chronic hepatitis B during NUC therapy.Lay summary: Serum HBV-RNA levels are indicative of the intrahepatic transcriptional activity of covalently closed circular DNA and are associated with liver histological changes in patients with chronic B hepatitis who are receiving nucleos(t) ide analogue therapy. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.