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慢性乙型肝炎功能性治愈的多维度诊断标志物
DOI: 10.12449/JCH260708
利益冲突声明：本文不存在任何利益冲突。
作者贡献声明：高沿航、牛俊奇负责文章内容设计及最后定稿；孙鹤鸣、孔菲和王星语负责查阅文献并绘制表格；孙鹤鸣、高沿航、牛俊奇、孔菲和王星语参与文章撰写及修改。
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摘要: 慢性乙型肝炎是全球重要公共卫生问题。乙型肝炎病毒共价闭合环状DNA持续存在及病毒基因组整合，是限制慢性乙型肝炎实现病毒学治愈的主要障碍。功能性治愈已成为当前慢性乙型肝炎抗病毒治疗的重要目标，其准确判定和疗效预测依赖于多维度诊断标志物的综合评估。本文系统综述了慢性乙型肝炎功能性治愈相关诊断标志物的研究进展，重点阐述乙型肝炎表面抗原定量、乙型肝炎病毒DNA等血清学及病毒学指标，基因组学、转录组学、蛋白质组学和代谢组学标志物，以及宿主固有免疫和适应性免疫相关指标的临床价值，并探讨了统一检测标准、构建多标志物联合预测模型等未来研究方向，以推动慢性乙型肝炎功能性治愈的精准评估和个体化管理。Abstract: Chronic hepatitis B （CHB） is a significant public health issue worldwide. The persistent presence of covalently closed circular DNA of the hepatitis B virus （HBV） and the integration of the viral genome are the main obstacles limiting the achievement of virological cure in CHB. Functional cure has now become an important goal in antiviral therapy for CHB， and its accurate determination and efficacy prediction rely on a comprehensive assessment of multidimensional diagnostic markers. This article systematically reviews the research advances in diagnostic markers associated with functional cure in CHB， focusing on the clinical value of serological and virological indicators （HBsAg quantification and HBV DNA）， genomic， transcriptomic， proteomic， and metabolomic markers， and indicators associated with host innate immunity and adaptive immunity. Furthermore， it discusses future research directions such as the establishment of unified detection standards and the construction of predictive models combining multiple markers， in order to promote the precise assessment and individualized management of functional cure in CHB.
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Key words:
- Hepatitis B， Chronic /
- Functional Cure /
- Biomarkers
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表 1 CHB功能性治愈相关诊断标志物及其临床意义
Table 1. Diagnostic markers related to functional cure of CHB and their clinical significance
标志物类别 代表性指标 主要反映内容 临床价值 主要局限性 血清学 qHBsAg 病毒抗原负荷 目前应用最成熟，可预测HBsAg
清除及停药后持续应答不能区分HBsAg来源于cccDNA
还是整合型HBV DNA病毒复制 HBV DNA 病毒复制水平 抗病毒治疗疗效评估和功能性
治愈判定的基础指标与肝内cccDNA水平不完全
一致病毒转录 HBV RNA cccDNA转录活性 可反映NA治疗背景下残余病
毒转录活性，具有早期疗效预
测价值检测方法和临床阈值尚未完
全标准化病毒抗原相
关指标HBcrAg cccDNA功能状态及
病毒转录活性较qHBsAg更特异性地反映
cccDNA活性，可辅助预测
HBeAg血清学转换和HBsAg
清除临床普及度有限，不同检测平
台结果可比性不足血清学转换 HBeAg、HBeAb 病毒复制活跃程度及
免疫控制状态可用于疾病分期、疗效分层及
治疗应答判断对HBsAg清除的直接预测能
力有限体液免疫 HBsAb、qHBcAb 体液免疫恢复及免疫
记忆HBsAb可反映治愈深度和持久
性；qHBcAb有助于评估免疫应
答基础HBsAb并非功能性治愈必要
条件，阈值仍需验证肝内病毒库
指标cccDNA、整合型HBV
DNA肝内病毒储存库及
HBsAg持续表达来源评估病毒学治愈深度的重要
依据主要依赖肝组织检测，有创性
限制临床应用组学 基因组学、转录组学、
蛋白质组学、代谢组学宿主遗传背景、肝内免
疫微环境和代谢重塑有助于揭示功能性治愈机制并
筛选新型预测标志物多处于研究阶段，临床转化和
标准化不足固有免疫 NK细胞、树突状细胞、
单核/巨噬细胞先天抗病毒免疫激活 可反映免疫重建及局部病毒清
除能力检测复杂，外周血指标未必代
表肝内状态适应性免疫 HBV特异性的CD8⁺ T细
胞、CD4⁺ T细胞和B细胞特异性抗病毒免疫
恢复判断功能性治愈持久性和免疫
控制的重要依据缺乏统一检测流程和临床判
定标准免疫检查点 PD-1/PD-L1、TIM-3、
CTLA-4等T细胞耗竭及免疫抑
制状态可辅助评估免疫恢复程度及干
扰素治疗应答临床应用证据仍需前瞻性研
究验证注：CHB，慢性乙型肝炎；HBV，乙型肝炎病毒；HBsAg，HBV表面抗原；HBcrAg，HBV核心相关抗原；HBeAg，HBV e抗原；HBeAb，HBV e抗体；HBsAb，HBV表面抗体；qHBsAg，HBV表面抗原定量；qHBcAb，HBV核心抗体定量；cccDNA，共价闭合环状DNA；NK细胞，自然杀伤细胞；PD-1，程序性死亡受体1；PD-L1，程序性死亡配体1；TIM-3，T细胞免疫球蛋白黏蛋白分子3；CTLA-4，细胞毒性T淋巴细胞相关抗原4；NA，核苷（酸）类似物。
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