慢性HBV感染者组织学免疫耐受状态无创诊断指标及相关模型的建立与评价  

Noninvasive diagnostic indicators for histologically defined immune tolerance state in patients with chronic HBV infection and establishment and assessment of related models

作　　者：杜欣雨 李嘉[2] 蒋贝[3] 赵坤宇 胡月 王凤梅 鲁凤民 DU Xinyu;LI Jia;JIANG Bei;ZHAO Kunyu;HU Yue;WANG Fengmei;LU Fengmin(Precision Medicine Center,Academy of Medical Sciences,Zhengzhou University,Zhengzhou 450052,China;Department of Liver Disease,Tianjin Second People’s Hospital,Tianjin 300192,China;Tianjin Hepatopathy Research Institute,Tianjin Second People’s Hospital,Tianjin 300192,China;Peking University People’s Hospital,Peking University Hepatology Institute,Beijing 100044,China;Department of Hepatology,Tianjin First Central Hospital,Tianjin 300192,China;Department of Microbiology&Infectious Disease Center,School of Basic Medical Sciences,Peking University Health Science Center,Beijing 100191,China)

机构地区：[1]郑州大学医学科学院精准医学中心,郑州450052 [2]天津市第二人民医院肝病科,天津300192 [3]天津市第二人民医院天津市肝病医学研究所,天津300192 [4]北京大学人民医院,北京大学肝病研究所,北京100044 [5]天津市第一中心医院肝内科,天津300192 [6]北京大学基础医学院病原生物学系暨北京大学感染病研究中心,北京100191

出　　处：《临床肝胆病杂志》2024年第12期2392-2398,共7页Journal of Clinical Hepatology

基　　金：国家自然科学基金(82372235,62301362);天津市医学重点学科建设项目(TJYXZDXK-059B)。

摘　　要：目的慢性HBV感染自然史多有组织学意义上的免疫耐受状态,免疫耐受状态一旦打破,需立即启动抗病毒治疗。通过对免疫介导的肝损伤与HBV病毒学指标进行相关性分析,精准定义肝组织学免疫耐受状态的患者。方法以2010年1月—2022年12月中国人民解放军总医院第五医学中心、天津市第二人民医院、上海瑞金医院和浙江省台州医院收集的HBe Ag阳性且HBV DNA>2×10^(6) IU/mL未经抗病毒治疗的577例慢性乙型肝炎患者为研究对象。通过肝组织活检确定肝损伤情况,检测血清ALT、AST水平及病毒学指标。分析现有各大指南无创指标特别是HBV DNA载量界值不同的情况下,肝组织免疫耐受状态患者所占比例。进一步尝试以与肝组织免疫病理损伤程度相关性消失时的血清HBV DNA为新的阈值,联合多因素指标建立组织学免疫耐受状态的诊断模型。计量资料两组间比较采用Mann-Whitney U检验。计数资料两组间比较采用χ^(2)检验。采用Spearman法进行相关性分析。采用二元Logistic回归分析建立多因素诊断模型,并应用受试者工作特征曲线下面积(AUC)明确各模型的诊断效能,AUC的比较采用Z检验。结果中国2022版、EASL 2017版、AASLD 2018版、APASL 2015版慢性乙型肝炎防治指南病毒学无创指标所鉴定出的免疫耐受状态患者中符合本研究定义(HBV DNA>2×10^(6) IU/m L)的组织学免疫耐受状态的比例分别为47.0%、38.5%、36.0%、44.6%,均未超过50%。当将血清HBV DNA阈值升至>2×10^(8) IU/m L时,尽管免疫介导的肝损伤与HBV DNA相关性消失(r=-0.029,P=0.704),此时肝组织免疫耐受状态患者所占比例也仅为52.0%。在血清HBV DNA>1×10^(8)的HBeAg阳性患者队列(n=251)中,显著肝损伤组(n=140)和无显著肝损伤组(n=111)HBsAg、HBeAg、HBV DNA、ALT及AST水平比较,差异均有统计学意义(P值均<0.05),进一步多因素二元Logistic回归分析结果显示,AST、HBV DNA、HBeAg是患Objective The natural history of chronic HBV infection often involves a histologically defined immune tolerance state,and once such immune tolerance state is broken,antiviral therapy should be initiated immediately.This study aims to investigate the correlation between immune-mediated liver injury and virological indicators for HBV and precisely identify the patients with a histologically defined immune tolerance state.Methods This study was conducted among 577 HBeAg-positive chronic hepatitis B(CHB)patients with HBV DNA>2×10^(6) IU/mL who did not receive antiviral therapy in The Fifth Medical Center of PLA General Hospital,Tianjin Second People’s Hospital,Shanghai Ruijin Hospital,and Taizhou Hospital of Zhejiang Province from January 2010 to December 2022.Liver biopsy was performed to determine the extent of liver injury,and the serum levels of alanine aminotransferase(ALT),aspartate aminotransferase(AST),and virological indicators were measured.The proportion of patients with a histologically defined immune tolerance state was analyzed based on the cut-off values of noninvasive indicators recommended in various guidelines,especially HBV load.In addition,a diagnostic model was established for the histologically defined immune tolerance state based on serum HBV DNA at the time when its correlation with liver immunopathological injury disappeared as the new threshold in combination with multiple indicators.The Mann-Whitney U test was used for comparison of continuous data between two groups,and the chi-square test was used for comparison of categorical data between two groups.The Spearman method was used for correlation analysis.The binary Logistic regression analysis was used to establish a multivariate diagnostic model;the area under the receiver operating characteristic curve(AUC)was used to investigate the diagnostic efficiency of different models,and the Z test was used for comparison of AUC.Results Among the patients with an immune tolerance state defined by the noninvasive indicators in the Chinese guide

关 键 词：乙型肝炎 慢性 免疫耐受 诊断 

分 类 号：R512.62[医药卫生—内科学]