【作者】 梅玫；

【导师】 陆伟；

【作者基本信息】 天津医科大学 ， 临床医学（专业学位）， 2022， 博士

【摘要】 研究背景随着乙肝疫苗的广泛普及,HBV感染率已大幅降低,另外抗病毒药物不断推陈出新,使得丙型病毒肝炎(HCV)治愈成为现实,但由于我国人口基数大,现存慢性病毒性肝炎数量仍然很多,仍是发展至严重肝病(肝硬化、肝癌、肝衰竭)的主要病因。而且即使HCV、HBV得到很好控制,发展至严重肝病的风险仍然较普通人群高。其基本病理改变包括反复持续的肝脏炎症、肝纤维化形成及肝细胞的再生。早期合理的治疗可以明显改善慢性肝病预后,所以及时诊断评估慢性病毒性肝病的病情,并予以适当的干预,可以减少严重肝病的发生。在我国慢性乙型肝炎病毒感染(CBI)及非酒精性脂肪肝(NAFLD)是两种最为常见的慢性肝病,两种疾病同时存在的情况非常普遍,因此评估这部分病人的肝脏炎症、肝纤维化状况,对于决定抗病毒治疗时机,改善疾病预后有重要的意义。肝穿刺活组织检查是评价肝脏炎症、肝纤维化的金标准,但因有创性、抽样误差、普及度不高等原因,越来越多的无创诊断指标及模型被开发、应用。CBI合并NAFLD发生肝脏炎症是否需要进行抗HBV治疗是当前临床面临的常见问题,除肝组织病理检查外,用于鉴别其肝脏炎症来源的无创模型的研究较少,所以急需此方面简单易行、经济有效、无创诊断技术和方法,更好地服务于临床诊断和评估。肝纤维化无创评估模型公式众多,诊断效能参差不齐,还需要进一步验证和改进,适用医疗机构也需要进一步探讨。目的对CBI合并NAFLD患者进行肝脏炎症病因的诊断性研究。以肝组织病理为金标准,通过分析临床常规参数,构建无创诊断模型,来识别需要抗乙型肝炎病毒治疗的患者。其次通过慢性病毒性肝炎肝纤维化评估检测方法的比较及组合,优化无创指标的诊断性能,随后筛选适用于基层医院的CBI肝纤维化的最优无创诊断指标。方法1.CBI合并NAFLD肝脏炎症无创评估:选用来自2017年1月至2020年12月期间天津市第二人民医院,303例经肝活检证实为NAFLD合并CBI患者,根据病理将其分为HBV相关炎症组(HBV-RI,HAI≥4,176例)和非HBV相关性炎症组(非HBV-RI,HAI<4,127例)。收集患者1周内完成的血生化、常规及HBV-DNA等化验及肝硬度(LSM)及受控衰减系数(CAP)检查结果,应用单因素分析和多因素logistic回归分析的方法,构建CBI合并NAFLD患者的HBV相关炎症模型(HBV-I)。应用受试者工作曲线分析评估模型诊断性能,并对模型进行拟优检验。再前瞻性筛选2021年1月至2022年1月115例CBI合并NAFLD患者作为验证组进行模型诊断效能验证。2.慢性病毒性肝炎肝纤维化无创评估:1)纳入174名连续接受肝活检的单纯慢性病毒性肝炎患者。收集一周内完成的相关检查并完善如下指标数据:Forns评分(Forn)、肝纤维化4因子指数(FIB-4)、γ-谷氨酰转肽酶/血小板指数(GPR)、天冬氨酸氨基转移酶/血小板比值指数(APRI)、声辐射力脉冲弹性成像(ARFI)、瞬时弹性成像(TE)。应用ROC曲线的方法来评价以上单个及联合指标的诊断效能2)纳入436例连续接受肝活检的单纯HBV患者。收集一周内进行的天冬氨酸/丙氨酸氨基转移酶比率(AAR)、年龄-血小板指数(API)、APRI、FIB-4、Forns、GPR、S指数和TE等检查结果。应用AUC以确定诊断效果,并使用De Long test进行诊断性能比较。结果1.CBI合并NAFLD病人中,HBV-RI组和非HBV-RI组在人口学数据、生化指标、免疫功能、甲状腺功能、病毒学指标、血常规指标等方面均有统计学差异(P<0.05),HBV-RI组的LSM显著高于非HBV-RI组(P<0.05),而CAP显著低于非HBV-RI组(P<0.05);2.建立了可以识别HBV相关炎症患者的新模型:HBV-I=-0.020×CAP+0.424×LSM+0.376×lg(HBV DNA)+0.049×AST,AUROC为0.907,临界值为0.671,敏感性为89.30%,特异性为77.80%,阳性预测值为90.34%,阴性预测值为81.89%,总准确率为86.96%。3.TE和ARFI在纤维化分级方面有较好的诊断效能,其在纤维化程度≥S2,≥S3和S4的慢性病毒性肝炎患者中AUC均大于0.8,优于ARPI、FIB-4、GPR和Forns。在纤维化≥S3时,ARFI在诊断上优于TE。TE联合某些血清标记物显示出比单一弹性成像技术更高的诊断优势。Forns是评估肝纤维化相对最有效的血清标志物。Forns联合FIB-4可显著提高S1期诊断效率。4.Forns和S指数在诊断≥S3期纤维化阶段时与TE有相似的诊断性能。联合血清模型的诊断价值提高有限。结论1.新型HBV-I模型[结合CAP、LSM、lg(HBV DNA)和AST]在预测伴有NAFLD合并CBI患者的HBV相关炎症方面具有较高的准确性和可重复性,这可有助于临床应用。2.ARFI和TE对肝纤维化的诊断优于APRI、FIB-4、GPR和Forns等血清学指标。ARFI在≥S3时诊断上优于TE,TE联合某些血清标记物显示出比单一弹性成像技术更高的诊断优势。3.Forns和S指数可作为基层医院筛查HBV患者进展期肝纤维化的有效工具。更多还原

【Abstract】 Background With the wide application of hepatitis B vaccine,the infection rate of hepatitis B virus(HBV)has been greatly reduced.In addition,antiviral drugs have been continuously developed,which makes the cure of hepatitis C virus(HCV)become a reality.However,due to the large population base in China,the number of existing chronic viral hepatitis is still large,which is still the main cause of severe liver disease.Chronic hepatitis B virus infection(CBI)and nonalcoholic fatty liver disease(NAFLD)are the two most common chronic liver diseases in China.The coexistence of the two diseases is very common.Therefore,evaluating the status of liver inflammation and liver fibrosis is of great significance to determine the timing of antiviral treatment and improve the prognosis of the disease.Due to liver biopsy’s invasive and low popularity,more and more noninvasive diagnostic models have been developed.There are many noninvasive evaluation model formulas of liver fibrosis,but the diagnostic efficiency is uneven.It needs to be further verified and improved,and the applicable medical institutions also need to be further discussed.Whether anti HBV treatment is needed for liver inflammation caused by CBI combined with NAFLD is a common clinical issue.In addition to liver histopathological examination,there is no noninvasive model for identifying the source of liver inflammation,so there is an urgent need for simple,effective diagnostic methods in order to serve the clinic better.Objective A non-invasive diagnostic model was constructed to identify patients who need anti-hepatitis B virus(HBV)therapies in CBI Patients with concurrent NAFLD by analyzing clinical routine parameters.To evaluate the value of noninvasive method in the diagnosis of liver fibrosis in patients with chronic viral hepatitis.To screen noninvasive methods with evaluation and diagnostic value for significant and advanced fibrosis stage of CBI patients in basic hospitals.Methods1.Noninvasive assessment of liver inflammation: 303 CBI patients with concurrent NAFLD proven by liver biopsy were enrolled,and they were divided into HBVrelated inflammation group(HBV-RI,HAI ≥ 4,176cases)and non-HBV-related inflammation group(non-HBV-RI,HAI<4,127 cases)according to hepatic pathology.Logistic regression analysis was performed on the two groups of patients,and then the HBV-related inflammation model(HBV-I)of CBI patients with concurrent NAFLD was constructed.The area under the ROC curve,the best cut-off value,specificity,sensitivity,diagnostic accuracy,were calculated.Another 115 CBI patients with concurrent NAFLD proven by liver biopsy were enrolled as the validation group.2.Noninvasive assessment of liver fibrosis: 1)174 chronic hepatitis virus patients who underwent liver biopsy were enrolled.Forns,FIB-4,GPR,APRI,ARFI and TE were obtained.The ROCs were calculated to determine the diagnostic efficacy,and compared with De Long test.2)436 HBV patients who underwent liver biopsy were enrolled.AAR,API,APRI,FIB-4,Forns,GPR,S-index and TE were obtained.The histologic fibrosis grades were according to the METAVIR scoring(S0-S4).The AUCs were calculated to determine the diagnostic efficacy and De Long test was used for comparisons.Results 1.There were some statistical differences in demographic data and blood indicators between the two groups(P<0.05),and LSM in the HBV-RI group were significantly higher than those in the non-HBV-RI group(P<0.05),While CAP was lower(P<0.05);2.We developed a novel model by logistic regression analysis which can identify patients with HBV-RI: HBV-I =-0.020 × CAP + 0.424 × LSM + 0.376 × lg(HBV DNA)+ 0.049 × AST,and the accuracy rate was 82.5%.3.Validation group analysis :The AUC of HBV-I in the validation group was 0.871,and the overall accuracy rate is 86.96%.4.The diagnostic performance of both TE and ARFI in assessing hepatic fibrosis was good for fibrosis grades ≥S2,≥S3 and S4(all AUCs > 0.8).ARFI was superior to TE in ≥S3.TE combined with some serum markers showing diagnostic superiority than single elastography technique.Forns combined with FIB-4 can significantly improve the diagnostic efficacy than any single in diagnosing S1.5.Forns and S-index showed similar diagnostic performance with TE when diagnosing fibrosis stage ≥S3.Conclusion 1.Our novel model HBV-I [combining CAP,LSM,lg(HBV DNA)and AST] shows promising utility for predicting HBV-related inflammation in CBI patients with concurrent NAFLD with high accuracy and repeatability.2.Single markers(TE,ARFI and Forns)and combined markers(TE combined with some serum markers,Forns combined with FIB-4)were selected as the preferred noninvasive evaluation method for the diagnosis of hepatic fibrosis in patients with CHV.3.Forns and S-index may be used as the effective tools for screening the advanced fibrosis of HBV patients in basic hospitals.更多还原