【作者】 张峰；

【导师】 徐元宏；

【作者基本信息】 安徽医科大学 ， 临床检验诊断学， 2017， 硕士

【摘要】 背景:乙型肝炎病毒(hepatitis B virus,HBV)约造成了全球2.4亿人慢性感染,是一个重大的全球公共健康问题。慢性乙型肝炎病毒感染容易导致肝纤维化,进而发展为肝硬化或肝脏代偿失调。HBV基因型分布具有人种和地域性的差异,并且与肝纤维化进展和抗病毒治疗响应性有关。在中国,主要以B和C基因型病毒感染为主,其造成的慢性乙型肝炎是是导致肝硬化和肝细胞癌的重要因素。肝纤维化是慢性乙肝患者(反复的肝炎发生)向终末期肝病进展的重要病理阶段。因此,早期诊断不仅对于指导抗病毒治疗具有重要意义,而且能够逆转肝纤维化。尽管肝组织活检仍然是诊断肝纤维化和肝硬化的金标准,但由于其操作过程具有创伤、容易造成并发症、价格高、病人接受度差等因素,难以普遍推广,不能达到及早筛查的目的。鉴于此,多种基于血检指标的无创诊断模型(如FIB-4和APRI)由于其性价比高、操作流程简便等优势已经被WHO治疗指南推广在基层医院或是资源有限的地区用于肝纤维化的筛查。但APRI和FIB-4仍然面临着敏感度和阳性预测值较低的问题,不能精准的诊断肝纤维化。目的:本研究拟在检测不同肝纤维化程度慢性HBV感染患者的HBV基因分型差异的基础上,进一步分析无创诊断模型γ-谷氨酰转肽酶(γ-GT)与乙肝表面抗原(HBs Ag)定量比值(Gq HBs R)对慢性HBV患者肝纤维化程度的诊断价值,并比较其诊断效能与APRI和FIB-4的差异。方法:收集安徽医科大学阜阳传染病临床学院附属阜阳市第二人民医院2013年5月~2016年6月行肝穿刺后活组织病理检测,确诊为慢性乙型肝炎病毒感染的317例患者血液标本及临床资料。采用荧光定量PCR法进行HBV基因分型检测,并分析基因型与肝纤维化程度和HBe Ag血清转换的关系。分析Gq HBs R与γ-GT、Hbs Ag两项单因子与肝纤维化分期的关系,平行比较Gq HBs R与FIB-4和APRI两种常用诊断模型对肝纤维化程度的诊断效能及其相关性。结果:317例HBV感染患者主要以C基因型为主,两种基因型:B和C基因型在不同肝纤维化分期患者中的分布差异均有统计学意义(P<0.01);并且B基因型比例在显著肝纤维化(≥S2)组中的比例显著低于无显著肝纤维化组(<S2)。HBe Ag血清学转换分析发现HBe Ag阳性比例(72.7%)在C基因型感染患者中显著高于B基因型(37.5%)。γ-GT、Gq HBs R值及FIB-4随肝纤维化分期级别的增高而同步增高,Hbs Ag定量则逐渐降低,不同肝纤维化分期患者的γ-GT、Hbs Ag定量、Gq HBs R值及肝纤维化评分差异有统计学意义(P<0.01),肝纤维化评分与Gq HBs R值呈正相关性(r=0.4235,P<0.0001);Gq HBs R、γ-GT、Hbs Ag、FIB-4、APRI诊断显著肝纤维化的受试者工作曲线下面积(AUC)分别为0.860、0.599、0.590、0.789、0.775,Gq HBs R对显著肝纤维化的诊断价值明显更高;Gq HBs R诊断各期肝纤维化的AUC均在0.9左右,Se、Sp、PPV及NPV值均较高(>75%)。结论:安徽阜阳地区慢性HBV感染伴有显著性肝纤维化患者主要以C基因型(64.7%)HBV为主。在C基因型感染患者中,HBe Ag血清学阳性比例显著高于B基因型。Gq HBs R模型对慢性HBV感染患者肝纤维化程度较之FIB-4和APRI具较高诊断价值,可在一定程度上降低此类患者接受肝穿刺活检比例。更多还原

【Abstract】 Backgrund: Infection with hepatitis B virus(HBV)is a public health problem worldwide,and more than 240 million people are estimated to have persistent HBV infection.Chronic hepatitis B virus infection is the main cause of liver fibrosis,and thus the development of liver cirrhosis or liver decompensation.HBV genotype distribution has ethnic and regional differences,and influences the progress of liver fibrosis and anti-viral treantment response.In China,HBV genotype mainly composed by B and C genotype,which caused chronic hepatitis B is the important hazard factor for liver cirrhosis and hepatocellular carcinoma(HCC).Hepatic fibrosis is an important pathological stage of chronic hepatitis B(recurrent hepatitis)to advanced stage of liver diseases progression.Therefore,early diagnosis is not only important for guiding antiretroviral therapy,but also with the potential to reverse liver fibrosis.Although liver biopsy is the gold standard for the diagnosis of liver fibrosis and cirrhosis,it is an invasive procedure with complex process,high price and poor compliance.Thus,it is difficult to applicate in resource-constrained settings and also can not achieve early screening purpose.In view of this,a variety of noninvasive diagnostic models based on blood characteristics have been developed.Among those indices,the aspartate transaminase(AST)-to-platelet ratio index(APRI)and fibrosis index based on four factors(Fib-4)have the advantage of comprising only inexpensive laboratory tests,which are available in primary care,and have been recommended for the diagnosis of cirrhosis in resource-limited settings by the WHO guidelines.In spite of the fact that they were recommended to diagnose cirrhosis by WHO guidelines,APRI and FIB-4 have faced some problems,such as the low level of sensitivity and positive predictive value,and the lack of enough diagnostic accuracy for liver fibrosis.Objective: The aim of this study was to investigate the difference of HBV genotype,the noninvasive model of γ-glutamyl transpeptidase(γ-GT)and hepatitis B surface antigen(HBs Ag)(Gq HBs R)in the diagnosis of hepatic fibrosis in patients with chronic HBV.And then compare the diagnostic efficacy of Gq HBs R with APRI and FIB-4.Methods: Blood samples and clinical data of 317 patients with chronic hepatitis B virus infection(CHB patients)were collected from Fuyang Second People’s Hospital,affiliated to Fuyang Institute of Infectious Diseases of Anhui Medical University from may,2013 to June,2016.Fibrosis was evaluated by liver biopsy.HBV genotype of CHB patients was examined by q RT-PCR and then analyzed the relationship between genotype and liver fibrosis or HBe Ag seroconversion.The relationship between Gq HBs R,γ-GT,Hbs Ag and hepatic fibrosis staging were analyzed.The diagnostic efficacy and correlation of Gq HBs R with FIB-4 or APRI were evaluated.Results: HBV was mainly C genotype in 317 patients.The proportion of C and B genotype was statistically significant in different stages of CHB patients with liver fibrosis(P <0.01).The genotype ratio of B genotype was significantly lower in CHB patients with significant hepatic fibrosis(≥S2)than that of the patients with no obvious liver fibrosis(<S2).HBe Ag serological conversion analysis showed that the HBe Ag positive ratio was significantly higher in the C genotype than in the B genotype.The level of γ-GT,score of Gq HBs R and FIB-4 were gradually increased with the increase of liver fibrosis staging,and the level of Hbs Ag was gradually decreased(p<0.01).Gq HBs R showed a positive correlation with FIB-4 in CHB patients with liver fibrosis(R = 0.4235,P <0.0001).The value of Gq HBs R(AUC=0.860)in diagnosis of hepatic fibrosis was significantly higher than that ofγ-GT,Hbs Ag,FIB-4 and APRI,the AUC values were 0.599,0.590,0.789 and 0.775,respectively.The AUC value of Gq HBs R was about 0.9 for thediagnosis of different stages of liver fibrosis.Furthermore,Se,Sp,PPV and NPV was relatively high(>75%).Conclusions: CHB patients with significant liver fibrosis(≥S2)is mianly infected by C genotype of HBV in Anhui province.C genotype is correlated with HBe Ag serological conversion and likely to cause severe liver fibrosis than B genotype.The diagnostic value of Gq HBs R model is significantly higher than FIB-4 and APRI,and exhibits a better performance for identifying stages of liver fibrosis.Thus,to a certain extent,Gq HBs R reduce the proportion of patients undergoing liver biopsy.更多还原