【作者】 张静；

【导师】 胡鹏；

【作者基本信息】 重庆医科大学 ， 内科学（专业学位）， 2024， 硕士

【摘要】 背景:准确判断慢性乙型肝炎(Chronic hepatitis B,CHB)患者的免疫状态,有助于做出合理的治疗决策及判断疾病的预后。根据美国肝脏病研究学会(American Association for the Study of Liver Diseases,AASLD)、欧洲肝脏病研究学会(European Association for the Study of the Liver,EASL)和中华医学会(Chinese Medical Association,CMA)发布的不同指南,慢性乙型肝炎患者按照自然史可被分为四期,以AASLD为例,分别称为免疫耐受期、免疫活动期、非活动期和再活动期。不符合上述四期的诊断标准的免疫状态被定义为自然史对应的“灰区”(Gray zone,GZ)。目前对于这类患者是否需要进行抗病毒治疗,不同国家/地区的指南或专家共识仍存在争议,而存在显著的肝组织炎症或纤维化是慢性乙型肝炎患者抗病毒治疗的重要指征。本研究旨在分析在不同指南下CHB“灰区”患者的分布、肝脏组织病理和临床特征,对比各指南对CHB患者临床管理的指导意义。方法:本研究回顾性纳入1997年1月至2021年12月期间于重庆医科大学附属第二医院接受肝穿刺活检的未接受抗病毒治疗的CHB患者667例。根据AASLD2018、EASL2017,CMA2019和CMA2022指南,基于ALT、HBV DNA水平和HBe Ag状态将CHB患者分为四个自然史分期:A组(免疫耐受期)、B组(免疫活动期)、C组(非活动期)、D组(再活动期)。不属于上述四个分期的患者被认为处于“灰区”,进一步将CHB“灰区”患者分成以下4个亚组:GZ-A/GZ-B/GZ-C/GZ-D,分别对应四个自然史分期A/B/C/D。收集临床和肝组织病理学数据,并进行统计分析,以评估不同指南下“灰区”患者的分布及特征。Scheuer评分系统用于评估肝脏炎症分级(G0-G4)和纤维化分期(S0-S4)。结果:1.根据不同指南,在CMA2019指南定义下的“灰区”患者最少(193/667,28.9%),而按照AASLD2018的分组标准,“灰区”患者最多(321/667,46.8%)。2.不同指南下,各自然史分期和其对应的“灰区”患者之间的年龄、性别差异均无统计学意义(p>0.05)。对比其他三个指南,在AASLD2018指南下,GZ-A组和GZ-C的ALT最低,差异具有统计学意义(GZ-A:20.81,p=0.001;GZ-C:24.76,p=0.003)。3.不论其HBe Ag状态或ALT水平,相当一部分“灰区”患者存在明显的炎症和/或纤维化。在AASLD指南下在GZ-A组和GZ-C组中具有显著炎症和纤维化的患者比例最高,但各灰区的肝组织炎症分级(G)和纤维化分期(S)分布在四个指南中没有显著差异。4.根据不同指南,CMA2022、CMA2019、EASL2017、AASLD2018定义下真正的GZ-A、GZ-C组的错误分组率递增(GZ-A:13.7%、14.9%、31.0%、63.6%;GZ-C:7.9%、54.5%、54.9%、64.2%)。无创肝纤维化检测在降低“灰区”错误分组率方面帮助十分有限。5.根据不同指南,结合肝组织病理学结果,各“灰区”患者中均有超过70%的患者应当接受抗病毒治疗,尤其是GZ-A组和GZ-C组。结论:相比于其他指南,CMA2019及CMA2022指南定义下的“灰区”患者较少。肝活检结果提示相当一部分“灰区”患者存在显著的炎症或纤维化。与其他指南相比,在CMA2022指南中,免疫耐受期和非活动期CHB患者相对应的“灰区”的错误分组率最低,其对免疫耐受期及非活动期CHB患者的定义最准确。无论何种指南,不同自然史对应的“灰区”患者中均有很大比例的患者存在抗病毒指征。更多还原

【Abstract】 Background:Accurate judgment of the immune states of patients with chronic hepatitis B is helpful for making reasonable treatment decisions and judging disease prognosis.According to different guidelines,issued by American Association for the Study of Liver Diseases(AASLD),European Association for the Study of Liver(EASL)and Chinese Medical Association(CMA),chronic hepatitis B(CHB)can be classified into four immune states.Each immune state has its corresponding state defined as the‘gray zone(GZ)’,which do not meet criteria of the usual immune states.This study is aimed to analyse the distribution,liver histopathology and clinical characteristics of patients with CHB‘gray zone’under different guidelines,and to compare the significance of each guideline for the clinical management of patients with CHB.Methods:CHB patients without antiviral therapy who underwent liver biopsy from 1997 to 2021 were retrospectively enrolled in this analysis.The usual immune states and gray zones were classified by HBe Ag status,ALT and HBV DNA levels according to guidelines.The immune states of patients with CHB were defined according to different guidelines:Group A:immune-tolerant,Group B:immune-active,Group C:inactive,Group D:re-active.Patients who did not fall into any of these four stages were considered to be in the‘gray zone’.Patients in the‘gray zone’of CHB were further classified into four subgroups:GZ-A,GZ-B,GZ-C,and GZ-D,corresponding to the four natural history stages A,B,C,and D,respectively.RESULTS:1.According to the different guidelines,patients in the‘gray zone’as defined by the CMA2019 guidelines were the fewest(193/667,28.9%),whereas according to the grouping criteria of AASLD2018,patients in the"gray zone"were the most numerous(321/667,46.8%).2.There was no statistically significant difference between the median age and sex ratio of patients in each‘gray zone’under the different guidelines(p>0.05).The differences in age and gender between the natural history stages and their corresponding‘gray zone’patients were not statistically significant(p>0.05)under different guidelines.Compared with the other three guidelines,the median ALT levels were lowest in the GZ-A and GZ-C groups under the AASLD2018 guidelines,and the difference was statistically significant(GZ-A:20.81,p=0.001;GZ-C:24.76,p=0.003).3.A significant proportion of‘gray zone’patients had significant inflammatory or fibrotic disease,regardless of their HBe Ag status or ALT levels.AASLD guidelines showed that the highest proportion of patients with significant inflammation and fibrosis was found in GZ-A and GZ-C.However,the distribution of hepatic tissue inflammation grade(G)and fibrosis stage(S)in each gray zone did not differ significantly among the four guidelines.4.According to different guidelines,the rate of misclassification in the true GZ-A and GZ-C groups under the definitions of CMA2022,CMA2019,EASL2017,and AASLD2018 was increasing(GZ-A:13.7%,15.0%,32.0%,63.6%;GZ-C:7.9%,54.6%,54.9%,64.2%).Non-invasive liver fibrosis test was of little help in reducing the rate of‘gray zone’misclassification.5.According to the different guidelines,and taking into account the results of liver histopathology,more than 70%of patients in all‘gray zone’should receive antiviral therapy,especially in the GZ-A and GZ-C groups.CONCLUSION:Fewer patients in the‘gray zone’as defined by the CMA2019 and CMA2022 guidelines than other guidelines.Liver biopsy results suggest significant inflammation or fibrosis in a significant proportion of patients with‘gray zone’CHB.Compared with other guidelines,the CMA 2022 guideline had the lowest rate of misclassification of gray areas corresponding to patients with immune-tolerant and inactive CHB,and it most accurately defined patients with immune-tolerant and inactive CHB.Regardless of the guideline,a significant proportion of patients with CHB in the‘gray zone’corresponding to different natural histories had an antiviral indication.更多还原