血清miR-199、miR-448表达与慢性乙型肝炎组织学特征以及进展为肝硬化的相关性分析

Correlation analysis of serum miR-199 and miR-448 expression with histological characteristics of chronic hepatitis B and progression to cirrhosis

目的:探讨血清miR-199、miR-448表达与慢性乙型肝炎组织学特征以及进展为肝硬化的相关性。方法:选择2009年2月至2021年3月收治的慢性乙型肝炎患者269例,根据METAVIR炎症活动分级将患者分为G_(0~1)组(68例)、G_(2)组(104例)、G_(3~4)组(97例);根据纤维化分期将患者分为S_(0~1)组(71例)、S_(2)组(110例)、S_(3)组(88例)。所有患者均定期随访至2021年10月,统计随访期间乙型肝炎进展为肝硬化的发生情况。检测患者入组时(T_(0))、入组1个月(T_(1))、入组3个月(T_(2))和末次随访时(T_(3))血清miR-199、miR-448表达,比较不同炎症活动分级和纤维化分期的慢性乙型肝炎患者T_(0)血清miR-199、miR-448表达差异。多因素Logistic回归分析慢性乙型肝炎进展为肝硬化的因素。受试者工作特征曲线(ROC)分析miR-199、miR-448诊断慢性乙型肝炎进展为肝硬化的价值。结果:慢性乙型肝炎患者G_(3~4)、S_(3)组T_(0)血清miR-199表达高于G_(2)和G_(0~1)组、S_(2)和S_(0~1)组(P<0.05),miR-448表达低于G_(2)和G_(0~1)组、S_(2)和S_(0~1)组(P<0.05)。中位随访51(7~152)个月,失访14例,121例发生乙型肝炎肝硬化(肝硬化组),134例未发生乙型肝炎肝硬化(肝炎组)。肝炎组、肝硬化组T_(0)、T_(1)、T_(2)、T_(3)血清miR-199表达呈持续增高趋势,miR-448表达呈持续降低趋势(P<0.05),肝硬化组T_(0)、T_(1)、T_(2)、T_(3)血清miR-199表达高于肝炎组(P<0.05),miR-448表达低于肝炎组(P<0.05)。ALT、HBV DNA载量、T_(3)血清miR-199、T_(3)血清miR-448与慢性乙型肝炎进展为肝硬化有关(P<0.05)。T_(3)血清miR-199、miR-448诊断慢性乙型肝炎进展为肝硬化的曲线下面积为0.742、0.765,联合T_(3)血清miR-199、miR-448的曲线下面积为0.924,高于单独T_(3)血清miR-199、miR-448(P<0.05)。结论:miR-199高表达、miR-448低表达与慢性乙型肝炎患者炎症分级、肝硬化分期以及进展为肝硬化有关。

Objective:To investigate the relationship between the expression of serum miR-199 and miR-448 and the histological characteristics of chronic hepatitis B and the progression of cirrhosis.Methods:A total of 269 patients with chronic hepatitis B admitted to our hospital from February 2009 to March 2021 were selected.According to METAVIR inflammatory activity grade and fibrosis stage,patients in the hepatitis group were divided into G_(0~1)group(n=68),G_(2)group(n=104),G_(3~4)group(n=97).S_(0~1)group(71 cases),S_(2)group(110 cases),S_(3)group(88 cases).All patients with chronic hepatitis B were followed up regularly until October 2021,and the incidence of hepatitis B cirrhosis was analyzed during the follow-up period.The expressions of miR-199 and miR-448 in serum were detected at enrollment(T_(0)),1month(T_(1))and 3 months(T_(2)),and at the last follow-up(T_(3)).The differences in the expressions of miR-199 and miR-448 in serum of CHRONIC hepatitis B patients with different inflammatory activity grades and fibrosis stages were compared.Multivariate Logistic regression analysis of chronic hepatitis B progression as a factor of cirrhosis.The value of receiver operating characteristic curve(ROC)analysis of miR-199 and miR-448 in the diagnosis of chronic hepatitis B progression to cirrhosis.Results:The expression of serum miR-199 at T_(0)in G_(3~4)and S_(3)groups was higher than that in G_(2)and G_(0~1)groups,S_(2)and S_(0~1)groups(P<0.05),and the expression of miR-448 was lower than that in G_(2)and G_(0~1)groups,S_(2)and S_(0~1)groups(P<0.05).During the median follow-up of 51(7~152)months,14 cases were lost to follow-up,121cases developed hepatitis B cirrhosis(cirrhosis group),and 134 cases did not develop hepatitis B cirrhosis(hepatitis group).The expression of miR-199 in serum T_(0~3)of hepatitis group and cirrhosis group was continuously increased and the expression of miR-448 was continuously decreased(P<0.05).The expression of miR-199 in serum T_(0~3)of cirrhosis group was higher than that of hepatitis group(P<0.05),and the expression of miR-448 was lower than that of hepatitis group(P<0.05).ALT,HBV DNA load,T_(3)miR-199,T_(3)miR-448 were associated with the progression of chronic hepatitis B to cirrhosis(P<0.05).The area under the curve of T_(3)miR-199 and miR-448 for the diagnosis of chronic hepatitis B progression to cirrhosis was 0.742 and 0.765,and the area under the curve of combined T_(3)miR-199 and miR-448 was0.924,which was higher than T_(3)miR-199 and miR-448 alone(P<0.05).Conclusion:The high expression of miR-199 and the low expression of miR-448 are related to the grade of inflammation,stage of cirrhosis and progression of cirrhosis in patients with chronic hepatitis B.