Wnt/β-catenin通路相关蛋白在乙型肝炎肝纤维化进程中的临床意义

Clinical significance of Wnt/β-catenin pathway related proteins in the process of hepatitis B liver fibrosis

目的:探讨Wnt/β-catenin通路相关蛋白在乙型肝炎肝纤维化进程中的变化。方法:选取275例患者,包含HBV携带者或非活动性乙肝表面抗原(HBsAg)携带者(HBV组,n=130例)和慢性乙型肝炎患者(n=145例)。根据肝活检病理学评估,慢性乙型肝炎患者中29例患者未发生肝纤维化(CHB组),另116例患者发生肝纤维化(肝纤维化组)。比较肝纤维化组不同肝纤维化分期(S0~S4)和炎症分级(G0~G4)患者血清Wnt/β-catenin通路相关蛋白水平。受试者工作特征(ROC)曲线分析血清标志物诊断不同肝纤维化分期的最佳切割点。多元Logistic线性回归模型分析血清标志物与肝纤维化进展的关系。结果:与HBV组和CHB组比较,肝纤维化组患者血清Wnt-3a、Wnt-5a、β-catenin、Wnt诱导分泌蛋白-1(WISP-1)水平升高,同时Wnt信号通路抑制分子Dickkopf-1(DKK-1)水平降低(均P<0.05)。与S1~S2期患者比较,S3~S4期患者血清Wnt-5a、WISP-1水平升高,且血清DKK-1水平降低(均P<0.05)。此外炎症分级G4级患者血清Wnt-3a、Wnt-5a、β-catenin、WISP-1水平高于G1~G3级,同时DKK-1水平低于G1~G3级(P<0.05)。经相关性分析,Wnt-5a、β-catenin、WISP-1与肝纤维4项呈正相关性(P<0.05),而DKK-1与Ⅲ型前胶原(PCⅢ)、CIV、层黏连蛋白(LN)则呈负相关性(P<0.05)。经ROC曲线和多元Logistic回归分析,血清Wnt-5a、WISP-1、DKK-1标记物异常与肝纤维化进展风险独立相关(P<0.05)。结论:乙型肝炎肝纤维化患者血清Wnt-3a、Wnt-5a、β-catenin、WISP-1水平普遍升高,同时DKK-1水平下降,检测血清Wnt-5a、WISP-1、DKK-1水平有助于判断乙型肝炎肝纤维化患者的疾病进展程度。

Objective:To investigate the changes and clinical significance of Wnt/β-catenin pathway related proteins in the process of hepatitis B liver fibrosis.Methods:An analysis of 275 patients in our hospital from June 2017 to November 2020,including patients with HBV or inactive hepatitis B surface Antigen(HBSAG)(HBV group,n=130 cases)and patients with chronic hepatitis B(n=145 cases).According to liver biopsy pathological evaluation,29 patients did not develop liver fibrosis as CHB group,another 116 patients developed liver fibrosis as a result of HBV liver fibrosis.The serum levels of Wnt/β-catenin pathway-related proteins in patients with different liver fibrosis stages(S0~S4)and inflammation grades(G0~G4)in the liver fibrosis group were compared.Receiver operating characteristic(ROC)curve analysis is the best cut point for serum markers to diagnose different liver fibrosis stages.A multivariate Logistic linear regression model was used to analyze the relationship between serum markers and the progression of liver fibrosis.Results:Compared with the HBV group and CHB group,serum Wnt-3a,Wnt-5a,β-catenin,and Wnt-induced secretory protein-1(WISP-1)levels increased in patients with liver fibrosis,while the level of Wnt signaling pathway inhibitor Dickkopf-1(DKK-1)decreased,P<0.05.Compared with patients with stage S1~S2,serum Wnt-5a and WISP-1 levels of patients with stage S3~S4 increased,and serum DKK-1 levels decreased,both P<0.05.In addition,serum Wnt-3a,Wnt-5a,β-catenin,and WISP-1 levels of patients with inflammation grade G4 were higher than those of G1~G3,while DKK-1 levels were lower than G1~G3(P<0.05).After correlation analysis,Wnt-5a,β-catenin,WISP-1 and liver fiber were positively correlated(P<0.05),while DKK-1 was correlated with typeⅢprocollagen(PCⅢ),CIV,laminin(LN)Was negatively correlated(P<0.05).After ROC curve and multivariate Logistic regression analysis,abnormal serum Wnt-5a,WISP-1,DKK-1 markers were independently associated with the risk of liver fibrosis progression(P<0.05).Conclusion:Serum Wnt-3a,Wnt-5a,β-catenin,and WISP-1 levels in hepatitis B liver fibrosis patients generally increased,while DKK-1 levels decreased.Detection of serum Wnt-5a,WISP-1,DKK-1 levels is helpful to judge the disease progression of patients with hepatitis B liver fibrosis.