血清N-聚糖生物标志物诊断ALT水平正常慢性乙型肝炎患者显著肝纤维化和肝硬化的临床意义

Serum N-Glycan Markers for Diagnosing Significant Liver Fibrosis and Cirrhosis in Chronic Hepatitis B Patients with Normal Alanine Aminotransferase Levels

本研究目的是探讨血清N-聚糖模型在285例丙氨酸转移酶(alanine aminotransferase,ALT)水平正常(<40 U·L^(-1))的慢性乙型肝炎(慢性乙肝)患者中诊断显著肝纤维化和肝硬化的临床意义。入组患者均进行肝组织活检,并使用Ishak评分系统评估患者肝组织纤维化程度。应用基于DNA测序仪的荧光糖电泳技术检测患者血清N-聚糖图谱,每例患者的血清样本中共鉴定出9个N-聚糖峰。利用机器学习算法,即随机森林(random forest,RF)构建更理想的血清N-聚糖模型,以诊断显著肝纤维化(≥F3)和肝硬化(≥F5),并比较血清N-聚糖模型和其他纤维化标志物的诊断效能。肝组织活检结果显示,有显著肝纤维化和肝硬化患者分别占63.86%(182/285)和16.49%(47/285),有显著炎症患者为4.91%(14/285)。血清N-聚糖RF-A模型具有很好的诊断显著肝纤维化(≥F3)的效能,其受试者工作特征曲线下面积(area under receiver operating characteristic curve,AUROC)为0.94,与肝活检的符合率为90.45%。在诊断肝硬化(≥F5)时,血清N-聚糖RF-B模型的AUROC为0.97,与肝组织活检的符合率为88.94%。血清N-聚糖模型(RF-A和RF-B)的诊断效能优于肝硬度值测量(liver stiffness measurement,LSM)、基于4因子的纤维化指数(fibrosis index based on the four factors,FIB-4)和天冬氨酸转氨酶与血小板比率指数(aspartate aminotransferase-to-platelet ratio index,APRI)。在ALT水平正常的慢性乙肝患者中,血清N-聚糖模型可作为诊断显著肝纤维化或肝硬化的潜在生物标志物。

The aim of this study was to explore the role of serum N-glycomic-derived models in diagnosing significant liver fibrosis and cirrhosis in 285 chronic hepatitis B(CHB)patients with normal(<40 IU·L^(-1))alanine aminotransferase(ALT)levels.Liver biopsies were performed in all enrolled patients,and the stages of liver fibrosis were assessed using the Ishak scoring system.Serum N-glycan profiles were tested using DNA sequencer-assisted fluorophore-assisted carbohydrate electrophoresis(DSA-FACE).A total of nine N-glycan peaks were identified in serum samples for each subject.A machine learning method-namely,random forest(RF)analysis-was adopted to construct more ideal serum N-glycan models in order to distinguish significant liver fibrosis(≥F3)and cirrhosis(≥F5).The diagnostic value of the constructed N-glycan models and other fibrotic markers was evaluated.The liver biopsy results revealed that 63.86%(182/285)and 16.49%(47/285)of patients had significant liver fibrosis and cirrhosis,respectively,and 4.91%(14/285)of patients had significant inflammation.In distinguishing significant liver fibrosis,the diagnostic efficiency of the serum N-glycan RF model constructed for distinguishing significant liver fibrosis(≥F3;RF-A model)was excellent(area under receiver operating characteristic(AUROC)curve:0.94),and the coincidence rate of the serum N-glycan RF-A model compared with liver biopsy was 90.45%.In distinguishing liver cirrhosis,the diagnostic AUROC curve of the serum N-glycan RF model constructed for distinguishing liver cirrhosis(≥F5;RF-B model)was 0.97,and the coincidence rate was 88.94%.The diagnostic efficiency of the constructed serum N-glycan models(RF-A and RF-B)was superior to that of liver stiffness measurement(LSM),the fibrosis index based on the four factors(FIB-4),and the aspartate aminotransferase-to-platelet ratio index(APRI).Serum N-glycan models are promising markers for the differentiation of significant liver fibrosis and cirrhosis in CHB patients with normal ALT levels.