摘要
目的 评估血清生长分化因子15(GDF15)、microRNA-122(miR-122)、甲胎蛋白(AFP)和异常凝血酶原(PIVKA-Ⅱ)联合检测在监测乙肝病毒(HBV)感染肝硬化患者中肝细胞癌(HCC)的风险预测价值.方法 将2017年12月至2022年1月在首都医科大学附属北京友谊医院就诊的45例HBV相关肝硬化患者、50例HCC患者纳入横断面研究,设为肝硬化组和HCC组;另选22例监测期间新确诊HCC的HBV肝硬化患者纳入纵向研究队列,分别对肝硬化组和HCC组患者以及监测期间新确诊HCC的HBV肝硬化患者的系列血清标本[新确诊HCC前12～18个月(T1)、新确诊HCC前6～12个月(T2)以及HCC诊断时(T3)]进行检测,测定GDF15、miR-122、AFP和PIVKA-Ⅱ水平.比较各组患者每项标志物的检测水平,采用受试者工作特征(ROC)曲线分析GDF15、miR-122、AFP和PIVKA-Ⅱ单独或联合检测对HCC患者的诊断价值,评估标志物的组合预测HBV感染肝硬化患者的HCC风险.结果 横断面研究中,HCC 组患者血清 GDF15、AFP 和 PIVKA-Ⅱ 水平分别为 1 760.64 pg/mL、40.24 ng/mL、106.37 mAU/mL,均显著高于肝硬化组患者(1 357.63 pg/mL、9.07 ng/mL、22.59 mAU/mL),miR-122 水平为 38.72,则显著低于肝硬化组患者(75.70),差异均有统计学意义(P＜0.05).GDF15、miR-122、AFP和PIVKA-Ⅱ单独诊断HCC时,曲线下面积(AUC)分别为0.734、0.644、0.776、0.823;AFP 和 GDF15 两项联合,AUC 为 0.835;GDF15、AFP 和 PIVKA-Ⅱ 三项联合,AUC 为 0.860;GDF15、miR-122、AFP和PIVKA-Ⅱ四项联合,AUC最佳为0.876.区分肝硬化和HCC时,PIVKA-Ⅱ具有较高的敏感度(72.5％);GDF15具有较高的特异度(83.2％);AFP和PIVKA-Ⅱ联合,特异度最高(92.0％);四项联合,敏感度增加(82.2％),约登指数最高(0.622).纵向研究结果未观察到每种单一生物标志物随时间的变化,而GDF15、AFP和PIVKA-Ⅱ三项联合以及GDF15、miR-122、AFP和PIVKA-Ⅱ四项联合,在三个时间点的检测值差异有统计学意义(P＜0.01).肝硬化患者横截面和纵向(T1)之间观察到四项组合的差异有统计学意义(P＜0.05),提示标志物的联合应用可有效区分即将发生HCC和不会发生HCC的肝硬化患者.结论 GDF15、miR-122、AFP和PIVKA-Ⅱ联合检测可以提高对HBV相关肝硬化和HCC患者的分辨力,且在HBV相关的肝硬化中,GDF15、miR-122、AFP和PIVKA-Ⅱ的组合能够识别HCC发展风险较高的患者,具有临床价值.
Abstract
Objective To evaluate the predictive value of combined detection of serum growth differentiation factor 15(GDF15),mi-croRNA-122(miR-122),alpha fetoprotein(AFP)and abnormal prothrombin-Ⅱ(PIVKA-Ⅱ)in monitoring the risk of hepatocellular car-cinoma(HCC)in patients with liver cirrhosis infected by hepatitis B virus(HBV).Methods Forty-five HBV related liver cirrhosis patients and 50 HCC patients who visited Beijing Friendship Hospital,Capital Medical University from December 2017 to January 2022 were included in a cross-sectional study and as the liver cirrhosis group and HCC group.Another 22 HBV cirrhosis patients newly diagnosed with HCC during the monitoring period were selected and included in the longitudinal study queue.Levels of GDF15(ELISA method),miR-122(real-time quanti-tative PCR),AFP(chemiluminescence method),and PIVKA-Ⅱ(chemiluminescence method)were measured in patients of liver cirrhosis group,HCC group and patients who newly dignosed with HCC,as well as a series of serum samples(12-18 months before newly diagnosed HCC T1,6-12 months before newly diagnosed HCC T2,and at HCC diagnosis T3)during the monitoring period were detected.The detection levels of each biomarker in each group of patients were compared and the receiver operating characteristic curve(ROC)was used to analyze the diagnostic value of GDF15,miR-122,AFP,and PIVKA-Ⅱ alone and jointly in HCC patients,and the combination of biomarkers to predict the risk of hepatocellular carcinoma in HBV infected liver cirrhosis patients was evaluated.Results In the cross-sectional study,the levels of serum GDF15,AFP,and PIVKA-Ⅱ in HCC group patients were 1760.64 pg/mL,40.24 ng/mL,and 106.37 mAU/mL,respectively,which were significantly higher than those in liver cirrhosis group patients(1357.63 pg/mL,9.07 ng/mL,22.59 mAU/mL),the level of miR-122 was 38.72,which was significantly lower than that in liver cirrhosis group patients(75.70),and the differences were statistically significant(P＜0.05).When GDF15,miR-122,AFP,and PIVKA-Ⅱ were applied in the diagnosis of HCC separately,the area under the curve(AUC)were 0.734,0.644,0.776,and 0.823,respectively.While the combination of AFP and GDF15 resulted in an AUC of 0.835,and combination of GDF15,AFP,and PIVKA-Ⅱ caused an AUC of 0.860,and the combination of GDF15,miR-122,AFP,and PIVKA-Ⅱ resulted in an optimal AUC of 0.876.When distinguishing between liver cirrhosis and HCC,PIVKA-Ⅱ had a high sensitivity of 72.5％and GDF15 with a high specificity of 83.2％.And the combination of AFP and PIVKA-Ⅱ had got the highest specificity of 92.0％,while four combinations resul-ted in an increase in sensitivity(82.2％)and the highest Jordan index(0.622).The results of longitudinal study did not observe any changes in each single biomarker over time,while the combination of GDF15,AFP,and PIVKA-Ⅱ,as well as the combination of GDF15,miR-122,AFP,and PIVKA-Ⅱ,showed statistically significant differences in detection values at the three time points(P＜0.05).There was statistically significant difference in the four combinations observed between cross-sectional and longitudinal(T1)in patients with liver cirrhosis(P＜0.05),indicating that the combined use of biomarkers can effectively distinguish between those who are about to develop HCC and those who will not.Conclusion The combined detection of GDF15,miR-122,AFP,and PIVKA-Ⅱ can improve the ability to distinguish between HBV related liver cirrhosis and HCC patients and the combination of GDF15,miR-122,AFP,and PIVKA-Ⅱ can identify patients with higher risk of HCC development,which has clinical guiding significance.
维普
万方数据