多个血液学指标联合对于甲胎蛋白阴性肝癌患者的诊断效能分析

Analysis of the diagnostic efficiency of combining multiple laboratory hematological indicators in alpha-fetoprotein-negative hepatocellular carcinoma

目的建立联合多个实验室血液学指标诊断甲胎蛋白(AFP)阴性肝细胞癌(AFP-NHCC)的模型,探讨其临床诊断效能。方法纳入2011年12月到2017年6月在解放军总医院首次确诊为AFP-NHCC的住院患者124例,男110例,女14例,年龄[M(Q1,Q3)]为57(51,66)岁;以同期331例非癌人群作为对照组,男279例,女52例,年龄为58(51,63)岁,包括47例乙型肝炎、40例肝硬化、64例肝血管瘤或囊肿、7例肝结节、8例脂肪肝、146例非肝病患者以及19名健康体检者。将AFP-NHCC组和对照组人群分为训练组与验证组:训练组共纳入196例受试者,包括103例AFP-NHCC患者和93例非癌人群(包括19名健康体检者、25例乙型肝炎患者、22例肝硬化患者、23例肝血管瘤和囊肿患者以及4例肝结节患者),用来分析实验室指标的差异和建立不同AFP水平下AFP-NHCC的诊断模型;验证组共纳入259例受试者,其中包括113例肝病患者,用来验证诊断模型对AFP-NHCC的诊断效能。采用受试者工作特征(ROC)曲线对不同模型的诊断效能进行灵敏度及特异度分析,采用曲线下面积(AUC)评估不同模型的诊断效能。结果在训练组中,AFP≤5μg/L时所建立的AFP-NHCC诊断模型包括血小板(PLT)、凝血酶原活动度(PTA)、血清白蛋白(ALB)、凝血酶原时间(PT)和糖类抗原19-9(CA19-9),AUC为0.848(95%CI:0.786~0.911);AFP≤10μg/L时所建立的AFP-NHCC诊断模型包括PLT、PTA、ALB、PT和红细胞压积(HCT),AUC为0.839(95%CI:0.780~0.897);AFP≤20μg/L时所建立的AFP-NHCC诊断模型包括PLT、PTA、ALB、PT、HCT和AFP,AUC为0.866(95%CI:0.815~0.917);这3种模型的AUC值均高于AFP和CA19-9单项诊断AFP-NHCC时的AUC值[0.634(95%CI:0.560~0.709)、0.691(95%CI:0.620~0.761),均P<0.05]。将这3种模型筛选出的指标联合,建立最终诊断模型,包括PLT、PTA、ALB、PT、HCT、CA19-9和AFP,其AUC为0.873(95%CI:0.824~0.923),灵敏度为78.6%(81/103),特异度为81.7%(76/93)。在验证组中,最终诊断模型在肝病患者中的预测AUC为0.892(95%CI:0.832~0.951),灵敏度为100%(21/21),特异度为71.7%(66/92);在全部验证人群中的预测AUC为0.931(95%CI:0.890~0.972),灵敏度为100.0%(21/21),特异度为75.6%(180/238)。结论建立的最终诊断模型包括PLT、PTA、ALB、PT、HCT、CA19-9和AFP,其灵敏度和特异度均较高,对于临床诊断AFP-NHCC具有较好的诊断效能。

Objective To establish a diagnostic model for alpha-fetoprotein-negative hepatocellular carcinoma(AFP-NHCC)by combining multiple laboratory hematological indicators and explore its clinical diagnostic efficiency.Methods A total of 124 inpatients,including 110 males and 14 females,aged 57(51,66)years,who were first diagnosed with AFP-NHCC in the PLA General Hospital were included from December 2011 to June 2017.Meanwhile,331 cases of non-HCC were enrolled as the control group,including 279 males and 52 females,aged 58(51,63)years old,with 47 cases of hepatitis B virus(HBV)infection,40 cases of liver cirrhosis,64 cases of hepatic hemangioma or cysts,7 cases of liver nodules,8 cases of fatty liver,146 cases of non-liver disease and 19 health controls.Subjects in the AFP-NHCC group and the control group were divided into a training group and a validation group.A total of 196 subjects were involved in the training group,including 103 AFP-NHCC patients and 93 non-HCC patients(19 healthy controls,25 patients with HBV infection,22 patients with liver cirrhosis,23 patients with hepatic hemangioma or cyst,and 4 patients with liver nodules).The differences in laboratory parameters were analyzed,and a diagnostic model of AFP-NHCC under different AFP levels was established.Likewise,259 subjects,including 113 patients with liver disease,were involved in the validation group to verify the diagnostic efficiency of the model for AFP-NHCC.The receiver operating characteristic(ROC)curve was used to analyze the sensitivity and specificity of different models,and the area under the curve(AUC)was calculated to evaluate the diagnostic performance of different models.Results In the training group,the indicators of AFP-NHCC diagnostic model included platelet(PLT),prothrombin activity(PTA),serum albumin(ALB),prothrombin time(PT)and carbohydrate antigen 19-9(CA19-9),and the AUC of the model was 0.848(95%CI:0.786-0.911)when AFP≤5μg/L.Similarly,the indicators of AFP-NHCC diagnostic model included PLT,PTA,ALB,PT and hematocrit(HCT),and the AUC of the model was 0.839(95%CI:0.780-0.897)when AFP≤10μg/L.When AFP≤20μg/L,the indicators of AFP-NHCC diagnostic model contained PLT,PTA,ALB,PT,HCT and AFP,and the AUC of the model was 0.866(95%CI:0.815-0.917).The AUC values of these three models were higher than those of AFP and CA19-9 alone for the diagnosis of AFP-NHCC[0.634(95%CI:0.560-0.709),0.691(95%CI:0.620-0.761),all P<0.05].The indicators screened by these three models were combined to establish the final diagnostic model,and the AUC of the model was 0.873(95%CI:0.824-0.923),with the sensitivity of 78.6%(81/103)and the specificity of 81.7%(76/93).In the validation group,the predictive AUC of the final model in liver disease patients was 0.892(95%CI:0.832-0.951),with the sensitivity of 100%(21/21)and the specificity of 71.7%(66/92),while in the total validation population,the predictive AUC was 0.931(95%CI:0.890-0.972),with the sensitivity of 100.0%(21/21)and the specificity of 75.6%(180/238).Conclusion The final diagnostic model includes PLT,PTA,ALB,PT,HCT,CA19-9 and AFP,which has higher sensitivity and specificity,and has good diagnostic efficiency for the clinical diagnosis of AFP-NHCC.