AFP、CA19-9、CEA联合检测对原发性肝癌的早期诊断价值

Value of combined detection of AFP,CA19-9,and CEA in early diagnosis of primary liver cancer

目的研究AFP、CA19-9、CEA联合检测对原发性肝癌进行早期诊断的临床价值。方法收集2014年10月-2016年12月东南大学附属第二医院门诊和住院的肝病患者248例,分为原发性肝癌组(n=88)和非肿瘤性肝病组(n=160),另选取130例健康体检者为正常对照组。采用Roche cobas e 411 analyzer检测3组患者的血清肿瘤标志物AFP、CA19-9、CEA水平,分析3种肿瘤标志物单个检测和联合检测的灵敏度和特异度。采用Beckman Coulter AU5800检测肝功能生化指标。采用Biotek ELX808检测HBV血清学标志物和HCV抗体。应用受试者工作特征曲线(ROC曲线)对原发性肝癌患者的血清AFP、CA19-9、CEA及3者联合检测结果进行分析评价。计量资料多组间比较采用单因素方差分析,进一步两两比较采用SNK-q检验,2组间比较采用t检验;计数资料组间比较采用χ~2检验。相关性分析采用Spearman分析。结果在原发性肝癌组和非肿瘤性肝病组中,肝功能异常患者的AFP、CA19-9均显著高于肝功能正常组(原发性肝癌组:t值分别为35.64、3.38,P值均<0.05;非肿瘤性肝病组:t值分别为12.51、8.19,P值均<0.05);原发性肝癌组中肝功能正常患者的CEA均明显高于非肿瘤性肝病组中肝功能正常患者和正常对照组(P值均<0.05);原发性肝癌组中肝功能异常患者的AFP、CA19-9、CEA水平均明显高于非肿瘤性肝病组中的肝功能异常患者和正常对照组(P值均<0.05)。血清AFP、CA19-9、CEA水平随Child Pugh分级的升高而升高,在原发性肝癌组肝功能异常患者中,AFP、CA19-9、CEA水平B级较A级,C级较B级均显著升高(P值均<0.05);在非肿瘤性肝病组肝功能异常患者中,AFP、CA19-9水平B级较A级,C级较B级均显著升高(P值均<0.05),CEA水平C级显著高于A、B级(P值均<0.05)。原发性肝癌组AFP、CA19-9、CEA的阳性率高于非肿瘤性肝病组和正常对照组(P值均<0.05);各组的联合检测阳性率显著高于单项检测阳性率(P值均<0.05)。原发性肝癌组中,三项联合检测的灵敏度和特异度分别为86.36%和92.35%,单项检测中AFP、CA19-9、CEA的灵敏度分别为71.59%、52.27%和39.77%,原发性肝癌患者的血清AFP、CA19-9、CEA及三者联合检测ROC曲线下面积分别为0.776、0.704、0.681及0.817。AFP在原发性肝癌组中与GGT相关(r=0.54,P=0.04),在正常对照组中与IBil相关(r=0.50,P=0.01);CA19-9在原发性肝癌组与ALT、DBil、IBil、TBil、TBA存在不同程度相关(r值分别为0.58、0.63、0.61、0.65、0.58,P值均<0.05),在非肿瘤性肝病组与ALT、ALP、DBil、IBil、TBil、TBA存在不同程度相关(r值分别为0.51、0.63、0.66、0.64、0.70、0.59,P值均<0.05)。结论 AFP能较好地反映肝损伤,但对原发性肝癌的诊断仍有部分假阴性;CEA轻度升高对原发性肝癌的指示性不强;CA19-9受ALP、胆红素等因素影响明显,假阳性较高;联合检测可提高原发性肝癌诊断的灵敏度,优于AFP、CA19-9、CEA的单项检测,可为早期诊断和早期治疗提供有力的依据。

Objective To investigate the value of combined measurement of alpha-fetoprotein（AFP）,carbohydrate antigen 19-9（CA19-9）,and carcinoembryonic antigen（CEA） in the early diagnosis of primary liver cancer.Methods A total of 248 patients who visited the outpatient service or were hospitalized in The Second Hospital of Nanjing from October 2014 to December 2016 were enrolled and divided into primary liver cancer group with 88 patients and non-tumor liver disease group with 160 patients.A total of 130 healthy subjects who underwent physical examination were enrolled as normal control group.The Roche cobas e 411 analyzer was used to measure the serum levels of the tumor markers AFP,CA19-9,and CEA,and the sensitivities and specificities of these markers or a combination of them were analyzed.Beckman Coulter AU5800 was used to measure biochemical parameters for liver function,and Biotek ELX808 was used to measure hepatitis B virus markers and HCV antibody.The receiver operating characteristic（ROC） curve was used to analyze the results of measurements of serum AFP,CA19-9,and CEA alone or in combination in patients with primary liver cancer.A one-way analysis of variance was used for comparison of continuous data between multiple groups and the SNK-q test was used for further comparison between two groups;the t-test was used for comparison of continuous data between two groups.The chi-square test was used for comparison of categorical data between groups.The Spearman correlation analysis was also performed.Results In the primary liver cancer group and the non-tumor liver disease group,the patients with abnormal liver function had significantly higher levels of AFP and CA19-9 than those with normal liver function（primary liver cancer group：t=35.64 and 3.38,both P〈0.05;non-tumor liver disease group：t=12.51 and 8.19,both P〈0.05）.Among the patients with normal liver function,the primary liver cancer group had a significantly higher level of CEA than the non-tumor liver disease group and the normal control group（all P〈0.05）.Among the patients with abnormal liver function,the primary liver cancer group had significantly higher levels of AFP,CA19-9,and CEA than the non-tumor liver disease group and the normal control group（all P〈0.05）.The serum levels of AFP,CA19-9,and CEA increased with the increase in Child-Pugh class.Among the patients with abnormal liver function in the primary liver cancer group,Child-Pugh class B patients had significant increases in the levels of AFP,CA19-9,and CEA compared with Child-Pugh class A patients,and Child-Pugh class C patients had significant increases compared with Child-Pugh class B patients（all P〈0.05）.Among the patients with abnormal liver function in the non-tumor liver disease group,Child-Pugh class B patients had significant increases in the levels of AFP and CA19-9 compared with Child-Pugh class A patients,and Child-Pugh class C patients had significant increases compared with Child-Pugh class B patients（all P〈0.05）;Child-Pugh class C patients had a significant increase in the level of CEA than Child-Pugh class A/B patients（P〈0.05）.The primary liver cancer group had significantly higher positive rates of AFP,CA19-9,and CEA than the non-tumor liver disease group and the normal control group（all P〈0.05）,and the positive rates of these tumor markers were significantly higher when measured in combination than when measured alone（all P〈0.05）.In the primary liver cancer group,a combination of the three tumor markers had a sensitivity of 86.36% and a specificity of 92.35%,while AFP,CA19-9,and CEA measured alone had sensitivities of 71.59%,52.27%,and 39.77%,respectively.In the patients with primary liver cancer,the areas under the ROC curve for serum AFP,CA19-9,CEA,and a combination of them were 0.776,0.704,0.681,and0.817,respectively.AFP was positively correlated with gamma-glutamyl transpeptidase in the primary liver cancer group（r=0.54,P=0.04） and was positively correlated with indirect bilirubin（IBil） in the normal control group（r=0.50,P=0.01）.In the primary liver cancer group,CA19-9 was positively correlated with alanine aminotransferase（ALT）,direct bilirubin（DBil）,IBil,total bilirubin（TBil）,and total bile acid（TBA）（r=0.58,0.63,0.61,0.65,and 0.58,all P〈0.05）,and in the non-tumor liver disease group,CA19-9 was positively correlated with ALT,alkaline phosphatase（ALP）,DBil,IBil,TBil,and TBA（r=0.51,0.63,0.66,0.64,0.70,and 0.59,all P〈0.05）.Conclusion AFP can well reflect liver injury,but it may yield false-negative results in the diagnosis of primary liver cancer.4A mild increase in CEA does not strongly indicate primary cancer.CA19-9 is easily influenced by the factors including ALP and bilirubin and has a high false-positive rate.Combined measurement of AFP,CA19-9,and CEA can improve the sensitivity of the diagnosis of primary liver cancer and is better than single measurement of AFP,CA19-9,or CEA.Therefore,it provides a strong basis for early diagnosis and treatment.