血清甲胎蛋白、Dickkopf相关蛋白1、细胞骨架蛋白4联合检测对肝细胞癌的诊断价值
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摘要
目的探讨血清甲胎蛋白(AFP)、分泌型蛋白Dickkopf-1(DKK1)、细胞骨架蛋白4(CKAP4)联合检测对肝细胞癌(HCC)的临床诊断价值。方法纳入2013年1月至2017年12月苏州大学附属第一医院收治的122例HCC患者(76例早期患者)、152例肝硬化患者、105例慢性乙型肝炎患者,同期从门诊体检部选取健康体检者101例,作为健康对照组。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LSD-t检验;计数资料多组间比较采用χ~2检验。用二分类变量logistic回归进行分析,产生新变量(预测概率),并对各单项指标、预测概率进行受试者工作特征(ROC)曲线分析,评估单项及联合检测的ROC曲线下面积(AUC)、敏感度及特异度。结果 HCC组患者的血清AFP、DKK1、CKAP4水平均明显高于肝硬化、慢性乙型肝炎和健康对照组,差异均有统计学意义(F值分别为121. 618、84. 559、91. 769,P值均<0. 001)。由AFP、DKK1、CKAP4联合形成的新变量判断HCC的AUC为0. 967[95%置信区间(95%CI):0. 950～0. 984],敏感度为0. 869,特异度为0. 980,显著高于各项指标单独检测(P值均<0. 05)。新变量判断早期HCC的AUC为0. 965(95%CI:0. 942～0. 988),敏感度为0. 868,特异度为0. 980,显著高于各项指标单独检测(P值均<0. 05)。结论血清AFP、DKK1、CKAP4联合检测提高了HCC诊断的准确度、敏感度及特异度,对HCC高危人群的筛查及早期诊断有重要的临床参考价值。
Objective To investigate the value of combined measurement of serum alpha-fetoprotein(AFP),Dickkopf-1(DKK1),and cytoskeleton-associated protein 4(CKAP4) in the diagnosis of hepatocellular carcinoma(HCC). Methods A total of 122 patients with HCC(76 patients in the early stage),152 patients with liver cirrhosis,and 105 patients with chronic hepatitis B,who were admitted to The First Affiliated Hospital of Soochow University from January 2013 to December 2017,were enrolled,and 101 individuals who underwent physical examination during the same period of time were enrolled as healthy control group. A one-way analysis of variance was used for comparison of continuous data between multiple groups,and the least significant difference t-test was used for further comparison between two groups; the chi-square test was used for comparison of categorical data between multiple groups. A binary logistic regression analysis was used to obtain the new variable of predicted probability,and the receiver operating characteristic(ROC) curve analysis was performed for each index and predicted probability to investigate the area under the ROC curve(AUC),sensitivity,and specificity of the three indices used alone or in combination. Results The HCC group had significantly higher serum levels of AFP,DKK1,and CKAP4 than the liver cirrhosis group,the chronic hepatitis B group,and the healthy control groups(F = 121. 618,84. 559,and 91. 769,P < 0. 001). The combination of AFP,DKK1,and CKAP4 had an AUC of 0. 967(95% confidence interval [CI]: 0. 950-0. 984),a sensitivity of 0. 869,and a specificity of 0. 980,which were significantly higher than the AUCs,sensitivities,and specificities of the three indices used alone(all P <0. 05). The combination of the three indices had an AUC of 0. 965(95% CI: 0. 942-0. 988),a sensitivity of 0. 868,and a specificity of0. 980 in the diagnosis of early-stage HCC,which were significantly higher than the AUCs,sensitivities,and specificities of the three indices used alone(all P < 0. 05). Conclusion Combined measurement of serum AFP,DKK1,and CKAP4 improves the accuracy,sensitivity,and specificity of HCC diagnosis and thus has an important clinical value in the screening for and early diagnosis of HCC.
Objective To investigate the value of combined measurement of serum alpha-fetoprotein(AFP),Dickkopf-1(DKK1),and cytoskeleton-associated protein 4(CKAP4) in the diagnosis of hepatocellular carcinoma(HCC). Methods A total of 122 patients with HCC(76 patients in the early stage),152 patients with liver cirrhosis,and 105 patients with chronic hepatitis B,who were admitted to The First Affiliated Hospital of Soochow University from January 2013 to December 2017,were enrolled,and 101 individuals who underwent physical examination during the same period of time were enrolled as healthy control group. A one-way analysis of variance was used for comparison of continuous data between multiple groups,and the least significant difference t-test was used for further comparison between two groups; the chi-square test was used for comparison of categorical data between multiple groups. A binary logistic regression analysis was used to obtain the new variable of predicted probability,and the receiver operating characteristic(ROC) curve analysis was performed for each index and predicted probability to investigate the area under the ROC curve(AUC),sensitivity,and specificity of the three indices used alone or in combination. Results The HCC group had significantly higher serum levels of AFP,DKK1,and CKAP4 than the liver cirrhosis group,the chronic hepatitis B group,and the healthy control groups(F = 121. 618,84. 559,and 91. 769,P < 0. 001). The combination of AFP,DKK1,and CKAP4 had an AUC of 0. 967(95% confidence interval [CI]: 0. 950-0. 984),a sensitivity of 0. 869,and a specificity of 0. 980,which were significantly higher than the AUCs,sensitivities,and specificities of the three indices used alone(all P <0. 05). The combination of the three indices had an AUC of 0. 965(95% CI: 0. 942-0. 988),a sensitivity of 0. 868,and a specificity of0. 980 in the diagnosis of early-stage HCC,which were significantly higher than the AUCs,sensitivities,and specificities of the three indices used alone(all P < 0. 05). Conclusion Combined measurement of serum AFP,DKK1,and CKAP4 improves the accuracy,sensitivity,and specificity of HCC diagnosis and thus has an important clinical value in the screening for and early diagnosis of HCC.
引文
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[12]Chinese Society of Hepatology and Chinese Society of Infectious Diseases Chinese,Medical Association.The guideline of prevention and treatment for chronic hepatitis B:A 2015 update[J].J Clin Hepatol,2015,31(12):1941-1960.(in Chinese)中华医学会肝病学分会,中华医学会感染病学分会.慢性乙型肝炎防治指南(2015年更新版)[J].临床肝胆病杂志,2015,31(12):1941-1960.
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[14]XIE RZ,CHEN SH.Diagnostic value of combined serum AFP,TK1 and DKK1 levels in primary liver cancer[J].Int J Lab Med,2018,39(8):939-941,946.(in Chinese)谢荣章,陈树华.联合血清AFP、TK1及DKK1水平检测对原发性肝癌诊断价值研究[J].国际检验医学杂志,2018,39(8):939-941,946.
[15]BLANK S,WANG Q,FIEL MI,et al.Assessing prognostic significance of preoperative alpha-fetoprotein in hepatitis B-associated hepatocellular carcinoma:Normal is not the new normal[J].Ann Surg Oncol,2014,21(3):986-994.
[16]KIM SU,PARK JH,KIM HS,et al.Serum dickkopf-1 as a biomarker for the diagnosis of hepatocellular carcinoma[J].Yonsei Med J,2015,56(5):1296-1306.
[17]LI SX,LIU LJ,DONG LW,et al.CKAP4 inhibited growth and metastasis of hepatocellular carcinoma through regulating EG-FR signaling[J].Tumour Biol,2014,35(8):7999-8005.
[18]LI SX,TANG GS,ZHOU DX,et al.Prognostic significance of cytoskeleton-associated membrane protein 4 and its palmitoyl acyltransferase DHHC2 in hepatocellular carcinoma[J].Cancer,2014,120(10):1520-1531.
[2]FU J,WANG H.Precision diagnosis and treatment of liver cancer in China[J].Cancer Lett,2018,412(1):283-288.
[3]ZENG H,CHEN W,ZHENG R,et al.Changing cancer survival in China during 2003-15:A pooled analysis of 17 population-based cancer registries[J].Lancet Glob Health,2018,6(5):e555-e567.
[4]ATTWA MH,El-ETREBY SA.Guide for diagnosis and treatment of hepatocellular carcinoma[J].World J Hepatol,2015,7(12):1632-1651.
[5]MARRERO JA,FENG Z,WANG Y,et al.Alpha-fetoprotein,des-gamma carboxyprothrombin,and lectin-bound alphafetoprotein in early hepatocellular carcinoma[J].Gastroenterology,2009,137(1):110-118.
[6]GLINKA A,WU W,DELIUS H,et al.Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction[J].Nature,1998,391(6665):357-362.
[7]SHEN Q,FAN J,YANG XR,et al.Serum DKK1 as a protein biomarker for the diagnosis of hepatocellular carcinoma:Alarge-scale,multicentre study[J].Lancet Oncol,2012,13(8):817-826.
[8]KIMURA H,FUMOTO K,SHOJIMA K,et al.CKAP4 is a Dickkopf1 receptor and is involved in tumor progression[J].J Clin Invest,2016,126(7):2689-2705.
[9]BRUIX J,SHERMAN M.Management of hepatocellular carcinoma[J].Hepatology,2005,42(5):1208-1236.
[10]LLOVET JM,DI BISCEGLIE AM,BRUIX J,et al.Design and endpoints of clinical trials in hepatocellular carcinoma[J].JNatl Cancer Inst,2008,100(10):698-711.
[11]Experts in combined team of the Major Special Project of Ministry of Science and Technology supported by China’s“Twelfth Five-Year Plan”.Management of clinical diagnosis,evaluation,and antiviral therapy for HBV-related cirrhosis[J].J Clin Hepatol,2014,30(2):99-108.(in Chinese)科技部十二五重大专项联合课题组专家.乙型肝炎病毒相关肝硬化的临床诊断、评估和抗病毒治疗的综合管理[J].临床肝胆病杂志,2014,30(2):99-108.
[12]Chinese Society of Hepatology and Chinese Society of Infectious Diseases Chinese,Medical Association.The guideline of prevention and treatment for chronic hepatitis B:A 2015 update[J].J Clin Hepatol,2015,31(12):1941-1960.(in Chinese)中华医学会肝病学分会,中华医学会感染病学分会.慢性乙型肝炎防治指南(2015年更新版)[J].临床肝胆病杂志,2015,31(12):1941-1960.
[13]SHEN Q,YANG XR,TAN Y,et al.High level of serum protein DKK1 predicts poor prognosis for patients with hepatocellular carcinoma after hepatectomy[J].Hepat Oncol,2015,2(3):231-244.
[14]XIE RZ,CHEN SH.Diagnostic value of combined serum AFP,TK1 and DKK1 levels in primary liver cancer[J].Int J Lab Med,2018,39(8):939-941,946.(in Chinese)谢荣章,陈树华.联合血清AFP、TK1及DKK1水平检测对原发性肝癌诊断价值研究[J].国际检验医学杂志,2018,39(8):939-941,946.
[15]BLANK S,WANG Q,FIEL MI,et al.Assessing prognostic significance of preoperative alpha-fetoprotein in hepatitis B-associated hepatocellular carcinoma:Normal is not the new normal[J].Ann Surg Oncol,2014,21(3):986-994.
[16]KIM SU,PARK JH,KIM HS,et al.Serum dickkopf-1 as a biomarker for the diagnosis of hepatocellular carcinoma[J].Yonsei Med J,2015,56(5):1296-1306.
[17]LI SX,LIU LJ,DONG LW,et al.CKAP4 inhibited growth and metastasis of hepatocellular carcinoma through regulating EG-FR signaling[J].Tumour Biol,2014,35(8):7999-8005.
[18]LI SX,TANG GS,ZHOU DX,et al.Prognostic significance of cytoskeleton-associated membrane protein 4 and its palmitoyl acyltransferase DHHC2 in hepatocellular carcinoma[J].Cancer,2014,120(10):1520-1531.
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