血清高尔基蛋白73、甲胎蛋白异质体3、甲胎蛋白和α-L-岩藻糖苷酶水平诊断原发性肝癌的效能分析
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摘要
目的探讨应用血清高尔基蛋白体73(GP73)、甲胎蛋白异质体3(AFP-L3)、AFP和α-L-岩藻糖苷酶(AFU)水平诊断原发性肝癌(PLC)患者的效能。方法 2015年1月～2017年3月我院诊治的PLC患者261例,乙型肝炎肝硬化患者201例,慢性乙型肝炎患者238例和体检健康人200例,采用酶联免疫吸附试验法检测血清GP73水平,采用亲和吸附离心管法检测血清AFP-L3,采用全自动化学发光仪检测血清AFP,采用商用试剂盒检测血清AFU水平。绘制血清GP73、AFP-L3、AFP和AFU诊断PLC的ROC曲线,确定截断点(cut-off-value),计算ROC曲线下面积(AUC),判断它们的诊断效能。结果肝癌组血清GP73水平显著低于慢性肝炎组和肝硬化组,差异有统计学意义(P<0.05),血清AFP-L3显著高于其他3组,差异有统计学意义(P<0.05),血清AFU水平显著高于健康人和肝硬化组,但低于慢性肝炎组,差异有统计学意义(P<0.05);以非肝癌人群为对照,血清GP73、AFP-L3、AFP和AFU诊断肝癌的ROC曲线下面积分别为0.564 (95%CI:0.485～0.636)、0.724 (95%CI:0.555～0.786)、0.745(95%CI:0.654～0.806)和0.571(95%CI:0.385～0.536),血清AFP-L3联合AFP诊断肝癌的截断点分别为8.25%和49.25 ng/ml,其灵敏度(Se)为55.5%,特异度(Sp)为85.0%,正确性(Ac)为80.1%,显著高于血清AFP-L3诊断的55.5%、85.0%和76.4%或AFP诊断的57.1%、82.7%和75.2%(P<0.05);在261例肝癌患者中,血清AFP<9.6 ng/ml者71例(27.2%),其中PG73>106.5 ng/ml者30例(42.3%),提示GP73对AFP阴性肝癌有一定的诊断价值;在201例肝硬化患者中,血清AFP<9.6 ng/ml者98例(48.8%),其中PG73>106.5 ng/ml者52例(53.1%),提示血清GP73水平容易受到肝硬化的影响。结论应用血清AFP联合AFP-L3检测能够提高诊断肝癌的效能,但它们的灵敏度都还不够高,影响因素较多。临床医生需结合病史、影像学检查和动态血清学检测才能做出更为科学的结论。
Objective To investigate the clinical implications of serum Golgi protein 73(GP73),lentil lectin-reactive alpha-fetoprotein-L3(AFP-L3),AFP,and α-L-fucosidase(AFU) in patients with primary liver cancer(PLC). Methods 261 patients with PLC,201 patients with hepatitis B liver cirrhosis(LC),238 patients with chronic hepatitis B(CHB) and 200 healthy individuals were recruited in this study betweem January 2015 and March 2017,and serum levels of GP73,AFP-L3,AFP and AFU were detected. The efficacy of diagnosis was performed by Logistic fitting and the ROC curve were drawn to calculate their diagnostic efficacy. Results Serum GP73 level in patients with PLC was significantly lower than in patients with CHB or in patients with LC(P<0.05),serum AFP-L3 level was much higher than those in patients with CHB,with LC or healthy persons(P <0.05),and serum AFU level was much higher than in healthy persons or in patients with LC,but much lower than in patients with CHB(P <0.05);the AUC of serum GP73,AFP-L3,AFP and AFU in diagnosing PLC based on comparison with non-PLC individuals were 0.564(95% CI:0.485-0.636),0.724(95% CI:0.555-0.786),0.745(95%CI:0.654-0.806) and 0.571(95%CI:0.385-0.536),and the cut-off-value of serum AFP-L3 and serum AFP combination were 8.25% and 49.25 ng/mL,with the sensitivity(Se) of 55.5%,specificity(Sp) of 85.0% and accurracy(Ac) of 80.1%,significantly higher than 55.5%,85.0% and 76.4% by serum AFP-L3 or 57.1%,82.7% and 75.2%(P<0.05) by serum AFP alone;out of 261 patients with PLC,71 patients(27.2%) had serum AFP<9.6 ng/ml,and 30(42.3%) of them had serum PG73>106.5 ng/ml,suggesting the latter might be useful in diagnosing PLC patients with lower or negative serum AFP;out of 201 patients with LC,serum AFP levels were less than 9.6 ng/ml in 98(48.8%),and 53.1% of them(52/98) had serum PG73 level being greater than 106.5 ng/ml,hinting that liver cirrhosis might impact serum GP73 level. Conclusion Serum GP73 level is associated with liver injury and fibrosis and serum AFU level is of little significance for the diagnosis of patients with PLC. The application serum AFP combined with AFP-L3 might improve the efficacy in diagnosing patients with PLC,while the Se and Sp are still not high. The clinicians should take this into consideration and make a relatively accurate diagnosis by detailed illness history,comprehensive physical examination and necessary imaging.
Objective To investigate the clinical implications of serum Golgi protein 73(GP73),lentil lectin-reactive alpha-fetoprotein-L3(AFP-L3),AFP,and α-L-fucosidase(AFU) in patients with primary liver cancer(PLC). Methods 261 patients with PLC,201 patients with hepatitis B liver cirrhosis(LC),238 patients with chronic hepatitis B(CHB) and 200 healthy individuals were recruited in this study betweem January 2015 and March 2017,and serum levels of GP73,AFP-L3,AFP and AFU were detected. The efficacy of diagnosis was performed by Logistic fitting and the ROC curve were drawn to calculate their diagnostic efficacy. Results Serum GP73 level in patients with PLC was significantly lower than in patients with CHB or in patients with LC(P<0.05),serum AFP-L3 level was much higher than those in patients with CHB,with LC or healthy persons(P <0.05),and serum AFU level was much higher than in healthy persons or in patients with LC,but much lower than in patients with CHB(P <0.05);the AUC of serum GP73,AFP-L3,AFP and AFU in diagnosing PLC based on comparison with non-PLC individuals were 0.564(95% CI:0.485-0.636),0.724(95% CI:0.555-0.786),0.745(95%CI:0.654-0.806) and 0.571(95%CI:0.385-0.536),and the cut-off-value of serum AFP-L3 and serum AFP combination were 8.25% and 49.25 ng/mL,with the sensitivity(Se) of 55.5%,specificity(Sp) of 85.0% and accurracy(Ac) of 80.1%,significantly higher than 55.5%,85.0% and 76.4% by serum AFP-L3 or 57.1%,82.7% and 75.2%(P<0.05) by serum AFP alone;out of 261 patients with PLC,71 patients(27.2%) had serum AFP<9.6 ng/ml,and 30(42.3%) of them had serum PG73>106.5 ng/ml,suggesting the latter might be useful in diagnosing PLC patients with lower or negative serum AFP;out of 201 patients with LC,serum AFP levels were less than 9.6 ng/ml in 98(48.8%),and 53.1% of them(52/98) had serum PG73 level being greater than 106.5 ng/ml,hinting that liver cirrhosis might impact serum GP73 level. Conclusion Serum GP73 level is associated with liver injury and fibrosis and serum AFU level is of little significance for the diagnosis of patients with PLC. The application serum AFP combined with AFP-L3 might improve the efficacy in diagnosing patients with PLC,while the Se and Sp are still not high. The clinicians should take this into consideration and make a relatively accurate diagnosis by detailed illness history,comprehensive physical examination and necessary imaging.
引文
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[7]肖潇,何羽童,房萌,等.甲胎蛋白异质体在原发性肝癌临床诊断中的应用.实用肝脏病杂志,2017,20(5):567-570.
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[10]Zhao J,Guo LY,Yang JM,et al.Sublingual vein parameters,AFP,AFP-L3,and GP73 in patients with hepatocellular carcinoma.Genet Mol Res,2015,14(2):7062-7067.
[11]Marrero JA,Romano PR,Nikolaeva O,et al.GP73,a resident Golgi glycoprotein,is a novel serum marker for hepatocellular carcinoma.J Hepatol,2005,43(6):1007-1012.
[12]Iftikhar R,Kladney RD,Havlioglu N,et al.Disease-and cell-specific expression of GP73 in human liver disease.Am JGastroenterol,2004,99(6):1087-1096.
[13]Park SJ,Jang JY,Jeong SW,et al.Usefulness of AFP,AFP-L3,and PIVKA-II,and their combinations in diagnosing hepatocellular carcinoma.Medicine,2017,96(11):e5811.
[14]Durazo FA,Blatt LM,Corey WG,et al.Des-gamma-carboxyprothrombin,alpha-fetoprotein and AFP-L3 in patients with chronic hepatitis,cirrhosis and hepatocellular carcinoma.JGastroenterol Hepatol,2008,23(10):1541-1548.
[15]Setsu T,Tsuchiya A,Watanabe T,et al.Early detection of hepatocellular carcinoma recurrence using the highly sensitive fucosylated fraction of alpha-fetoprotein.Case Rep Gastroenterol,2017,11(1):142-147.
[16]Zuo D,Chen L,Liu X,et al.Combination of miR-125b and miR-27a enhances sensitivity and specificity of AFP-based diagnosis of hepatocellular carcinoma.Tumour Biol,2016,37(5):6539-6549.
[17]Zhang N,Gu J,Yin L,et al.Incorporation of alpha-fetoprotein(AFP)into subclassification of BCLC C stage hepatocellular carcinoma according to a 5-year survival analysis based on the SEER database.Oncotarget,2016,7(49):81389-81401.
[18]Junna Z,Gongde C,Jinying X,et al.Serum AFU,5'-NT and AFP as biomarkers for primary hepatocellular carcinoma diagnosis.Open Med,2017,12(1):354-358.
[19]Mossad NA,Mahmoud EH,Osman EA,et al.Evaluation of squamous cell carcinoma antigen-immunoglobulin M complex(SCCA-IGM)and alpha-L-fucosidase(AFU)as novel diagnostic biomarkers for hepatocellular carcinoma.Tumour Biol,2014,35(11):11559-11564.
[20]Choi JY,Jung SW,Kim HY,et al.Diagnostic value of AFP-L3 and PIVKA-II in hepatocellular carcinoma according to total-AFP.World J Gastroenterol,2013,19(3):339-346.
[2]Desantis CE,Lin CC,Mariotto AB,et al.Cancer treatment and survivorship statistics,2014.CA Cancer J Clin,2012,62(4):220-226.
[3]Hiraoka A,Ishimaru Y,Kawasaki H,et al.Tumor markers AFP,AFP-L3,and DCP in hepatocellular carcinoma refractory to transcatheter arterial Chemoembolization.Oncology,2015,89(3):1-8.
[4]Li B,Li B,Guo T,et al.Artificial neural network models for early diagnosis of hepatocellular carcinoma using serum levels ofα-fetoprotein,α-fetoprotein-L3,des-γ-carboxy prothrombin,and Golgi protein 73.Oncotarget,2017,8(46):80521-80530.
[5]Zeng MD,Li YM,Chen CW,et al.Guidelines for the diagnosis and treatment of alcoholic liver disease.J Dig Dis,2008,9(2):113-116.
[6]孔颖,蔺淑梅,王维娟,等.血清高尔基体蛋白73诊断原发性肝癌价值探讨.实用肝脏病杂志,2013,16(4):341-343.
[7]肖潇,何羽童,房萌,等.甲胎蛋白异质体在原发性肝癌临床诊断中的应用.实用肝脏病杂志,2017,20(5):567-570.
[8]Ghouri YA,Mian I,Rowe JH.Review of hepatocellular carcinoma:Epidemiology,etiology,and carcinogenesis.J Carcinog,2017,16(1):1-12.
[9]Wang NY,Wang C,Li W,et al.Prognostic value of serum AFP,AFP-L3,and GP73 in monitoring short-term treatment response and recurrence of hepatocellular carcinoma after radiofrequency ablation.Asian Pac J Cancer Prev,2014,15(4):1539-1544.
[10]Zhao J,Guo LY,Yang JM,et al.Sublingual vein parameters,AFP,AFP-L3,and GP73 in patients with hepatocellular carcinoma.Genet Mol Res,2015,14(2):7062-7067.
[11]Marrero JA,Romano PR,Nikolaeva O,et al.GP73,a resident Golgi glycoprotein,is a novel serum marker for hepatocellular carcinoma.J Hepatol,2005,43(6):1007-1012.
[12]Iftikhar R,Kladney RD,Havlioglu N,et al.Disease-and cell-specific expression of GP73 in human liver disease.Am JGastroenterol,2004,99(6):1087-1096.
[13]Park SJ,Jang JY,Jeong SW,et al.Usefulness of AFP,AFP-L3,and PIVKA-II,and their combinations in diagnosing hepatocellular carcinoma.Medicine,2017,96(11):e5811.
[14]Durazo FA,Blatt LM,Corey WG,et al.Des-gamma-carboxyprothrombin,alpha-fetoprotein and AFP-L3 in patients with chronic hepatitis,cirrhosis and hepatocellular carcinoma.JGastroenterol Hepatol,2008,23(10):1541-1548.
[15]Setsu T,Tsuchiya A,Watanabe T,et al.Early detection of hepatocellular carcinoma recurrence using the highly sensitive fucosylated fraction of alpha-fetoprotein.Case Rep Gastroenterol,2017,11(1):142-147.
[16]Zuo D,Chen L,Liu X,et al.Combination of miR-125b and miR-27a enhances sensitivity and specificity of AFP-based diagnosis of hepatocellular carcinoma.Tumour Biol,2016,37(5):6539-6549.
[17]Zhang N,Gu J,Yin L,et al.Incorporation of alpha-fetoprotein(AFP)into subclassification of BCLC C stage hepatocellular carcinoma according to a 5-year survival analysis based on the SEER database.Oncotarget,2016,7(49):81389-81401.
[18]Junna Z,Gongde C,Jinying X,et al.Serum AFU,5'-NT and AFP as biomarkers for primary hepatocellular carcinoma diagnosis.Open Med,2017,12(1):354-358.
[19]Mossad NA,Mahmoud EH,Osman EA,et al.Evaluation of squamous cell carcinoma antigen-immunoglobulin M complex(SCCA-IGM)and alpha-L-fucosidase(AFU)as novel diagnostic biomarkers for hepatocellular carcinoma.Tumour Biol,2014,35(11):11559-11564.
[20]Choi JY,Jung SW,Kim HY,et al.Diagnostic value of AFP-L3 and PIVKA-II in hepatocellular carcinoma according to total-AFP.World J Gastroenterol,2013,19(3):339-346.