血清铁蛋白和甲胎蛋白及甲胎蛋白异质体－L3单项与联合检测对原发性肝癌辅助诊断的临床应用价值

摘要

目的：评价血清铁蛋白（FER）、甲胎蛋白（AFP）及甲胎蛋白异质体－L3（AFP－L3）3项肿瘤标志物单一及联合检测对原发性肝癌（ PHC）的诊断价值。方法采用病例对照研究，选取2014年1至12月首都医科大学附属北京佑安医院就诊的PHC患者212例（其中Ⅰ期45例，Ⅱ期78例，Ⅲ期81例，Ⅳ期8例），肝硬化患者127例，慢性肝炎患者101例及健康体检者98名作为研究对象，检测血清中FER、AFP、AFP－L3的水平。其中FER和AFP测定采用电化学发光法，AFP－L3测定先采用亲和吸附分离，然后再采用电化学发光法检测。各组间FER、AFP及AFP－L3水平采用非参数秩和检验进行差异分析，并对3者水平进行组间的独立和联合诊断性能分析，结合Logistic回归分析，绘制ROC曲线并计算及比较曲线下面积（ AUC）评价各指标单项及联合检测的诊断价值。结果 PHC组、肝硬化组、慢性肝炎组及健康对照组血清FER浓度分别为：308．45（148．98～662．80）、151．70（51．44～507．40）、298．20（157．30～701．80）、113．50（54．98～221．38）μg／L；AFP浓度分别为48．50（5．25～748．40）、3．91（1．80～17．53）、4．76（2．29～30．56）、2．57（0．93～3．68）μg／L；AFP－L3浓度分别为4．75（0．61～127．95）、0．61（0．61～2．50）、0．61（0．61～2．85）、0．61（0．61～0．61）μg／L，各组间3项指标的差异均有统计学意义（χ2＝67．66、146．31、119．02，P＜0．001）。随着病理分期（Ⅰ～Ⅳ）的加重，FER、AFP及AFP－L3的血清水平均显著增高，差异有统计学意义（χ2＝21．63、22．68、21．98，P＜0．001）。单项检测诊断PHC时，FER的敏感度最高（75．00％），AFP－L3的特异度最高（82．52％）；双项目检测方案中，FER／AFP的敏感度最高（89．15％），FER＋AFP－L3和AFP＋AFP－L3特异度较高（均86．20％）；3项目检测时， FER／AFP／AFP－L3敏感度高达89．15％， FER＋AFP＋AFP－L3特异度高达86．50％。3者联合检测的ROC曲线AUC为0．803±0．019（95％ CI：0．765～0．841），显著高于FER （0．748±0．022，95％ CI：0．705～0．790，Z＝4．67，P＜0．001）及 AFP－L3（0．726±0．024，95％ CI：0．679～0．772，Z＝3．64，P＜0．001）单独检测，但与AFP单独检测相比差异无统计学意义（0．776±0．021，95％CI：0．735～0．818，Z＝1．34，P＝0．18）。结论 FER检测在PHC辅助诊断中具有重要价值，FER、AFP及AFP－L3三项联合检测可提高PHC患者的诊断率。（中华检验医学杂志，2016，39：604－608）%Objective To investigate the diagnostic value of serum FER, AFP and AFP-L3 alone or in combination for diagnosis of primary hepatic carcinoma( PHC).Methods This was a case-control study. Serum FER, AFP and AFP-L3 were determined in 212 patients with PHC ( StageⅠ45 cases, StageⅡ78 cases, StageⅢ81 cases, StageⅣ8 cases) , 127 patients with cirrhosis, 101 patients with chronic hepatitis and 98 controls in the Beijing Youan Hospital affiliated to Capital Medical University from January 2014 to December 2014.Levels of FER, AFP and AFP-L3 were measured by chemiluminescence, while serum samples were pre-treatment with affinity adsorption before AFP-L3 detection.FER, AFP and AFP-L3 levels were analyzed using the nonparametric Wilcoxon test among all groups.Diagnostic performance were analyzed among the groups with the three biomarkers independently and combined.Logistic regression, plotted ROC curve and calculated the area under ROC curve ( AUC) were applied to assess the diagnostic value of each index.Results Serum concentration of FER in PHC, cirrhosis, chronic hepatitis groups and healthy controls were 308.45 ( 148.98 -662.80 ) , 151.70 ( 51.44 -507.40 ) , 298.20 ( 157.30 -701.80 ) , 113.50( 54.98-221.38) μg/L, respectively.The concentration of AFP were 48.50(5.25 -748.40), 3.91(1.80-17.53), 4.76 (2.29-30.56), 2.57 (0.93-3.68) μg/L in each group.The serum levels of AFP-L3 in each group were 4.75(0.61-127.95), 0.61 (0.61-2.50), 0.61 (0.61-2.85), 0.61 (0.61-0.61) μg/L.The concentration of FER, AFP and AFP-L3 differs statistically in PHC, cirrhosis, chronic hepatitis group and healthy controls (χ2 =67.66,146.31,119.02,P<0.001).The content of serum FER, AFP and AFP-L3 increased gradually as the stage level aggravating ( StageⅠ-Ⅳ) , there was significant differences among groups (χ2 =21.63,22.68,21.98, P<0.001) .When using one serum marker, FER had the highest sensitivity (75.00%) , while AFP-L3 had the highest specificity (82.52%). While using two serum markers, FER/AFP had the highest sensitivity (89.15%) , FER+AFP-L3 and AFP+AFP-L3 had a higher specificity (86.20%).The combined detection of FER/AFP/AFP-L3 improved the sensitivity of the test to 89.15%, while FER+AFP+AFP-L3 had a specificity of 86.50%.The AUC of combination of FER, AFP and AFP-L3 was 0.803 ±0.019 (95% CI:0.765-0.841), which was higher than the AUC of either FER(0.748 ±0.022,95% CI:0.705-0.790, Z=4.67,P<0.001) and AFP-L3 (0.726 ±0.024,95% CI: 0.679 -0.772, Z=3.64,P<0.001).However, there was no significant difference in AUC between AFP alone ( 0.776 ±0.021, 95% CI: 0.735 -0.818 ) and the combined detection ( Z=1.34, P=0.18 ) .Conclusions FER was a potential marker for PHC diagnosis.The combination of FER, AFP and AFP-L3 has higher value of clinical applications than one of them independently.