文 君， 李 嘉， 王春妍， 馬 瑩

(天津市第二人民醫(yī)院 肝?、蚩?， 天津 300193)

血清異常凝血酶原復(fù)合物、甲胎蛋白、鐵蛋白檢測(cè)對(duì)HBV相關(guān)肝細(xì)胞癌的輔助診斷意義

文 君， 李 嘉， 王春妍， 馬 瑩

(天津市第二人民醫(yī)院 肝?、蚩?， 天津 300193)

目的探討血清異常凝血酶原復(fù)合物(PIVKA-Ⅱ)、甲胎蛋白(AFP)、鐵蛋白(FER)單項(xiàng)及聯(lián)合檢測(cè)在HBV相關(guān)肝細(xì)胞癌(HCC)輔助診斷中的意義。方法收集2016年6月-2017年2月于天津市第二人民醫(yī)院住院的40例HBV相關(guān)HCC、41例乙型肝炎肝硬化、44例慢性乙型肝炎患者及36例健康體檢者的血清，并檢測(cè)PIVKA-Ⅱ、AFP、FER水平，分別分析三者單獨(dú)及聯(lián)合檢測(cè)診斷HBV相關(guān)HCC的受試者工作曲線(xiàn)下面積(AUC)、敏感度和特異度。非正態(tài)分布的計(jì)量資料組間比較采用非參數(shù)Kruskal-WallisH檢驗(yàn)， 進(jìn)一步兩兩比較采用Mann-WhitneyU檢驗(yàn)。采用二元logistic 進(jìn)行逐步回歸分析產(chǎn)生三項(xiàng)指標(biāo)聯(lián)合預(yù)測(cè)概率的新變量pre。結(jié)果血清AFP及PIVKA-Ⅱ水平在乙型肝炎肝硬化、慢性乙型肝炎、HBV相關(guān)HCC及健康對(duì)照組間的差異均具有統(tǒng)計(jì)學(xué)意義(χ2值分別為51.446、59.613，P值均<0.001)。AFP水平在HBV相關(guān)HCC組顯著高于乙型肝炎肝硬化組、慢性乙型肝炎組及健康對(duì)照組(Z值分別為 -4.609、-6.026、-6.031，P值均<0.001)，乙型肝炎肝硬化AFP水平也明顯高于對(duì)照組(Z=-2.30，P=0.021)；PIVKA-Ⅱ水平在HBV相關(guān)HCC組顯著高于乙型肝炎肝硬化組、慢性乙型肝炎組及健康對(duì)照組(Z值分別為 -6.080、-6.595、-5.608，P值均<0.001)，慢性乙型肝炎組PIVKA-Ⅱ水平也明顯高于對(duì)照組(Z=-2.153，P=0.031)；FER水平在HBV相關(guān)HCC患者組顯著高于慢性乙型肝炎患者(Z=-2.177，P=0.029)。單項(xiàng)指標(biāo)檢測(cè)診斷HBV相關(guān)HCC時(shí)，AFP的敏感度最高(79.49%)，但FER的特異度最高(94.28%)；雙項(xiàng)目檢測(cè)方案中，AFP/PIVKA-Ⅱ方案的敏感度最高(89.74%)，F(xiàn)ER+AFP和FER+PIVKA-Ⅱ方案特異度較高(97.14%)；三項(xiàng)目檢測(cè)時(shí)，F(xiàn)ER/AFP/PIVKA-Ⅱ方案的敏感度較高(92.31%)，F(xiàn)ER+AFP+PIVKA-Ⅱ特異度較高(97.14%)。結(jié)論P(yáng)IVKA-Ⅱ、AFP、FER三項(xiàng)聯(lián)合檢測(cè)可提高單獨(dú)檢測(cè)的敏感度及特異度。血清PIVKA-Ⅱ和AFP對(duì)HCC診斷具有較高的臨床應(yīng)用價(jià)值，單項(xiàng)即可很好輔助診斷，二者聯(lián)合未提高診斷率。

癌， 肝細(xì)胞； 鐵蛋白質(zhì)類(lèi)； 甲胎蛋白類(lèi)； 異常凝血酶原； 診斷

原發(fā)性肝癌是我國(guó)最常見(jiàn)的惡性腫瘤之一，在我國(guó)該病發(fā)生率和病死率均占全球的50%以上，由于起病隱匿，進(jìn)展較迅速，確診時(shí)很多患者已經(jīng)達(dá)到局部晚期或發(fā)生遠(yuǎn)處轉(zhuǎn)移，因此早期發(fā)現(xiàn)及早期治療是提高療效的關(guān)鍵。其中肝細(xì)胞癌(HCC)占原發(fā)性肝癌的90%以上，是最常見(jiàn)的一種病理類(lèi)型。HBV感染在HCC的發(fā)生、發(fā)展中起重要作用。目前我國(guó)HCC主要依靠影像學(xué)改變、腫瘤標(biāo)志物的檢測(cè)以及相應(yīng)臨床表現(xiàn)來(lái)診斷。血清異常凝血酶原(protein induced by vitamin K absence or antagonist-Ⅱ, PIVKA-Ⅱ)即γ-羧基凝血酶原，也被稱(chēng)為維生素K缺乏或拮抗劑誘導(dǎo)的蛋白質(zhì)，為肝臟合成凝血酶原過(guò)程中凝血酶原前體未完全羧化形成的異常產(chǎn)物[1]。研究[2-3]顯示PIVKA-Ⅱ已逐漸成為臨床上診斷HCC的特異性腫瘤標(biāo)志物，具有較高的診斷特異度，能較好地反映HCC的病理特征及預(yù)后。AFP也是診斷HCC的重要指標(biāo)和特異度強(qiáng)的腫瘤標(biāo)志物，但根據(jù)對(duì)國(guó)內(nèi)外多篇文獻(xiàn)的 Meta分析發(fā)現(xiàn)其對(duì)HCC診斷敏感度僅為54%～63%，特異度為82%～89%[4]。鐵蛋白(ferritin, FER)是主要的貯鐵蛋白，對(duì)調(diào)節(jié)鐵的儲(chǔ)存及代謝和體內(nèi)平衡至關(guān)重要，且可保護(hù)細(xì)胞免受氧化損傷，其中血清FER水平可作為體內(nèi)儲(chǔ)鐵情況的指標(biāo)。近年來(lái)，研究[5]表明HCC的發(fā)生與FER水平異常緊密相關(guān)。本研究旨在通過(guò)對(duì)HBV相關(guān)HCC患者進(jìn)行PIVKA-Ⅱ、AFP、FER檢測(cè)，了解其對(duì)HCC的診斷效果及價(jià)值，探討3 種指標(biāo)聯(lián)合檢測(cè)對(duì)HCC輔助診斷的意義。

1 對(duì)象與方法

1.1 研究對(duì)象 選取本院2016年6月-2017年2月住院患者與健康體檢者共161例，包括男97例，女64例，年齡18～74歲，平均(44.8±14.2)歲。其中HBV相關(guān)HCC患者40例，男23例，女17例，平均(58.5±10.1)歲；乙型肝炎肝硬化患者41例，男21例，女20例，平均(48.7±12.1)歲；慢性乙型肝炎患者44例，男32例，女12例，平均(33.0±10.2)歲。HBV相關(guān)HCC、乙型肝炎肝硬化、慢性乙型肝炎診斷標(biāo)準(zhǔn)符合《原發(fā)性肝癌診療規(guī)范》[6]和《慢性乙型肝炎防治指南》[7]中的診斷標(biāo)準(zhǔn)。健康體檢者36例，男21例，女15例，平均(39.6±8.9)歲。

1.2 標(biāo)本要求及檢測(cè)方法 采集所有受試者空腹靜脈血4 ml，室溫放置1 h，2000 r/min離心8 min，分離后的血清于-80 ℃冰箱保存待檢。PIVKA-Ⅱ 采用化學(xué)發(fā)光酶免疫檢測(cè)法，試劑盒購(gòu)自日本富士瑞必歐公司；AFP采用化學(xué)發(fā)光免疫法檢測(cè)，AXSYM免疫化學(xué)發(fā)光儀及配套試劑購(gòu)自美國(guó)雅培公司；血清FER采用免疫比濁法檢測(cè)，試劑盒購(gòu)自上海景源生物公司。

2 結(jié)果

2.1 不同組間血清FER、AFP及PIVKA-Ⅱ水平 血清AFP及PIVKA-Ⅱ水平在乙型肝炎肝硬化組、慢性乙型肝炎組、HBV相關(guān)HCC組及健康對(duì)照組間的差異均具有統(tǒng)計(jì)學(xué)意義(P值均<0.001)。AFP水平在HBV相關(guān)HCC組顯著高于乙型肝炎肝硬化組、慢性乙型肝炎組及健康對(duì)照組(Z值分別為 -4.609、-6.026、-6.031，P值均<0.001)，乙型肝炎后肝硬化AFP水平也明顯高于對(duì)照組(Z=-2.30，P=0.021)；PIVKA-Ⅱ水平在HBV相關(guān)HCC組顯著高于乙型肝炎肝硬化組、慢性乙型肝炎組及健康對(duì)照組(Z值分別為 -6.080、-6.595、-5.608，P值均<0.001)，慢性乙型肝炎組PIVKA-Ⅱ水平也明顯高于對(duì)照組(Z=-2.153，P=0.031)。FER水平在各組間差異無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05)(表1)。

2.2 FER、AFP及PIVKA-Ⅱ單項(xiàng)及聯(lián)合檢測(cè)對(duì)HBV相關(guān)HCC的輔助診斷價(jià)值 單項(xiàng)指標(biāo)檢測(cè)診斷HBV相關(guān)性HCC時(shí)，AFP的敏感度最高(79.49%)，但FER的特異度最高(94.28%)；雙項(xiàng)目檢測(cè)方案中，AFP/PIVKA-Ⅱ方案的敏感度最高(89.74%)，F(xiàn)ER+AFP和FER+PIVKA-Ⅱ方案特異度較高(97.14%)；三項(xiàng)目檢測(cè)時(shí)， FER/AFP/PIVKA-Ⅱ方案的敏感度較高(92.31%)，F(xiàn)ER+AFP+PIVKA-Ⅱ特異度較高(97.14%)(表2)。

2.3 FER、AFP及PIVKA-Ⅱ 單項(xiàng)及聯(lián)合檢測(cè)診斷HBV相關(guān)HCC的ROC曲線(xiàn)分析 單項(xiàng)檢測(cè)時(shí)，F(xiàn)ER的AUC為0.630(0.499～0.762)，AFP的AUC為0.908(0.836～0.980)，PIVKA-Ⅱ的AUC為0.879(0.799～0.959)(圖1)。以FER、AFP、PIVKA-Ⅱ檢測(cè)結(jié)果為檢驗(yàn)變量，以診斷結(jié)果為狀態(tài)變量，用向后條件方法做二元logistic回歸分析，得出HBV相關(guān)HCC概率預(yù)測(cè)模型：P=1/[1+e-(-5.562+0.383AFP-0.068PIVKA-Ⅱ)]，算出各個(gè)體預(yù)測(cè)值的預(yù)測(cè)變量pre，其中FER沒(méi)有納入模型中。對(duì)上述logistic回歸模型進(jìn)行似然比檢驗(yàn)，結(jié)果顯示差異有統(tǒng)計(jì)學(xué)意義(χ2=67.425，P<0.001)。以預(yù)測(cè)變量pre為檢驗(yàn)變量，診斷結(jié)果為狀態(tài)變量，做AFP及PIVKA-Ⅱ二者聯(lián)合檢測(cè)的ROC曲線(xiàn)分析，其AUC為0.941(0.879～1.000)，高于各指標(biāo)單項(xiàng)檢測(cè)，但與AFP及PIVKA-Ⅱ相比，AUC差異沒(méi)有統(tǒng)計(jì)學(xué)意義(Z值分別為0.351、0.618，P值均>0.05)。

表1 各組血清AFP、FER、PIVKA-Ⅱ水平比較[M(P25～P75)]

注：與HBV相關(guān)HCC組比較，1)P<0.001；與健康對(duì)照組比較，2)P<0.05

表2 血清FER、AFP及PIVKA-Ⅱ單項(xiàng)及聯(lián)合檢測(cè)對(duì)HBV相關(guān)性HCC的輔助診斷價(jià)值比較

注：“+”表示聯(lián)合檢測(cè)，“/”表示其中任一項(xiàng)

圖1 FER、AFP及PIVKA-Ⅱ單項(xiàng)及AFP聯(lián)合PIVKA-Ⅱ檢測(cè)診斷HBV相關(guān)HCC的ROC曲線(xiàn)

3 討論

PIVKA-Ⅱ是HCC在缺乏或?qū)S生素K攝取及利用障礙時(shí)，由依賴(lài)維生素K的γ-谷氨酰羧化酶及輔酶活性降低、肝癌細(xì)胞內(nèi)質(zhì)網(wǎng)產(chǎn)生凝血酶原前體蛋白N端谷氨酸羧化不全所致，這些不成熟的凝血酶原釋放入血，具有刺激癌細(xì)胞生長(zhǎng)作用。PIVKA-Ⅱ具有敏感度、特異度高的優(yōu)點(diǎn)，且其濃度與HCC的組織分化、病灶大小、門(mén)靜脈浸潤(rùn)及臨床分期等有關(guān)。大量臨床資料顯示，PIVKA-Ⅱ水平與平均肝癌體積、瘤灶數(shù)量、腫瘤大小均呈正相關(guān)，即隨腫瘤的增大而升高，也隨腫瘤TNM分期增高而升高；與平均生存時(shí)間呈負(fù)相關(guān)，與HCC的惡性程度呈正相關(guān)性。手術(shù)切除瘤灶后，PIVKA-Ⅱ水平下降低于臨界值可能說(shuō)明手術(shù)效果良好，但如果血清 PIVKA-Ⅱ水平再次升高，可能預(yù)示HCC復(fù)發(fā)或遠(yuǎn)處轉(zhuǎn)移。動(dòng)態(tài)監(jiān)測(cè) PIVKA-Ⅱ變化，能較好地協(xié)助臨床正確評(píng)價(jià)HCC的發(fā)生、發(fā)展、浸潤(rùn)轉(zhuǎn)移或復(fù)發(fā)等變化。PIVKA-Ⅱ已成為臨床用于評(píng)價(jià)患者預(yù)后的一個(gè)重要指標(biāo)[8-15]。AFP作為HCC的經(jīng)典腫瘤標(biāo)志物，在半個(gè)多世紀(jì)的臨床應(yīng)用中發(fā)現(xiàn)其敏感度和特異度均受到臨床需求的挑戰(zhàn)，如AFP陰性易導(dǎo)致HCC的漏診和誤診，又因AFP水平在約30%的肝硬化、慢性肝病等非HCC患者中也有不同程度的升高[16]，致使伴有肝硬化的部分HCC患者經(jīng)有效治療后血清AFP仍處于較高水平[17]，從而影響HCC的療效監(jiān)測(cè)等。FER在肝臟合成，在肝內(nèi)的含量最多，肝細(xì)胞損傷或被破壞時(shí)就會(huì)釋放大量的FER。 有研究[18]表明，肝細(xì)胞、巨噬細(xì)胞、癌細(xì)胞可以分泌合成FER，且體內(nèi)血清FER主要來(lái)源于巨噬細(xì)胞，因此肝癌細(xì)胞增殖可使FER分泌增加。

本研究表明血清AFP及PIVKA-Ⅱ水平在乙型肝炎肝硬化、慢性乙型肝炎、HCC及健康對(duì)照組間的差異均具有統(tǒng)計(jì)學(xué)意義。與其他研究不同，本研究中與另外幾組比較HCC組FER水平較高，但差異無(wú)統(tǒng)計(jì)學(xué)意義，可能與機(jī)體感染肝炎病毒時(shí)，肝細(xì)胞發(fā)生炎癥反應(yīng)，血清合成FER增多，同時(shí)肝細(xì)胞炎癥可引起肝細(xì)胞實(shí)質(zhì)性損害，從而對(duì)血清FER清除能力下降，導(dǎo)致FER水平明顯升高[19]，故各組間無(wú)統(tǒng)計(jì)學(xué)差異。此外，亦有可能與選取病例數(shù)不足，樣本量不足，或未進(jìn)行HCC的更為細(xì)致的臨床分期相關(guān)，需進(jìn)一步的臨床研究來(lái)證實(shí)。本研究表明，AFP、PIVKA-Ⅱ在HBV相關(guān)HCC輔助診斷中具有重要價(jià)值，兩者單項(xiàng)檢測(cè)即可很好的預(yù)測(cè)診斷HCC，聯(lián)合檢測(cè)不會(huì)提高HBV相關(guān)HCC的診斷率。單項(xiàng)指標(biāo)檢測(cè)診斷HBV相關(guān)HCC時(shí)，敏感度最高者為AFP，特異度最高者為FER，這與大量臨床報(bào)道相符合[20-21]。雙項(xiàng)目檢測(cè)方案中，敏感度最高方案為AFP/PIVKA-Ⅱ；三項(xiàng)目檢測(cè)時(shí)，敏感度較高方案為FER/AFP/PIVKA-Ⅱ，特異度較高方案為FER+AFP+PIVKA-Ⅱ?？傊?，三項(xiàng)聯(lián)合檢測(cè)可以起到互補(bǔ)作用，可顯著提高HBV相關(guān)HCC的檢出率，與單項(xiàng)檢測(cè)相比診斷效能大大提高。

綜上，在條件允許的情況下，上述3項(xiàng)指標(biāo)的聯(lián)合檢測(cè)對(duì)HBV相關(guān)HCC的確定診斷、減少漏診具有較高的臨床應(yīng)用價(jià)值。 當(dāng)然，以上各項(xiàng)檢測(cè)手段僅能作為輔助方式，HBV相關(guān)HCC的診斷尚需病原學(xué)、影像學(xué)、病理學(xué)的綜合診斷。如條件允許，可進(jìn)一步研究上述3項(xiàng)指標(biāo)在治療前后的對(duì)比，為HBV相關(guān)HCC治療療效評(píng)價(jià)提供依據(jù)。

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(本文編輯：王 瑩)

ValueofserumPIVKA-Ⅱ,alpha-fetoprotein,andferritininassistingthediagnosisofHBV-relatedhepatocellularcarcinoma

WENJun,LIJia,WANGChunyan,etal.

(SecondDepartmentofHepatology,TianjinSecondPeople′sHospital,Tianjin300193,China)

ObjectiveTo investigate the value of serum PIVKA-Ⅱ, alpha-fetoprotein (AFP), and ferritin (FER) measured alone or in combination in assisting the diagnosis of HBV-related hepatocellular carcinoma (HCC).MethodsA total of 40 patients with hepatitis B virus (HBV)-related HCC, 41 patients with liver cirrhosis after hepatitis B, 44 patients with chronic hepatitis B (CHB), and 36 controls who underwent physical examination were enrolled. Their serum samples were collected and the serum levels of PIVKA-Ⅱ, AFP, and FER were measured. The area under the ROC curve (AUC), sensitivity, and specificity of PIVKA-Ⅱ, AFP, and FER measured alone or in combination in the diagnosis of HBV-related HCC were analyzed. The non-parametric Kruskal-WallisHtest was used for comparison of non-normally distributed continuous data between groups, and the Mann-WhitneyUtest was used for further comparison between two groups. A binary logistic stepwise regression analysis was used to determine the new variable pre of predicted probability of combined measurement of these three indices.ResultsThere were significant differences in the serum levels of AFP and PIVKA-Ⅱ between the liver cirrhosis group, CHB group, HBV-related HCC group, and healthy control group (χ2=51.446 and 59.613, bothP<0.001). The HBV-related HCC group had a significantly higher serum level of AFP than the liver cirrhosis group, CHB group, and healthy control group (Z=-4.609, -6.026, and -6.031, allP<0.001), and the liver cirrhosis group also had a significantly higher serum level of AFP than the healthy control group (Z=-2.30,P=0.021). The HBV-related HCC group had a significantly higher serum level of PIVKA-Ⅱ than the liver cirrhosis group, CHB group, and healthy control group (Z=-6.080, -6.595, and -5.608, allP<0.001), and the CHB group had a significantly higher serum level of PIVKA-Ⅱ than the healthy control group (Z=-2.153,P=0.031). The HBV-related HCC group had a significantly higher serum level of FER than the CHB group (Z=-2.177,P=0.029). When measured alone, AFP had the highest sensitivity in the diagnosis of HBV-related HCC (79.49%), and FER had the highest specificity (94.28%). When any two of these indices were measured, PIVKA-Ⅱ/AFP had the highest sensitivity (89.74%), and FER+AFP and FER+PIVKA-Ⅱ had a high specificity (97.14%). FER/AFP/PIVKA had a sensitivity of 92.31% and the combined measurement of FER, AFP, and PIVKA-Ⅱ had a specificity of 97.14%.ConclusionCombined measurement of PIVKA-Ⅱ, AFP, and FER can improve the sensitivity and specificity of single measurement. Serum PIVKA-Ⅱ and AFP have a high clinical value in the diagnosis of HCC; single measurement can well assist the diagnosis, and combined measurement does not increase the diagnostic rate.

carcinoma, hepatocellular; ferritins; alpha-fetoproteins; protein induced by vitamin K absence or antagonist-Ⅱ; diagnosis

10.3969/j.issn.1001-5256.2017.09.020

2017-03-20；

2017-05-22。

文君(1985-)，女，主治醫(yī)師，主要從事肝病學(xué)及內(nèi)鏡學(xué)研究。

李嘉,電子信箱: 18622663700@163.com。

R735.7

：A

：1001-5256(2017)09-1729-05