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. 2024 Feb 1;53(1):131–139. [Article in Chinese] doi: 10.3724/zdxbyxb-2023-0483

血清学标志物甲胎蛋白、PIVKA-Ⅱ和磷脂酰肌醇蛋白聚糖3联合诊断肝癌的meta分析

Combination of serum alpha-fetoprotein, PIVKA-Ⅱ and glypican-3 in diagnosis of hepatocellular carcinoma: a meta-analysis

SONG Hongliang 1,2,1, WANG Jianguo 1,2, ZHANG Hui 1,2, WU Yongfeng 2, WANG Kai 1,2,✉,✉, WANG Xiaobo 2,✉,✉, XU Xiao 2,✉,✉
Editors: 余 方, 刘 丽娜
PMCID: PMC10945496  PMID: 38310085

Abstract

Objective

To assess the value of serum alpha-fetoprotein (AFP), protein induced by vitamin K absence or antagonist-Ⅱ (PIVKA-Ⅱ) and glypican-3 (GPC-3) in the diagnosis of hepatocellular carcinoma (HCC).

Methods

Studies of AFP, PIVKA-Ⅱ, GPC-3 or in combination for the diagnosis of HCC since 2002 were searched in PubMed, Web of Science and Embase databases. The literature was screened according to the inclusion and exclusion criteria, the quality of the included articles was evaluated by QUADAS checklist, and relevant data were extracted by Meta DiSc, Review Manager 5.4 and Stata 15.1. The diagnostic values of AFP, PIVKA-Ⅱ and GPC-3 alone or in combination for HCC were assessed with receiver operating characteristic (ROC) curve.

Results

A total of 32 articles were included in the study. Meta-analysis showed that when a single marker was used to diagnose HCC, the area under the ROC curve (AUC) of PIVKA-Ⅱ was the highest (0.88, 95%CI: 0.85-0.91), followed by GPC-3 and AFP. The AUC of combination of serum markers was higher than that of a single marker, and the AUC of PIVKA-Ⅱ combined with GPC-3 was the highest (0.90, 95%CI: 0.87-0.92). When a single marker was used for diagnosis, the sensitivity of PIVKA-Ⅱ and GPC-3 were relatively high (0.75 and 0.76), while the specificity of PIVKA-Ⅱ (0.88) and AFP (0.87) were higher than that of GPC-3 (0.81). The sensitivity of the combination of serum markers was higher than that of a single marker, while the specificity was not significantly improved. When a single marker is used to diagnose HCC, the diagnostic odds ratio (DOR) of PIVKA-Ⅱ was the highest (22, 95%CI: 13-36), followed by GPC-3 and AFP. The DOR of the combination of two markers in the diagnosis of HCC was higher than that of a single marker, and the DOR of AFP combined with GPC-3 was the highest (25, 95%CI: 9-67). The DOR of the combination of the three markers was significantly reduced to 10 (95%CI: 7-45).

Conclusions

When a single marker is used, PIVKA-Ⅱ has a higher diagnostic value for HCC. The combination of two markers can significantly improve the diagnostic sensitivity, and AFP combined with PIVKA-Ⅱ is recommended for the diagnosis of HCC. The combination of all three markers failed to further improve the diagnostic value.

Keywords: Hepatocellular carcinoma, Serum markers, Alpha-fetoprotein, Protein induced by vitamin K absence or antagonist-Ⅱ, Glypican-3, Diagnosis, Meta-analysis

肝细胞癌（以下简称肝癌）是中国60岁以下成年男性病死率最高的肿瘤，且发现时患者往往已是晚期，失去了最佳的手术治疗时机，因此肝癌的早筛早诊至关重要。目前，临床上用于筛查及诊断肝癌的血清学标志物有AFP、PIVKA-Ⅱ和GPC-3等［1］。血清AFP水平是临床上应用最广泛的肝癌血清学标志物［1-2］，但其在妊娠期、慢性活动性肝炎时也可显著升高［3］，且有近50%的肝癌患者AFP水平始终低于常用截断值（20 ng/mL）［4］，加之其敏感性较低，所以在筛查肝癌时需要与超声等影像学检查结合使用。PIVKA-Ⅱ在诊断肝癌时有较高的准确性，但其表达水平与肿瘤大小相关［5］，因此用于诊断早期肝癌存在局限性。研究发现，GPC-3在肝癌患者血清中表达上调［6］，目前已成为诊断肝癌的主要血清标志物之一。但目前有关GPC-3单独用于肝癌诊断的研究结果差异较大，无统一的标准，仍需要进一步研究。目前认为，PIVKA-Ⅱ在单独用于诊断肝癌时的诊断价值高于AFP和GPC-3，且三者间任意两者联用诊断肝癌的准确度均优于单独使用［7-9］。但三种标志物联用是否能进一步提高肝癌诊断的准确度目前尚无定论。本研究拟通过汇总三种标志物单独和联合应用的文献，比较这三种标志物单独或联合应用于肝癌诊断的准确度，以期为肝癌诊断提供参考。

1. 材料与方法

1.1. 文献检索

检索PubMed、Web of Science和Embase系统中2002年1月1日至2023年8月1日发表的关于AFP、PIVKA-Ⅱ和GPC-3单独或联合诊断肝癌的文献，检索词包括“AFP”“alpha-fetoprotein”“alpha fetoprotein”“PIVKA-Ⅱ”“des-gamma-carboxy-pro-thrombin”“protein induced by vitamin K absence”“GPC-3”“glypican-3”“glypican 3”“serums”“blood serum”“hepatomas”“hepatocellular carcinoma”“liver cancer”“carcinoma，hepatocellular”“diagnosis”“dia-gnoses”“diagnoses and examinations”“sensitivity”“specificity”“ROC”“AUC”。检索词根据数据库进行调整，采用MeSH（PubMed）、Emtree（EMBASE）等主题词与自由词相结合的方式。同时，查阅相关文章的参考文献，以发现可能漏掉的研究。

1.2. 纳入及排除标准

纳入标准：①临床诊断性实验研究；②肝癌的诊断经组织病理学检查确诊或基于公认指南的影像学（超声、CT或MRI）特征作出判断；③经组织病理学检查确诊或基于公认指南的影像学特征证实的肝癌患者为病例组，非肝癌患者为对照组；④能从文献中完整提取真阳性例数、假阳性例数、假阴性例数和真阴性例数等数据。排除标准：①同时合并其他恶性肿瘤，无法获取单独的肝癌数据；②继发性肝癌患者或采集血样前经历过肝癌的相关治疗；③无法完整提取数据；④动物实验；⑤重复、评论、荟萃分析、会议摘要、病例报告、信件或其他不完整的报告；⑥非诊断性研究；⑦样本来源重复。

由两位研究人员独立按照纳入和排除标准对查找到的文献进行筛选。若遇分歧，则由第三位研究者决定文献是否纳入研究。

1.3. 文献质量评价

利用Review Manager 5.4软件使用QUADAS检查表评估研究的质量。其中包含专门开发的四大类共14个项目，用于评估诊断测试主要研究的质量。每个项目的评分为“是”、“否”或“不清楚”。

1.4. 资料提取

从文献中提取第一作者姓名、研究对象的国家/地区、文献发表年份、研究对象数、AFP、PIVKA-Ⅱ及GPC-3的检测方法、敏感度、特异度、生物标志物阈值等数据。

1.5. 数据分析

利用Meta Disc软件和Stata 15.1软件进行数据分析，包括阈值效应分析、异质性检验、发表偏倚、汇总敏感度、汇总特异度以及汇总受试者工作特征曲线下面积等。采用敏感度对数与（1－特异度）对数之间的Spearman相关系数来判断有无阈值效应。采用Cochran-Q检验和I ²进行非阈值效应异质性检验。当I ²值>50%时为异质性显著，采用随机效应模型；否则，选择固定效应模型。使用Deeks漏斗图评估发表偏倚。

2. 结果

2.1. 文献检索结果

共检索到文献3987篇，通过筛选及阅读其他文献最终纳入32篇文献［10-41］。筛选流程见图1。

图1. 文献筛选流程图.

图1

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2.2. 纳入文献的基本特征

纳入文献的研究人群分布较为广泛，其中以中国人群最多。32篇研究文献均涉及AFP诊断效能研究，25篇文献对PIVKA-Ⅱ的诊断效能进行研究，14篇文献对GPC-3的诊断效能进行研究。在标志物的检测方法上，纳入的文献以常用的ELISA为主，可以降低因检测方式引起的偏倚。纳入文献中病例组共3453例，对照组共4512例。纳入文献的基本特征见附表1。

2.3. 纳入研究的质量评价结果

根据QUADAS检查表，本次研究纳入的文献均为质量高、偏倚风险低及临床适用性高的文献（图2和附图1）。

图2. QUADAS检查表评价结果.

图2

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2.4. 纳入研究异质性检验结果

2.4.1. 阈值效应异质性

阈值效应分析结果显示，除AFP+PIVKA-Ⅱ联合检测存在阈值效应（P<0.05）外，其他检测方式均不存在阈值效应（均P>0.05），见表1，提示纳入研究的异质性基本不受阈值效应影响。

表1.

阈值效应异质性检验结果

标志物 Spearman相关系数 P值
AFP 0.247 >0.05
PIVKA-Ⅱ 0.061 >0.05
GPC-3 －0.048 >0.05
AFP+PIVKA--Ⅱ 0.513 <0.05
AFP+GPC-3 －0.064 >0.05
PIVKA-Ⅱ+GPC-3 0.400 >0.05
AFP+PIVKA-Ⅱ+GPC-3 0.400 >0.05
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AFP：甲胎蛋白；PIVKA-Ⅱ：维生素K缺失或拮抗剂Ⅱ诱导的蛋白质；GPC：磷脂酰肌醇蛋白聚糖.

2.4.2. 非阈值效应异质性

对三种标志物单独或联合使用诊断肝癌的DOR进行Cochran-Q检验，结果显示P值均小于0.01，表明均存在非阈值效应异质性。除PIVKA-Ⅱ+GPC-3的阴性似然比的I²值为30.3%外，所有检测方式的敏感度、特异度、阳性似然比、阴性似然比和DOR的I²值均大于50%，表明研究存在较大异质性，遂采用随机效应模型进行以上五个效应量的合并。

2.5. 纳入研究发表偏倚检验结果

Deeks漏斗图显示，AFP、PIVKA-Ⅱ、GPC-3、AFP+PIVKA-Ⅱ、AFP+GPC-3、PIVKA-Ⅱ+GPC-3和AFP+PIVKA-Ⅱ+GPC-3的P值均大于0.05，见图3。表明研究均不存在发表偏倚。

图3. 检测文献发表偏倚Deeks漏斗图.

图3

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2.6. meta分析结果

由于三种标志物单独或联合检测均存在较强异质性，遂采用随机效应模型对来自不同报告的数据进行荟萃分析。

2.6.1. AUC值

单个标志物用于诊断肝癌时，PIVKA-Ⅱ的AUC值最高，为0.88（95%CI：0.85~0.91），其次是GPC-3和AFP。多个标志物联合用于诊断肝癌的AUC均高于单个标志物，其中PIVKA-Ⅱ联合GPC-3诊断的AUC值最高，为0.90（95%CI：0.87~0.92）。见表2和附图2。

表2.

三种标志物单独或联合诊断肝癌的合并效应量

标志物 AUC 敏感度 特异度 DOR 阳性似然比 阴性似然比
AFP 0.78（0.74~0.81） 0.64（0.60~0.68） 0.87（0.82~0.91） 12（8~18） 4.9（3.5~6.9） 0.41（0.37~0.46）
PIVKA-Ⅱ 0.88（0.85~0.91） 0.75（0.69~0.80） 0.88（0.83~0.92） 22（13~36） 4.2（4.4~8.9） 0.29（0.23~0.36）
GPC-3 0.84（0.81~0.87） 0.76（0.66~0.84） 0.81（0.66~0.91） 14（4~44） 4.1（2.0~8.3） 0.29（0.18~0.47）
AFP+PIVKA-Ⅱ 0.89（0.85~0.91） 0.79（0.73~0.85） 0.83（0.78~0.88） 19（13~29） 4.8（3.7~6.2） 0.25（0.19~0.32）
AFP+GPC-3 0.89（0.86~0.92） 0.81（0.71~0.88） 0.85（0.73~0.93） 25（9~67） 5.5（2.8~11.0） 0.22（0.14~0.36）
PIVKA-Ⅱ+GPC-3 0.90（0.87~0.92） 0.88（0.78~0.93） 0.74（0.50~0.89） 20（6~68） 3.3（1.5~7.2） 0.17（0.09~0.32）
AFP+PIVKA-Ⅱ+GPC-3 0.80（0.85~0.91） 0.85（0.75~0.92） 0.75（0.45~0.91） 10（7~45） 3.5（1.5~7.9） 0.19（0.13~0.30）
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括号中数据为95%置信区间. AFP：甲胎蛋白；PIVKA-Ⅱ：维生素K缺失或拮抗剂Ⅱ诱导的蛋白质；GPC：磷脂酰肌醇蛋白聚糖；AUC：受试者工作特征曲线下面积；DOR：诊断比值比.

2.6.2. 敏感度和特异度

由于不同AFP研究使用的阈值不同，敏感度和特异度的范围很广，敏感度为28.80%~84.10%，特异度为29.00%~100.00%，汇总后的敏感度和特异度为0.64（95%CI：0.60~0.68）和0.87（95%CI：0.82~0.91）。单个标志物用于诊断肝癌时，PIVKA-Ⅱ和GPC-3的敏感度相对较高，但GPC-3的特异度不如PIVKA-Ⅱ和AFP；多个标志物联合用于诊断肝癌的敏感度较单个标志物诊断时有所提高，但特异度无明显提高。见表2和附图3。

2.6.3. DOR、阳性似然比和阴性似然比

单个标志物用于诊断肝癌时，PIVKA-Ⅱ的DOR最高，为22（95%CI：13~36），其后是GPC-3和AFP；AFP的阳性似然比最高，PIVKA-Ⅱ和GPC-3阴性似然比基本一致，且均低于AFP。两个标志物联合用于诊断肝癌的DOR均高于单个标志物，其中AFP联合GPC-3诊断的DOR最高，为25（95%CI：9~67）；AFP联合GPC-3的阳性似然比最高，PIVKA-Ⅱ联合GPC-3的阴性似然比最低。三个标志物联合用于诊断肝癌时的DOR为10（95%CI：7~45）。见表2。

综上所述，单个标志物诊断肝癌时PIVKA-Ⅱ的诊断价值最高；两个标志物的联合应用诊断价值优于单个标志物，其中PIVKA-Ⅱ联合GPC-3的诊断价值最高。

3. 讨论

作为发生率和病死率均较高的恶性肿瘤［42］，肝癌的早筛、早诊极为重要。长期以来，血清学标志物AFP因其具有样本易获得、创伤小、可重复等特点已广泛应用于肝癌的筛查和预警［43-45］。1956年，AFP在人胎儿血清中首次发现［46］。从妊娠第四周开始，由于胎儿肝脏等器官的分泌，AFP水平持续升高［47］，待胎儿出生后则持续下降并维持在极低水平，但在肝癌发生时其水平又会异常上升。有研究认为，肝癌患者血清AFP水平升高与位于人类4号染色体长臂上的相关基因有关，该基因上的独立增强子抑制的阻断和沉默子的缺失导致启动子的活性恢复，最终使得AFP过表达［1， 48］。也有研究证明，AFP可以通过启动环AMP-蛋白激酶A途径、钙离子内流和caspase-3介导的凋亡信号促进肿瘤增殖［49-51］。但是，临床上有约30%的AFP阴性肝癌患者，且其特异度较低，所以目前AFP用于诊断肝癌饱受争议［52］。目前研究显示，PIVKA-Ⅱ诊断肝癌的效能高于AFP，有着较高的敏感度和特异度［5］。PIVKA-Ⅱ可通过增强细胞增殖、肿瘤血管生成等方式促进肿瘤的增殖和转移［53］。目前，PIVKA-Ⅱ在肝癌中过表达的机制尚无定论，肝癌中PIVKA-Ⅱ过表达可能与缺氧微环境、维生素K代谢受损及凝血酶原前体过表达相关。但是，PIVKA-Ⅱ水平不仅在肝癌患者血清中升高，在维生素K缺乏症及服用维生素K拮抗剂患者的血液中也会异常升高，这也使得PIVKA-Ⅱ在诊断肝癌时存在一定局限［54］。GPC-3是GPC家族一员，在正常肝脏组织中几乎不表达，但其在肝癌组织中的阳性率高达90%。其通过Wnt/β-catenin信号通路参与肝癌的发生、增殖和转移，是肝癌的重要血清标志物之一［55］。

为了更好地在临床实践中对肝癌血清标志物进行选择，本研究采取荟萃分析来研究AFP、PIVKA-Ⅱ和GPC-3及其联合在诊断肝癌时的效能。与之前的荟萃分析比较，本研究纳入了更多的近期相关研究，且增加了三个标志物联合（AFP+PIVKA-Ⅱ+GPC-3）的比较。本文资料显示，应用单个标志物诊断肝癌时，PIVKA-Ⅱ的AUC值为0.88，高于AFP的0.78和GPC-3的0.84；在汇总特异度相近的情况下，PIVKA-Ⅱ的汇总敏感度为0.75，明显优于AFP。

从检验诊断学角度来看，PIVKA-Ⅱ的敏感度和诊断准确度最高。然而，单一标志物对于肿瘤的检测往往存在敏感度或特异度的不足，因此需要在单一标志物检测基础上进一步提高肝癌的诊断准确度。分析以往的研究发现，AFP联合PIVKA-Ⅱ诊断肝癌的AUC值多介于0.85~0.90［7， 56-57］，而AFP联合GPC-3的AUC值多介于0.75~0.90［58-60］，本研究分析结果与其接近，但三种标志物联合应用并未进一步提高诊断准确度。综合之前的一些荟萃分析结果，本研究认为在临床上使用两个标志物的联合可以在一定程度上增加诊断效能。虽然本文资料显示PIVKA-Ⅱ联合GPC-3的AUC值最高，但相比AFP联合PIVKA-Ⅱ提高较少，同时AFP早已广泛应用于临床，而GPC-3的临床应用很少，再加上其高昂的检测价格，难以在临床推广应用。综合上述考虑，本研究建议临床诊断肝癌时可以联合应用AFP和PIVKA-Ⅱ这两个指标，PIVKA-Ⅱ可以降低对AFP阴性肝癌患者漏诊的可能，AFP可以减少对维生素K缺乏及服用维生素K拮抗剂患者的误诊。

但是，本研究仍有一定的局限性。首先，纳入的GPC-3相关研究较少，可能会使GPC-3相关结果存在误差。其次，纳入的都是回顾性研究，且有个别研究是在肝癌高危人群中进行的，使得研究资料存在异质性。因此，本研究结果还需要通过临床试验进一步验证。

Supplementary information

本文附表和附图见电子版。

Acknowledgments

研究得到浙江省重点研发计划（2019C03050）支持

Acknowledgments

This work was supported by the Key R&D Plan of Zhejiang Province (2019C03050)

［缩略语］

甲胎蛋白（alpha-fetoprotein，AFP）；维生素K缺失或拮抗剂Ⅱ诱导的蛋白质（protein induced by vitamin K absence or antagonist-Ⅱ，PIVKA-Ⅱ）；磷脂酰肌醇蛋白聚糖（glypican，GPC）；受试者工作特征曲线（receiver operating characteristic curve，ROC曲线）；ROC曲线下的面积（area under ROC curve，AUC）；计算机断层扫描（computed tomography，CT）；磁共振成像（magnetic resonance imaging，MRI）；诊断准确性研究的质量评价（Quality Assessment of Diagnostic Accuracy Studies，QUADAS）；酶联免疫吸附法（enzyme linked immunosorbent assay，ELISA）；诊断比值比（diagnostic odds ratio，DOR）；置信区间（confidence interval，CI）；胱天蛋白酶（cysteine aspartic acid specific protease，caspase）

利益冲突声明

所有作者均声明不存在利益冲突

Conflict of Interests

The authors declare that there is no conflict of interests

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