甲胎蛋白阴性肝细胞癌早期诊断生物标志物研究进展

赵思汝; 熊枝繁

doi:10.12449/JCH251129

甲胎蛋白阴性肝细胞癌早期诊断生物标志物研究进展

DOI: 10.12449/JCH251129

赵思汝,
熊枝繁^, ,

华中科技大学同济医学院附属梨园医院消化内科，武汉 430060

基金项目:

华中科技大学同济医学院梨园医院院内科研基金 (2023LYYYCXTD0002)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：赵思汝负责查找文献，撰写论文；熊枝繁负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
熊枝繁， xiongzhifan@126.com （ORCID： 0000-0001-7190-8073）

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出版历程
- 收稿日期: 2025-05-28
- 录用日期: 2025-06-27
- 出版日期: 2025-11-25

Research advances in biomarkers for the early diagnosis of alpha-fetoprotein-negative hepatocellular carcinoma

Siru ZHAO,
Zhifan XIONG^{,
,}

Department of Gastroenterology，Liyuan Hospital，Tongji Medical College，Huazhong University of Science and Technology，Wuhan 430060，China

Research funding:

Intramural Scientific Research Fund of Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology (2023LYYYCXTD0002)

More Information

Corresponding author: XIONG Zhifan， xiongzhifan@126.com （ORCID： 0000-0001-7190-8073）

摘要

摘要: 肝细胞癌（HCC）是全球癌症相关死亡的主要原因之一，也是我国临床最常见恶性肿瘤之一。HCC起病隐匿且进展迅速，大多数患者在诊断时已处于中晚期，预后较差。其中甲胎蛋白阴性HCC占HCC病例总数的30%～40%，传统诊断标志物血清甲胎蛋白在该人群中敏感性不足，容易造成漏诊。本综述探讨了经典生物标志物、新型蛋白质标志物、液体活检标志物及代谢组学标志物对甲胎蛋白阴性HCC早期筛查的潜力，旨在提高甲胎蛋白阴性HCC早期诊断率，减轻肝癌疾病负担。
- 甲胎蛋白 /
- 癌，肝细胞 /
- 液体活组织检查 /
- 生物标记，肿瘤
Abstract: Hepatocellular carcinoma （HCC） is one of the leading causes of cancer-related mortality worldwide and is also one of the most common malignant tumors in clinical practice in our country. HCC is characterized by insidious onset and rapid progression， and most patients are in the advanced stage at the time of diagnosis， resulting in a poor prognosis. Alpha-fetoprotein （AFP）-negative hepatocellular carcinoma （ANHCC） accounts for approximately 30% — 40% of all HCC cases， and the traditional diagnostic biomarker， serum AFP， has insufficient sensitivity in this population， which can easily lead to missed diagnoses. This article reviews the potential of classic biomarkers， novel protein markers， liquid biopsy markers， and metabolomics markers in the early screening for ANHCC， in order to improve the early diagnosis rate of ANHCC and reduce the disease burden of liver cancer.
- alpha-Fetoproteins /
- Carcinoma， Hepatocellular /
- Liquid Biopsy /
- Biomarkers， Tumor

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表 1 对AFP阴性HCC诊断具有潜在价值的血清蛋白质标志物

Table 1. Serum protein biomarkers with potential value for the diagnosis of AFP-negative HCC

标志物	AUC	敏感度	特异度	价值
AFP-L3^［7］	0.824	71.7%	83.8%	较影像学提前数月预警HCC的发生
PIVKA-Ⅱ^［11］	0.88	78.33%	91.3%	对肝硬化背景下诊断AFP阴性HCC效能明显
GP73^［13］	0.843	75.6%	93%	在AFP阳性HCC患者与AFP阴性HCC患者中表达无差异
AKR1B10^［14］	0.891	71.2%	92.6%	在AFP阴性HCC早期诊断和术后复发中具有较高价值
MDK^［15］	0.91	88.5%	83.9%	在早期HCC中，有效区分AFP阴性HCC与非HCC、肝硬化
OPN^［17］	0.75	65%	68%	与肿瘤进展密切相关，已被提议作为癌症治疗的靶点
LC-SPIK^［20］	0.78～0.91			对AFP阴性患者诊断准确率>70%
IL-41^［23］		96.63%	68.42%	目前单独诊断AFP阴性HCC最敏感的血清学标志物

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表 2 液体活检标志物对AFP阴性HCC的诊断价值

Table 2. The diagnostic value of liquid biopsy biomarkers for AFP-negative HCC

标志物	类别	敏感度	特异度
ctDNA甲基化^［25］	ctDNA	75.1%
miR-21^［28］	EV（miRNA）	81.2%	83.2%
lnc85^［30］	EV（lncRNA）	80.0%	76.5%
CTC^［33］	CTC	77.7%	95.0%

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