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Volume 41 Issue 11
Nov.  2025
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Article Navigation >  Journal of Clinical Hepatology  > 2025  >  41(11): 2390-2396

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

DOI: 10.12449/JCH251129

  • 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）
  • Received Date: 2025-05-28
  • Accepted Date: 2025-06-27
  • Published Date: 2025-11-25
    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.

     

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    • References(37)
  • [1]
    RUMGAY H, FERLAY J, de MARTEL C, et al. Global, regional and national burden of primary liver cancer by subtype[J]. Eur J Cancer, 2022, 161: 108- 118. DOI: 10.1016/j.ejca.2021.11.023.
    [2]
    RUMGAY H, ARNOLD M, FERLAY J, et al. Global burden of primary liver cancer in 2020 and predictions to 2040[J]. J Hepatol, 2022, 77( 6): 1598- 1606. DOI: 10.1016/j.jhep.2022.08.021.
    [3]
    HAN BF, ZHENG RS, ZENG HM, et al. Cancer incidence and mortality in China, 2022[J]. J Natl Cancer Cent, 2024, 4( 1): 47- 53. DOI: 10.1016/j.jncc.2024.01.006.
    [4]
    SHE S, XIANG Y, YANG M, et al. C-reactive protein is a biomarker of AFP-negative HBV-related hepatocellular carcinoma[J]. Int J Oncol, 2015, 47( 2): 543- 554. DOI: 10.3892/ijo.2015.3042.
    [5]
    WANG T, ZHANG KH. New blood biomarkers for the diagnosis of AFP-negative hepatocellular carcinoma[J]. Front Oncol, 2020, 10: 1316. DOI: 10.3389/fonc.2020.01316.
    [6]
    TZARTZEVA K, OBI J, RICH NE, et al. Surveillance imaging and alpha fetoprotein for early detection of hepatocellular carcinoma in patients with cirrhosis: A meta-analysis[J]. Gastroenterology, 2018, 154( 6): 1706- 1718. DOI: 10.1053/j.gastro.2018.01.064.
    [7]
    CHOI JY. Diagnostic value of AFP-L3 and PIVKA-II in hepatocellular carcinoma according to total-AFP[J]. World J Gastroenterol, 2013, 19( 3): 339. DOI: 10.3748/wjg.v19.i3.339.
    [8]
    KIM H, SOHN A, YEO I, et al. Clinical assay for AFP-L3 by using multiple reaction monitoring-mass spectrometry for diagnosing hepatocellular carcinoma[J]. Clin Chem, 2018, 64( 8): 1230- 1238. DOI: 10.1373/clinchem.2018.289702.
    [9]
    TAKETA K, ENDO Y, SEKIYA C, et al. A collaborative study for the evaluation of lectin-reactive alpha-fetoproteins in early detection of hepatocellular carcinoma[J]. Cancer Res, 1993, 53( 22): 5419- 5423.
    [10]
    LIU Z, DU XH, CHAI WG. Efficacy of des-γ-carboxy-prothrombin in the diagnosis of hepatocellular carcinoma and its association with the clinical features of hepatocellular carcinoma[J]. J Clin Hepatol, 2024, 40( 10): 2014- 2018. DOI: 10.12449/JCH241014.

    刘智, 杜晓宏, 柴文刚. 异常凝血酶原对肝细胞癌的诊断效能及其与肿瘤临床特征的相关性分析[J]. 临床肝胆病杂志, 2024, 40( 10): 2014- 2018. DOI: 10.12449/JCH241014.
    [11]
    FENG HL, LI BL, LI Z, et al. PIVKA-II serves as a potential biomarker that complements AFP for the diagnosis of hepatocellular carcinoma[J]. BMC Cancer, 2021, 21( 1): 401. DOI: 10.1186/s12885-021-08138-3.
    [12]
    WEI FY, RUAN XL, MENG JY, et al. The value of combined detection of PLT, PIVKA-Ⅱ and ALB in the differential diagnosis of AFP-negative hepatocellular carcinoma and cirrhosis[J]. Lab Med Clin, 2024, 21( 15): 2155- 2158. DOI: 10.3969/j.issn.1672-9455.2024.15.003.

    韦芳沂, 阮学莲, 蒙继煜, 等. PLT、PIVKA-Ⅱ、ALB联合检测在AFP阴性肝细胞癌和肝硬化中的鉴别诊断价值[J]. 检验医学与临床, 2024, 21( 15): 2155- 2158. DOI: 10.3969/j.issn.1672-9455.2024.15.003.
    [13]
    HE L, ZHANG C, LIU LL, et al. Development of a diagnostic nomogram for alpha-fetoprotein-negative hepatocellular carcinoma based on serological biomarkers[J]. World J Gastrointest Oncol, 2024, 16( 6): 2463- 2475. DOI: 10.4251/wjgo.v16.i6.2463.
    [14]
    YE X, LI CY, ZU XY, et al. A large-scale multicenter study validates aldo-keto reductase family 1 member B10 as a prevalent serum marker for detection of hepatocellular carcinoma[J]. Hepatology, 2019, 69( 6): 2489- 2501. DOI: 10.1002/hep.30519.
    [15]
    LU QQ, LI J, CAO H, et al. Comparison of diagnostic accuracy of Midkine and AFP for detecting hepatocellular carcinoma: A systematic review and meta-analysis[J]. Biosci Rep, 2020, 40( 3): BSR20192424. DOI: 10.1042/BSR20192424.
    [16]
    ZHU WW, GUO JJ, GUO L, et al. Evaluation of midkine as a diagnostic serum biomarker in hepatocellular carcinoma[J]. Clin Cancer Res, 2013, 19( 14): 3944- 3954. DOI: 10.1158/1078-0432.ccr-12-3363.
    [17]
    SHANG SF, PLYMOTH A, GE SK, et al. Identification of osteopontin as a novel marker for early hepatocellular carcinoma[J]. Hepatology, 2012, 55( 2): 483- 490. DOI: 10.1002/hep.24703.
    [18]
    ZHU MY, ZHENG J, WU F, et al. OPN is a promising serological biomarker for hepatocellular carcinoma diagnosis[J]. J Med Virol, 2020, 92( 12): 3596- 3603. DOI: 10.1002/jmv.25704.
    [19]
    WU MT, ZOU F, HE SY, et al. Serum osteopontin enhances hepatocellular carcinoma diagnosis and predicts anti-PD-L1 immunotherapy benefit[J]. J Hepatocell Carcinoma, 2025, 12: 729- 745. DOI: 10.2147/JHC.S514144.
    [20]
    LU F, OTT C, BISTA P, et al. Three-dimensional structure of novel liver cancer biomarker liver cancer-specific serine protease inhibitor kazal(LC-SPIK) and its performance in clinical diagnosis of hepatocellular carcinoma(HCC)[J]. Diagnostics, 2024, 14( 7): 725. DOI: 10.3390/diagnostics14070725.
    [21]
    CAVIGLIA GP, NICOLOSI A, ABATE ML, et al. Liver cancer-specific isoform of serine protease inhibitor kazal for the detection of hepatocellular carcinoma: Results from a pilot study in patients with dysmetabolic liver disease[J]. Curr Oncol, 2022, 29( 8): 5457- 5465. DOI: 10.3390/curroncol29080431.
    [22]
    CHENG K, CAI N, ZHU JH, et al. Tumor-associated macrophages in liver cancer: From mechanisms to therapy[J]. Cancer Commun, 2022, 42( 11): 1112- 1140. DOI: 10.1002/cac2.12345.
    [23]
    LI YZ, WANG HY, REN DF, et al. Interleukin-41: A novel serum marker for the diagnosis of alpha-fetoprotein-negative hepatocellular carcinoma[J]. Front Oncol, 2024, 14: 1408584. DOI: 10.3389/fonc.2024.1408584.
    [24]
    HAO MD, YANG YZ, WANG MD, et al. Application strategy of circulating tumor DNA in entire process of precision medicine for hepatocellular carcinoma[J]. Chin J Dig Surg, 2025, 24( 1): 86- 92. DOI: 10.3760/cma.j.cn115610-20241224-00578.

    赫明达, 杨钰泽, 王明达, 等. 循环肿瘤DNA在肝细胞癌精准医疗全程中的应用策略[J]. 中华消化外科杂志, 2025, 24( 1): 86- 92. DOI: 10.3760/cma.j.cn115610-20241224-00578.
    [25]
    GUO DZ, HUANG A, WANG YC, et al. Early detection and prognosis evaluation for hepatocellular carcinoma by circulating tumour DNA methylation: A multicentre cohort study[J]. Clin Transl Med, 2024, 14( 5): e1652. DOI: 10.1002/ctm2.1652.
    [26]
    LU CY, CHEN SY, PENG HL, et al. Cell-free methylation markers with diagnostic and prognostic potential in hepatocellular carcinoma[J]. Oncotarget, 2017, 8( 4): 6406- 6418. DOI: 10.18632/oncotarget.14115.
    [27]
    ZENG YL, HU SY, LUO Y, et al. Exosome cargos as biomarkers for diagnosis and prognosis of hepatocellular carcinoma[J]. Pharmaceutics, 2023, 15( 9): 2365. DOI: 10.3390/pharmaceutics15092365.
    [28]
    GUO X, LV XH, LV X, et al. Circulating miR-21 serves as a serum biomarker for hepatocellular carcinoma and correlated with distant metastasis[J]. Oncotarget, 2017, 8( 27): 44050- 44058. DOI: 10.18632/oncotarget.17211.
    [29]
    WU CH, QIAN CR, YIN GY, et al. Expression and clinical prognostic value of serum exosomal LncRNA 00853 and LncRNA FAM72D-3 in AFP-negative hepatocellular carcinoma patients[J]. Int J Lab Med, 2023, 44( 11): 1353- 1358. DOI: 10.3969/j.issn.1673-4130.2023.11.015.

    武彩虹, 钱成荣, 银广悦, 等. 血清外泌体LncRNA 00853、LncRNA FAM72D-3在AFP阴性肝细胞癌患者中的表达及临床预后价值[J]. 国际检验医学杂志, 2023, 44( 11): 1353- 1358. DOI: 10.3969/j.issn.1673-4130.2023.11.015.
    [30]
    HUANG XJ, SUN LY, WEN S, et al. RNA sequencing of plasma exosomes revealed novel functional long noncoding RNAs in hepatocellular carcinoma[J]. Cancer Sci, 2020, 111( 9): 3338- 3349. DOI: 10.1111/cas.14516.
    [31]
    MENG J, WANG JQ, FEI XC, et al. Establishment and validation of a plasma exosome-derived circular RNA model for HCC diagnosis[J]. Lab Med, 2022, 37( 1): 1- 10. DOI: 10.3969/j.issn.1673-8640.2022.01.001.

    孟俊, 王俊青, 费晓春, 等. 血浆外泌体circRNA诊断HCC联合检测模型的建立与验证[J]. 检验医学, 2022, 37( 1): 1- 10. DOI: 10.3969/j.issn.1673-8640.2022.01.001.
    [32]
    SUN N, ZHANG C, LEE YT, et al. HCC EV ECG score: An extracellular vesicle-based protein assay for detection of early-stage hepatocellular carcinoma[J]. Hepatology, 2022, 77( 3): 774- 788. DOI: 10.1002/hep.32692.
    [33]
    WANG L, HE WX, XIE P, et al. Changes in circulating tumor cells(CTCs) before and after surgery and their correlation with pathological factors in colorectal cancer patients[J]. Clin J Med Offic, 2023, 51( 12): 1291- 1293. DOI: 10.16680/j.1671-3826.2023.12.22.

    王立, 何维新, 谢鹏, 等. 循环肿瘤细胞在结直肠癌患者手术前后变化及其与肿瘤病理因素相关性[J]. 临床军医杂志, 2023, 51( 12): 1291- 1293. DOI: 10.16680/j.1671-3826.2023.12.22.
    [34]
    GUO W, SUN YF, SHEN MN, et al. Circulating tumor cells with stem-like phenotypes for diagnosis, prognosis, and therapeutic response evaluation in hepatocellular carcinoma[J]. Clin Cancer Res, 2018, 24( 9): 2203- 2213. DOI: 10.1158/1078-0432.ccr-17-1753.
    [35]
    LIANG WJ, XU ZG, KONG FY, et al. Circulating tumour cell combined with DNA methylation for early detection of hepatocellular carcinoma[J]. Front Genet, 2022, 13: 1065693. DOI: 10.3389/fgene.2022.1065693.
    [36]
    ZHANG Q, RONG Y, YI KZ, et al. Circulating tumor cells in hepatocellular carcinoma: Single-cell based analysis, preclinical models, and clinical applications[J]. Theranostics, 2020, 10( 26): 12060- 12071. DOI: 10.7150/thno.48918.
    [37]
    LIN ZY, LI HG, HE CY, et al. Metabolomic biomarkers for the diagnosis and post-transplant outcomes of AFP negative hepatocellular carcinoma[J]. Front Oncol, 2023, 13: 1072775. DOI: 10.3389/fonc.2023.1072775.
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