异常凝血酶原在肝细胞癌诊疗中的应用进展

摘要/Abstract

摘要： 异常凝血酶原即维生素K缺乏或拮抗剂-Ⅱ诱导的蛋白质（protein induced by vitamin K absence or antagonist-Ⅱ,PIVKA-Ⅱ）,目前主要用于肝细胞癌的补充诊断。但越来越多的研究发现,PIVKA-Ⅱ在联合其他血清学指标进行高特异度、高敏感度的诊断、治疗前的疗效评估及治疗后的预后评价等方面均具有一定价值,其水平的变化可以为肝移植术、肝切除术时机的选择及微血管侵犯提供新的依据。本文对PIVKA-Ⅱ在肝细胞癌诊疗中应用的研究进展进行综述。

关键词: 异常凝血酶原, 肝细胞癌, 诊断, 治疗

Abstract: Protein induced by vitamin K absence or antagonist-Ⅱ(PIVKA-Ⅱ) is mainly used for the complementary diagnosis of hepatocellular carcinoma, but now more and more studies have found that PIVKA-Ⅱ is valuable in combination with other serological indices for highly specific and sensitive diagnosis, pre-treatment efficacy assessment and post-treatment prognosis evaluation, and its level changes can provide a new basis for choice of surgery timing of liver transplantation and hepatectomy and for microvascular invasion. This article will review and discuss the role of PIVKA-Ⅱ in the above diagnosis and treatment, aiming to provide more comprehensive theoretical support for the function of PIVKA-Ⅱ in hepatocellular carcinoma.

Key words: Protein induced by vitamin K absence or antagonist-Ⅱ, Hepatocellular carcinoma, Diagnosis, Therapy

王雅宁, 盛基尧, 王赈霄, 张学文. 异常凝血酶原在肝细胞癌诊疗中的应用进展[J]. 肝癌电子杂志, 2023, 10(1): 39-44.

Wang Yaning, Sheng Jiyao, Wang Zhenxiao, Zhang Xuewen. Progress on protein induced by vitamin K absence or antagonist-Ⅱ in the diagnosis and therapy of hepatocellular carcinoma[J]. Electronic Journal of Liver Tumor, 2023, 10(1): 39-44.

参考文献

[1] 应倩, 汪媛. 肝癌流行现况和趋势分析[J]. 中国肿瘤, 2020, 29(3): 185-191.
[2] SIA D, VILLANUEVA A, FRIEDMAN S L, et al.Liver Cancer Cell of Origin, Molecular Class, and Effects on Patient Prognosis[J]. Gastroenterology, 2017, 152(4): 745-761.
[3] 中华人民共和国国家卫生健康委员会.原发性肝癌诊疗指南(2022年版)[J/CD].肿瘤综合治疗电子杂志,2022, 8(2): 16-53.
[4] BEHNE T, COPUR M S.Biomarkers for hepatocellular carcinoma[J]. Int J Hepatol, 2012: 859076.
[5] BASILE U, MIELE L, NAPODANO C, et al.The diagnostic performance of PIVKA-Ⅱ in metabolic and viral hepatocellular carcinoma: a pilot study[J]. Eur Rev Med Pharmacol Sci, 2020, 24(24): 12675-12685.
[6] LEE K C, CROWE A J, BARTON M C. p53-mediated repression of alpha-fetoprotein gene expression by specific DNA binding[J]. Mol Cell Biol, 1999, 19(2): 1279-1288.
[7] XIE Z, ZHANG H, TSAI W, et al.Zinc finger protein ZBTB20 is a key repressor of alpha-fetoprotein gene transcription in liver[J]. Proc Natl Acad Sci U S A, 2008, 105(31): 10859-10864.
[8] PERINCHERI S, DINGLE R W, PETERSON M L, et al.Hereditary persistence of alpha-fetoprotein and H19 expression in liver of BALB/cJ mice is due to a retrovirus insertion in the Zhx2 gene[J]. Proc Natl Acad Sci U S A, 2005, 102(2): 396-401.
[9] STENFLO J, SUTTIE J W.Vitamin K-Dependent Formation of γ-Carboxyglutamic Acid[J]. Ann Rev Biochem, 1977, 46(1): 157-172.
[10] CARR B I, KANKE F, WISE M, et al.Clinical Evaluation of Lens Culinaris Agglutinin-Reactive α-Fetoprotein and Des-γ-Carboxy Prothrombin in Histologically Proven Hepatocellular Carcinoma in the United States[J]. Dig Dis Sci, 2007, 52(3): 776-782.
[11] JI J, WANG H, LI Y, et al.Diagnostic Evaluation of Des-Gamma-Carboxy Prothrombin versus α-Fetoprotein for Hepatitis B Virus-Related Hepatocellular Carcinoma in China: A Large-Scale, Multicentre Study[J]. PLoS One, 2016, 11(4): e0153227.
[12] SONG T, WANG L, XIN R, et al.Evaluation of serum AFP and DCP levels in the diagnosis of early-stage HBV-related HCC under different backgrounds[J]. J Int Med Res, 2020, 48(10): 300060520969087.
[13] JOHNSON P J, PIRRIE S J, COX T F, et al.The detection of hepatocellular carcinoma using a prospectively developed and validated model based on serological biomarkers[J]. Cancer Epidemiol Biomarkers Prev, 2014, 23(1): 144-153.
[14] BERHANE S, TOYODA H, TADA T, et al. Role of the GALAD and BALAD-2 Serologic Models in Diagnosis of Hepatocellular Carcinoma and Prediction of Survival in Patients[J]. Clin Gastroenterol Hepatol, 2016, 14(6): 875-886.e6.
[15] BEST J, BECHMANN L P, SOWA J P, et al. GALAD Score Detects Early Hepatocellular Carcinoma in an International Cohort of Patients With Nonalcoholic Steatohepatitis[J]. Clin Gastroenterol Hepatol, 2020, 18(3): 728-735.e4.
[16] BERHANE S, JOHNSON P J, TADA T, et al.SAT-097 - Serial changes in serum biomarkers (GALAD model) prior to detection of HCC by ultrasound surveillance; application of statistical process control methodology[J]. J Hepatol, 2017, 66(1, Supplement): S628.
[17] TOYODA H, KUMADA T, OSAKI Y, et al.Staging hepatocellular carcinoma by a novel scoring system (BALAD score) based on serum markers[J]. Clin Gastroenterol Hepatol, 2006, 4(12): 1528-1536.
[18] KITAI S, KUDO M, MINAMI Y, et al. Validation of a new prognostic staging system for hepatocellular carcinoma: a comparison of the biomarker-combined Japan Integrated Staging Score, the conventional Japan Integrated Staging Score and the BALAD Score[J]. Oncology, 2008, 75 Suppl 1: 83-90.
[19] TOYODA H, TADA T, JOHNSON P J, et al.Validation of serological models for staging and prognostication of HCC in patients from a Japanese nationwide survey[J]. J Gastroenterol, 2017, 52(10): 1112-1121.
[20] WANG Q, CHEN Q, ZHANG X, et al.Diagnostic value of gamma-glutamyltransferase/aspartate aminotransferase ratio, protein induced by vitamin K absence or antagonist Ⅱ, and alpha-fetoprotein in hepatitis B virus-related hepatocellular carcinoma[J]. World J Gastroenterol, 2019, 25(36): 5515-5529.
[21] WANG G, LU X, DU Q, et al.Diagnostic value of the gamma-glutamyltransferase and alanine transaminase ratio, alpha-fetoprotein, and protein induced by vitamin K absence or antagonist Ⅱ in hepatitis B virus-related hepatocellular carcinoma[J]. Sci Rep, 2020, 10(1): 13519.
[22] CAVIGLIA G P, ABATE M L, GAIA S, et al.Risk of hepatocellular carcinoma in HBV cirrhotic patients assessed by the combination of miR-122, AFP and PIVKA-Ⅱ[J]. Panminerva Med, 2017, 59(4): 283-289.
[23] TIAN Z, YU T, WEI H, et al.Clinical value of LHPP-associated microRNAs combined with protein induced by vitamin K deficiency or antagonist-Ⅱ in the diagnosis of alpha-fetoprotein-negative hepatocellular carcinoma[J]. J Clin Lab Anal, 2020, 34(2): e23071.
[24] YANG T, XING H, WANG G, et al.A Novel Online Calculator Based on Serum Biomarkers to Detect Hepatocellular Carcinoma among Patients with Hepatitis B[J]. Clin Chem, 2019, 65(12): 1543-1553.
[25] FUJIKI M, TAKADA Y, OGURA Y, et al.Significance of des-gamma-carboxy prothrombin in selection criteria for living donor liver transplantation for hepatocellular carcinoma[J]. Am J Transplant, 2009, 9(10): 2362-2371.
[26] KUDO A, SHINODA M, ARIIZUMI S, et al.Des-gamma-carboxy prothrombin affects the survival of HCC patients with marginal liver function and curative treatment: ACRoS1402[J]. J Cancer Res Clin Oncol, 2020, 146(11): 2949-2956.
[27] LEE H W, SONG G W, LEE S G, et al.Patient Selection by Tumor Markers in Liver Transplantation for Advanced Hepatocellular Carcinoma[J]. Liver Transpl, 2018, 24(9): 1243-1251.
[28] HWANG S, SONG G W, LEE Y J, et al.Multiplication of Tumor Volume by Two Tumor Markers Is a Post-Resection Prognostic Predictor for Solitary Hepatocellular Carcinoma[J]. J Gastrointest Surg, 2016, 20(11): 1807-1820.
[29] HWANG S, JOH J W, WANG H J, et al.Prognostic Prediction Models for Resection of Large Hepatocellular Carcinoma: A Korean Multicenter Study[J]. World J Surg, 2018, 42(8): 2579-2591.
[30] KAMIYAMA T, ORIMO T, WAKAYAMA K, et al.Survival outcomes of hepatectomy for stage B Hepatocellular carcinoma in the BCLC classification[J]. World J Surg Oncol, 2017, 15(1): 156.
[31] TSUKAMOTO M, NITTA H, IMAI K, et al.Clinical significance of half-lives of tumor markers alpha-fetoprotein and des-gamma-carboxy prothrombin after hepatectomy for hepatocellular carcinoma[J]. Hepatol Res, 2018, 48(3): E183-E193.
[32] OKAMURA Y, SUGIURA T, ITO T, et al.The Half-Life of Serum Des-Gamma-Carboxy Prothrombin Is a Prognostic Index of Survival and Recurrence After Liver Resection for Hepatocellular Carcinoma[J]. Ann Surg Oncol, 2016, 23(Suppl 5): 921-928.
[33] MORIYA K, NAMISAKI T, TAKAYA H, et al.Identification of the Response-Related Biomarker of Bimonthly Hepatic Arterial Infusion Chemotherapy[J]. J Clin Med, 2021, 10(4): 629.
[34] ZHAO S M, QIU L W, ZHAO H, et al.Prognostic nomogram for hepatocellular carcinoma patients after transarterial chemoembolization based on des-gamma-carboxy prothrombin reactivity and modified Response Evaluation Criteria in Solid Tumors[J]. J Cancer Res Ther, 2021, 17(3): 707-714.
[35] SAITO M, SEO Y, YANO Y, et al.A high value of serum des-γ-carboxy prothrombin before hepatocellular carcinoma treatment can be associated with long-term liver dysfunction after treatment[J]. J Gastroenterol, 2012, 47(10): 1134-1142.
[36] LEE S, RHIM H, KIM Y S, et al.Post-ablation des-gamma-carboxy prothrombin level predicts prognosis in hepatitis B-related hepatocellular carcinoma[J]. Liver Int, 2016, 36(4): 580-587.
[37] YURI Y, NISHIKAWA H, ENOMOTO H, et al.Implication of Psoas Muscle Index on Survival for Hepatocellular Carcinoma Undergoing Radiofrequency Ablation Therapy[J]. J Cancer, 2017, 8(9): 1507-1516.
[38] POON R T, FAN S T, LO C M, et al.Difference in tumor invasiveness in cirrhotic patients with hepatocellular carcinoma fulfilling the Milan criteria treated by resection and transplantation: impact on long-term survival[J]. Ann Surg, 2007, 245(1): 51-58.
[39] WANG S B, CHENG Y N, CUI S X, et al.Des-gamma-carboxy prothrombin stimulates human vascular endothelial cell growth and migration[J]. Clin Exp Metastasis, 2009, 26(5): 469-477.
[40] RYU T, TAKAMI Y, WADA Y, et al.A Clinical Scoring System for Predicting Microvascular Invasion in Patients with Hepatocellular Carcinoma Within the Milan Criteria[J]. J Gastrointest Surg, 2019, 23(4): 779-787.
[41] OKAMURA Y, SUGIURA T, ITO T, et al.The Predictors of Microscopic Vessel Invasion Differ Between Primary Hepatocellular Carcinoma and Hepatocellular Carcinoma with a Treatment History[J]. World J Surg, 2018, 42(11): 3694-3704.
[42] OKAMURA Y, SUGIURA T, ITO T, et al.Anatomical resection is useful for the treatment of primary solitary hepatocellular carcinoma with predicted microscopic vessel invasion and/or intrahepatic metastasis[J]. Surg Today, 2021, 51(9): 1429-1439.
[43] YAMASHITA Y I, IMAI K, YUSA T, et al.Microvascular invasion of single small hepatocellular carcinoma ≤3 cm: Predictors and optimal treatments[J]. Ann Gastroenterol Surg, 2018, 2(3): 197-203.
[44] YOH T, SEO S, OGISO S, et al.Quantitative assessment of microvascular invasion in hepatocellular carcinoma using preoperative serological and imaging markers[J]. HPB (Oxford), 2021, 23(7): 1039-1045.
[45] NARAKI T, KOHNO N, SAITO H, et al.gamma-Carboxyglutamic acid content of hepatocellular carcinoma-associated des-gamma-carboxy prothrombin[J]. Biochim Biophys Acta, 2002, 1586(3): 287-298.
[46] TAMEDA M, SHIRAKI K, SUGIMOTO K, et al.Des-gamma-carboxy prothrombin ratio measured by P-11 and P-16 antibodies is a novel biomarker for hepatocellular carcinoma[J]. Cancer Sci, 2013, 104(6): 725-731.
[47] CHIEH J J, HUANG K W, CHUANG C P, et al.Immunomagnetic Reduction Assay on Des-Gamma-Carboxy Prothrombin for Screening of Hepatocellular Carcinoma[J]. IEEE Trans Biomed Eng, 2016, 63(8): 1681-1686.
[48] HUANG Y, ZHANG S, ZHENG Q, et al.Development of up-converting phosphor technology-based lateral flow assay for quantitative detection of serum PIVKA-Ⅱ: Inception of a near-patient PIVKA-Ⅱ detection tool[J]. Clin Chim Acta, 2019, 488: 202-208.
[49] TAKEJI S, HIROOKA M, KOIZUMI Y, et al.Des-gamma-carboxy prothrombin identified by P-11 and P-16 antibodies reflects prognosis for patients with hepatocellular carcinoma[J]. J Gastroenterol Hepatol, 2013, 28(4): 671-677.
[50] CUI S X, ZHANG Y S, CHU J H, et al.Des-gamma-carboxy prothrombin (DCP) antagonizes the effects of gefitinib on human hepatocellular carcinoma cells[J]. Cell Physiol Biochem, 2015, 35(1): 201-212.
[51] SUZUKI M, SHIRAHA H, FUJIKAWA T, et al.Des-gamma-carboxy prothrombin is a potential autologous growth factor for hepatocellular carcinoma[J]. J Biol Chem, 2005, 280(8): 6409-6415.
[52] FUJIKAWA T, SHIRAHA H, YAMAMOTO K.Significance of des-gamma-carboxy prothrombin production in hepatocellular carcinoma[J]. Acta Med Okayama, 2009, 63(6): 299-304.
[53] INAGAKI Y, QI F, GAO J, et al.Effect of c-Met inhibitor SU11274 on hepatocellular carcinoma cell growth[J]. Biosci Trends, 2011, 5(2): 52-56.
[54] GAO J, FENG X, INAGAKI Y, et al.Des-γ-carboxy prothrombin and c-Met were concurrently and extensively expressed in hepatocellular carcinoma and associated with tumor recurrence[J]. Biosci Trends, 2012, 6(4): 153-159.