image: PIVKA-II, protein induced by vitamin K absence or antagonist-II. PIVKA-II, also known as des-γ-carboxy prothrombin (DCP), is an aberrant isoform of prothrombin characterized by defective γ-carboxylation within its Gla domain. In physiologically active prothrombin, the Gla domain contains ten fully carboxylated glutamic acid residues, which enable the protein to bind calcium ions and interact with phospholipid membranes. This is an essential step for anchoring prothrombin to the surface of injured blood vessels. In contrast, PIVKA-II contains incompletely carboxylated Gla residues, resulting in markedly reduced calcium-binding capacity and a failure to adopt the functional conformation required for coagulation activity.Site-directed mutagenesis studies have demonstrated that carboxylation at positions 16, 26, and 29 is critical for maintaining procoagulant function. Loss of γ-carboxylation at these key sites reduces the coagulation activity of PIVKA-II to less than 1% of that of native prothrombin. Moreover, structural analyses have revealed that the conformational flexibility of the Gla domain in PIVKA-II is significantly diminished, which disrupts the spatial organization of the kringle and protease domains and further compromises its biological function.
Credit: Liaoyun Zhang
Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, particularly in regions with high hepatitis B virus prevalence. Early detection is challenging due to the limited sensitivity of conventional biomarkers such as alpha-fetoprotein (AFP). Protein induced by vitamin K absence or antagonist-II (PIVKA-II), an abnormal prothrombin variant, has emerged as a promising serological biomarker with significant diagnostic, prognostic, and therapeutic relevance in HCC. This review synthesizes current knowledge on the molecular basis, clinical utility, and future directions of PIVKA-II in HCC management.
Introduction
HCC is the most common form of primary liver cancer, often diagnosed at an advanced stage due to its asymptomatic onset. The inadequacy of AFP, especially in AFP-negative HCC (AFP-NHCC), underscores the need for more reliable biomarkers. PIVKA-II, first identified in 1984, has gained attention for its close association with tumor biology and its superior diagnostic performance in certain clinical contexts.
Biological Significance and Characteristics of PIVKA-II
PIVKA-II, also known as des-γ-carboxy prothrombin (DCP), is generated under conditions of vitamin K deficiency or antagonism. In HCC, its production is linked to hypoxia, reduced vitamin K levels, and impaired γ-glutamyl carboxylase activity. Structurally, PIVKA-II lacks normal coagulation function due to incomplete carboxylation of glutamic acid residues in its Gla domain. Beyond being a metabolic byproduct, PIVKA-II actively promotes HCC progression by activating oncogenic pathways such as c-Met/JAK1/STAT3 and Ras/Raf/MEK/ERK, and by stimulating angiogenesis through the KDR/PLCγ/MAPK axis. A specialized variant, next-generation DCP (NX-DCP), exhibits higher specificity for HCC and correlates with microvascular invasion and tumor burden.
PIVKA-II as an HCC Biomarker
Early Detection:
PIVKA-II demonstrates higher diagnostic sensitivity and specificity than AFP, particularly in AFP-NHCC and in tumors ≥5 cm. Guidelines from the Japanese Society of Hepatology and the Chinese Diagnosis and Treatment Guidelines for Primary Liver Cancer endorse its use in high-risk populations. To improve early detection, multi-parametric models such as GALAD, GAAD, ASAP, and aMAP integrate PIVKA-II with demographic and biochemical variables, significantly enhancing diagnostic accuracy and enabling dynamic risk stratification.
Distinguishing HCC from Intrahepatic Cholangiocarcinoma (ICC):
While PIVKA-II shows limited elevation in ICC, its combination with other markers (e.g., CA19-9, CA125) in nomograms improves differential diagnosis. The interplay between PIVKA-II and hepatitis B virus status further aids in distinguishing HCC from ICC.
Efficacy Assessment and Prognosis Analysis:
PIVKA-II serves as a valuable tool for predicting treatment response and prognosis across various HCC therapies—including resection, ablation, transarterial chemoembolization, immunotherapy, and targeted therapy. Elevated baseline levels and dynamic changes in PIVKA-II correlate with tumor invasiveness, recurrence risk, survival outcomes, and even adverse events during immunotherapy. Post-treatment declines in PIVKA-II are associated with better clinical outcomes and longer recurrence-free survival.
Comparative Analysis with Other Biomarkers
Compared to AFP, AFP-L3, glypican-3 (GPC3), and neutrophil-to-lymphocyte ratio (NLR), PIVKA-II exhibits advantages in early detection, applicability across diverse etiologies, and monitoring of therapeutic response. However, its performance varies with tumor size, etiology, and geographic population, necessitating combined use with other markers for optimal clinical utility.
Shortcomings and Future Prospects
Detection Methods:
Current immunoassays (ELISA, CLEIA) are confounded by vitamin K deficiency, anticoagulant therapy, and liver conditions. Standardization of assays and cut-off values across platforms and populations is urgently needed. Emerging sensor technologies and next-generation assays hold promise for improving specificity and clinical applicability.
PIVKA-II in Non-HCC Diseases:
Elevated PIVKA-II is also observed in non-HCC conditions such as gallbladder cancer, pancreatic cancer, chronic kidney disease, and vitamin K deficiency states. This broadens its potential clinical relevance but also necessitates careful interpretation within a comprehensive diagnostic framework.
Future Directions:
Integration of PIVKA-II with artificial intelligence and deep learning may enhance early diagnosis and prognostic stratification. Further research is needed to clarify its role as a driver versus surrogate of malignancy, to standardize detection protocols, and to validate its utility in diverse clinical and etiological settings.
Conclusion
PIVKA-II has evolved from a serological anomaly to a cornerstone biomarker in HCC diagnosis, prognosis, and treatment monitoring. Its integration into multi-parametric models and clinical guidelines underscores its translational value. Future efforts should focus on assay standardization, mechanistic insights, and personalized implementation to fully realize its potential in improving HCC outcomes.
Full text
https://www.xiahepublishing.com/2310-8819/JCTH-2025-00377
The study was recently published in the Journal of Clinical and Translational Hepatology.
The Journal of Clinical and Translational Hepatology (JCTH) is owned by the Second Affiliated Hospital of Chongqing Medical University and published by XIA & HE Publishing Inc. JCTH publishes high quality, peer reviewed studies in the translational and clinical human health sciences of liver diseases. JCTH has established high standards for publication of original research, which are characterized by a study’s novelty, quality, and ethical conduct in the scientific process as well as in the communication of the research findings. Each issue includes articles by leading authorities on topics in hepatology that are germane to the most current challenges in the field. Special features include reports on the latest advances in drug development and technology that are relevant to liver diseases. Regular features of JCTH also include editorials, correspondences and invited commentaries on rapidly progressing areas in hepatology. All articles published by JCTH, both solicited and unsolicited, must pass our rigorous peer review process.
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Journal
Journal of Clinical and Translational Hepatology
Article Title
Protein Induced by Vitamin K Absence or Antagonist II in Primary Liver Cancer: Basic Research Insights and Clinical Applications
Article Publication Date
28-Oct-2025