Protein induced by vitamin K absence or antagonist-II in hepatocellular carcinoma with normal alpha-fetoprotein: Current advances and controversies

Table 1 Potential mechanisms of protein induced by vitamin K absence/antagonist-II in hepatocellular carcinoma

Ref.	Year	Potential mechanism
Bhatti et al[30]	2021	Association with invasive tumor phenotype
Qian et al[31]	2023	Complementary value in AFP-normal HCC
Dong et al[10]	2023	Value for recurrence surveillance
Kudo[32]	2024	Abnormal vitamin K-dependent carboxylation
Chen et al[33]	2025	Dynamic marker of treatment response

AFP: Alpha-fetoprotein; HCC: Hepatocellular carcinoma.

Table 2 Recent developments in protein induced by vitamin K absence/antagonist-II-based risk stratification for alpha-fetoprotein-normal hepatocellular carcinoma patients

Ref.	Year	Number of subjects	Primary role of PIVKA-II
Wang et al[45]	2022	46	PIVKA-II may be used as a marker for predicting transarterial chemoembolization response
Devillers et al[46]	2023	203	PIVKA-II’s better prediction of microvascular invasion suggests its role in identifying high-risk HCC recurrence post LT
Yu et al[47]	2023	809	PIVKA-II contributed to the development of prediction and diagnostic models for AFP-negative populations
Zhu et al[48]	2024	258	Serum AFP and PIVKA-II were evaluated for the detection of recurrent HCC, with PIVKA-II showing superior diagnostic performance
Lin et al[49]	2025	639	Serum glypican-3 and PIVKA-II were evaluated for detection and prognostic assessment in AFP-negative HCC
Gongor et al[50]	2025	707	Preoperative PIVKA-II, alone or in combination with AFP, may serve as an accessible long-term risk assessment marker for HCC recurrence and mortality following LDLT
Chen et al[33]	2025	61	PIVKA-II response was evaluated as an early marker of radiological and clinical outcomes in non-AFP-secreting HCC undergoing systemic therapy
Bhatti et al[51]	2025	400	Pre-transplant AFP and PIVKA-II were evaluated as biomarkers for recurrence risk assessment and selection of liver transplantation candidates with HCC
Zhang et al[52]	2025	751	PIVKA-II and AFP were evaluated for HCC diagnosis, with PIVKA-II showing superior diagnostic accuracy and complementary value for early detection
Abbas et al[53]	2026	113	PIVKA-II was evaluated for identifying aggressive disease and prognostic risk in HCC patients with normal AFP levels
Gao et al[54]	2026	117	PIVKA-II combined with MRI features, including intratumoral arteries and tumor ADC values, was evaluated for predicting microvascular invasion in HCC

PIVKA-II: Protein induced by vitamin K absence/antagonist-II; AFP: Alpha-fetoprotein; HCC: Hepatocellular carcinoma; LT: Liver transplantation; LDLT: Living donor liver transplantation; MRI: Magnetic resonance imaging; ADC: Apparent diffusion coefficient.