Female and Diabetes are risk factors for Alpha-fetoprotein and Vitamin K deficiency or antagonist -II negative in Hepatocellular Carcinoma

Abstract Background &Aim: Hepatocellular carcinoma (HCC) is a common type of tumor with a high incidence. Alpha-fetoprotein (AFP) and protein induced by vitamin K deficiency or antagonist-II (PIVKA-II or DCP) are proven effective biomarkers for HCC. Combining them can enhance detection rates. However, when both AFP and PIVKA-II are negative, clinical diagnosis may be missed. This study aims to explore the risk factors for AFP and PIVKA-II negativity in HCC, thereby reducing missed diagnoses. Methods A retrospective study enrolled 609 HCC patients at Shandong Public Health Clinical Center Affiliated with Shandong University from January 2010 to March 2022. Patients with negative AFP and PIVKA-II were the observed group, and others with at least one positive were controls. Epidemiological, clinical, laboratory, and radiological data were collected and analyzed to identify the frequency and factors influencing AFP and PIVKA-II negativity. ROC curves were used to assess the prediction model's ability to detect negative AFP and PIVKA-II in HCC. Results Gender(P = 0.045, 95%CI = 1.013–3.277), diabetes mellitus (P = 0.018, 95%CI = 1.151–4.422), tumor size(P = 0.000, 95%CI = 0.677–0.841), glutamate transpeptidase (GGT) (P = 0.003, 95%CI = 0.239–0.737), total bilirubin (TB) (P = 0.001, 95% CI = 0.235–0.705), and HBV-associated infections (P = 0.007, 95%CI = 0.077–0.661) were significantly associated with AFP and PIVKA-II negativity in HCC. The prediction model had an AUC of 0.832 (P < 0.001, 95%CI = 0.786–0.877), with a sensitivity of 81.2% and specificity of 75.5% in all HCC patients. Conclusions Female diabetic patients with elevated GGT and TB are more likely to develop AFP and PIVKA-II-negative HCC. Imaging is crucial for screening liver cancer in these patients.