Female and diabetes are risk factors for alpha-fetoprotein and protein induced by vitamin K absence or antagonist-II negative in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a common type of tumor with a high incidence. Alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II or des-gamma-carboxy prothrombin) 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. 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 1 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. Receiver operating characteristic (ROC) curves were used to assess the prediction model's ability to detect negative AFP and PIVKA-II in HCC. Gender (P = .045, 95% confidence interval [95%CI] = 1.013-3.277), diabetes mellitus (P = .018, 95%CI = 1.151-4.422), tumor size (P = .000, 95%CI = 0.677-0.841), glutamate transpeptidase (P = .003, 95%CI = 0.239-0.737), total bilirubin (P = .001, 95%CI = 0.235-0.705), and hepatitis B virus-associated infections (P = .007, 95%CI = 0.077-0.661) were significantly associated with AFP and PIVKA-II negativity in HCC. The prediction model had an area under curve of 0.832 (P < .001, 95%CI = 0.786-0.877), with a sensitivity of 81.2% and specificity of 75.5% in all HCC patients. Female diabetic patients with levels closer to normal for glutamate transpeptidase and total bilirubin are more likely to develop AFP and PIVKA-II-negative HCC. Imaging is crucial for screening liver cancer in these patients.