Modeling the time-related fluctuations of AFP and PIVKA-II serum levels in patients with cirrhosis undergoing surveillance for hepatocellular carcinoma

Article type: Research Article

Authors: Ricco, Gabriele^{a; h} | Cosma, Chiara^b | Bedogni, Giorgio^c | Biasiolo, Alessandra^d | Guarino, Maria^e | Pontisso, Patrizia^d | Morisco, Filomena^e | Oliveri, Filippo^a | Cavallone, Daniela^a | Bonino, Ferruccio^{c; f; g} | Plebani, Mario^b | Brunetto, Maurizia Rossana^{a; f; h; *}

Affiliations: [a] Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Center of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, Pisa, Italy | [b] Department of Laboratory Medicine, University-Hospital of Padua, Padua, Italy | [c] Italian Liver Foundation (Fondazione Italiana Fegato, FIF), Basovizza, Trieste, Italy | [d] Department of Medicine, University of Padua, Padua, Italy | [e] Gastroenterology Unit, Department of Clinical Medicine and Surgery, University of Naples “Federico II”, Naples, Italy | [f] Institute of Biostructure and Bioimaging, National Research Council, Naples, Italy | [g] University of Pittsburgh Medical Center Institute for Health, Chianciano Terme, Siena, Italy | [h] Internal Medicine, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

Correspondence: [*] Corresponding author: Maurizia Rossana Brunetto, Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Center of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, Via Paradisa 2, Pisa, 56124, Italy. Tel.: +39 50 99 68 57; Fax: +39 50 99 54 57; E-mail: [email protected].

Abstract: BACKGROUND: The time-related variability of HCC biomarkers has not been investigated so far. OBJECTIVE: To assess the changes of alpha-fetoprotein (AFP) and protein induced by vitamin-K absence/antagonist-II (PIVKA-II) in patients with HCC (HCC+) as compared to patients without HCC (HCC-). METHODS: AFP and PIVKA-II were measured by a single laboratory using an automated chemiluminescent-enzyme-immunoassay (Fujirebio Inc., Tokyo, Japan) in 1163 sera of 418 cirrhotics (31.1% HBV, 58.6% HCV, 10.3% non-viral etiology) undergoing ultrasound HCC surveillance. The mean (range) number of effective time-points available for analysis was 2.8 (2.0 to 3.0); 124 patients with HCC were matched with 294 who remained HCC free for at least 12 months after the last specimen. AFP and PIVKA-II changes were estimated over time by means of a random-effect generalized least squares (RE-GLS) regression model under the missingness at random assumption. RESULTS: Patients with and without HCC had comparable chronic liver disease etiology and staging. AFP/PIVKA-II median (25th; 75th percentile) values at the latest time-point were 4.2 (2.6; 8.6) ng/mL/32 (25; 42) mAU/mL in HCC- and 8.4 (4.4; 32.1) ng/mL/66 (32; 192) mAU/mL in HCC+ (p< 0.001). Log10AFP and log10PIVKA-II time-changes differed in HCC+ and HCC- patients. In HCC+ patients, both log10AFP and log10PIVKA-II showed an increasing trend over time. In HCC- patients, log10PIVKA-II variations were minimal as compared to log10AFP variations. The percent increase of log10AFP at 6 months vs. baseline was 11% (95%CI 5 to 17%) and 5% (95%CI 1 to 8%) for log10PIVKA-II in HCC+vs. HCC- patients. CONCLUSIONS: The present retrospective study of the biological variability of AFP and PIVKA-II suggests that their time-related changes may serve as potential predictors of HCC. This topic needs to be addressed by longitudinal studies.

Keywords: AFP, biomarkers, cirrhosis, hepatocellular carcinoma, PIVKA-II, surveillance

DOI: 10.3233/CBM-190118

Journal: Cancer Biomarkers, vol. 29, no. 2, pp. 189-196, 2020