High levels of serum Mac-2-binding protein glycosylation isomer (M2BPGi) predict the development of hepatocellular carcinoma in hepatitis B patients treated with nucleot(s)ide analogues

Background: Nucleot(s)ide analogues (NA) can reduce the risk of hepatocellular carcinoma (HCC), but not completely prevent its development. Methods: Two hundred and thirty-four chronic hepatitis B patients virologically well controlled with entecavir or tenofovir disoproxil fumarate for more than 1 year were enrolled in this study. Over the median observation period of 51 (12–142) months, 24 of 234 patients developed HCC. We quantified HBV markers, alpha-fetoprotein (AFP) and Mac-2-binding protein glycosylation isomer (M2BPGi) at baseline and 48 weeks after therapy. Results: Serum AFP and M2BPGi tended to decline from baseline to 48 weeks after treatment both in patients who did and those who did not develop HCC. Univariate Cox regression analysis indicated that serum M2BPGi levels ≥ 1.215 COI at 48 weeks were associated with HCC development [hazard ratio (HR) 5.73; p ≤ 0.001]. Multivariate analysis showed that male sex (HR 5.6; p = 0.01), AFP ≥ 9.65 ng/ml (HR 22.01; p ≤ 0.001), M2BPGi ≥ 1.215 (HR 5.07; p = 0.004) at 48 weeks were significant independent predictive factors for HCC development. Based on a scoring system consisting of three factors above described, Kaplan–Meier analysis for four groups (score 0, 1, 2, ≥ 3), revealed significant differences in cumulative HCC occurrence for each group within 2 years. The rate of incidence of HCC was 0, 5.4, 23.4, and 75% in each group, respectively. Conclusions: In patients receiving NA therapy, higher M2BPGi at 48 weeks, as well as male sex and higher AFP at 48 weeks were independent risk factors for HCC development.