Elevated serum M2BPGi is associated with a 4.61 hazard ratio for hepatocellular carcinoma developmentElevated M2BPGi Levels Linked to Higher Risk of Liver Cancer

BackgroundHepatocellular carcinoma (HCC) kills about 830,000 people each year, and most cases arise in chronic viral hepatitis. Better risk markers would let clinicians focus surveillance where it matters. Mac-2 binding protein glycosylation isomer (M2BPGi) is a serum glycobiomarker of liver fibrosis. Several cohort studies tie elevated M2BPGi to HCC. No quantitative synthesis has pooled this evidence across viral etiologies.MethodsWe searched PubMed/MEDLINE, Embase, the Cochrane Library, Web of Science, and Scopus through April 2026 for longitudinal studies that reported hazard ratios (HRs) for HCC linked to elevated M2BPGi in chronic hepatitis B (CHB) or C (HCV). We registered the protocol with PROSPERO. The primary pool restricted to longitudinal studies with categorical cutoffs that reported HRs. We used random-effects meta-analysis with restricted maximum likelihood and the Hartung–Knapp adjustment.ResultsTwenty-three publications (24 study entries) met inclusion criteria. The primary pool of 15 longitudinal categorical HR-reporting studies covered 12,161 participants and at least 1,189 HCC events. The pooled HR was 4.61 (95% CI 3.24–6.54; p < 0.0001) with low heterogeneity (I2 = 25.6%). The 95% prediction interval ran from 2.08 to 10.18. The effect held across etiology (CHB k = 5 HR 4.12; HCV k = 10 HR 5.07; p_subgroup = 0.62) and across measurement timing (baseline HR 3.21; on/post-treatment HR 5.62; post-SVR HR 5.45; p_subgroup = 0.23). Two sensitivity pools re-introducing OR-based studies gave HR 4.71 (k = 16) and HR 4.89 (k = 17). Egger’s test was positive (p = 0.0003); trim-and-fill imputed six studies and pulled the adjusted HR to 3.53.ConclusionElevated serum M2BPGi is strongly and consistently associated with HCC development in patients with chronic hepatitis B and C. The effect holds across etiology, treatment status, and measurement timing–including after sustained virological response. Funnel asymmetry suggests the true effect is closer to a 3.5-fold than a 4.6-fold risk increase, still large enough to matter clinically. M2BPGi is a credible candidate to layer onto current viral hepatitis surveillance, particularly for risk stratification after virological control.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/view/CRD420261372566, identifier CRD420261372566.