Serum M2BPGi as a predictor of hepatocellular carcinoma development in chronic hepatitis B and C: a systematic review and meta-analysis.

BACKGROUND

Hepatocellular 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.

METHODS

We 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.

RESULTS

Twenty-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.

CONCLUSION

Elevated 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 REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/view/CRD420261372566, identifier CRD420261372566.