Alcohol involvement may modify the association between previous hepatitis B virus infection and hepatocellular carcinoma risk in steatotic liver disease.

Abstract

Background/aims: Metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction and alcohol-related liver disease (MetALD), and alcohol-related liver disease (ALD) are emerging hepatocellular carcinoma (HCC) etiologies. Prior-HBV-infection (pHBV) has been linked to HCC in HBsAg-negative populations, but phenotype-specific effects across steatotic liver disease (SLD) remain unclear. We examined whether pHBV modifies 5-year HCC risk by SLD etiology.

Methods: We analyzed 623 of 1116 patients with hepatic steatosis managed at a single center (2009-2024). pHBV was defined as HBsAg- and HBV DNA-negative status with anti-HBc and/or anti-HBs positivity. The primary endpoint was the 5-year cumulative HCC incidence. Kaplan-Meier, PSM, IPTW, and Cox interaction models were used.

Results: pHBV was present in 152 patients (24.4%). Overall, pHBV was not associated with 5-year HCC after PSM (150 pairs; 6.58% vs. 5.60%; log-rank P = 0.701) or IPTW (3.80% vs. 4.27%; HR 0.97, 95% CI 0.37-2.54; P = 0.874). In MASLD/cryptogenic SLD, pHBV was associated with lower HCC incidence (PSM 1.32% vs. 9.53%, P = 0.027; IPTW 0.86% vs. 4.35%, P = 0.048). In ALD/MetALD, pHBV showed a borderline higher incidence (PSM 16.17% vs. 3.45%, P = 0.053; IPTW 12.78% vs. 3.99%, P = 0.073). Interaction analyses supported heterogeneity across etiologies (IPTW HR 12.96, P = 0.024; PSM HR 25.87, P = 0.034, Cox HR 7.83, P = 0.057).

Conclusions: In HBsAg-negative SLD, the association between pHBV and HCC risk appears to differ according to alcohol involvement, with a potentially increased HCC risk in ALD/MetALD and a lower observed HCC incidence in MASLD/cryptogenic disease that requires cautious interpretation.