Metabolic dysfunction-associated steatotic liver disease increases the risk of primary open-angle glaucoma.

Purpose: Liver disease is associated with a range of extrahepatic complications, which have recently been expanded to include ophthalmic conditions. However, evidence is lacking regarding its impact on primary open-angle glaucoma (POAG). This study aimed to investigate whether major liver diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD), alcoholic liver disease (ALD), viral hepatitis, and liver fibrosis and cirrhosis, were associated with POAG.

Design: A prospective study based on the UK Biobank cohort with a two-sample Mendelian randomization (MR) analysis for inferring causality.

Participants: A total of 332,345 UK Biobank participants free of glaucoma recruited between 2006 and 2010.

Methods: The exposure of interest was severe liver diseases defined as hospital admission, including MASLD, ALD, viral hepatitis, and liver fibrosis and cirrhosis. Cox proportional hazards models were used with each liver disease treated as a time-varying exposure. The MR analysis was further conducted based on the genome-wide association studies of a histologically characterized cohort for MASLD (n = 19,264) and Internation Glaucoma Genetics Consortium cohort for POAG (n = 216,257).

Main Outcome Measures: Risk of POAG estimated by hazard ratio (HR) and 95% confidence interval (CI) in observation analysis, and odds ratio (OR) and 95% CI in MR analysis.

Results: Severe MASLD was associated with a 45% increased risk of POAG (HR 1.45; 95% CI 1.12-1.87; P = 0.005), whereas no association was identified between ALD (P = 0.953), viral hepatitis (P = 0.519), or liver fibrosis and cirrhosis (P = 0.794) and incident POAG. Subgroup analysis showed the risk of POAG in relation to MASLD was higher in individuals having more physical activity (HR 1.53; 95% CI 1.04-2.25 vs. HR 1.39; 95% CI 0.99-1.95, P for interaction = 0.033). MR analysis provided evidence that MASLD was causally associated with greater risk of POAG (inverse-variance weighted model: OR 1.035; 95% CI 1.010-1.061; P = 0.005).

Conclusions: Severe MASLD was longitudinally associated with an increased risk of incident POAG, with MR analyses suggesting a potential causal link. These findings suggest POAG examination should be considered in the holistic management of MASLD, and further underscore the impact of the liver on eye health.