Female reproductive factors and metabolic dysfunction-associated steatotic liver disease: an integrated analysis of population cohort, liver imaging, and genetic data

Abstract

Background

Although premenopausal women are at lower risk for metabolic dysfunction-associated steatotic liver disease than men within the same age group, the sex advantage becomes minimal after menopause, suggesting a role for female hormones.

Objective

This study aimed to elucidate the role of reproductive factors in the development of female metabolic dysfunction-associated steatotic liver disease, using an integrated analysis.

Study Design

Up to 269,607 women without metabolic dysfunction-associated steatotic liver disease during baseline recruitment (2006–2010) of the UK Biobank were included. Among these, 21,017 women did not develop metabolic dysfunction-associated steatotic liver disease across the follow-up period (through December 2021) and had the measure of liver proton density fat fraction quantified by magnetic resonance imaging since 2014. Multivariable Cox regression models were applied to assess the prospective relationships of various reproductive factors with incident metabolic dysfunction-associated steatotic liver disease. Multiple linear regression models were used to explore the relationships of reproductive factors with liver proton density fat fraction. A 2-sample Mendelian randomization analysis was conducted to investigate causality in the relationships of certain reproductive factors with metabolic dysfunction-associated steatotic liver disease.

Results

During a median of 12.65 years of follow-up, 3077 incident cases of metabolic dysfunction-associated steatotic liver disease were identified. Early menarche, a greater number of live births, younger age at first live birth, and oral contraceptives or hormone replacement therapy initiated at a young age were associated with an elevated risk of metabolic dysfunction-associated steatotic liver disease and higher levels of liver proton density fat fraction. Several other reproductive factors (ie, a greater number of miscarriages, surgical menopause at a young age, and prolonged use of hormone replacement therapy) were associated with incident metabolic dysfunction-associated steatotic liver disease but not with liver proton density fat fraction. In the Mendelian randomization analysis, genetically determined earlier age at menarche and younger age at first live birth were substantially associated with increased risk of metabolic dysfunction-associated steatotic liver disease.

Conclusion

Several reproductive factors were associated with the risk of and histologic features of metabolic dysfunction-associated steatotic liver disease, supporting the role of female hormones in the pathogenesis of metabolic dysfunction-associated steatotic liver disease.