Sex- and menopause-specific inverse associations between metabolic dysfunction–associated steatotic liver disease and serum lipoprotein(a) concentrations: evidence from SHIP and UK Biobank

Background The association between metabolic dysfunction-associated steatotic liver disease (MASLD) and serum lipoprotein(a) (Lp[a]) levels remains controversial, with no sex- or menopausal status-stratified analyses. We aimed to analyse the associations between MASLD, liver fat content (LFC) and transaminases with Lp(a) concentrations stratified by sex and menopausal status. Methods We analysed data from 3825 individuals (1961 females; 51.3%) aged 32 to 70 years from the SHIP-START-0 cohort, and from 28,504 individuals (14,926 females; 52.4%) aged 38 to 72 years from the UK Biobank cohort. MASLD was determined by liver ultrasound examinations in SHIP-STAR-0 and by magnetic resonance imaging in UK Biobank. We examined sex- and menopausal status-specific associations of MASLD, LFC, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase (GGT) with lipoprotein(a) [Lp(a)] concentrations, after adjustment for age, body mass index, haemoglobin A1c, glucose-lowering medication use, hypertension, smoking, and alcohol consumption. Results In SHIP-START-0, MASLD, higher ALT, AST, and GGT levels were independently associated with lower Lp(a) concentrations only in males but not in females. However, after stratification by menopausal status, higher ALT levels were associated with lower Lp(a) concentrations in postmenopausal females, but not in premenopausal females. In UK Biobank, MASLD severity (moderate and severe), higher LFC, and higher serum transaminase levels were independently associated with lower Lp(a) concentrations in males. Higher LFC was also associated with lower Lp(a) concentrations in females, but serum liver enzymes were not. After stratification by menopausal status, MASLD severity and higher LFC were associated with lower Lp(a) concentrations in postmenopausal females, but not in premenopausal females. Males with MASLD had 24% and 9% lower Lp(a) concentrations than those without MASLD in SHIP-START-0 and UK Biobank. Conclusions Our findings from two large community-based studies show that MASLD and higher LFC and ALT values were independently associated with lower Lp(a) concentrations in postmenopausal females and males. Future studies are needed to determine whether the cardiovascular risk in patients with MASLD remains elevated even when Lp(a) concentrations are reduced and whether these patients require more intensive treatment to further reduce Lp(a) concentrations below the currently recommended cut-off values.