PARADOXICAL ASSOCIATION OF LOW LIPOPROTEIN (A) WITH METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE SEVERITY: FINDINGS FROM THE UK BIOBANK

Abstract

Therapeutic Area: ASCVD/CVD Risk Factors Background: Metabolic dysfunction-associated steatotic liver disease (MASLD), previously non-alcoholic fatty liver disease (NAFLD), enhances atherosclerotic cardiovascular disease (ASCVD) risk. Previous studies have shown lower plasma lipoprotein (a) [Lp(a)] correlating with increased NAFLD severity by histology. Given emerging Lp(a)-lowering medications, the mechanisms and implications of this relationship are important. We investigated whether this observation persists utilizing new MASLD diagnostic criteria within the UK Biobank. Methods: Patients with pre-existing ASCVD, significant alcohol intake, or other chronic liver diseases were excluded. Those with plasma Lp(a) and liver magnetic resonance imaging data were stratified into Lp(a) concentration quartiles. MASLD was defined as at least 1 cardiometabolic derangement, per the recent multi-society Delphi consensus statement, with proton density fat-fraction >5%. Metabolic dysfunction-associated steatohepatitis (MASH) was defined as at least 1 cardiometabolic derangement with iron-corrected T1 >800 ms. Prevalence of MASLD and MASH across quartiles were compared using Pearsons’ chi-squared test. We then calculated odds of prevalent MASLD and MASH in the lowest quartile compared with the rest of the cohort. Results: The final cohort was 14,957 patients (51% women, median age 55 years). Plasma Lp(a) was measured using a molar (nmol/L) assay and the median concentration was 20.39 (IQR 9.5-62.30). Participants were stratified using Lp(a) quartiles: 62.3 (N=3,742). Their respective median Lp(a) concentrations were 6.30, 13.59, 34.33 and 118.18. The prevalence of MASLD in each quartile was 25%, 24%, 22% and 23% (p=0.025). The odds ratio (OR) of MASLD in the lowest Lp(a) quartile was 1.08 (95% CI 0.99-1.18, p=0.07). The prevalence of MASH in each was 5.7%, 5.0%, 4.0% and 4.9% (p=0.006). The OR of MASH in the lowest Lp(a) quartile was 1.26 (95% CI 1.07-1.48, p=0.006). Conclusions: In this novel population, very low plasma Lp(a) level is associated with prevalent MASH, but not MASLD overall, which corroborates prior investigations of non-alcoholic steatohepatitis and NAFLD. A similar relationship with insulin resistance and type 2 diabetes has also been reported. These findings raise important questions regarding hepatic safety of Lp(a)-lowering medications. It is unclear whether low Lp(a) precedes or follows MASH, necessitating further research.