Abstract
BACKGROUND & AIMS: Lipoprotein(a) (Lp(a)) is an emerging biomarker for cardiometabolic factors. We studied the role of Lp(a) in the full spectrum of metabolic dysfunction-associated steatotic liver disease (MASLD).
METHODS: Three independent analyses were implemented using a multi-center, cross-sectional, liver biopsy-based study (n = 332) (Study 1) and the UK Biobank prospective study (n = 270,004) (Study 2; median follow-up, 12.47 years). In Study 1, we studied the cross-sectional association between Lp(a) mass and MASLD stages (Analysis A). In Study 2, we studied the prospective association between Lp(a) concentration and MASLD, liver cirrhosis, and hepatocellular carcinoma (Analysis B). Finally, these analyses were accompanied by a prospective analysis using LPA Genetic Risk Score (Analysis C).
RESULTS: In Study 1, an inverse association between Lp(a) and at-risk metabolic dysfunction-associated steatohepatitis (odds ratioper 1-SD increase, 0.64; 95% confidence interval [CI], 0.42-0.97) was observed. In contrast, when similar associations were examined prospectively (Study 2), subjects with Lp(a) <10.75 nmol/L had a higher risk for cirrhosis (hazard ratio, 1.49; 95% CI, 1.22-1.81) and HCC (hazard ratio, 1.69; 95% CI, 1.12-2.56) compared with subjects with Lp(a) within the 10.75 to 21.5 nmol/L range. Above these levels, the risk increased significantly and positively. Similarly, genetic analysis showed an L-shaped association with LPA Genetic Risk Score.
CONCLUSIONS: The inverse association observed in cross-sectional studies should be attributed to reverse causality (ie, the presence of liver disease may decrease Lp(a) levels). Genetically predicted very low Lp(a) levels are also associated with impaired liver health prospectively. Clinical trials evaluating Lp(a)-lowering agents should thus be monitored carefully for adverse liver effects in subjects attaining extremely low concentrations.