Lipoprotein(a) levels across histological severity in metabolic dysfunction–associated steatotic liver disease

Abstract

Background: Metabolic dysfunction–associated steatotic liver disease (MASLD) encompasses a spectrum ranging from simple steatosis to metabolic dysfunction–associated steatohepatitis (MASH) and cirrhosis. Lipoprotein(a) [Lp(a)] is a well-established atherogenic risk factor, but its relationship with MASLD and its histological severity has been poorly investigated. The aim of this study was to describe plasma Lp(a) levels across different histological stages and features of MASLD.
Methods: Eighty-eight patients enrolled in the PLINIO study (ClinicalTrials.gov Identifier: NCT04036357) who underwent liver biopsy were included. Plasma Lp(a) levels were measured using a specific ELISA kit. Patients were stratified according to histological diagnosis into simple steatosis (MASLD-SS), MASH, and cirrhosis. In a subgroup of 29 patients, immunohistochemical analysis was performed to assess hepatic Lp(a) expression on liver biopsy samples.
Results: Plasma Lp(a) levels increased progressively with histological severity (MASLD-SS: 22.1 [20.2–26.6] mg/dL; MASH: 28.7 [24.2–32.8] mg/dL; cirrhosis: 31.1 [29.4–33.1] mg/dL; p=0.001). Plasma Lp(a) correlated positively with fibrosis stage (rS=0.401, p<0.001), inflammation grade (rS=0.214, p=0.045), hepatocellular ballooning (rS=0.383, p<0.001), and NAFLD Activity Score (rS=0.410, p<0.001). In multivariable regression analysis including demographic and clinical variables, plasma Lp(a) was independently associated with LDL cholesterol (β=0.003, p=0.012) after adjustment for age, sex, ALT, and diabetes. At immunohistochemical analysis, no overall correlation was found between hepatic and plasma Lp(a) or histological features. However, after excluding cirrhotic patients, hepatic and plasma Lp(a) levels correlated significantly (rS=0.436, p=0.033). Among patients with MASH, hepatic Lp(a) expression was higher in those with more severe ballooning (p=0.043).
Conclusions: In this histologically characterized MASLD cohort, Lp(a) levels increased with disease severity and correlated with fibrosis and activity parameters. These findings suggest a potential role for Lp(a) in MASLD progression and warrant further studies to clarify its contribution to liver disease pathogenesis and cardiovascular risk in this population.