Phd in EXPERIMENTAL AND CLINICAL HEPATO-GASTROENTEROLOGY

Thesis title: Ruolo della Lipoproteina(a) nei pazienti con Steatosi e Fibrosi Epatica

Background and Aims Metabolic dysfunction–associated steatotic liver disease (MASLD) encompasses a continuum ranging from simple steatosis to steatohepatitis (MASH) and cirrhosis. Lipoprotein(a) [Lp(a)] is a well-established cardiovascular risk factor; however, its behavior across the histological spectrum of MASLD remains poorly characterized. The aim of this study was to describe the pattern of plasma Lp(a) levels according to histological diagnosis (simple steatosis, MASH, and MASLD-related cirrhosis) and to explore their association with histological features of activity (NAS) and fibrosis stage within the PLINIO cohort. A total of 1,186 subjects were enrolled; 918 showed ultrasound-detected steatosis, and 88 underwent liver biopsy. Methods and Results Patients who underwent liver biopsy and had plasma Lp(a) measurement available were analyzed. Histological groups were compared, and associations between Lp(a) levels and clinical, metabolic, and histological variables were assessed. Across the three histological categories, Lp(a) levels exhibited a clear increasing gradient from simple steatosis to MASLD-related cirrhosis, with intermediate values in MASH. Regarding histological features, Lp(a) increased in parallel with fibrosis stage and was associated with necroinflammatory activity indices, including lobular inflammation, hepatocellular ballooning, and NAS; descriptively, median Lp(a) levels progressively rose from F0 to F4. From a clinical-metabolic perspective, Lp(a) levels were higher in subjects with diabetes and correlated with fasting glucose, total cholesterol, and transaminases. An immunohistochemical substudy on biopsy samples suggested a borderline-significant concordance—more evident after excluding cirrhotic patients—between hepatic Lp(a) staining and plasma concentrations; in MASH, tissue staining intensity was greater in the presence of marked ballooning. In the overall biopsy cohort, age, sex, and BMI were comparable among groups, whereas diabetes and metabolic syndrome were more prevalent in MASH and cirrhosis compared with simple steatosis, consistent with a more pronounced insulin-resistance profile (HOMA-IR and TyG index). Conclusions In the MASLD cohort of the PLINIO study, plasma Lp(a) levels exhibited a progressive increase along the gradient of histological severity and showed consistent associations with fibrosis stage and histological activity parameters (NAS, inflammation, and ballooning). The correlation between plasma Lp(a) and hepatic fibrosis stage, together with immunohistochemical findings, supports the hypothesis of a biological involvement of Lp(a) in the more advanced stages of disease. These results, considered within the typical clinical–metabolic context of MASLD, suggest a potential role for Lp(a) as an indicator of histological burden, warranting confirmation in larger prospective studies specifically designed to evaluate both cardiovascular and hepatic outcomes.