Association of Estimated Liver Fibrosis with Carotid but not Femoral Atherosclerotic Burden: the ILERVAS Cohort.

Jose Leon-Mengibar^1*María M. Malagón²Marcelino Bermúdez-Lopez³Jose Manuel Valdivielso³Reinald Pamplona³Gerard Torres³Didac Mauricio⁴Eva Castro³Elvira Fernandez³Assumpta Caixàs⁵Marta Hernandez¹Carolina López Cano¹Ana Gordon²Rocio Guzman-Ruiz²Kenneth Cusi⁶Albert Lecube¹

• ¹Endocrinology Department. Hospital Universitario Arnau de Vilanova, Lérida. Spain., Hospital Universitari Arnau de Vilanova, Lleida, Spain
• ²Instituto Maimonides de Investigacion Biomedica de Cordoba, Córdoba, Spain
• ³Institut de Recerca Biomedica de Lleida, Lleida, Spain
• ⁴Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
• ⁵Institut d'Investigacio i Innovacio Parc Tauli, Sabadell, Spain
• ⁶University of Florida, Gainesville, United States

ABSTRACT Introduction: Advanced liver fibrosis, a key complication of metabolic dysfunction-associated steatotic liver disease, has been increasingly linked to extrahepatic conditions, including type 2 diabetes, obesity, and cardiovascular disease. However, the specific association of liver fibrosis in the development and progression of subclinical atheromatous disease across vascular territories remains poorly understood. This study evaluates the utility of two non-invasive indices to predict liver fibrosis and their associations with subclinical atheromatous plaque burden and distribution. Methods: Atheromatous plaque burden (plaque presence, number, and total area) was assessed in the carotid and femoral territories via ultrasonography in 3,981 middle-aged participants without known cardiovascular disease, diabetes, or liver disease from the ILERVAS cohort (ClinicalTrials.gov Identifier: NCT03228459). The fibrosis-4 (FIB-4) and the NAFLD Fibrosis Score (NFS) were evaluated. FIB-4 risk categories were defined as low (<1.30), intermediate (1.30–2.67), and high (>2.67). Results: Participants in the intermediate and high-risk FIB-4 categories exhibited a higher prevalence of carotid atheromatous disease (56.8% vs. 49.5%, p<0.001), a greater number of plaques (p<0.001), and a larger total plaque area (p=0.007). Multivariable analyses confirmed FIB-4 as an independent predictor of carotid plaque burden (OR:1.09, 95%CI 1.01-1.19, p=0.023 1.14, 95% CI 1.05-1.24, p=0.003), even adjusting for traditional cardiovascular risk factors. Moving from low to high FIB-4 cut-offs was associated with 12.6% higher odds of carotid atherosclerosis. No significant associations were found in the femoral territory. The NFS was also independently associated with carotid atheromatosis (OR 1.10, 95% CI 1.05–1.15, p<0.001). demonstrated limited predictive power. No significant associations were found in the femoral territory for either index. Conclusions: Estimated liver fibrosis, particularly FIB-4, is a valuable marker for identifying carotid subclinical atherosclerosis in populations without known liver disease. These findings highlight the importance of vascular territory-specific evaluations and suggest support their FIB-4's potential utility in integrated establishing liver and cardiovascular risk assessment strategies.