Liver-Pancreas Fat Deposition: Impact on Cardiometabolic Multimorbidity and Cardiac Dysfunction

Background & aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) and pancreatic steatosis (PS) are interconnected ectopic fat conditions linked to cardiometabolic dysregulation. Their combined effect on the long-term risk of cardiometabolic multimorbidity (CMM; ≥ 2 of diabetes, hypertension, coronary heart disease, and stroke) and cardiac remodelling remains unclear. Methods: We examined cross-sectional associations between PS and the severity of MASLD histology in a biopsy-proven MASLD cohort from China. Subsequently, using the UK Biobank, we assessed the long-term risk of developing both incident CMM and cardiac structural/functional alterations (via cardiac magnetic resonance [CMR]) associated with single-organ versus dual-organ steatosis. Exploratory proteomic profiling was performed to identify potential molecular pathways. Results: In the biopsy-proven cohort (n = 482), both continuous pancreatic proton density fat fraction and PS status were associated with severe hepatic steatosis, lobular inflammation, and fibrosis (all p < 0.05). In the UK Biobank cohort (n = 16 408; median follow-up of 5.6 years), the coexistence of MASLD and PS additively increased the risk of new-onset CMM (HR = 2.013, 95% CI: 1.219-3.322, p = 0.006). Dual-organ steatosis was also associated with marked cardiac alterations, specifically increased left ventricular mass and impaired ventricular function. Proteomics revealed upregulation of lysosomal catabolic and glycosaminoglycan-degrading pathways in dual-organ steatosis compared to single-organ steatosis. Gene Ontology highlighted heparan sulphate proteoglycan catabolism as a hallmark of dual-organ involvement. Conclusion: PS is associated with greater severity of MASLD histology, and the concomitant involvement of both the liver and pancreas drives a higher risk of CMM and cardiac remodelling.