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

ABSTRACT 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.