Intra-pancreatic fat deposition links to widespread systemic health risks: UK Biobank prospective cohort study

INTRODUCTION: Intra-pancreatic fat deposition (IPFD) is associated with pancreatic diseases, but its systemic implications remain unclear. MATERIALS AND METHODS: We analyzed 25,547 UK Biobank participants (median follow-up 6.27 years) with MRI-derived pancreatic proton density fat fraction. Multi-variable Cox models, causal mediation, restricted cubic splines, and subgroup analyses assessed IPFD-disease associations. Significant associations were examined through bidirectional Mendelian randomization (MR) using the UK Biobank and FinnGen data. Receiver operating characteristic curves and the Youden index were used to identify a clinically relevant and statistically optimal IPFD threshold. RESULTS: Higher IPFD independently increased the risk of 12 multi-systemic diseases: non-insulin-dependent diabetes, primary hypertension, heart failure, cerebral infarction, cholelithiasis, gastritis and duodenitis, diaphragmatic hernia, chronic renal failure, gonarthrosis, disorders of refraction and accommodation, senile cataract, and sleep disorders. Causal mediation by non-insulin-dependent diabetes was negligible. Nonlinear dose-response patterns and effect modifications by sex, race, smoking, and obesity emerged. MR analysis supported the potential causal effects of IPFD on refractive/accommodation disorders and gonarthrosis. An IPFD cutoff of 7.35% (95% CI: 5.68-9.23%) optimally stratified the risk. CONCLUSION: IPFD is an independent risk factor for diverse conditions, including metabolic, cardiovascular, digestive, musculoskeletal, ophthalmologic, urinary, and mental/behavioral disorders. A pancreatic fat threshold of 7.35% may guide clinical screening and preventive strategies. CRITICAL RELEVANCE STATEMENT: This study critically establishes intra-pancreatic fat as a novel, causal multi-system disease risk factor and provides a 7.35% quantitative threshold to advance radiological screening and prevention protocols. KEY POINTS: Limited research exists on the systemic effects of IPFD. Pancreatic fat deposition independently raises risk for 12 multi-system diseases. A 7.35% pancreatic fat threshold can guide clinical screening and prevention.