Background: Pancreatic ductal adenocarcinoma (PDAC) has a poor survival rate, partly due to delayed diagnosis. Identifying high-risk individuals could lead to early detection and improve survival. A number of risk factors such as alcohol consumption and metabolic syndrome are associated with fatty infiltration of the pancreas. Experimental models show that a fatty pancreas promotes tissue inflammation and fibrosis, which could promote PDAC. Methods: We conducted a case-control study in a single-university tertiary hospital. Sixty-eight PDAC cases with recent non-contrast computed tomography (CT) and 235 controls were studied. The controls had no history of malignancy and underwent CT colonography for cancer screening in the same period. Pancreatic fat was estimated by calculating pancreatic (P) attenuation, corrected to splenic (S) attenuation, measured in three 1.0-cm² regions of the pancreas. The P.S100 value calculated was used to estimate fatty infiltration of the pancreas (FIP), with a lower P.S100 representing a higher FIP. Results: The PDAC patients had a lower BMI and a higher rate of type 2 diabetes mellitus. The P.S100 was lower in cases than in controls (86.452 vs. 92.414, p = 4.016e-06), suggesting that FIP is higher with PDAC. The risk of developing PDAC steadily increased significantly for the quartiles with a higher FIP compared to the low FIP quartile. No correlation between BMI and FIP (r = –0.1031179; 95% confidence interval [CI] –0.22267106 to 0.01949092) was found. Adjusting for confounders (age, sex, BMI, and DM), the risk of developing PDAC according to the FIP was estimated to be 3.75 (95% CI 1.9234408–7.993337; p = 0.000171). FIP was stable before and after the diagnosis of PDAC in 9 cases with prior CT scans when no pancreatic tumor was identifiable. Conclusion: Fatty pancreas is associated with an increased risk of pancreatic cancer. Once confirmed in larger-scale studies, these findings could help to identify at-risk individuals, particularly in high-risk groups such as chronic alcohol consumers

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