Excessive intrahepatic fat deposition (IPFD) appears to contribute to an increased risk of major pancreatic disease, suggests a recent study, noting the potential benefits of IPFD reduction in preventing pancreatitis and pancreatic cancer.
“Once thought to be a peripheral feature of obesity, excessive IPFD now stands as a central player in the pathogenesis of a broad spectrum of pancreatic diseases,” the researchers said. “The silent deposition of fat in the pancreas demands recognition (much like steatotic liver disease) as a central contender in both oncological and metabolic paradigms.”
A normal human pancreas has a minimum amount of IPFD, but excessive IPFD represents a pathological state. [Pediatr Radiol 2005;35:601-607; Am J Gastroenterol 2014;109:589-597]
Researchers accessed three electronic databases and conducted a systematic review to examine longitudinal cohort studies focusing on IPFD. They then calculated population-attributable fractions and E-values. Twenty-three studies met the eligibility criteria.
During follow-up, excessive IPFD at baseline correlated with a fourfold higher risk of acute pancreatitis, a threefold higher risk of pancreatic cancer, and a twofold increased risk of diabetes mellitus in the general population. [Am J Gastroenterol 2026;121:1071-1081]
Notably, elimination of excessive IPFD could lead to the prevention of 34 percent of acute pancreatitis cases, 23 percent of pancreatic cancer cases, and 21 percent of diabetes mellitus cases.
Unmeasured confounders fell short of elucidating the statistically significant associations in the studies of acute pancreatitis (E-value = 36), pancreatic cancer (E-value = 16) but not those of type 2 diabetes mellitus (E-value = 11).
“This systematic review brings to the fore excessive IPFD as a considerable health risk, which is present in around one-fifth of the general population,” the researchers said. “The consistently identified temporal precedence of excessive IPFD is important when considering whether excessive IPFD might be a possible cause of diseases of the exocrine pancreas and the endocrine pancreas.”
Lipotoxicity
Significant developments have been made in shedding light on the role of IPFD as a determinant of pancreatic diseases, supporting the tenets of the PANDORA* hypothesis, according to the researchers. [Lancet Gastroenterol Hepatol 2023;8:671-682]
Previous studies have pointed to lipotoxicity, driven by excessive IPFD, as an important pathological mechanism associated with diseases such as pancreatitis and pancreatic cancer. [Sci Transl Med 2011;3:107ra110; Front Endocrinol (Lausanne) 2018;9:384; Cell Rep Med 2024;5:101428]
“The cascading effects of fat-induced damage include inflammation, fibrosis, and calcification, which not only exacerbate acute and chronic pancreatitis but also lay fertile ground conducive to malignant transformation,” the researchers said. [Lab Invest 2025;105:104214]
The evidence from the current study supports the association between excessive IPFD and pancreatitis. Individuals with excessive IPFD showed an elevated risk of acute and chronic pancreatitis. [Environ Health Prev Med 2019;24:10; Am J Gastroenterol 2024;119:1158-1166]
“As our understanding deepens, multidisciplinary efforts will be required to translate these insights into preventive and interventional strategies, with a view to interrupting the destructive cascade of excessive IPFD and restoring pancreatic homeostasis,” the researchers said.
*PANcreatic Diseases Originating from intRa-pancreatic fAt) hypothesis