EPI can result from various underlying causes1

Examining the role of the pancreas in digestion can help clarify EPI's etiology. EPI is caused by inadequate production, delivery, or activity of the pancreatic enzymes needed for digestion.

EPI is caused by inadequate production, delivery, or activity of the pancreatic enzymes needed for digestion1

This can result from a defect in the pancreatic parenchyma or a decrease in enzymes despite intact parenchyma.15

EPI can result from various underlying causes15,16:

Image of Pancreatic fibrosis

Pancreatic fibrosis

of pancreatic enzymes

Loss of functional pancreatic parenchyma or reduced endogenous stimulation of the pancreas can result in decreased production of enzymes

Image of ultrasound of pancreatic cancer

Ultrasound of pancreatic cancer

of pancreatic enzymes to the duodenum

An obstruction in the duct can cause a decrease in the delivery of pancreatic enzymes to the duodenum

Diagram of Gastric bypass surgery

Gastric bypass surgery

of pancreatic enzymes

Activity of enzymes can be reduced due to intraluminal inactivation or postcibal asynchrony

Conditions and surgical procedures associated with EPI:

Chronic pancreatitis (CP)9,17,18

  • Destruction of functioning pancreatic parenchyma results in insufficient amounts of enzymes being secreted into the duodenum, and EPI
  • ∼6%-22% of patients with CP have EPI at the time of CP diagnosis*
  • The probability of developing EPI increases to 50% 12 years after onset of CP

*Based on a US, retrospective analysis.

†Based on a US, retrospective study evaluating patients with onset of alcoholic or late-onset idiopathic CP.

Cystic fibrosis (CF)9,19

  • Highly concentrated and viscous pancreatic juice blocks the pancreatic ducts leading to acinar atrophy, pancreatic fibrosis, and EPI
  • Approximately 9 out of 10 patients with CF have EPI

‡Based on a US, multi-center study.

Pancreatic cancer1,9,20-25

  • Obstruction of the pancreatic duct by tumors, destruction of the pancreas by tumor growth, and loss of pancreatic tissue from surgery often lead to EPI
  • Prior to surgery: 42%-68% of patients with resectable pancreatic cancer have EPI§
  • Post surgery: 55%-89% of patients with resectable pancreatic cancer have EPI§

§While the majority of these studies included patients who underwent pancreatoduodenectomy for pancreatic adenocarcinoma, some studies include patients who underwent different surgical procedures and/or patients with cancer of the pancreatic region including, but not limited to, periampullary, bile duct, and/or duodenal carcinoma. Additionally, this data includes US and European patient populations.


  • EPI is a common complication of partial or complete removal of the pancreas. EPI has been diagnosed after partial resection of the pancreas including pancreatoduodenectomy (Whipple procedure)

Gastric surgery9

  • Gastric surgical procedures can result in asynchrony between gastric emptying and discharge of bile and pancreatic enzymes resulting in EPI

Obstruction of the biliary or pancreatic duct9,27

  • Blockage of the biliary or pancreatic duct may prevent the release of digestive enzymes into the duodenum leading to EPI

Diabetes mellitus (type I and type IIIC)9,28-34

  • Pancreatic exocrine and endocrine tissue are closely linked both anatomically and physiologically. Conditions that affect one tissue type can cause an impairment in the other
  • Type I diabetes is an autoimmune disease characterized by chronic inflammation of pancreatic islet cells, leading to insulin deficiency, pancreatic fibrosis, and atrophy. The pathophysiological mechanism resulting in EPI is not yet fully understood
  • Type IIIC diabetes, or pancreatogenic diabetes, is a form of secondary diabetes caused by pancreatic conditions, such as chronic pancreatitis

References: 1. Lindkvist B. Diagnosis and treatment of pancreatic exocrine insufficiency. World J Gastroenterol. 2013;19(42):7258-7266. 2. Röder PV, Wu B, Liu Y, Han W. Pancreatic regulation of glucose homeostasis. Exp Mol Med. 2016;48:e219. 3. Gorelick FS, Jamieson JD. Structure-function relations in the pancreatic acinar cell. In: Johnson LR, ed. Physiology of the Gastrointestinal Tract. 4th ed. Burlington, MA: Elsevier Academic Press; 2006:1313-1335. 4. Pandol SJ. The Exocrine Pancreas. San Rafael, CA: Morgan & Claypool; 2011. 5. Molina PE. Endocrine pancreas. In: Molina PE, ed. Endocrine Physiology. 4th ed. New York, NY: McGraw-Hill; 2013:163-186. 6. Fieker A, Philpott J, Armand M. Enzyme replacement therapy for pancreatic insufficiency: present and future. Clin Exp Gastroenterol. 2011;4:55-73. 7. Alkaade S, Vareedayah AA. A primer on exocrine pancreatic insufficiency, fat malabsorption, and fatty acid abnormalities. Am J Manag Care. 2017;23(suppl 12):S203-S209. 8. Chandra R, Liddle RA. Neural and hormonal regulation of pancreatic secretion. Curr Opin Gastroenterol. 2009;25(5):441-446. 9. Keller J, Layer P. Human pancreatic exocrine response to nutrients in health and disease. Gut. 2005;54(suppl 6):vi1-vi28. 10. Ferrone M, Raimondo M, Scolapio JS. Pancreatic enzyme pharmacotherapy. Pharmacotherapy. 2007;27(6):910-920. 11. Domínguez-Muñoz JE. Pancreatic enzyme therapy for pancreatic exocrine insufficiency. Curr Gastroenterol Rep. 2007;9(2):116-122. 12. Lindkvist B, Phillips ME, Domínguez-Muñoz JE. Clinical, anthropometric and laboratory nutritional markers of pancreatic exocrine insufficiency: prevalence and diagnostic use. Pancreatology. 2015;15(6):589-597. 13. Dumasy V, Delhaye M, Cotton F, Deviere J. Fat malabsorption screening in chronic pancreatitis. Am J Gastroenterol. 2004;99(7):1350-1354. 14. Smith RC, Smith SF, Wilson J, et al; Working Party of the Australasian Pancreatic Club. Summary and recommendations from the Australasian guidelines for the management of pancreatic exocrine insufficiency. Pancreatology. 2016;16(2):164-180. 15. Durie P, Baillargeon JD, Bouchard S, Donnellan F, Zepeda-Gomez S, Teshima C. Diagnosis and management of pancreatic exocrine insufficiency (PEI) in primary care: consensus guidance of a Canadian expert panel. Curr Med Res Opin. 2018;34(1):25-33. 16. Pezzilli R, Andriulli A, Bassi C, et al; Exocrine Pancreatic Insufficiency collaborative (EPIc) Group. Exocrine pancreatic insufficiency in adults: a shared position statement of the Italian Association for the Study of the Pancreas. World J Gastroenterol. 2013;19(44):7930-7946. 17. Layer P, Yamamoto H, Kalthoff L, Clain JE, Bakken LJ, DiMagno EP. The different courses of early- and late-onset idiopathic and alcoholic chronic pancreatitis. Gastroenterology. 1994;107(5):1481-1487. 18. Sandhu BS, Hackworth WA, Stevens S, Bouhaidar DS, Zfass AM, Sanyal AJ. Recurrent flares of pancreatitis predict development of exocrine insufficiency in chronic pancreatitis. Clin Gastroenterol Hepatol. 2007;5(9):1085-1091. 19. Borowitz D, Baker SS, Duffy L, et al. Use of fecal elastase-1 to classify pancreatic status in patients with cystic fibrosis. J Pediatr. 2004;145(3):322-326. 20. Matsumoto J, Traverso LW. Exocrine function following the whipple operation as assessed by stool elastase. J Gastrointest Surg. 2006;10(9):1225-1229. 21. Belyaev O, Herzog T, Chromik AM, Meurer K, Uhl W. Early and late postoperative changes in the quality of life after pancreatic surgery. Langenbeck Arch Surg. 2013;398(4):547-555. 22. Sikkens EC, Cahen DL, de Wit J, Looman CW, van Eijck C, Bruno MJ. Prospective assessment of the influence of pancreatic cancer resection on exocrine pancreatic function. Br J Surg. 2014;101(2):109-113. 23. Halloran CM, Cox TF, Chauhan S, et al. Partial pancreatic resection for pancreatic malignancy is associated with sustained pancreatic exocrine failure and reduced quality of life: a prospective study. Pancreatology. 2011;11(6):535-545. 24. Roeyen G, Jansen M, Ruyssinck L, et al. Pancreatic exocrine insufficiency after pancreaticoduodenectomy is more prevalent with pancreaticogastrostomy than with pancreaticojejunostomy. A retrospective multicentre observational cohort study. HPB (Oxford). 2016;18(12):1017-1022. 25. Tran TC, van ‘t Hof G, Kazemier G, et al. Pancreatic fibrosis correlates with exocrine pancreatic insufficiency after pancreatoduodenectomy. Dig Surg. 2008;25(4):311-318. 26. Yuasa Y, Murakami Y, Nakamura H, et al. Histological loss of pancreatic exocrine cells correlates with pancreatic exocrine function after pancreatic surgery. Pancreas. 2012;41(6):928-933. 27. Hackert T, Schütte K, Malfertheiner P. The pancreas: causes for malabsorption. Viszeralmedizin. 2014;30(3):190-197. 28. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care. 2003;26(suppl 1):5S-20S. 29. Hardt PD, Hauenschild A, Jaeger C, Teichmann J, Bretzel RG, Kloer HU. High prevalence of steatorrhea in 101 diabetic patients likely to suffer from exocrine pancreatic insufficiency according to low fecal elastase 1 concentrations: a prospective multicenter study. Dig Dis Sci. 2003;48(9):1688-1692. 30. Cavalot F, Bonomo K, Fiora E, et al. Does pancreatic elastase-1 in stools predict steatorrhea in type 1 diabetes? Diabetes Care. 2006;29(3):719-721. 31. Hahn JU, Kerner W, Maisonneuve P, Lowenfels AB, Lankisch PG. Low fecal elastase 1 levels do not indicate exocrine pancreatic insufficiency in type-1 diabetes mellitus. Pancreas. 2008;36(3):274-278. 32. Bures J, Cyrany J, Kohoutova D, et al. Small intestinal bacterial overgrowth syndrome. World J Gastroenterol. 2010;16(24):2978-2990. 33. Czakó L, Hegyi P, Rakonczay Z, Wittmann T, Otsuki M. Interactions between the endocrine and exocrine pancreas and their clinical relevance. Pancreatology. 2009;9(4):351-359. 34. Clark M, Kroger CJ, Tisch RM. Type 1 diabetes: A chronic anti-self-inflammatory response. Front Immunol. 2017;8:1898.