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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 enzyme activity despite intact parenchyma.1

EPI can result from various underlying etiologies13,14:

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 postcibal asynchrony or intraluminal inactivation

EPI may be present in patients with the following underlying conditions or procedures:

Cystic fibrosis (CF)

  • EPI is present in 9 out of 10 patients with cystic fibrosis15
  • EPI results when highly concentrated and viscous pancreatic juice blocks the pancreatic ducts leading to acinar atrophy and pancreatic fibrosis9

Chronic pancreatitis (CP)​

  • Approximately 6%-22% of patients with chronic pancreatitis (CP) have EPI at the time of their diagnosis, with the probability increasing over time16,17
  • EPI results when the destruction of functioning pancreatic parenchyma and obstruction of the pancreatic duct leads to insufficient amounts of enzymes being secreted into the duodenum9,18
  • The probability of developing EPI increases over time to 28% at 5 years, 50% at 12 years, and 70% at 20 years after onset of CP; though prevalence may vary based on etiology, severity, and duration of CP16-18


  • EPI is a common complication of partial or complete removal of the pancreas, such as pancreatoduodenectomy (Whipple procedure)19,20
  • Frequency and severity of EPI may vary due to underlying condition, type and extent of surgery, and timing of EPI assessment21,22

Pancreatic cancer

  • Obstruction of the pancreatic duct by tumors, destruction of the pancreas by tumor growth, and loss of pancreatic tissue from surgery often lead to EPI1,9
  • 50%–92% of patients with unresectable pancreatic cancer have EPI23-25
  • 42%–68% of patients with resectable pancreatic cancer tumors have EPI prior to surgery. 55%–89% have EPI after surgery19,26-30

Other underlying conditions and procedures in which EPI has been reported include:

Acute pancreatitis​

  • EPI can be a potential complication of acute pancreatitis (AP) and may develop early in the recovery phase or later31,32
  • EPI due to AP may be transient or permanent33
  • Alcoholic etiology, severity of AP, extent of necrosis, and previous episodes of AP may increase risk of developing EPI34

Crohn’s disease

  • Crohn’s disease could lead to EPI via a variety of mechanisms, including35:
    • Production of pancreatic autoantibodies
    • Damage to the pancreatic duct due to duodenal reflux
    • Scarring or inflammation leading to reduced secretory hormone secretion
  • Drugs used for the treatment of Crohn’s disease have also been found to cause acute pancreatitis36

Celiac disease ​

  • Celiac disease may lead to altered synthesis, storage, and/or secretion of secretin and CCK due to defective postprandial response to intraluminal contents by an atrophic upper intestinal mucosa35
  • Pancreatic dysfunction is generally transient in patients with celiac disease and may improve with a gluten-free diet in some patients35

Type I diabetes

  • Pancreatic exocrine and endocrine tissue are closely linked both anatomically and physiologically. Conditions that affect one tissue type may cause an impairment in the other7,34,37
  • Potential causes of EPI in patients with type I diabetes include35:
    • Impaired acinar-islet interaction
    • Diminished trophic effects of insulin
    • Autonomic diabetic neuropathy
    • Diabetic microangiopathy
    • Autoantibodies against exocrine tissue 

Gastric resection/bypass​

  • Gastric surgical procedures can result in EPI due to14,38:
    • Physiological changes that disrupt neural or hormonal stimulation of pancreatic enzyme secretion
    • Anatomical changes that cause asynchrony between gastric emptying and release of bile and pancreatic enzymes, resulting in EPI
  • The prevalence of EPI after gastric surgery may vary widely based on the type and extent of surgery38

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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. 15. 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. 16. 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. 17. 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. 18. Kempeneers MA, Ahmed Ali U, Issa Y, et al. 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