Exocrine Pancreatic Insufficiency

Exocrine Pancreatic Insufficiency 

Exocrine pancreatic insufficiency (EPI) is a serious condition characterized by a deficiency in pancreatic digestive enzymes resulting in inadequate digestion of fats, carbohydrates, and proteins.

The most common cause of EPI is chronic pancreatitis (CP) in adults and cystic fibrosis (CF) in children. Clinically, EPI commonly results in fat malabsorption and is characterized by steatorrhea, weight loss, and maldigestion.

In mild cases, it may be asymptomatic or result in mild abdominal discomfort with normal appearing bowel movements.


  • Pancreatic insufficiency
  • EPI
  • Fat malabsorption

Epidemiology & Demographics


Approximately 40% in patients with CP and 90% in patients with CF

Predominant Sex & Age

More common in males than females

Risk Factors

•Excessive alcohol consumption, leading to recurrent pancreatitis and CP

•Cystic fibrosis


•Ductal obstruction (congenital or acquired- pancreatic malignancy, stones)


•Genetic predisposition

•Pancreatic resection

•History of inflammatory bowel disease

•History of celiac disease

•Type 1 and type 2 diabetes mellitus

Physical Findings & Clinical Presentation

EPI manifests as a malabsorption syndrome. The clinical features may mimic and coexist with common gastrointestinal conditions (i.e., irritable bowel syndrome [IBS], small-intestinal bacterial overgrowth [SIBO], celiac disease), which may delay diagnosis. Patients often limit dietary fat intake to avoid or reduce steatorrhea. Severity depends on the degree of pancreatic loss and can be categorized into mild or moderate-to-severe disease as follows:

  • Mild disease
    • 1.Asymptomatic
    • 2.Normal bowel movements
    • 3.Mild abdominal discomfort
    • 4.Bloating
  • Moderate-to-severe disease
    • 1.Chronic diarrhea
    • 2.Excessive weight loss
    • 3.Excessive flatulence
    • 4.Abdominal pain/bloating
    • 5.Voluminous and foul-smelling stools
    • 6.Fatty food intolerance
    • 7.Failure to thrive in children
    • 8.Steatorrhea (stool fat >6 g/day) when >90% of pancreatic glandular function is lost
  • •Edema (as a result of protein malnutrition and hypoalbuminemia)
  • •Fat-soluble vitamins deficiencies (rare):
    • 1.Vitamin A (impaired night vision)
    • 2.Vitamin D (osteoporosis, metabolic bone disease, hyperparathyroidism, hypocalcemia)
    • 3.Vitamin E (neuropathy, anemia)
    • 4.Vitamin K (ecchymosis)


EPI usually results from CP in adults or CF in children. Pancreatic exocrine insufficiency is also a common occurrence in patients recovering from severe acute pancreatitis, with the severity of symptoms correlating with the degree of pancreatic necrosis. Causative factors can generally be classified into pancreatic and extrapancreatic conditions.

Etiologies of Exocrine Pancreatic Insufficiencies

Acute/chronic pancreatitis (alcohol abuse, trauma, hereditary, idiopathic)Celiac disease
Pancreatic cancerInflammatory bowel disease
Pancreatic, ampullary, and duct obstructionAutoimmune pancreatitis
Cystic fibrosisZollinger-Ellison syndrome
Diabetes mellitus type 1 or 2Gastrointestinal surgeries (gastrectomy, gastric bypass, extensive small-bowel surgery)
Shwachman-Diamond syndrome (EPI with anemia, neutropenia, and bony abnormalities)

EPI, Exocrine pancreatic insufficiency.


The diagnosis of EPI is challenging because patients often present with nonspecific signs and symptoms, and reliable diagnostic tests are lacking.

Differential Diagnosis

With the exception of voluminous and foul-smelling stools, the following conditions may present in a manner similar to EPI:

  • •Celiac disease
  • •IBS
  • •Inflammatory bowel disease
  • •SIBO
  • •Short bowel syndrome


  • •A complete history, physical examination, and laboratory evaluation are essential to making the diagnosis and excluding other common causes of diarrhea and weight loss.
  • •Complete electrolyte panel to detect hypokalemia, hypocalcemia (in setting of vitamin D deficiency), hypomagnesemia, and metabolic acidosis from malabsorption and gastrointestinal losses. In children, genetic testing for cystic fibrosis transmembrane conductance regulator (CFTR) mutations should be carried out.
  • •Complete blood count (CBC) may reveal anemia from iron, vitamin B12, or folate deficiencies.
  • •Prolonged prothrombin times may be elevated because of vitamin K malabsorption.
  • •Alternative causes of maldigestion should be investigated, such as infection with Giardia lamblia, celiac serology, liver disease, and SIBO tests.

Laboratory Tests

Direct and indirect pancreatic function tests are available to diagnose EPI.

  • Indirect: Measures the level of pancreatic enzymes or the consequences of exocrine insufficiency. Used to monitor the effectiveness of pancreatic enzyme replacement therapy (PERT).
    • 1.Fecal fat quantification: Considered the gold standard for evaluating fat digestion. However, it does not distinguish between maldigestion and malabsorption.
    • 2.Fecal elastase-1 (FE-1): The most sensitive and specific test of pancreatic function. This enzyme is minimally degraded during intestinal transit. The test measures enzymatic production of FE-1 and can be used to screen for moderate-to-severe EPI with high sensitivity. FE-1 levels >200 μg/g are normal, levels of 100 to 200 μg/g are considered mild, and levels <100 μg/g are severe for EPI. Liquid stool can lead to falsely low results because of dilution.
    • 3.Fecal chymotrypsin: Sensitive and specific test of pancreatic function. Variably degraded during transit in the intestinal lumen. Accurate levels require an interruption of PERT, generally for 2 days before testing.
    • 4.Serum trypsinogen: Reflects pancreatic acinar cell mass. Highly sensitive for severe EPI when levels <20 ng/ml. This test is not commonly employed in clinical practice.
    • 5.13 C-Triglyceride breath test: Monitors the digestion of isotope-labeled fat meal to reflect absorption and metabolization ofproduct. It is used to measure the efficacy of PERT.
  • Direct: Most sensitive and specific diagnostic tests for the diagnosis of EPI. Tests use hormonal secretagogues to stimulate the pancreas and then collect duodenal fluid to measure secretory content. Tests use CCK, secretin, and CCK-secretin.
    • 1.Endoscopic pancreatic function test: Requires fluoroscopic placement of an oro-duodenal collection tube with topical anesthesia. Gastric and duodenal ports sample duodenal fluid for serial measurements of bicarbonate over one hour. Severe EPI is reflected by a peak bicarbonate concentration of <50 mEq/L
    • 2.Traditional direct pancreatic function test: Endoscopic procedure performed under sedation for the collection of duodenal fluid. Generally, better tolerated by patients. A peak bicarbonate concentration <80mEq/L is considered abnormal for one hour testing.

Imaging Studies

  • •Computed tomography (CT): First-line imaging study of choice. Permits visualization of calcifications, cysts, deformation/obstruction of bile ducts, pancreatic/peripancreatic tumors, fibrosis, and parenchyma loss.
  • •Magnetic resonance cholangiopancreatography: Provides 3D-imaging of the pancreatic-biliary ductal system


The management of EPI includes dietary and lifestyle modifications, as well as PERT and vitamin supplementation, to relieve maldigestion-related symptoms and restore normal nutritional health. Underlying diseases leading to EPI should also be treated.

Nonpharmacologic Therapy

Nutritional therapy aims to relieve maldigestion-related symptoms and ensure normal nutritional status. Patients should be encouraged to consume small and frequent meals. In addition, patients should abstain from consuming alcohol and smoking. Limiting dietary fat has not been shown to improve outcomes.

Pharmacologic Therapy

Oral administration of pancreatic enzyme replacements (Table 2) is the method of choice for treatment of EPI. It is indicated for patients with weight loss, symptomatic steatorrhea, or steatorrhea of >15 g/day. The aim of PERT is to compensate for the deficiencies of normal pancreatic enzyme secretion and increase fat absorption. Doses are individually tailored and depend upon residual pancreatic function and fat content of the meal, but usually start at 25,000 to 40,000 IU of lipase in the form of enteric-coated mini-microspheres per main meal. PERT improves malabsorption of fat and protein and helps to relieve symptoms of abdominal pain, steatorrhea, and flatulence. Inadequate responses can be managed by either dose escalation or the addition of proton pump inhibitors or H2 antagonists to prevent acid inactivation of lipase.

Enzyme Products for the Treatment of Chronic Pancreatitis

From Feldman M et al: Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Elsevier.

ProductFormulationLipase Content per Pill or Capsule (USP units)
CreonEnteric-coated capsule3000; 6000; 12,000; 24,000; 36,000
ZenpepEnteric-coated capsule3000; 5000; 10,000; 15,000; 20,000; 25,000
PancreazeEnteric-coated capsule4200; 10,500; 16,800; 21,000
UltresaEnteric-coated capsule13,800; 20,700; 23,000
PertzyeEnteric-coated with bicarbonate8000; 16,000
ViokaseNon–enteric-coated tablet 10,440; 20,880

The total dose of lipase per meal should be titrated based on response but usually requires at least 60,000 and usually 90,000 USP units (30,000 IU) of lipase per meal and half that amount with snacks. The dose should be split equally during the meal and immediately after the meal.

USP, United States Pharmacopeia.

∗ Non–enteric-coated agents require cotreatment with an H2 receptor antagonist or proton pump inhibitor to avoid denaturation of the enzymes by gastric acid.


  • •Consider further evaluation in patients with persistent weight loss and steatorrhea.


  • •Consultation with a gastroenterologist can help expedite diagnosis and rule out alternate diagnoses.
  • •Referral to a nutritionist can aid the patient with malnutrition and alleviate symptoms.

 Pearls & Considerations

  • •The pancreas has an important role in the digestion of all nutrients, but fats in particular.
  • •EPI is a condition related to decreased pancreatic enzyme release resulting from loss of pancreatic parenchyma, inadequate pancreatic stimulation, pancreatic duct obstruction, or pancreatic enzyme inactivation.
  • •Common symptoms of EPI include weight loss, steatorrhea, and abdominal bloating.
  • •Timely diagnosis and adequate treatment with PERT therapy by the clinician is crucial because delay may impair growth in children, and lead to adverse outcomes of malnutrition, and increased morbidity and mortality in patients of all ages.
  • •Individualized dietary advice together with the appropriate PERT are the cornerstones of EPI therapy.

Seek Additional Information

  1. Dominguez-Munoz J.E.: Management of pancreatic exocrine insufficiency. Curr Opin Gastroenterol 2019; 35 (5): pp. 455-459.
  2. Othman M.O.: Introduction and practical approach to exocrine pancreatic insufficiency for the practicing clinician. Int J Clin Pract 2018; 72 (2): 29405509.
  3. Singh V.K., Schwarzenberg S.J.: Pancreatic insufficiency in cystic fibrosis. J Cyst Fibros 2017; 16 (Suppl 2): pp. S70-S78.


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