AUTHORS: Lakshmi Ravindra, MD and Ross W. Hilliard, MD, FACP
DefinitionExocrine pancreatic insufficiency (EPI) is a 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.1
SynonymsPancreatic insufficiency
EPI
Fat malabsorption
| ICD-10CM CODE | | K86.81 | Exocrine pancreatic insufficiency |
|
Epidemiology & DemographicsPrevalenceEPI occurs in 20% to 30% of patients after acute pancreatitis and 60% to 90% of patients within 10 to 12 yr of chronic pancreatitis diagnosis. It is present in 90% of patients with CF. For chronic pancreatitis, which has an estimated prevalence 50 per 100,000 persons, this equates to ∼164,000 cases in the U.S. alone.1
Predominant Sex & AgeDemographic data strictly for EPI are lacking; however, chronic pancreatitis is the most common cause of EPI and has a slight male predominance (55%) with a mean age of diagnosis of 45 yr. Given the natural history of EPI as noted above, this would equate to a typical age of onset of approximately 55 to 57 yr old.1
Risk Factors
- Pancreatitis (chronic and acute)
- Cystic fibrosis
- Surgery (i.e., pancreaticoduodenectomy, gastrectomy, esophagectomy)
- Toxin exposure (tobacco, alcohol, antiretroviral medication)
- Pancreatic adenocarcinoma
- Neuroendocrine neoplasm (with or without treatment with somatostatin analogs)
- Ductal obstruction (congenital or acquired)
- Genetic predisposition
- History of autoimmune disorders (type 1 diabetes mellitus, inflammatory bowel disease, Sjögren syndrome)
- Type 2 diabetes mellitus
- Celiac disease
Physical Findings & Clinical PresentationMany patients may be asymptomatic or only present with mild symptoms, as clinically significant EPI may not appear until 90% of pancreatic enzyme production has been lost. Symptoms may include steatorrhea, bloating, and belching. 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
- Asymptomatic
- Normal bowel movements
- Mild abdominal discomfort
- Bloating
- Moderate-to-severe disease
- Chronic diarrhea
- Excessive weight loss
- Excessive flatulence
- Abdominal pain/bloating
- Voluminous and foul-smelling stools
- Fatty food intolerance
- Failure to thrive in children
- Steatorrhea (stool fat >6 g/day)
- Edema (as a result of protein malnutrition and hypoalbuminemia)
- Fat-soluble vitamin deficiencies (rare):
- Vitamin A (impaired night vision)
- Vitamin D (osteoporosis, metabolic bone disease, hyperparathyroidism, hypocalcemia)
- Vitamin E (neuropathy, anemia)
- Vitamin K (ecchymosis)
EtiologyEPI usually results from CP in adults or CF in children leading to fibrosis, necrosis, or lack of function of pancreatic acinar cells. It is also a common, self-limited 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 (Table 1).1
TABLE 1 Etiologies of Exocrine Pancreatic Insufficiencies
| Pancreatic | Extrapancreatic |
|---|
| Acute/chronic pancreatitis (alcohol abuse, trauma, hereditary, idiopathic) | Celiac disease |
| Pancreatic cancer | Inflammatory bowel disease |
| Pancreatic, ampullary, and duct obstruction | Autoimmune pancreatitis |
| Cystic fibrosis | Zollinger-Ellison syndrome |
| Diabetes mellitus type 1 or 2 | Gastrointestinal surgeries (gastrectomy, gastric bypass, extensive small-bowel surgery) |
| Shwachman-Diamond syndrome (EPI with anemia, neutropenia, and bony abnormalities) | |
| Hemochromatosis | |
EPI, Exocrine pancreatic insufficiency.
EPI is a clinical diagnosis for those with a history of pancreatic disease. For those without a history of pancreatic disease, but symptoms consistent with EPI, workup can include both indirect and direct measures of pancreatic function. Indirect measures include measurement of pancreatic enzymes in the stool or serum. Direct measures include endoscopic evaluation and collection of pancreatic fluids after administration of secretagogues. Although these measures can be helpful in unclear cases, they have not been standardized and a clinically proven algorithm does not exist.1,2
Differential DiagnosisThe following conditions may present in a manner similar to EPI:
- Celiac disease
- IBS
- Inflammatory bowel disease
- SIBO
- Short bowel syndrome
Workup
- 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.
- 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 TestsDirect and indirect pancreatic function tests are available to diagnose EPI.1,2
- Indirect: Measures the level of pancreatic enzymes or the consequences of exocrine insufficiency.
- 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 levels due to dilution.
- Fecal chymotrypsin: Sensitive and specific test of pancreatic function. Variably degraded during transit in the intestinal lumen.
- 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.
- 13C-Triglyceride breath test: Monitors the digestion of isotope-labeled fat meal to reflect absorption and metabolization of product.
- Direct: The most sensitive and specific diagnostic tests for the diagnosis of EPI are invasive. Tests use hormonal secretagogues (CCK, secretin, or CCK-secretin) to stimulate the pancreas and then collect duodenal fluid to measure secretory content.
- Double-lumen gastroduodenal (Dreiling) collection tube: Placement of an orogastroduodenal tube with one lumen collecting pancreatic juices and the other suctioning from the stomach to prevent acid contamination. Placement is cumbersome and time consuming and requires fluoroscopy to confirm the proper locations. Serial measurements of bicarbonate are obtained over 1 h. Severe EPI is reflected by a peak bicarbonate concentration of <50 mEq/L.
- Endoscopic pancreatic function test: Endoscopic procedure performed under sedation for the collection of duodenal fluid. Generally, it is better tolerated by patients than Dreiling collection. A peak bicarbonate concentration <80 mEq/L is considered abnormal for 1-h testing.
Imaging Studies
- Computed tomography (CT): First-line imaging study of choice. Permits visualization of the pancreas for evaluation of calcifications, cysts, deformation/obstruction of bile ducts, pancreatic/peripancreatic tumors, fibrosis, and parenchyma loss.
- Magnetic resonance cholangiopancreatography (MRCP): Provides 3D imaging of the pancreatic-biliary ductal system.1
- Endoscopic ultrasound has not been shown to be diagnostic for EPI, although it can better assess the morphology of the pancreas in those with suspected chronic pancreatitis.2
The management of EPI includes dietary and lifestyle modifications, as well as pancreatic enzyme replacement therapy (PERT) and vitamin supplementation, to relieve maldigestion-related symptoms and restore normal nutritional health. Unfortunately, the disease is often underdiagnosed and subsequently undertreated, despite data showing that in certain circumstances, such as pancreatic malignancy, PERT can improve quality of life and lead to a longer life expectancy. Underlying diseases leading to EPI should also be treated.1
Nonpharmacologic TherapyNutritional 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.3
Pharmacologic TherapyOral administration of pancreatic enzyme replacements (Table 2) is the method of choice for treatment of EPI. 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.3
TABLE 2 Enzyme Products for the Treatment of Chronic Pancreatitis
| Product | Formulation | Lipase Content per Pill or Capsule (USP units) |
|---|
| Creon | Enteric-coated capsule | 3000; 6000; 12,000; 24,000; 36,000 |
| Zenpep | Enteric-coated capsule | 3000; 5000; 10,000; 15,000; 20,000; 25,000 |
| Pancreaze | Enteric-coated capsule | 4200; 10,500; 16,800; 21,000 |
| Ultresa | Enteric-coated capsule | 13,800; 20,700; 23,000 |
| Pertzye | Enteric-coated with bicarbonate | 8000; 16,000 |
| Viokase | Nonenteric-coated tablet∗ | 10,440; 20,880 |
USP, United States Pharmacopeia. 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.
Pediatric patients with EPI due to CF have shown improvement in pancreatic function with treatment of CFTR modulator, such as ivacaftor.4
Disposition
- Consider further evaluation in patients with persistent weight loss and steatorrhea despite pancreatic enzyme replacement therapy.
- Patients diagnosed with EPI should also get a DEXA scan to evaluate for osteoporosis or osteopenia.
Referral
- 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.
