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Supplements Perspectives in Exocrine Pancreatic Insufficiency
A Primer on Exocrine Pancreatic Insufficiency, Fat Malabsorption, and Fatty Acid Abnormalities
Samer Alkaade, MD and Ashley A. Vareedayah, MD
Guidance for Supplemental Enteral Nutrition Across Patient Populations
Douglas L. Nguyen, MD
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Options for Addressing Exocrine Pancreatic Insufficiency in Patients Receiving Enteral Nutrition Supplementation
Steven D. Freedman, MD, PhD

Options for Addressing Exocrine Pancreatic Insufficiency in Patients Receiving Enteral Nutrition Supplementation

Steven D. Freedman, MD, PhD
Pancreatic Enzyme Replacement Therapy
More than 80% of patients with CP and CF are treated with pancreatic enzymes.3,9 Pancreatic enzyme replacement therapy (PERT) products are a mixture of porcine-derived pancreatic digestive enzymes indicated for oral administration in patients with EPI.18-23 The FDA-approved PERT products differ greatly in enzymatic activity due to different delivery of enzymes (ie, coating, microspheres, tablets, or capsules) and varying enzyme content (ie, lipase, protease, and amylase).8,24 As a result, inconsistent clinical efficacy has been demonstrated when comparing PERT products in patients with EPI.8,24 

All but one of available PERT formulations are enteric-coated pancreatic enzyme microspheres or microtablets.18-21 This coating represents an attempt to increase resistance to degradation by gastric acid pH and proteases in the stomach to ensure delivery to the duodenum.17 Although the proteolytic pancreatic enzymes are more acid stable, lipase is irreversibly inactivated at a pH of 4 or less and subject to loss after administration if not protected.24 The PERT microspheres dissolve at a pH higher than 5.5, to protect enzymatic activity until they clear the stomach and enter the intestinal lumen.12,17,24 Enteric coated PERT may have variable efficacy for relief of steatorrhea based on the varying gastric and duodenal pH across patient populations with EPI.20,24 Both CP and CF are characterized by a progressive destruction of pancreatic cells. This results in enzymatic depletion and inadequate bicarbonate production and the inability to neutralize acidic chyme or solubilize lipolytic products for digestion. Patients with advanced CP and CF may also have increased gastric acid production. Therefore, CF and CP are characterized by a more acidic intraduodenal pH of 3 to 5 and PERT-derived lipase may never be released from the coating, limiting efficacy.1,4,25

The non-enteric coated PERT products must be used with a bicarbonate or acid-suppression medication (proton pump inhibitor) to raise gastric pH and prevent immediate degradation in the stomach.17,22,24 Administration of a 650-mg tablet of sodium bicarbonate (8 mEq) 2 or 3 times daily in conjunction with meals and PERT is recommended, with additional tablets administered at 1 hour and 2 hours after each meal although the effectiveness of this strategy is questionable.24 Another PERT formulation is buffered with bicarbonate for delayed release.23 In this way, the duodenal pH would theoretically increase without the need for concurrent acid-suppressive therapy.24 However, the low amounts of bicarbonate (2.5 mEq) in capsule PERT formulations may be insufficient to buffer the acidic gastric environment and prevent enzymatic degradation.23,26

Prior to 2010, the FDA did not regulate PERT products and the enzymatic activity of these products was unknown.17,24 In 2004, the FDA required manufacturers to meet efficacy and safety standards.24 Clinical trials of PERT efficacy enrolled fewer than 50 patients and measured short term efficacy compared with placebo treatment.17,18-20,22,24,27 The efficacy of PERT was demonstrated by improvements in fat absorption based on 72-hour stool collections. The primary end point of these randomized control trials was improvement in steatorrhea, as demonstrated by the mean difference in the coefficient of fecal fat absorption (CFA) with PERT compared with placebo treatment. Although CFA is more informative than the clinical presence or absence of steatorrhea, it does not directly measure fat maldigestion caused by EPI. PERT products demonstrated a 26% to 41% increase in CFA compared with placebo.18,20-23,28 However, some clinical trials included only patients who had achieved CFA improvements during a run-in phase with PERT therapy; as these trials excluded nonresponders to PERT, outcomes to PERT therapy may not be representative of the clinically treated population.19,24

Challenges with PERT treatment include limited guidelines for appropriate administration and lack of dosing standards between therapies (as none are bioequivalent).4,8,17 Enzymatic replacement therapy should be administered in the correct dosage in parallel with nutrients to coordinate gastric emptying, maximize efficacy, and ensure optimal absorption by mimicking the natural pancreatic secretion response to a meal.17,24 There is an unmet need for guidelines and standardization of therapy for patients with EPI (Table 21,12,17,29).

Selection of the PERT product and quantity of tablets needed for enzymatic activity is determined based on individual needs, such as dietary fat consumption, age, body weight, and disease state.17 Recommendations from various international societies (the Australian Pancreatic Club, the Italian Association for the Study of the Pancreas, and the Spanish Pancreatic Club) recommend 25,000 to 50,000 lipase units per meal.17 Many current dosing guidelines are for patients with CF or CP; in these patients, improvement of fat absorption has been reported using 40,000 units of lipase per meal and 20,000 units per snack. Other studies used anywhere from 40,000 to 80,000 lipase units with main meals 3 times a day, in addition to 20,000 to 50,000 with snacks 2 to 3 times a day on 100-gram fat diet.12

Cost is an additional consideration. The cost of PERT products can range from $0.92 per capsule (for a 4200 lipase unit capsule) to $8 per capsule (for a 36,000 lipase unit capsule).24 Furthermore, despite the expense and pill burden of PERT in patients with EPI, many patients still have symptoms.1 In a study from the Netherlands, 70% of patients with EPI caused by CP were undertreated and had steatorrhea-related symptoms, despite PERT treatment with 6 capsules of 25,000 units daily.17

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