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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
Patients with exocrine pancreatic insufficiency (EPI) have suboptimal secretion of pancreatic digestive enzymes and experience a range of clinical symptoms related to the malabsorption of fat. In patients with EPI unable to meet their nutritional requirements, enteral nutrition (EN) support is used to augment nutritional status. In addition to protein and carbohydrate, EN formulas contain fats as a calorie source, as well as vitamins and minerals to help prevent nutritional deficiencies related to malabsorption. Semielemental enteral nutrition formulas are advantageous as they contain hydrolyzed protein, shorter chain carbohydrates, and may contain medium chain triglycerides as a fat source. However, severely pancreatic insufficient patients may be unable to absorb complex long-chain triglycerides provided by EN formulas due to insufficient pancreatic lipase; replacement pancreatic enzyme products are recommended for these patients. Currently, none of the FDA-approved pancreatic enzyme replacement therapy (PERT) products are indicated for use in patients receiving enteral nutrition and administration of enzymes by mixing into enteral nutrition formula is not supported by guidelines as this route is associated with risks. RELiZORB (immobilized lipase) is a novel in-line digestive cartridge that has been designed to address the unmet need for PERT in patients receiving enteral nutrition. RELiZORB efficacy and compatibility with a range of commercially available polymeric and semielemental formulas with varying nutrient, caloric content, and triglyceride chain lengths have been demonstrated. In most formulas, RELiZORB efficiently hydrolyzed greater than 90% of fats within the formula into absorbable fatty acids and monoglycerides.
Am J Manag Care. 2017;23:-S0
Lipase Activity
Patients with exocrine pancreatic insufficiency (EPI) have suboptimal secretion of pancreatic digestive enzymes causing disruptions in the well-regulated digestive process, and patients with EPI experience a range of clinical symptoms related to the malabsorption of fat. Even with decreased enzymatic production from the pancreas, patients with EPI maintain physiological levels of protein and carbohydrate digestion due to the activity of extra-pancreatic amylase and proteolytic enzymes from gastric and salivary sources.1-3 However, pancreatic lipase is the principal enzyme responsible for lipolysis, digesting 40% to 70% of total triglycerides.4 Although lipolysis of triglycerides occurs in multiple sites throughout the digestive system, there is no redundancy in pancreatic lipase activity.2 More specifically, pancreatic lipase is required for the hydrolysis of the essential long-chain polyunsaturated fatty acids (LCPUFAs).5

Gastric lipase is responsible for 5% to 40% of dietary fatty acid breakdown products released in the stomachand hydrolyzes medium-chain fatty acid triglycerides (MCTs) with higher efficiency than long-chain fatty acid triglycerides (LCTs).4,5 Gastric lipase preferentially cleaves at the sn-3 position releasing a 1,3-diacylglycerol and a free fatty acid molecule.5 These lipolysis products stimulate a duodenal endocrine response, triggering the secretion of pancreatic enzymes including pancreatic lipase. Gastric lipase continues its enzymatic activity in conjunction with pancreatic lipase in the duodenum.4

The majority of lipid digestion and absorption occurs in the proximal small intestine, where pancreatic lipase cleaves triglycerides of any length at the sn-1 and sn-3 positions to generate 2 free fatty acids and a 2-monoglyceride molecule.4 Lingual lipase is secreted by lingual serous glands post-prandially and displays lipolytic activity in the stomach and duodenum. Lingual lipase acts on the sn-3 position to produce free fatty acid and diacylglycerol molecules, and is responsible for the breakdown of 10% to 30% of total dietary triglycerides with a 5- to 8-fold higher selectivity for MCTs compared with LCTs.6,7

As EPI progresses, dysfunctional pancreatic cells cannot produce adequate sodium bicarbonate to neutralize the highly acidic gastric secretions as they leave the stomach. The low pH leads to degradation of pancreatic and extra-pancreatic lipases and denaturation of bile salts.2,4 As a result, patients with EPI experience inadequate lipid digestion and nutritional deficiencies, and over time, may experience an increase in symptom severity due to insufficient redundancy of lipolytic activity throughout the digestive process.2 Consequences of abnormal lipid digestion include malnutrition, weight loss, abdominal discomfort, abdominal swelling, and fatty, loose, foul-smelling stools, or steatorrhea (defined as >7 g of fat in stool per 24 hours).2,4,8 Patients with EPI will most often require exogenous pancreatic enzyme supplements and may require enteral nutrition (EN) support to relieve malnutrition and clinical symptoms of fat malabsorption.3,9 In order to address the unmet needs associated with these treatments alone, a novel digestive enzyme cartridge (RELiZORB) has been developed to connect in-line with enteral feeding pumps for patients with EPI.

Enteral Nutrition
Approximately 44% of patients with cystic fibrosis (CF) require oral supplementation with EN; 11% require enteral tube feeding.9,10 Of the 10% to 15% of patients with chronic pancreatitis (CP) that require oral nutritional supplement, 5% of patients are indicated for enteral tube feeding.3 Given the insufficient pancreatic lipase activity in patients with EPI, lipid absorption varies depending on the content and structure of triglycerides available in a given EN formula (Table 15,6,11) Generally, 40% to 70% of the fat in semielemental and polymeric formulas contain primarily saturated MCTs (6-12 carbons), partially eliminating the need for pancreatic lipase or its cofactors for absorption.11-14 These EN formulas may help avoid nutritional deficiencies caused by the malabsorption of lipid-soluble vitamins (A, D, E, K) and macronutrients associated with EPI.8,12,15 However, essential LCPUFAs such as linoleic acid or linolenic acid still require pancreatic lipase for optimal hydrolysis.11 Linolenic acid serves as the precursor to the synthesis of omega-3 fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA); linoleic acid is the parent fatty acid to omega-6 fatty acids, such as arachidonic acid (AA). These essential fatty acids are involved in lipid homeostasis and critical for normal cell function, growth, as well as immune and vascular functions. As they cannot be synthesized de novo, adequate essential fatty acid levels depend entirely on dietary intake of the parent lipids or their derivatives for breakdown by pancreatic lipase, absorption, and transformation within the body.5,11,16

LCTs provide more calories per gram (higher energy density) than MCTs and provide LCPUFAs.3,11 Semielemental formulas may contain fixed amounts of LCTs to address caloric needs and provide essential fatty acids (Table5,6,11).11-13 However, severely pancreatic insufficient patients may be unable to absorb these complex chains appropriately without pancreatic lipase and as a result, patients with EPI may lack sufficient levels of essential fatty acids.3,11,12 Essential fatty acid deficiency has been reported in approximately 85% of patients with CF.5 As a solution, clinicians use exogenous pancreatic enzyme supplements to aid in the digestion and absorption of LCTs.11,17

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