High-Dose Pancreatic-Enzyme Supplements and Fibrosing Colonopathy in Children with Cystic Fibrosis

FitzSimmons, Stacey C.; Burkhart, Greg A.; Borowitz, Drucy; Grand, Richard J.; Hammerstrom, Thomas; Durie, Peter R.; Lloyd-Still, John D.; Lowenfels, Albert B.

doi:10.1056/nejm199705013361803

Cited by 269 publications

(143 citation statements)

References 20 publications

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“…47 A similar US study found only the dose of lipase to be a factor. 48 The age of the patient, the clinician's view on the importance of the copolymer Eudragit L30 D55 (in the coating of some preparations) as a factor causing FC (see below), the dose of enzyme that is required to control malabsorption, the cost, and local availability will also influence which preparation is used.…”

Section: Choice Of Pancreatic Enzyme Preparationmentioning

confidence: 99%

Diagnosis and Treatment of Intestinal Malabsorption in Cystic Fibrosis

Littlewood

Wolfe

Conway

2005

Pediatric Pulmonology

102

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Summary. Intestinal malabsorption is severe and of early onset in virtually all people who have cystic fibrosis. The main cause is deficiency of pancreatic enzymes. Bicarbonate deficiency, abnormal bile salts, mucosal transport problems, motility differences, and anatomical structural changes are other contributory factors. Effective treatment should allow a normal to high-fat diet to be taken, control symptoms, correct malabsorption, and achieve a normal nutritional state and growth. Appropriate pancreatic enzyme replacement therapy will achieve normal or near-normal absorption in most people with cystic fibrosis. Early identification and treatment of intestinal malabsorption is critical to achieving optimal nutritional status. The occurrence of fibrosing colonopathy in a few patients on very high doses of those enzymes which have the copolymer Eudragit L30 D55 in their covering resulted in guidelines in the UK to avoid doses equivalent to more than 10,000 IU lipase per kg per day, and also to avoid preparations containing this copolymer in children and adolescents. For patients not responding to 10,000 IU lipase per kg per day review of adherence to treatment, change of enzyme preparation, variation in time of administration, and reduction in gastric acid may improve absorption. The importance of early investigation to exclude other gastrointestinal disorders as a cause of the patient's symptoms, rather than merely increasing the dose of enzymes, is stressed. With modern pancreatic enzymes in doses up to or only slightly in excess of 10,000 IU lipase per kg per day, adequate control of gastrointestinal symptoms and absorption can be achieved, and a normal nutritional state and growth rate maintained in most people with cystic fibrosis.

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Section: Choice Of Pancreatic Enzyme Preparationmentioning

confidence: 99%

Diagnosis and Treatment of Intestinal Malabsorption in Cystic Fibrosis

Littlewood

Wolfe

Conway

2005

Pediatric Pulmonology

102

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“…However, it has been shown that an increase in the dose of pancreatic enzymes does not completely correct fat malabsorption (13). In addition, the use of high-strength pancreatic enzyme supplements to increase lipolysis has been reported to be associated with fibrosing colonopathy (14)(15)(16)). …”

Section: Introductionmentioning

confidence: 99%

Fat malabsorption in cystic fibrosis patients receiving enzyme replacement therapy is due to impaired intestinal uptake of long-chain fatty acids

Kalivianakis

Minich

Bijleveld

et al. 1999

The American Journal of Clinical Nutrition

109

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Background: Pancreatic enzyme replacement therapy frequently fails to correct intestinal fat malabsorption completely in cystic fibrosis (CF) patients. The reason for this failure is unknown. Objective: We investigated whether fat malabsorption in CF patients treated with pancreatic enzymes is caused by insufficient lipolysis of triacylglycerols or by defective intestinal uptake of long-chain fatty acids. Design: Lipolysis was determined on the basis of breath 13 CO 2 recovery in 10 CF patients receiving pancreatic enzyme replacement therapy after they ingested 1,3-distearoyl,2[1- 13 Results: Fecal fat excretion ranged from 5.1 to 27.8 g/d (x -± SD: 11.1 ± 7.0 g/d) and fat absorption ranged from 79% to 93% (89 ± 5%). There was no relation between breath 13 CO 2 recovery and dietary fat absorption (r = 0.04) after ingestion of [ 13 C]MTG. In contrast, there was a strong relation between 8-h plasma [ 13 C]LA concentrations and dietary fat absorption (r = 0.88, P < 0.001). Conclusion: Our results suggest that continuing fat malabsorption in CF patients receiving enzyme replacement therapy is not likely due to insufficient lipolytic enzyme activity, but rather to incomplete intraluminal solubilization of long-chain fatty acids, reduced mucosal uptake of long-chain fatty acids, or both. Am J Clin Nutr 1999;69:127-34. KEY WORDSBreath test, mixed triacylglycerol, [13 C]linoleic acid, fat malabsorption, fat balance, lipolysis, stable isotopes, cystic fibrosis, recommended dietary allowance, children, long-chain fatty acids INTRODUCTIONIn humans, triacylglycerols composed of long-chain fatty acids constitute 92-96% of dietary fats (1). Absorption of these fats is by 2 main processes. Lipolysis, by lipolytic enzymes originating predominantly in the pancreas, leads to hydrolysis of triacylglycerols into fatty acids and 2-monoacylglycerols. Second, intestinal uptake involves the formation of mixed micelles composed of bile components and lipolytic products, followed by the disintegration of the mixed micelles in the unstirred water layer and the translocation of the lipolytic products across the intestinal epithelium (1-4).Most cystic fibrosis (CF) patients malabsorb dietary fats because of pancreatic insufficiency, which leads to impaired lipolysis (5, 6). The symptoms of pancreatic insufficiency, such as steatorrhea and poor growth, can be alleviated by oral supplementation with pancreatic enzymes. However, despite recent improvements in the pharmacokinetics of these supplements, many patients continue to experience a certain degree of steatorrhea (7-9), with 10-20% of the dietary fat they consume being malabsorbed. It has not been elucidated whether this malabsorption is due to insufficient pancreatic enzyme replacement therapy. This possibility is likely because decreased pancreatic bicarbonate secretion may negatively affect enzyme activity by sustaining a low pH in the duodenum (10, 11). At a low duodenal pH, the release of enzymes from the microcapsules is inhibited and denaturation of the enzymes is stimul...

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“…Because of exocrine PI, CF patients depend on pancreatic enzyme supplements. However, the use of high doses of pancreatic enzymes does not always normalize fat absorption and may lead to fibrosing colonopathy (51). This led to an interest in increasing the level of gastric lipase (the only endogenous digestive lipase not affected by CF) by nutritional adaptation as previously reported in animals (24 -27) and in healthy adults (28).…”

Section: Discussionmentioning

confidence: 99%

Gastric Function in Children with Cystic Fibrosis: Effect of Diet on Gastric Lipase Levels and Fat Digestion

et al. 2004

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The effect of diet, usual (44 Ϯ 4% energy as fat), high-fat (49 Ϯ 4% energy as fat), and moderate-fat (33 Ϯ 2% energy as fat), on gastric function (lipase and pepsin activities, pH, emptying rate) and intragastric digestion of fat were assessed in six children with cystic fibrosis. Fasting and postprandial activity of digestive enzymes, gastric pH, and gastric volume measured before, during, and after 120 min of feeding did not differ significantly as a function of fat intake. Postprandial gastric lipase output (units per kilogram of body weight) during usual, moderate-fat, and high-fat diets was close to or higher than (38.8 Ϯ 7.2, 44.9 Ϯ 8.6, and 54.8 Ϯ 5.5 U/kg per 20 min) gastric lipase output of premature infants (22.5 Ϯ 6.4 to 28.3 Ϯ 6.6 U/kg per 20 min) or of healthy adults (5.4 Ϯ 0.4 U/kg per 15 min) fed a high-fat diet. Postprandial pepsin output was higher (4749 Ϯ 797, 6117 Ϯ 925, and 5444 Ϯ 819 U/kg per 20 min) than in premature infants (597 Ϯ 77 to 743 Ϯ 97 U/kg per 20 min) or healthy adults (781 Ϯ 56 U/kg per 15 min). Eighty minutes after feeding gastric lipolysis reached 20 to 36%. This study shows that gastric lipase activity is high in cystic fibrosis patients maintained on diets providing 32% to 49% energy as fat, and that gastric lipase level did not increase over the ranges of dietary fat intake tested. CF is the most common autosomal recessive disorder in Caucasians and results in pulmonary, gastrointestinal, metabolic and nutritional disturbances (1-3). The basic defect in CF involves faulty regulation of the epithelial cell chloride channel caused by mutations in the CFTR gene (4). Deletion of phenylalanine at amino acid position 508 (⌬F508) in the CFTR protein accounts for 70% of CF gene abnormalities in patients of Northern European ancestry (5). The ⌬F508 mutation leads to defective maturation of CFTR and absence of the protein at the apical membrane (6). Greater than 98% of ⌬F508 homozygotes have PI.PI, resulting in fat malabsorption, is found in at least 85% of CF patients (7-9). Lacking pancreatic enzymes, CF patients are dependent on pancreatic enzyme supplements (10 -12). However, the degree to which fat is absorbed by these patients varies, and even when pancreatic lipase activity is completely absent, dietary fat is absorbed. Indeed, Ross (13) reported fat absorption of 26 to 81% in a group of children with CF, although most of them did not have detectable pancreatic lipase activity. Lapey et al. (14) reported greater than 50% fat absorption in 15 patients with exocrine PI secondary to CF, without any oral enzyme supplementation. Ross and Sammons (15) have therefore postulated the presence of compensatory lipolytic activity in PI. It was shown subsequently that this compensation is provided by gastric lipase, the enzyme that initiates fat digestion in the stomach (16,17

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High-Dose Pancreatic-Enzyme Supplements and Fibrosing Colonopathy in Children with Cystic Fibrosis

Cited by 269 publications

References 20 publications

Diagnosis and Treatment of Intestinal Malabsorption in Cystic Fibrosis

Diagnosis and Treatment of Intestinal Malabsorption in Cystic Fibrosis

Fat malabsorption in cystic fibrosis patients receiving enzyme replacement therapy is due to impaired intestinal uptake of long-chain fatty acids

Gastric Function in Children with Cystic Fibrosis: Effect of Diet on Gastric Lipase Levels and Fat Digestion

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