551838
research-article2014
NCPXXX10.1177/0884533614551838Nutrition in Clinical PracticeDeclercq et al
Clinical Research
Nutrition and Pancreatic Enzyme Intake in Patients With Cystic Fibrosis With Distal Intestinal Obstruction Syndrome
Nutrition in Clinical Practice Volume 30 Number 1 February 2015 134–137 © 2014 American Society for Parenteral and Enteral Nutrition DOI: 10.1177/0884533614551838 ncp.sagepub.com hosted at online.sagepub.com
Dimitri Declercq, MSc1; Stephanie Van Biervliet, MD, PhD1; and Eddy Robberecht, MD, PhD1
Abstract Background: The etiology of distal intestinal obstruction syndrome (DIOS) remains unclear. Food intake and pancreatic enzyme replacement therapy (PERT) are often blamed for its occurrence. This study evaluates the nutrition intake and PERT of patients with cystic fibrosis (CF) at a first episode of DIOS. Methods: All patients with CF perform annually a 3-day intake diary to evaluate their caloric, protein, fat, dietary fiber, liquid, and PERT intake. Patients diagnosed with a first episode of DIOS (n = 12) retrospectively completed an intake diary of the 3 days preceding the DIOS episode supervised by an expert dietitian. Results were compared with those of 1 year before and also with 36 CF controls matched for age, sex, genotype, and disease severity. All were pancreatic insufficient. Results: A first DIOS episode was diagnosed in 12 patients with CF. Only the absolute median fat intake (P = .015) and pancreatic enzyme intake (P = .035) were higher at the time of the DIOS attack in comparison to the preceding year. This could result from the difference in data collection or from the recommendations to increase fat intake and concomitant enzyme intake, since this trend was also found in the control group. The significant difference disappears when enzyme intake is expressed as units of lipase/g of fat. No other significant dietary differences were found. Conclusions: This study provides no indications for a potential role of nutrition factors or pancreatic enzymes in the first occurrence of DIOS. (Nutr Clin Pract. 2015;30:134-137)
Keywords exocrine pancreatic insufficiency; nutrition therapy; pancrelipase; distal intestinal obstruction syndrome; cystic fibrosis; pancreatic enzyme replacement therapy
With significant advances in the management of cystic fibrosis (CF), most patients survive well into adulthood.1 This change in life expectancy causes an increase in the frequency of complications such as distal intestinal obstruction syndrome (DIOS), previously termed meconium ileus equivalent.2,3 Because of vagueness in terminology and confusion with constipation, the European Society of Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) CF Working Group decided to seek consensus on the definition of this condition in CF. Distinction was made between complete and incomplete or impending DIOS. Complete DIOS was defined as the combination of complete intestinal obstruction, confirmed by vomiting of bilious material and/or fluid levels in the small intestine on an abdominal radiography with a fecal mass in the ileocecum and abdominal pain and/or distension occurring over a few days. Incomplete or impending DIOS was defined as a short history (days) of abdominal pain and/or distension and a fecal mass in the ileocecum but without signs of complete obstruction.4 While its clinical features are well known, the paucity of scientific facts on the etiology and pathogenesis is striking. This is largely compensated by an abundant number of anecdotes on the role of nutrition and pancreatic enzyme replacement therapy (PERT),3,5-7 but the relationship between the occurrence of DIOS and nutrition factors such as
energy, protein, fat, liquid and dietary fiber intake, or PERT has not been frequently studied. DIOS is not a life-threatening condition, but it is painful and troublesome because of its high recurrence rate.3,4 Specific preventive measures would therefore be welcome but are not available since the exact etiology and precipitating factors in the development of DIOS are unknown. On the basis of the above, this study has attempted to collect information on the possible relationship between the occurrence of DIOS and nutrition intake or PERT by comparing food and enzyme intake around the first DIOS episode with the intake of the preceding year. The nutrition intake and PERT in patients who had their first DIOS episode were also compared with the intake of matched CF controls. From 1Cystic Fibrosis Centre, Department of Paediatrics, Ghent University Hospital, Belgium. Financial disclosure: None declared. This article originally appeared online on October 6, 2014. Corresponding Author: Dimitri Declercq, MSc, Cystic Fibrosis Centre, Department of Paediatrics, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium. Email: [email protected]
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Table 1. Median Intake of Different Macronutrients and Pancreatic Enzyme Replacement Therapy in the Subgroups. Characteristic Caloric intake, kcal Protein, g Fat, g Fiber, g Water, L Lipase, IU Enzymes, IU/g fat Fat/kg body weight, g
DIOS (n = 12)
Controls (n = 36)
DIOSbefore (n = 12)
Controlsbefore (n = 36)
2735 (1736–3370) 99 (57–140) 114 (75–154) 16 (6–25) 1.8 (0.8–3) 63.75 × 104 (3 × 105–8.75 × 105) 5635 (2080–7868) 2.8 (1.5–5.3)
2759 (1364–3786) 106 (34–186) 123 (55–201) 16 (5–27) 1.6 (0.5–3.3) 52 × 104 (7.5 × 104–125 × 104) 4379 (825–15,162) 2.8 (0.9–5.1)
2638 (1683–3264) 93 (66–140) 96 (*1) (68–139) 17 (10–24) 1.8 (1–3.5) 48.75 × 104 (*2) (22.5 × 104–9 × 105) 5112 (1730–11,204) 2.3 (0.8–5.1)
2590 (1156–3859) 93 (31–141) 109 (*3) (41–176) 13,9 (4.1–39.7) 1.6 (0.2–4) 46.25 × 104 (7.5 × 104–150 × 104) 4191 (1838–12,711) 3.1 (*4) (1.4–7.3)
The range is presented in parentheses. DIOS is a group patients with cystic fibrosis (CF) experiencing a first episode of distal intestinal obstruction syndrome. Controls is an age-, sex-, genotype-, and disease severity–matched group without DIOS. DIOSbefore and Controlsbefore represent the nutrition data from 1 year prior to the study year (n = number of patients). Significant differences: group DIOS vs DIOSbefore: (*1): P = .015; (*2): P = .035; Controls and Controlsbefore: (*3): P = .046; (*4): P < .001.
Materials and Methods Patients with CF (children and adults) at our center (diagnosed by 2 sweat tests and genetic analysis) complete annually a prospective 3-day nutrition and PERT intake diary.8 Based on this diary, intakes of calories, protein, fat, dietary fiber, liquid, and pancreatic enzymes are calculated. The dietitian of the center uses these calculations to give patients dietary advice at least annually on how to adapt their intakes to their individual needs based on the European guidelines for nutrition in CF.9 Patients are advised to spread their enzymes over the meal, approximately one-fourth in the beginning, one-half in the middle, and one-fourth at the end of the meal. At the moment of the first DIOS attack, a retrospective dietary diary was completed by the patient and parents, which was carefully reviewed by the dietitian to evaluate dietary and PERT intake over the last 3 days prior to the attack (DIOS). From the diary data of the annual prospective 3-day intake diary, the data of 1 year before the attack (DIOSbefore) were used to compare with the data at the time of the first DIOS attack. All evaluations of the dietary dairies were performed by the same dietitian, who is associated with the CF center. For each patient with DIOS, 3 controls matched for age, sex, genotype, and disease severity were chosen from the database of the Ghent CF center (controls). The disease severity included pulmonary function, pancreatic function, nutrition status, and CF-related diseases such as diabetes mellitus and liver disease. The dietary diaries from the controls were compared with those of the DIOS patients (DIOS). To evaluate the effect of consecutive dietary advice given at the CF center, the dietary data of the controls from the prior year were compared with the results of the study year (Controlsbefore). All patients’ intakes of calories, protein, fat, dietary fiber, and liquid were calculated with a professional program for
dietary calculations (BECEL version 5.00 [BVP]; 1995 Hartog–Union en Van den Bergh, the Netherlands). The amount of PERT taken per meal was also noted. All patients used Creon Forte (Solvay S.A., Belgium; 25,000 U lipase, 18,000 U amylase, and 1000 U protease per capsule). Patients had been educated to adjust their dose of pancreatic enzymes according to the fat content of the meal and increase the dose in response to the presence of steatorrhea. No information was given on a specific amount of lipase units per gram of fat, and a minimum or maximum dose was not taken into account. Statistical analysis was performed with SPSS version 20 (SPSS, Inc, an IBM Company, Chicago, IL) by using nonparametric tests: the Mann-Whitney U test, Wilcoxon signed rank test, and Kruskal-Wallis test. The study protocol was approved by the Ethics Committee of Ghent University Hospital, 2005/411. Patients were informed about the implications of the study protocol. No objections were made.
Results Over a 6-year period, a first DIOS attack was diagnosed in 12 (DIOS) of 160 patients with CF followed at the CF center. The median age was 18 years (4.4–33.4 years), and 8 were male. All were pancreatic insufficient with a fecal elastase I concentration below 15 µg/g.10 Patients were further classified based on the definitions of the ESPGHAN CF Working Group4: 9 patients had an incomplete and 3 a complete DIOS attack. The median age of the patients in the control group (n = 36) was 18.4 years (2.6–39.1 years), and 24 were male. Table 1 shows the results of the intake of nutrients and pancreatic enzymes in the different groups. Values are presented as median (range). There was no significant difference between DIOS patients and controls for the macronutrient intake.
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However, the DIOS patients had a significantly higher fat intake than did the DIOSbefore patients (P = .015). The median fat intake increased from 96 g/d (68–139) to 114 g/d (75–154) in DIOSbefore and DIOS patients, respectively. An increased intake was seen from 2.3 g/kg body weight (0.8–5.1) to 2.8 g/ kg body weight (1.5–5.3). The absolute daily amount of lipase units taken was also significantly higher in DIOS compared with DIOSbefore (P = .035). However, this significance disappeared when PERT was expressed per gram of ingested fat. The control group displayed the same evolution regarding the fat intake (P = .046). However, the enzyme intake showed only a nonsignificant increasing trend (P = .07). The median intake of pancreatic enzymes, expressed in lipase units, was in all groups above the recommended upper limit of 4000 U lipase/g fat.
Discussion Due to the unexpected occurrence of these DIOS attacks, the collection of retrospective data from the preceding days is the only possible way to get information on nutrition and PERT intake. To minimize the inaccuracy of gathering retrospective data, we double-checked them.8 Patients or their families were asked to complete a retrospective 3-day dietary diary of the days prior to the event at diagnosis, which was then carefully reviewed by a specialized dietitian to verify as much as possible the nutrition regime just before DIOS occurred. The data of these patients from the year before and the control patients were obtained from the more accurate prospective 3-day diaries.8 The only observed difference within the DIOS group was the increased absolute fat and PERT intake at the DIOS attack. This might be explained by the different method in obtaining the data or the fact that, in the intervening year, patients from the DIOS group had constantly been encouraged to increase fat consumption, as it is the general recommendation for nearly all patients with CF. An increased fat intake was also noted in the control group when data of 2 consecutive years were compared. Consequently, enzyme intake is also higher as patients are instructed to align it to the increased fat intake, although this was not significant for the controls. Therefore, the increased enzyme intake could also be a result of the abdominal complaints experienced as part of a developing DIOS. Nutrition or PERT has been blamed in different reports3,5,6,11 to be main causes in the occurrence of DIOS, although there are very few studies looking into this aspect of DIOS. As in constipation, insufficient fiber and/or fluid intake is suggested to be in part responsible for this phenomenon.12 Only 2 studies, with contradicting results, have looked at the potential role of dietary fiber in the occurrence of gastrointestinal complaints but not specifically DIOS.13,14 These studies did not observe any difference in fiber intake before or at the DIOS attack or a difference with the control patients. On the other hand, only 5 patients (1 in the DIOS group, 4 in the
DIOSbefore group) met the recommendations of the American Health Foundation for fiber intake (age range + 5-10g/d).15 Increasing the liquid intake is also often recommended in this context.3,16 However, counting mere fluid intake is probably too simplistic to explain inspissations of ileal content. Although not investigated until now, other factors (eg, temperature or physical activity) could play a role in whether fluid intake is sufficient. This study could not discern any significant difference in liquid intake between the groups. The role of PERT in the development of DIOS provokes the most controversy. Both a presumed deficit3,5,6 and an overdose of more potent enzymes have been blamed,11 although scientific evidence is lacking for both hypotheses. Poorly controlled pancreatic insufficiency was thought to cause more sticky intestinal mucus.3,5,6 Therefore, poor adherence to PERT is suggested to play a promoting role in the development of DIOS.16,17 However, while DIOS is predominantly seen in patients with exocrine pancreatic insufficiency, it has also been reported in pancreatic-sufficient patients with CF.4,18 On the other hand, Littlewood et al19 suggest that the more aggressive treatment with PERT may result in less undigested material in the intestine and thus promote fecal impaction. The latter seems improbable as fiber, the most important nutrient in this aspect, is unaffected by PERT. Lowering PERT to prevent DIOS might, however, not be a good solution as complex interactions occur between the gastrointestinal tract and food. Unabsorbed nutrients, such as undigested fats, delivered to the distal small intestine cause a mechanism called “ileal brake.” It induces an inhibition of gastric and jejunal motility as well as a reduction of gastric acid and pancreatic secretion.20 If excessive pancreatic enzyme supplements had played a contributing role, a rise in the incidence of DIOS would have been expected after the introduction of the more potent acid-resistant, microsphere preparations. This was not the case.21,22 The present study cannot support an impact of PERT on the occurrence of DIOS since no significant difference was found between the DIOS group and their own control or the control group when the intake was expressed as international units (IU) of lipase/g of fat. The more complex etiology of DIOS is suggested by recent research indicating the importance of intrinsic factors rather than inspissations of intestinal luminal contents in the occurrence of this phenomenon. Hydration of the terminal ileum content is, in part, obtained by CFTR activation by apical sodium-dependent bile salt absorption, as demonstrated by Bijvelds et al.23 Smith et al24 also demonstrated the presence of leiomyositis and myenteric ganglionitis in DIOS. These known causes of intestinal dysmotility could enhance any tendency toward intestinal obstruction. This study is limited due to the small patient number and the difference in dietary information gathering at the time of the first DIOS episode compared with the year prior or the control population. In conclusion, the intake of calories, protein, fat, fiber, liquid, and pancreatic enzymes by patients with CF who had a
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first DIOS event was similar to that of matched CF controls. Compared with the intakes of 1 year earlier, similar results were obtained. This study cannot sustain a role for the intake of macronutrients or PERT in the occurrence of a first DIOS attack. Further larger studies are needed to support our findings.
References 1. Cystic Fibrosis Foundation. Cystic Fibrosis Foundation, Patient Registry 2005. Bethesda, MD: Cystic Fibrosis Foundation; 2006. 2. Goss CH, Rosenfeld M. Update on cystic fibrosis epidemiology. Curr Opin Pulm Med. 2004;10:510-514. 3. Dray X, Bienvenu T, Desmazes-Dufeu N, Dusser D, Marteau P, Hubert D. Distal intestinal obstruction syndrome in adults with cystic fibrosis. Clin Gastroenterol. 2004;H2:498-503. 4. Houwen RH, van der Doef HP, Sermet I, et al. Defining DIOS and constipation in cystic fibrosis with a multicenter study on the incidence, characteristics and treatment of DIOS. J Pediatr Gastr Nutr. 2009;49:54-58. 5. di Sant ‘Agnese PA, Davis PB. Cystic fibrosis in adults: 75 cases and a review of 232 cases in the literature. Am J Med. 1979;66:121-132. 6. Khoshoo V, Udall JN Jr. Meconium ileus equivalent in children and adults. Am J Gastroenterol. 1994;89:153-157. 7. Kopriva F, Michalkova K, Zapalka M, Maly J. Potato crisps without pancreatic extracts supplements: a potential cause of the distal intestinal obstruction in cystic fibrosis. Eur J Pediatr. 2007;166:696-670. 8. Trabulsi J, Schall JI, Ittenbach RF, et al. Energy balance and the accuracy of reported energy intake in preadolescent children with cystic fibrosis. Am J Clin Nutr. 2006;84:523-530. 9. Sinaasappel M, Stern M, Littlewood J, et al. Nutrition in patients with cystic fibrosis: a European consensus. J Cyst Fibros. 2002;1:51-75. 10. Meyts I, Wuyts W, Proesmans M, De Boeck K. Variability of fecal pancreatic elastase measurements in cystic fibrosis patients. J Cyst Fibros. 2002;1:265-268.
11. Camilleri M. Integrated upper gastrointestinal response to food intake. Gastroenterology. 2006;131:640-658. 12. van der Doef HP, Kokke FT, Beek FJ, Woestenenk JW, Froeling SP, Houwen RH. Constipation in pediatric cystic fibrosis patients: an underestimated medical condition. J Cyst Fibros. 2010;9:59-63. 13. Gavin J, Ellis J, Dewar AL, Rolles CJ, Connett GJ. Dietary fibre and the occurrence of gut symptoms in cystic fibrosis. Arch Dis Child. 1997;76:35-37. 14. Proesmans M, De Boeck K. Evaluation of Dietary fibre intake in Belgian children with cystic fibrosis: is there a link with gastrointestinal complaints? J Pediatr Gastr Nutr. 2002;35:610-614. 15. Williams CL, Bollella M, Wynder EL. A new recommendation for dietary fiber in childhood. Pediatrics. 1995;96:985-988. 16. Mascarenhas MR. Treatment of gastrointestinal problems in cystic fibrosis. Curr Treat Option. 2003;G6:427-441. 17. Littlewood JM. Gastrointestinal complications of cystic fibrosis. J R Soc Med. 1992;85:S13-S19. 18. Millar-Jones L, Goodchild MC. Cystic fibrosis, pancreatic sufficiency and distal intestinal obstruction syndrome: a report of four cases. Acta Paediatr. 1995;84:577-578. 19. Littlewood JM, Wolfe SP, Conway SP. Diagnosis and treatment of intestinal malabsorption in cystic fibrosis. Pediatr Pulm. 2006;41:35-49. 20. Haenni A, Sundberg B, Yazdanpandah N, Viberg A, Olsson J. Effect of fat emulsion (Fabuless) on orocecal transit time in healthy men. Scand J Gastroenterol. 2009;44:1186-1190. 21. Andersen HO, Hjelt K, Waever E, Overgaard K. The age-related incidence of meconium ileus equivalent in a cystic fibrosis population: the impact of high-energy intake. J Pediatr Gastr Nutr. 1990;11:356-360. 22. Rosenstein BJ, Zeitlin PL. Cystic fibrosis. Lancet. 1998;351:277-282. 23. Bijvelds MJC, Jorna H, Verkade HJ, et al. Activation of CFTR by ASBTmediated bile salt absorption. Am J Physiol Gastrointest Liver Physiol. 2005;L289:G870-G879. 24. Smith VV, Schäppi MG, Bisset WM, et al. Lymphocytic leiomyositis and myenteric ganglionitis are intrinsic features of cystic fibrosis: studies in distal intestinal obstruction syndrome and meconium ileus. J Pediatr Gastroenterol Nutr. 2009;49:42-51.
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research-article2014
NCPXXX10.1177/0884533614551838Nutrition in Clinical PracticeDeclercq et al
Clinical Research
Nutrition and Pancreatic Enzyme Intake in Patients With Cystic Fibrosis With Distal Intestinal Obstruction Syndrome
Nutrition in Clinical Practice Volume 30 Number 1 February 2015 134–137 © 2014 American Society for Parenteral and Enteral Nutrition DOI: 10.1177/0884533614551838 ncp.sagepub.com hosted at online.sagepub.com
Dimitri Declercq, MSc1; Stephanie Van Biervliet, MD, PhD1; and Eddy Robberecht, MD, PhD1
Abstract Background: The etiology of distal intestinal obstruction syndrome (DIOS) remains unclear. Food intake and pancreatic enzyme replacement therapy (PERT) are often blamed for its occurrence. This study evaluates the nutrition intake and PERT of patients with cystic fibrosis (CF) at a first episode of DIOS. Methods: All patients with CF perform annually a 3-day intake diary to evaluate their caloric, protein, fat, dietary fiber, liquid, and PERT intake. Patients diagnosed with a first episode of DIOS (n = 12) retrospectively completed an intake diary of the 3 days preceding the DIOS episode supervised by an expert dietitian. Results were compared with those of 1 year before and also with 36 CF controls matched for age, sex, genotype, and disease severity. All were pancreatic insufficient. Results: A first DIOS episode was diagnosed in 12 patients with CF. Only the absolute median fat intake (P = .015) and pancreatic enzyme intake (P = .035) were higher at the time of the DIOS attack in comparison to the preceding year. This could result from the difference in data collection or from the recommendations to increase fat intake and concomitant enzyme intake, since this trend was also found in the control group. The significant difference disappears when enzyme intake is expressed as units of lipase/g of fat. No other significant dietary differences were found. Conclusions: This study provides no indications for a potential role of nutrition factors or pancreatic enzymes in the first occurrence of DIOS. (Nutr Clin Pract. 2015;30:134-137)
Keywords exocrine pancreatic insufficiency; nutrition therapy; pancrelipase; distal intestinal obstruction syndrome; cystic fibrosis; pancreatic enzyme replacement therapy
With significant advances in the management of cystic fibrosis (CF), most patients survive well into adulthood.1 This change in life expectancy causes an increase in the frequency of complications such as distal intestinal obstruction syndrome (DIOS), previously termed meconium ileus equivalent.2,3 Because of vagueness in terminology and confusion with constipation, the European Society of Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) CF Working Group decided to seek consensus on the definition of this condition in CF. Distinction was made between complete and incomplete or impending DIOS. Complete DIOS was defined as the combination of complete intestinal obstruction, confirmed by vomiting of bilious material and/or fluid levels in the small intestine on an abdominal radiography with a fecal mass in the ileocecum and abdominal pain and/or distension occurring over a few days. Incomplete or impending DIOS was defined as a short history (days) of abdominal pain and/or distension and a fecal mass in the ileocecum but without signs of complete obstruction.4 While its clinical features are well known, the paucity of scientific facts on the etiology and pathogenesis is striking. This is largely compensated by an abundant number of anecdotes on the role of nutrition and pancreatic enzyme replacement therapy (PERT),3,5-7 but the relationship between the occurrence of DIOS and nutrition factors such as
energy, protein, fat, liquid and dietary fiber intake, or PERT has not been frequently studied. DIOS is not a life-threatening condition, but it is painful and troublesome because of its high recurrence rate.3,4 Specific preventive measures would therefore be welcome but are not available since the exact etiology and precipitating factors in the development of DIOS are unknown. On the basis of the above, this study has attempted to collect information on the possible relationship between the occurrence of DIOS and nutrition intake or PERT by comparing food and enzyme intake around the first DIOS episode with the intake of the preceding year. The nutrition intake and PERT in patients who had their first DIOS episode were also compared with the intake of matched CF controls. From 1Cystic Fibrosis Centre, Department of Paediatrics, Ghent University Hospital, Belgium. Financial disclosure: None declared. This article originally appeared online on October 6, 2014. Corresponding Author: Dimitri Declercq, MSc, Cystic Fibrosis Centre, Department of Paediatrics, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium. Email: [email protected]
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Table 1. Median Intake of Different Macronutrients and Pancreatic Enzyme Replacement Therapy in the Subgroups. Characteristic Caloric intake, kcal Protein, g Fat, g Fiber, g Water, L Lipase, IU Enzymes, IU/g fat Fat/kg body weight, g
DIOS (n = 12)
Controls (n = 36)
DIOSbefore (n = 12)
Controlsbefore (n = 36)
2735 (1736–3370) 99 (57–140) 114 (75–154) 16 (6–25) 1.8 (0.8–3) 63.75 × 104 (3 × 105–8.75 × 105) 5635 (2080–7868) 2.8 (1.5–5.3)
2759 (1364–3786) 106 (34–186) 123 (55–201) 16 (5–27) 1.6 (0.5–3.3) 52 × 104 (7.5 × 104–125 × 104) 4379 (825–15,162) 2.8 (0.9–5.1)
2638 (1683–3264) 93 (66–140) 96 (*1) (68–139) 17 (10–24) 1.8 (1–3.5) 48.75 × 104 (*2) (22.5 × 104–9 × 105) 5112 (1730–11,204) 2.3 (0.8–5.1)
2590 (1156–3859) 93 (31–141) 109 (*3) (41–176) 13,9 (4.1–39.7) 1.6 (0.2–4) 46.25 × 104 (7.5 × 104–150 × 104) 4191 (1838–12,711) 3.1 (*4) (1.4–7.3)
The range is presented in parentheses. DIOS is a group patients with cystic fibrosis (CF) experiencing a first episode of distal intestinal obstruction syndrome. Controls is an age-, sex-, genotype-, and disease severity–matched group without DIOS. DIOSbefore and Controlsbefore represent the nutrition data from 1 year prior to the study year (n = number of patients). Significant differences: group DIOS vs DIOSbefore: (*1): P = .015; (*2): P = .035; Controls and Controlsbefore: (*3): P = .046; (*4): P < .001.
Materials and Methods Patients with CF (children and adults) at our center (diagnosed by 2 sweat tests and genetic analysis) complete annually a prospective 3-day nutrition and PERT intake diary.8 Based on this diary, intakes of calories, protein, fat, dietary fiber, liquid, and pancreatic enzymes are calculated. The dietitian of the center uses these calculations to give patients dietary advice at least annually on how to adapt their intakes to their individual needs based on the European guidelines for nutrition in CF.9 Patients are advised to spread their enzymes over the meal, approximately one-fourth in the beginning, one-half in the middle, and one-fourth at the end of the meal. At the moment of the first DIOS attack, a retrospective dietary diary was completed by the patient and parents, which was carefully reviewed by the dietitian to evaluate dietary and PERT intake over the last 3 days prior to the attack (DIOS). From the diary data of the annual prospective 3-day intake diary, the data of 1 year before the attack (DIOSbefore) were used to compare with the data at the time of the first DIOS attack. All evaluations of the dietary dairies were performed by the same dietitian, who is associated with the CF center. For each patient with DIOS, 3 controls matched for age, sex, genotype, and disease severity were chosen from the database of the Ghent CF center (controls). The disease severity included pulmonary function, pancreatic function, nutrition status, and CF-related diseases such as diabetes mellitus and liver disease. The dietary diaries from the controls were compared with those of the DIOS patients (DIOS). To evaluate the effect of consecutive dietary advice given at the CF center, the dietary data of the controls from the prior year were compared with the results of the study year (Controlsbefore). All patients’ intakes of calories, protein, fat, dietary fiber, and liquid were calculated with a professional program for
dietary calculations (BECEL version 5.00 [BVP]; 1995 Hartog–Union en Van den Bergh, the Netherlands). The amount of PERT taken per meal was also noted. All patients used Creon Forte (Solvay S.A., Belgium; 25,000 U lipase, 18,000 U amylase, and 1000 U protease per capsule). Patients had been educated to adjust their dose of pancreatic enzymes according to the fat content of the meal and increase the dose in response to the presence of steatorrhea. No information was given on a specific amount of lipase units per gram of fat, and a minimum or maximum dose was not taken into account. Statistical analysis was performed with SPSS version 20 (SPSS, Inc, an IBM Company, Chicago, IL) by using nonparametric tests: the Mann-Whitney U test, Wilcoxon signed rank test, and Kruskal-Wallis test. The study protocol was approved by the Ethics Committee of Ghent University Hospital, 2005/411. Patients were informed about the implications of the study protocol. No objections were made.
Results Over a 6-year period, a first DIOS attack was diagnosed in 12 (DIOS) of 160 patients with CF followed at the CF center. The median age was 18 years (4.4–33.4 years), and 8 were male. All were pancreatic insufficient with a fecal elastase I concentration below 15 µg/g.10 Patients were further classified based on the definitions of the ESPGHAN CF Working Group4: 9 patients had an incomplete and 3 a complete DIOS attack. The median age of the patients in the control group (n = 36) was 18.4 years (2.6–39.1 years), and 24 were male. Table 1 shows the results of the intake of nutrients and pancreatic enzymes in the different groups. Values are presented as median (range). There was no significant difference between DIOS patients and controls for the macronutrient intake.
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However, the DIOS patients had a significantly higher fat intake than did the DIOSbefore patients (P = .015). The median fat intake increased from 96 g/d (68–139) to 114 g/d (75–154) in DIOSbefore and DIOS patients, respectively. An increased intake was seen from 2.3 g/kg body weight (0.8–5.1) to 2.8 g/ kg body weight (1.5–5.3). The absolute daily amount of lipase units taken was also significantly higher in DIOS compared with DIOSbefore (P = .035). However, this significance disappeared when PERT was expressed per gram of ingested fat. The control group displayed the same evolution regarding the fat intake (P = .046). However, the enzyme intake showed only a nonsignificant increasing trend (P = .07). The median intake of pancreatic enzymes, expressed in lipase units, was in all groups above the recommended upper limit of 4000 U lipase/g fat.
Discussion Due to the unexpected occurrence of these DIOS attacks, the collection of retrospective data from the preceding days is the only possible way to get information on nutrition and PERT intake. To minimize the inaccuracy of gathering retrospective data, we double-checked them.8 Patients or their families were asked to complete a retrospective 3-day dietary diary of the days prior to the event at diagnosis, which was then carefully reviewed by a specialized dietitian to verify as much as possible the nutrition regime just before DIOS occurred. The data of these patients from the year before and the control patients were obtained from the more accurate prospective 3-day diaries.8 The only observed difference within the DIOS group was the increased absolute fat and PERT intake at the DIOS attack. This might be explained by the different method in obtaining the data or the fact that, in the intervening year, patients from the DIOS group had constantly been encouraged to increase fat consumption, as it is the general recommendation for nearly all patients with CF. An increased fat intake was also noted in the control group when data of 2 consecutive years were compared. Consequently, enzyme intake is also higher as patients are instructed to align it to the increased fat intake, although this was not significant for the controls. Therefore, the increased enzyme intake could also be a result of the abdominal complaints experienced as part of a developing DIOS. Nutrition or PERT has been blamed in different reports3,5,6,11 to be main causes in the occurrence of DIOS, although there are very few studies looking into this aspect of DIOS. As in constipation, insufficient fiber and/or fluid intake is suggested to be in part responsible for this phenomenon.12 Only 2 studies, with contradicting results, have looked at the potential role of dietary fiber in the occurrence of gastrointestinal complaints but not specifically DIOS.13,14 These studies did not observe any difference in fiber intake before or at the DIOS attack or a difference with the control patients. On the other hand, only 5 patients (1 in the DIOS group, 4 in the
DIOSbefore group) met the recommendations of the American Health Foundation for fiber intake (age range + 5-10g/d).15 Increasing the liquid intake is also often recommended in this context.3,16 However, counting mere fluid intake is probably too simplistic to explain inspissations of ileal content. Although not investigated until now, other factors (eg, temperature or physical activity) could play a role in whether fluid intake is sufficient. This study could not discern any significant difference in liquid intake between the groups. The role of PERT in the development of DIOS provokes the most controversy. Both a presumed deficit3,5,6 and an overdose of more potent enzymes have been blamed,11 although scientific evidence is lacking for both hypotheses. Poorly controlled pancreatic insufficiency was thought to cause more sticky intestinal mucus.3,5,6 Therefore, poor adherence to PERT is suggested to play a promoting role in the development of DIOS.16,17 However, while DIOS is predominantly seen in patients with exocrine pancreatic insufficiency, it has also been reported in pancreatic-sufficient patients with CF.4,18 On the other hand, Littlewood et al19 suggest that the more aggressive treatment with PERT may result in less undigested material in the intestine and thus promote fecal impaction. The latter seems improbable as fiber, the most important nutrient in this aspect, is unaffected by PERT. Lowering PERT to prevent DIOS might, however, not be a good solution as complex interactions occur between the gastrointestinal tract and food. Unabsorbed nutrients, such as undigested fats, delivered to the distal small intestine cause a mechanism called “ileal brake.” It induces an inhibition of gastric and jejunal motility as well as a reduction of gastric acid and pancreatic secretion.20 If excessive pancreatic enzyme supplements had played a contributing role, a rise in the incidence of DIOS would have been expected after the introduction of the more potent acid-resistant, microsphere preparations. This was not the case.21,22 The present study cannot support an impact of PERT on the occurrence of DIOS since no significant difference was found between the DIOS group and their own control or the control group when the intake was expressed as international units (IU) of lipase/g of fat. The more complex etiology of DIOS is suggested by recent research indicating the importance of intrinsic factors rather than inspissations of intestinal luminal contents in the occurrence of this phenomenon. Hydration of the terminal ileum content is, in part, obtained by CFTR activation by apical sodium-dependent bile salt absorption, as demonstrated by Bijvelds et al.23 Smith et al24 also demonstrated the presence of leiomyositis and myenteric ganglionitis in DIOS. These known causes of intestinal dysmotility could enhance any tendency toward intestinal obstruction. This study is limited due to the small patient number and the difference in dietary information gathering at the time of the first DIOS episode compared with the year prior or the control population. In conclusion, the intake of calories, protein, fat, fiber, liquid, and pancreatic enzymes by patients with CF who had a
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first DIOS event was similar to that of matched CF controls. Compared with the intakes of 1 year earlier, similar results were obtained. This study cannot sustain a role for the intake of macronutrients or PERT in the occurrence of a first DIOS attack. Further larger studies are needed to support our findings.
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