Gastrointestinal Complications of Cystic Fibrosis
2012; Elsevier BV; Volume: 11; Issue: 4 Linguagem: Inglês
10.1016/j.cgh.2012.11.006
ISSN1542-7714
AutoresDaniel Gelfond, Drucy Borowitz,
Tópico(s)Infant Nutrition and Health
ResumoThe cystic fibrosis transmembrane regulator protein (CFTR) is an ion channel in the apical surface of epithelial membranes that regulates other ion channels. Dysfunction of CFTR leads to the clinical entity of CF when mutations in CFTR are inherited in an autosomal recessive fashion. Although airway obstruction, inflammation, and infection are usually the most serious consequences of CFTR dysfunction because they lead to respiratory failure, CFTR dysfunction affects the intestinal tract and the pancreatic and hepatobiliary ducts in a similar fashion, leading to significant morbidity. This review outlines pathophysiology and common gastrointestinal ailments in the CF population along with current medical and surgical management. The cystic fibrosis transmembrane regulator protein (CFTR) is an ion channel in the apical surface of epithelial membranes that regulates other ion channels. Dysfunction of CFTR leads to the clinical entity of CF when mutations in CFTR are inherited in an autosomal recessive fashion. Although airway obstruction, inflammation, and infection are usually the most serious consequences of CFTR dysfunction because they lead to respiratory failure, CFTR dysfunction affects the intestinal tract and the pancreatic and hepatobiliary ducts in a similar fashion, leading to significant morbidity. This review outlines pathophysiology and common gastrointestinal ailments in the CF population along with current medical and surgical management. Cystic fibrosis (CF) was reported in patients with gastrointestinal (GI) and nutritional deficits when Dr Dorothy H. Andersen, a pathologist, described autopsy findings in children whose deaths were thought to be due to celiac disease or vitamin A deficiency but who were found to have pancreatic and airway destruction.1Andersen D. Cystic fibrosis of the pancreas and its relation to celiac disease: a clinical and pathological study.Am J Dis Child. 1938; 56: 344-399Crossref Google Scholar Over the years with the growth of technology and biomedical sciences, much has been achieved in terms of further understanding of CF pathophysiology and genetics. In 1989, the cystic fibrosis transmembrane conductance regulator (CFTR) was identified and directly linked to CF.2Riordan J.R. Rommens J.M. Kerem B. et al.Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA.Science. 1989; 245: 1066-1073Crossref PubMed Scopus (6003) Google Scholar CFTR is a cyclic adenosine monophosphate–regulated chloride channel that also regulates the flow of bicarbonate (HCO3−) and other ions across the apical surface of epithelial cells. Dysfunction of CFTR results in altered electrolyte content in the environment external to the surface of epithelial membranes and in desiccation and reduced clearance of secretions from tubular structures lined by affected epithelia. In the sweat gland, CFTR dysfunction leads to inadequate resorption of sodium, chloride, and potassium. There have been great strides in the development of therapeutic interventions to treat nutritional, respiratory, and infectious complications in CF patients, who have overall prolonged life span and quality of life.3Rowe S.M. Miller S. Sorscher E.J. Cystic fibrosis.N Engl J Med. 2005; 352: 1992-2001Crossref PubMed Scopus (808) Google Scholar A novel breakthrough therapy was approved by the Food and Drug Administration (FDA) in the United States in May 2012 that targeted specific dysfunctional protein in CF patients with G551D mutation.4Ramsey B.W. Davies J. McElvaney N.G. et al.A CFTR potentiator in patients with cystic fibrosis and the G551D mutation.N Engl J Med. 2011; 365: 1663-1672Crossref PubMed Scopus (1678) Google Scholar It is likely that more therapeutic interventions specifically targeting a defective cellular pathway or protein will be developed for other mutations, which would enable true disease prevention in patients with CF. CFTR is found throughout all of the epithelia within the GI tract, including pancreatic5Marino C.R. Matovcik L.M. Gorelick F.S. et al.Localization of the cystic fibrosis transmembrane conductance regulator in pancreas.J Clin Invest. 1991; 88: 712-716Crossref PubMed Scopus (259) Google Scholar and hepatobiliary systems.6Cohn J.A. Strong T.V. Picciotto M.R. et al.Localization of the cystic fibrosis transmembrane conductance regulator in human bile duct epithelial cells.Gastroenterology. 1993; 105: 1857-1864Abstract Full Text PDF PubMed Scopus (318) Google Scholar A cephalad to caudad and crypt to villus gradient of CFTR can be demonstrated in intestinal tissue by using detection of mRNA7Strong T.V. Boehm K. Collins F.S. Localization of cystic fibrosis transmembrane conductance regulator mRNA in the human gastrointestinal tract by in situ hybridization.J Clin Invest. 1994; 93: 347-354Crossref PubMed Scopus (224) Google Scholar or protein.8Jakab R.L. Collaco A.M. Ameen N.A. Physiological relevance of cell-specific distribution patterns of CFTR, NKCC1, NBCe1, and NHE3 along the crypt-villus axis in the intestine.Am J Physiol Gastrointest Liver Physiol. 2011; 300: G82-G98Crossref PubMed Scopus (97) Google Scholar The GI manifestations of CF begin in infancy, with some patients presenting with meconium ileus (MI), a neonatal bowel obstruction.9Carlyle B.E. Borowitz D.S. Glick P.L. A review of pathophysiology and management of fetuses and neonates with meconium ileus for the pediatric surgeon.J Pediatr Surg. 2012; 47: 772-781Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar The vast majority of patients with CF have pancreatic insufficiency (PI), which is seen early in life in most patients with F508del or other "severe" mutations.10Walkowiak J. Sands D. Nowakowska A. et al.Early decline of pancreatic function in cystic fibrosis patients with class 1 or 2 CFTR mutations.J Pediatr Gastroenterol Nutr. 2005; 40: 199-201Crossref PubMed Scopus (60) Google Scholar Some of the clinical GI symptoms attributed to the intestinal and hepatobiliary systems are not exclusive to the CF population; however, there are unique features of CF in the GI tract that lead to a higher burden of GI complications in individuals with CF compared with the general population. This review will outline common GI ailments in the CF population along with the accepted medical and surgical management. The most common mutation of the CFTR gene is F508del, a 3 base-pair deletion of a phenylalanine residue at amino acid position 508 of CFTR. By the new nomenclature, its protein name is p.Phe508del, and its cDNA name is 1521_1523delCTT; it was previously termed ΔF508. In the United States, 48% of patients are homozygous for F508del, and 40% are heterozygous.11Cystic Fibrosis FoundationCystic Fibrosis Foundation Patient Registry, 2011 annual data report to the center directors. Cystic Fibrosis Foundation, Bethesda, MD2011Google Scholar Although there is no correlation between genotype and respiratory phenotype, genotype strongly predicts pancreatic functional status.12Ahmed N. Corey M. Forstner G. et al.Molecular consequences of cystic fibrosis transmembrane regulator (CFTR) gene mutations in the exocrine pancreas.Gut. 2003; 52: 1159-1164Crossref PubMed Scopus (140) Google Scholar Patients with PI tend to have class I–III mutations (those that result in CFTR that is absent or nonfunctional at the cell surface, "severe" mutations), and those with pancreatic sufficiency (PS) tend to have class IV–V mutations (those with partially functional CFTR at the cell surface)13Rowntree R.K. Harris A. The phenotypic consequences of CFTR mutations.Ann Hum Genet. 2003; 67: 471-485Crossref PubMed Scopus (276) Google Scholar (Figure 1). The earliest GI manifestation of CF is MI, a neonatal bowel obstruction. The most common genotypes in infants with MI are severe mutations (F508del, G542X, W1282X, R553X, G551D), although most patients with these mutations do not present with MI.9Carlyle B.E. Borowitz D.S. Glick P.L. A review of pathophysiology and management of fetuses and neonates with meconium ileus for the pediatric surgeon.J Pediatr Surg. 2012; 47: 772-781Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar Recent genome-wide association studies have been able to account for approximately 17% of the phenotypic variability,14Strug L. Symposium summaries: S19.1 the genetics basis of meconium ileus.Pediatric Pulmonology. 2011; 46: 200-201Google Scholar implying that other non-CFTR genetic factors also contribute to this clinical presentation. Despite difficulties in diagnosing liver disease in CF, the prevalence of cirrhosis is between 2% and 15%.11Cystic Fibrosis FoundationCystic Fibrosis Foundation Patient Registry, 2011 annual data report to the center directors. Cystic Fibrosis Foundation, Bethesda, MD2011Google Scholar, 15Colombo C. Russo M.C. Zazzeron L. et al.Liver disease in cystic fibrosis.J Pediatr Gastroenterol Nutr. 2006; 43: S49-S55Crossref PubMed Scopus (83) Google Scholar, 16Lindblad A. Glaumann H. Strandvik B. Natural history of liver disease in cystic fibrosis.Hepatology. 1999; 30: 1151-1158Crossref PubMed Scopus (260) Google Scholar Although more commonly associated with mutations predictive of PI, no specific CFTR mutations are directly predictive of cystic fibrosis-related liver disease (CFLD).17Wilschanski M. Rivlin J. Cohen S. et al.Clinical and genetic risk factors for cystic fibrosis-related liver disease.Pediatrics. 1999; 103: 52-57Crossref PubMed Scopus (111) Google Scholar Modifier genes such as the SERPINA1 Z allele increase the risk of CFLD,18Bartlett J.R. Friedman K.J. Ling S.C. et al.Genetic modifiers of liver disease in cystic fibrosis.JAMA. 2009; 302: 1076-1083Crossref PubMed Scopus (240) Google Scholar but this does not account for the majority of affected patients. A new tool for patients and clinicians to explore different genotypes is CFTR2, an international, curated database of CF mutations (http://www.CFTR2.org). More than 85% of patients who are cared for at U.S. Cystic Fibrosis Foundation–accredited centers take exogenous pancreatic enzyme supplements on a routine basis.11Cystic Fibrosis FoundationCystic Fibrosis Foundation Patient Registry, 2011 annual data report to the center directors. Cystic Fibrosis Foundation, Bethesda, MD2011Google Scholar PI leads to maldigestion and malabsorption of nutrients. The long-term sequelae of malnutrition are significant and include permanent stunting of stature,19Farrell P.M. Kosorok M.R. Laxova A. et al.Nutritional benefits of neonatal screening for cystic fibrosis: Wisconsin Cystic Fibrosis Neonatal Screening Study Group.N Engl J Med. 1997; 337: 963-969Crossref PubMed Scopus (345) Google Scholar, 20Farrell P.M. Kosorok M.R. Rock M.J. et al.Early diagnosis of cystic fibrosis through neonatal screening prevents severe malnutrition and improves long-term growth: Wisconsin Cystic Fibrosis Neonatal Screening Study Group.Pediatrics. 2001; 107: 1-13Crossref PubMed Scopus (416) Google Scholar cognitive dysfunction linked to vitamin E deficiency,21Koscik R.L. Farrell P.M. Kosorok M.R. et al.Cognitive function of children with cystic fibrosis: deleterious effect of early malnutrition.Pediatrics. 2004; 113: 1549-1558Crossref PubMed Scopus (123) Google Scholar, 22Koscik R.L. Lai H.J. Laxova A. et al.Preventing early, prolonged vitamin E deficiency: an opportunity for better cognitive outcomes via early diagnosis through neonatal screening.J Pediatr. 2005; 147: S51-S56Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar and more rapid decline in pulmonary function.23Konstan M.W. Butler S.M. Wohl M.E. et al.Growth and nutritional indexes in early life predict pulmonary function in cystic fibrosis.J Pediatr. 2003; 142: 624-630Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar, 24Peterson M.L. Jacobs Jr, D.R. Milla C.E. Longitudinal changes in growth parameters are correlated with changes in pulmonary function in children with cystic fibrosis.Pediatrics. 2003; 112: 588-592Crossref PubMed Scopus (132) Google Scholar, 25Steinkamp G. Wiedemann B. Relationship between nutritional status and lung function in cystic fibrosis: cross sectional and longitudinal analyses from the German CF quality assurance (CFQA) project.Thorax. 2002; 57: 596-601Crossref PubMed Scopus (230) Google Scholar, 26Lai H.J. Shoff S.M. Farrell P.M. et al.Recovery of birth weight z score within 2 years of diagnosis is positively associated with pulmonary status at 6 years of age in children with cystic fibrosis.Pediatrics. 2009; 123: 714-722Crossref PubMed Scopus (78) Google Scholar, 27Zemel B.S. Jawad A.F. FitzSimmons S. et al.Longitudinal relationship among growth, nutritional status, and pulmonary function in children with cystic fibrosis: analysis of the Cystic Fibrosis Foundation National CF Patient Registry.J Pediatr. 2000; 137: 374-380Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar, 28Stallings V.A. Stark L.J. Robinson K.A. et al.Evidence-based practice recommendations for nutrition-related management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a systematic review.J Am Diet Assoc. 2008; 108: 832-839Abstract Full Text Full Text PDF PubMed Scopus (501) Google Scholar PI patients require lifelong pancreatic enzyme supplements; therefore, it is important to define pancreatic functional status. In the past, tests to determine pancreatic functional status have been invasive (such as duodenal intubation and pancreatic stimulation) or unpleasant (such as determination of a coefficient of fat absorption) and required that patients discontinue pancreatic enzyme supplements during the test. In patients with CF, a human enzyme-linked immunosorbent assay for fecal elastase has been shown to be an excellent indicator of PI, with a sensitivity of 98%–100% and a specificity of 93%–100%, even while patients are taking pancreatic enzyme supplements.29Walkowiak J. Faecal elastase-1: clinical value in the assessment of exocrine pancreatic function in children.Eur J Pediatr. 2000; 159: 869-870Crossref PubMed Scopus (39) Google Scholar, 30Beharry S. Ellis L. Corey M. et al.How useful is fecal pancreatic elastase 1 as a marker of exocrine pancreatic disease?.J Pediatr. 2002; 141: 84-90Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar Fecal elastase can be performed on a random single stool sample and does not require special specimen handling. A serum test for trypsinogen can also be used to diagnose PI in patients with CF who are older than 8 years.31Couper R.T. Corey M. Moore D.J. et al.Decline of exocrine pancreatic function in cystic fibrosis patients with pancreatic sufficiency.Pediatr Res. 1992; 32: 179-182Crossref PubMed Scopus (63) Google Scholar The treatment of PI with pancreatic enzyme replacement therapy (PERT) that is taken with every meal and snack is life sustaining and can help prevent the most severe consequences of CF. Pancreatic enzyme preparations of porcine or bovine origin were available in the United States for treatment of PI before the enactment of the Federal Food, Drug, and Cosmetic Act of 1938. As such, these products previously were not subject to the New Drug Application32Baker S.S. Borowitz D. Duffy L. et al.Pancreatic enzyme therapy and clinical outcomes in patients with cystic fibrosis.J Pediatr. 2005; 146: 189-193Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar process described in the Code of Federal Regulations (21 CFR part 314). However, in 2004, after determining that PERT products did not meet the requirements of an over-the-counter preparation, the FDA announced that all PERT products must go through a New Drug Application process. As a result, every company marketing PERT products in the United States before April 2004 as well as those seeking marketing authorization for new PERT products was required to conduct clinical trials demonstrating efficacy and safety. As of 2012, five oral delayed-release pancreatic enzyme products have received FDA approval for treatment of PI. The recommended enzyme dose range should be less than 2500 lipase units/kg per meal or less than 4000 lipase units/g fat per day.33Sinaasappel M. Stern M. Littlewood J. et al.Nutrition in patients with cystic fibrosis: a European Consensus.J Cyst Fibros. 2002; 1: 51-75Abstract Full Text Full Text PDF PubMed Scopus (383) Google Scholar Weight-based enzyme dosing should begin at 500 lipase units/kg/meal for those older than 4 years.34Borowitz D.S. Grand R.J. Durie P.R. Use of pancreatic enzyme supplements for patients with cystic fibrosis in the context of fibrosing colonopathy: Consensus Committee.J Pediatr. 1995; 127: 681-684Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar No true dose-response studies have been conducted. PERTs are given with every meal and snack. Usually half the standard dose is given with snacks. In the registration studies for currently marketed PERTs, the products were given at the start of the meal. One study of older preparations suggested that some people with CF may benefit from distributing the dose throughout the meal.35Domínguez-Muñoz J.E. Iglesias-García J. Iglesias-Rey M. et al.Effect of the administration schedule on the therapeutic efficacy of oral pancreatic enzyme supplements in patients with exocrine pancreatic insufficiency: a randomized, three-way crossover study.Aliment Pharmacol Ther. 2005; 21: 993-1000Crossref PubMed Scopus (133) Google Scholar There is no ideal dosing strategy for patients who use nocturnal tube feedings. Most patients take their usual meal dose before tube feedings, and some add additional PERT doses in the middle or end of the feeding. The microencapsulated beads in delayed-release PERT should not be crushed to prevent inactivation of the enzymes within. The activity of most pancreatic enzymes, particularly pancreatic lipase/colipase, is greatly impaired in an acidic intraluminal environment; therefore, most commercially available PERTs are coated with an acid-resistant film to prevent the pancreatic enzymes from being denatured within the acidic environment of the stomach. Duodenal pH is regulated by high-volume, bicarbonate-rich pancreatic secretions and intestinal bicarbonate secretion, which neutralize gastric acid. In the pancreatic duct, CFTR may function directly as a bicarbonate channel that enables secretion of bicarbonate at high concentrations.36Park H.W. Nam J.H. Kim J.Y. et al.Dynamic regulation of CFTR bicarbonate permeability by [Cl-]i and its role in pancreatic bicarbonate secretion.Gastroenterology. 2010; 139: 620-631Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar Mouse models have demonstrated duodenal bicarbonate secretion by the epithelium by electroneutral secretion via a CFTR-assisted Cl−/HCO3− exchange process and electrogenic secretion of HCO3− via a CFTR conductance pathway.37Clarke L.L. Harline M.C. Dual role of CFTR in cAMP-stimulated HCO3 secretion across murine duodenum.Am J Physiol. 1998; 274: G718-G726Google Scholar In patients with CF, reduced duodenal bicarbonate secretion38Gelfond D. Ma C. Semler J. et al.Intestinal pH and gastrointestinal transit profiles in cystic fibrosis patients measured by wireless motility capsule.Dig Dis Sci. 2012 17 May; ([Epub ahead of print])Google Scholar may fail to neutralize gastric acid and thereby prevent or delay dissolution of the enteric coating until the microspheres have passed the major absorptive surface area in the duodenum and jejunum. In theory, duodenal pH can be made more alkaline by inhibiting gastric acid secretion with the use of H2-receptor antagonists or proton pump inhibitors.39DiMagno E.P. Gastric acid suppression and treatment of severe exocrine pancreatic insufficiency.Best Pract Res Clin Gastroenterol. 2001; 15: 477-486Crossref PubMed Scopus (38) Google Scholar In CF patients, gastric acid suppression by proton pump inhibitors may decrease malabsorption.40Proesmans M. De Boeck K. Omeprazole, a proton pump inhibitor, improves residual steatorrhoea in cystic fibrosis patients treated with high dose pancreatic enzymes.Eur J Pediatr. 2003; 162: 760-763Crossref PubMed Scopus (70) Google Scholar, 41Tran T.M. Van den Neucker A. Hendriks J.J. et al.Effects of a proton-pump inhibitor in cystic fibrosis.Acta Paediatr. 1998; 87: 553-558Crossref PubMed Google Scholar, 42Hendriks J.J. Kester A.D. Donckerwolcke R. et al.Changes in pulmonary hyperinflation and bronchial hyperresponsiveness following treatment with lansoprazole in children with cystic fibrosis.Pediatr Pulmonol. 2001; 31: 59-66Crossref PubMed Scopus (14) Google Scholar Fibrosing colonopathy, a severe intestinal fibrotic process associated with strictures and in some cases ascites, has been reported in patients who took large doses of PERTs.43FitzSimmons S.C. Burkhart G.A. Borowitz D. et al.High-dose pancreatic-enzyme supplements and fibrosing colonopathy in children with cystic fibrosis.N Engl J Med. 1997; 336: 1283-1289Crossref PubMed Scopus (224) Google Scholar This epidemic led to the upper limit on PERT dosing described above. Hyperuricosuria44Stapleton F.B. Kennedy J. Nousia-Arvanitakis S. et al.Hyperuricosuria due to high-dose pancreatic extract therapy in cystic fibrosis.N Engl J Med. 1976; 295: 246-248Crossref PubMed Scopus (77) Google Scholar and allergic reactions45Chamarthy L.M. Reinstein L.J. Schnapf B. et al.Desensitization to pancreatic enzyme intolerance in a child with cystic fibrosis.Pediatrics. 1998; 102: e13Crossref PubMed Scopus (12) Google Scholar have been reported as adverse effects of PERT but are rare. Because PERTs are biologics, there has been concern about porcine-derived viruses46Cherney B. Viral safety issues for the pancreatic enzyme product CREON.http://www.fda.gov/ohrms/dockets/ac/08/slides/2008-4402s1-02-FDA-Cherney%20.pdfGoogle Scholar; however, no human disease has been reported. PS patients are more likely to have mild rather than severe CFTR genotypes. Although these patients tend to be diagnosed at an older age and have lower sweat chloride levels and better lung function than those who are PI, they are at risk for pancreatitis. Approximately 10% of PS patients will develop pancreatitis.47Walkowiak J. Lisowska A. Blaszczyński M. The changing face of the exocrine pancreas in cystic fibrosis: pancreatic sufficiency, pancreatitis and genotype.Eur J Gastroenterol Hepatol. 2008; 20: 157-160Crossref PubMed Scopus (65) Google Scholar In one study, genotypes associated with mild PI prevalence scores had a hazard ratio of 2.4 for pancreatitis (P = .006).48Ooi C.Y. Dorfman R. Cipolli M. et al.Type of CFTR mutation determines risk of pancreatitis in patients with cystic fibrosis.Gastroenterology. 2011; 140: 153-161Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar In PS patients, pancreatic acinar tissue is preserved, but there is decreased ductal flow.49Kopelman H. Forstner G. Durie P. et al.Origins of chloride and bicarbonate secretory defects in the cystic fibrosis pancreas, as suggested by pancreatic function studies on control and CF subjects with preserved pancreatic function.Clin Invest Med. 1989; 12: 207-211PubMed Google Scholar If flow becomes more diminished, there can be scattered ductal obstruction that leads to enzymatic breakdown with trypsin activation and local inflammation modulated by interleukin-1, tumor necrosis factor, and platelet-activating factor. Systemic inflammation ensues with cytokines released by the Kupffer cells of the liver and in other organs if the patient progresses to multisystem organ failure. Treatment of recurrent acute or chronic pancreatitis in patients with CF is similar to the approach in those without CF. Hydration is a cornerstone along with management of pain, preferably with non-narcotic analgesics. Narcotic analgesics can precipitate increasing obstipation and potentially distal intestinal obstruction syndrome (DIOS). An exclusively fat-free diet may be needed acutely but should not be used for a prolonged period of time. More recent recommendations are strongly in favor of early enteral nutrition with close clinical and laboratory observation.50McClave S.A. Chang W.K. Dhaliwal R. et al.Nutrition support in acute pancreatitis: a systematic review of the literature.JPEN J Parenter Enteral Nutr. 2006; 30: 143-156Crossref PubMed Scopus (217) Google Scholar, 51Ioannidis O. Lavrentieva A. Botsios D. Nutrition support in acute pancreatitis.JOP. 2008; 9: 375-390PubMed Google Scholar Stones and microlithiasis originating from the gallbladder can trigger or further aggravate pancreatitis by obstructing the pancreatic duct and/or refluxing bile into the pancreatic duct. Pharmacologic intervention with ursodeoxycholic acid might be of benefit in reducing biliary cholesterol precipitation and stone formation.52Venneman N.G. van Brummelen S.E. van Berge-Henegouwen G.P. et al.Microlithiasis: an important cause of "idiopathic" acute pancreatitis?.Ann Hepatol. 2003; 2: 30-35Crossref PubMed Google Scholar It is important to minimize invasive testing and excessive cross-sectional imaging studies (which can be misleading). Of note, large cysts (pancreatic cystosis) can be seen in asymptomatic patients with CF and do not need drainage.53Berrocal T. Pajares M.P. Zubillaga A.F. Pancreatic cystosis in children and young adults with cystic fibrosis: sonographic, CT, and MRI findings.AJR Am J Roentgenol. 2005; 184: 1305-1309Crossref PubMed Scopus (39) Google Scholar There are no clear guidelines concerning endoscopic retrograde pancreatography, cholecystectomy or other surgical interventions, or celiac block for chronic pancreatitis. Adults with CF and PS should be discouraged from excessive alcohol ingestion. Gastroesophageal reflux disease (GERD) is reported in 30% of adult patients in the Cystic Fibrosis Patient Registry,54Cystic Fibrosis FoundationCystic Fibrosis Foundation Patient Registry, 2010 annual data report to the center directors. Cystic Fibrosis Foundation, Bethesda, MD2010Google Scholar and reflux symptoms are common. In one survey of 201 adults with CF, heartburn, acid brash, dysphagia, and dyspepsia were reported on a daily basis in 24% of patients; an additional 39% had occasional symptoms.55Sabati A.A. Kempainen R.R. Milla C.E. et al.Characteristics of gastroesophageal reflux in adults with cystic fibrosis.J Cyst Fibros. 2010; 9: 365-370Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar In another survey of 50 adults with CF, 94% had symptoms.56Ledson M.J. Tran J. Walshaw M.J. Prevalence and mechanisms of gastro-oesophageal reflux in adult cystic fibrosis patients.J R Soc Med. 1998; 91: 7-9Crossref PubMed Scopus (90) Google Scholar The principal mechanism causing GERD is transient (inappropriate) lower esophageal sphincter relaxation (TLESR), with gastric contents refluxing to the esophagus and causing clinical symptoms of pain and discomfort. This basic mechanism of GERD is the same in CF patients as in healthy controls, with equal numbers of TLESRs seen in both groups. However, TLESRs led to more frequent and more proximal reflux events in patients with CF, which were likely compounded by the underlying respiratory disease and its effect on the thoracic segment of the esophagus and lower esophageal sphincter. In one study that used 13C-octanoic acid breath testing that analyzed exhaled percentage of 13CO2 over an hour, delayed gastric emptying was seen in one-third of patients with CF, not all of whom had GERD.57Pauwels A. Blondeau K. Mertens V. et al.Gastric emptying and different types of reflux in adult patients with cystic fibrosis.Aliment Pharmacol Ther. 2011; 34: 799-807Crossref PubMed Scopus (48) Google Scholar In patients with GERD, those with delayed gastric emptying had increased numbers of reflux events and esophageal acid and bile exposure. There is a well-recognized relationship between GERD and chronic obstructive pulmonary disease.58Rabinovich R.A. MacNee W. Chronic obstructive pulmonary disease and its comorbidities.Br J Hosp Med (Lond). 2011; 72: 137-145Crossref PubMed Scopus (17) Google Scholar It has been suggested that pathologic reflux is associated with worse pulmonary outcome in patients with CF.59Navarro J. Rainisio M. Harms H.K. et al.Factors associated with poor pulmonary function: cross-sectional analysis of data from the ERCF—European Epidemiologic Registry of Cystic Fibrosis.Eur Respir J. 2001; 18: 298-305Crossref PubMed Scopus (146) Google Scholar, 60Stringer D.A. Sprigg A. Juodis E. et al.The association of cystic fibrosis, gastroesophageal reflux, and reduced pulmonary function.Can Assoc Radiol J. 1988; 39: 100-102PubMed Google Scholar, 61Palm K. Sawicki G. Rosen R. The impact of reflux burden on Pseudomonas positivity in children with cystic fibrosis.Pediatr Pulmonol. 2012; 47: 582-587Crossref PubMed Scopus (46) Google Scholar However, there is poor correlation between severity of GERD symptoms and forced expiratory volume in 1 second or forced vital capacity in the adult population.62Sabati A.A. Kempainen R.R. Milla C.E. et al.Characteristics of gastroesophageal reflux in adults with cystic fibrosis.J Cyst Fibros. 2010; 9: 365-370Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar Other complications of GERD have been reported in patients with CF, mostly in sporadic cases. These include esophagitis and strictures60Stringer D.A. Sprigg A. Juodis E. et al.The association of cystic fibrosis, gastroesophageal reflux, and reduced pulmonary function.Can Assoc Radiol J. 1988; 39: 100-102PubMed Google Scholar, 63Bendig D.W. Seilheimer D.K. Wagner M.L. et al.Complications of gastroesophageal reflux in patients with cystic fibrosis.J Pediatr. 1982; 100: 536-540Abstract Full Text PDF PubMed Scopus (53) Google Scholar and Barrett's esophagus.64Hassall E. Israel D.M. Davidson A.G. et al.Barrett's esophagus in children with cy
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