Cystic Fibrosis

Objectives After completing this article, readers should be able to: Cystic fibrosis (CF), one of the most common fatal genetic disorders in the United States,is recognized by a classic diagnostic triad of elevated sweat chloride concentration,pancreatic insufficiency, and chronic pulmonary disease, although many other organ systems can be involved. The cause of CF is a defect in a single gene on chromosome 7 that encodes a cAMP-regulated chloride channel called the cystic fibrosis transmembrane conductance regulator (CFTR), which usually resides on the apical membrane of epithelial cells lining the airways, biliary tree, intestines, vas deferens, sweat ducts, and pancreatic ducts. When the chloride ion cannot be transported by CFTR at these sites, fluid secretion is insufficient, and the protein portions of the secretions may become more viscid or precipitate and obstruct the ducts, leading to plugging and dysfunction at the organ level. At the cellular level, CFTR regulates the activity of other proteins that conduct ions and affects intracellular regulatory processes. For example, ordinarily CFTR downregulates activity of the epithelial sodium channel in the airway. In the absence of CFTR function,this downregulation is relieved, and sodium reabsorption increases, contributing to reduction in fluid volume and probably to the airway pathophysiology. CFTR also stimulates an outwardly rectifying chloride conductance that may augment its own chloride transport activity. In the absence of functional CFTR, this conductance also is silent.A number of other systems also are abnormal in CF. For example, epithelial cells lacking CFTR fail to express normal amounts of nitric oxide synthase-2 and, therefore, do not produce normal amounts of the ubiquitous regulator nitric oxide. This lack could contribute to increased sodium reabsorption and exaggerated inflammatory response as well as decreased bacterial killing. Epithelial cells lacking CFTR activity also display abnormal carbohydrate and sialic acid modification of proteins and lipids such as gangliosides; therefore, the surface properties of these cells are abnormal. For example, surface binding sites for Pseudomonas are increased in CF airway epithelial cells. Proinflammatory pathways are upregulated in CF airway epithelial cells, although the precise biochemical mechanisms for this dysregulation are not fully elucidated; it is probably multifactorial. Deficits in interleukin-10 production, inhibition of the Jak-Stat1 signaling cascade, and other abnormalities have been identified in the airways or airway epithelial cells of CF patients and mice. All of these factors can contribute to the cellular pathophysiology of CF in ways that only now are being elucidated and that in the aggregate produce disease.Although the CF disease process commonly involves the sweat ducts, pancreas, and airways, other organs are also affected. Discovery of the CF gene and the ability to perform DNA diagnostics has allowed identification of mutations in CFTR (Fig. 1), less severe at the functional level than the CF-related mutations, that are associated with specific abnormalities, such as congenital bilateral absence of the vas deferens (CBAVD). Some affected patients have two abnormal CF alleles. Persons who have a single abnormal CF allele appear to be at higher risk than the general population for such complications as pancreatitis and sinusitis. Thus, there is some blurring of the borders of what constitutes a CF diagnosis. For the purposes of this review, CF refers to patients who have multiorgan involvement, including the eventual development of pulmonary involvement and pancreatic involvement (if only bicarbonate secretion). Because most patients who have pulmonary disease also have dysfunction of the absorptive function of the sweat duct, the“sweat test” reliably identifies the vast majority of patients who have CF as defined in this review.CF is transmitted in an autosomal recessive pattern, that is, both copies of the CF gene must be abnormal if the patient has the disease. Abnormal CF genes are common among Americans; 4% to 5% have at least one CF allele. Among Caucasians, about 1 in 2,500 live births has CF compared with about 1 in 17,000 among African-Americans and 1 in 90,000 among Asians. Both parents of a child who has CF have at least one abnormal copy of the CF gene. Siblings of an affected child have a one in four chance of having the disease, a one in two chance of having a single abnormal CF allele, and a one in four chance of inheriting no abnormal CF allele. First cousins of a CF patient have about a 1 in 120 chance of having the disease.More than 800 different mutations have been described in the CF gene. The ΔF508 mutation, in which a phenylalanine residue is deleted at position 508 in this 1,480-amino acid protein, is present in about 70% of CF alleles in the United States. Thus,about 50% of American CF patients are homozygous for the ΔF508 mutation. Some mutations are concentrated in particular ethnic groups, such as the A455E mutation in Dutch CF patients and the W1282X mutation in Ashkenazi Jewish patients.The diagnosis of CF is suspected on clinical grounds or from the family history (TableT1). A few states in the United States and several countries screen newborns for CF by measuring immunoreactive trypsin (IRT) in blood. Most infants who have CF have elevated IRT, but there are also many false-positive results (∼80% of positive infants). Therefore, diagnosis must be confirmed by sweat test or by genotyping.Genotyping that reveals two alleles that have CF-causing mutations confirms the diagnosis. Conventional commercial genotyping tests for about 80 specific mutations in CFTR, including ΔF508, and identifies about 95% of all CF alleles. However, among the more than 800 reported CF alleles, many are“private” mutations that occur in only a single family. Thus, a patient in whom two CF alleles are not identified by commercial genotyping still can have CF.The diagnosis also can be made by a sweat chloride concentration greater than 60 mEq/L in the presence of some appropriate clinical manifestation (chronic pulmonary disease, pancreatic insufficiency, or both) or an appropriate family history (sibling or first cousin who has CF). The sweat test is extremely reliable and is an excellent discriminant for CF if it is performed by experienced personnel and the samples are handled carefully to avoid evaporation or contamination. Typically, the sweat test is performed by iontophoresis of pilocarpine into the skin to stimulate sweating. Sweat then is collected on a preweighed filter that is carefully shielded from evaporation or contamination,leached from the filter, and analyzed for chloride by titrametric analysis. Ordinarily, only laboratories certified as Cystic Fibrosis Foundation-accredited centers perform a sufficient number of tests to maintain proficiency. The accuracy of the test is compromised if the volume of sweat collected is less than 50 mg. However,the Wescor® system (Wescor Company, Logan,UT), because it is a closed system that requires no fluid transfers, can provide accurate readings with less sweat. If testing is attempted during the first month of life,the infant may not produce an adequate amount of sweat,and the test will not be useful. Usually, older infants and children produce sufficient sweat with stimulation by iontophoresis of pilocarpine into the skin in a localized area. Technical errors, except for errors in dilution of the sample, tend to produce elevated values, so a“positive” result always must be confirmed by a second test.Among children, very few conditions apart from CF produce sweat chloride concentrations above 60 mEq/L(Fig. 2). They include untreated Addison disease,ectodermal dysplasia, some types of glycogen storage diseases, and untreated hypothyroidism. A few normal adults, however, can have sweat chloride concentrations up to 80 mEq/L, so caution must be exercised in older patients. Very few patients who have CF exhibit sweat chloride values less than 60 mEq/L. Occasionally, in the face of malnutrition and edema, a CF patient will have a normal sweat chloride concentration that reverts to typical elevated values when the malnutrition is corrected. Fewer than 1% of CF patients have sweat chloride concentrations consistently below 60 mEq/L when they are well. Most of these have pancreatic sufficiency early in life and have specific, mild CF mutations in one allele, such as 3849 + 10kB C → T, a splice variant that results in production of very small amounts of otherwise normal CFTR.Many conditions prompt consideration of the diagnosis of CF (TableT1). In infancy, these include meconium ileus,meconium peritonitis, or prolonged jaundice. About 15% of patients who have CF present in the neonatal period with meconium ileus (obstruction of the distal ileum or proximal colon with thickened, viscid meconium). Sometimes, with complete obstruction, the gut may rupture and soil the peritoneum with meconium,resulting in meconium peritonitis. Meconium ileus is virtually diagnostic of CF, so the patient should be treated presumptively as having CF until a valid sweat test or genotyping can be obtained. A few affected infants present with prolonged jaundice. The precise mechanisms by which this jaundice arises are not well-established, but the malabsorption and malnutrition in CF may lead to hepatic steatosis, the disease can give rise to biliary obstruction, and the abnormal mucus secretions in the biliary tree also can contribute to obstruction.Because of their high ratio of surface area to volume,infants who have CF are prone to heat prostration. The frequency of CF infants presenting to Babies Hospital in New York City during the heat wave of 1949 stimulated di Sant’Agnese to study the sweat electrolyte content in CF and ultimately to identify the sweat defect. Because of their high salt loss, infants also may present with hypochloremic alkalosis.During infancy and beyond, a common presentation of CF is failure to thrive. A child who fails to gain weight despite good appetite and especially who produces frequent, bulky, foul-smelling, oily stools should be evaluated for CF. These children may suffer cramps after feeding and begin to avoid food, with resultant diminished oral intake that worsens the malnutrition. There may be excess flatus. These symptoms usually are the result of pancreatic insufficiency, the failure of the pancreas to produce sufficient digestive enzymes to allow breakdown and absorption of fats and protein. Affected infants also may present with hypoproteinemia with or without edema,anemia, and deficiency of the fat-soluble vitamins A, D,E, and K, which are poorly absorbed in the face of massive steatorrhea. Deficiency of vitamin K may contribute to prolonged prothrombin time, especially if it is present in combination with the liver disease of CF. Deficiency of vitamin E can result in shortened red blood cell survival time as well as peripheral neuropathy. Correction of vitamin E deficiency requires supplementation with a special water-miscible form of the vitamin.Much of the malabsorption in untreated CF can be corrected by providing pancreatic enzyme supplements to the patient, usually in microencapsulated form to improve their ability to survive gastric acid. Such supplementation usually restores both linear growth and weight gain. However, rarely is correction complete. If adequate growth cannot be achieved with supplementation of 2,500 U/kg lipase per meal or less, clinicians may consider adding inhibitors of gastric acid production to raise the pH of the intestinal contents and allow the enzymes to work at a pH that is closer to their optimum.Simply adding more pancreatic enzyme supplement is hazardous; high doses can lead to inflammation and strictures in the colon (fibrosing colonopathy).In addition to pancreatic enzyme supplementation and vitamins, patients who have CF require calories in excess of the usual daily requirement for age and need high energy density, which usually implies increased calories in the diet from fat. Provision of normal or high-fat diets also provides essential fatty acids, which are necessary for growth and development.With these approaches to therapy, children who have CF usually grow well. Therefore, diagnosis and treatment of pancreatic insufficiency is critical. Although the gold standard for diagnosis is measurement of pancreatic enzyme activity in duodenal fluid retrieved by intubation of the duodenum, it is such a frequent complication of CF that less invasive tests, such as measurement of stool fat, blood IRT in infants, or serum carotene, often are used. A test documenting the failure to hydrolyze orally administered benzyl-tyrosyl para-aminobenzoic acid to a metabolite that can be absorbed and measured in blood also may be substituted.Involvement of the lung by the CF disease process accounts for much of the morbidity and nearly all the mortality from the disease. Although the lungs are histologically normal at birth, patients soon acquire bacterial infection that is difficult to eradicate. In the first year of life, many types of bacteria, including enteric organisms, can be recovered from the CF infant’s lung, but later in childhood, three organisms predominate: Haemophilus influenzae,Staphylococcus aureus, and Pseudomonas aeruginosa. Haemophilus and Staphylococcusappear and disappear. Staphylococcus reaches maximum prevalence of about 50% at ages 6 to 17 years and declines thereafter, and Haemophilusis most prevalent (about 20% to 25% of patients) at ages 2 to 5 years.Pseudomonas eventually becomes established in the lungs of most CF patients, reaching 80% prevalence by age 18 years. Once established, it is not eradicated despite prolonged intensive antibiotic therapy. 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