Porth's Essentials of Pathophysiology, 4e

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Respiratory Function

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of Cl – into airway lumen is impaired. This ultimately leads to a series of secondary events, including increased absorption of Na + and water from the airways into the blood. This lowers the water content of the mucocili- ary blanket coating the respiratory epithelium, causing it to become more viscid. The resulting dehydration of the mucous layer leads to defective mucociliary function and accumulation of viscid secretions that obstruct the airways and predispose to recurrent pulmonary infec- tions. Similar transport abnormalities and pathophysi- ologic events take place in the pancreatic and biliary ducts and in the vas deferens in males. Manifestations Respiratory manifestations of CF are caused by an accumulation of viscid mucus in the bronchi, impaired mucociliary clearance, and lung infections. Chronic bronchiolitis and bronchitis are the initial lung manifes- tations, but after months and years, structural changes in the bronchial wall lead to bronchiectasis. In addi- tion to airway obstruction, the basic genetic defect that occurs with CF predisposes to chronic infection with a surprisingly limited number of organisms, the most common being Pseudomonas aeruginosa, Burkholderia cepacia, Staphylococcus aureus, and Haemophilus influ- enzae. 48–51 Soon after birth, initial infection with bacte- rial pathogens occurs and is associated with an excessive neutrophilic inflammatory response that appears to be independent of the infection itself. There is evidence that the airway secretions in persons with CF provide a favorable environment for harboring these organisms. Pseudomonas aeruginosa, in particular, has a propensity to undergo mucoid transformation in this environment. The complex polysaccharide produced by these organ- isms provides a hypoxic environment and generates a biofilm that protects Pseudomonas against antimicro- bial agents. Pulmonary inflammation is another cause of decline in respiratory function in persons with CF and may precede the onset of chronic infection. Exocrine pancreatic function is abnormal in more than 85% of affected children. 51 Steatorrhea, diarrhea, and abdominal pain are common. In the newborn, meconium ileus may cause intestinal obstruction, a fatal condition if left untreated. The degree of pancreatic involvement is highly variable. In some children, the defect is rela- tively mild, and in others, the involvement is severe and impairs intestinal absorption. In addition to exocrine pancreatic insufficiency, hyperglycemia may occur, espe- cially after 10 years of age, when approximately 8% of persons with CF develop diabetes mellitus. 51 Diagnosis andTreatment Early diagnosis and treatment are important in delaying the onset and severity of chronic illness in children with CF. Diagnosis is based on the presence of respiratory and gastrointestinal manifestations typical of CF, a his- tory of CF in a sibling, or a positive newborn screen- ing test result. Confirmatory laboratory tests include the sweat test and DNA tests for CFTR gene muta- tions. 51 The sweat test, using pilocarpine iontophoresis

Chromosome 7

CFTR gene mutation

Respiratory tract secretions

Airway epithelial cell

Na +

H 2

O

Cl -

Defective Cl - secretion with

excessive Na + and H 2

O absorption

Abnormal thick and viscid respiratory tract secretions

Defective mucociliary clearance

Development of a microenvironment that is protective of microbial agents

Chronic airway obstruction and bacterial infection

Neutrophil influx; release of elastase and inflammatory mediators

Development of chronic bronchitis, bronchiectasis, respiratory failure

FIGURE 23-12. Pathogenesis of cystic fibrosis.

Etiology and Pathogenesis Cystic fibrosis is caused by mutations in a single gene on the long arm of chromosome 7 that encodes for the cystic fibrosis transmembrane regulator (CFTR), which functions as a chloride channel in epithelial cell mem- branes. 49–51 Mutations in the CFTR gene render the epi- thelial membrane relatively impermeable to the chloride (Cl – ) ion (Fig. 23-12). The impact on impaired Cl – transport is relatively tissue specific. In the sweat glands, the concentration of sodium (Na + ) and Cl – secreted into the lumen of the gland remain unaffected, whereas the reabsorption of Cl – through the CFTR and accompanying reabsorption of Na + in the ducts of the gland fail to occur. This defect accounts for the high concentration of NaCl in the sweat of persons with CF. 50,51 In the normal airway epithelium, Cl – is secreted into airway lumen through the CFTR. As shown in Figure 23-12, in persons with CF, the transport