Cystic Fibrosis

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Abstract
1. Pamela B. Davis, MD, PhD* 1. 2. *Professor of Pediatrics, Medicine, Molecular Biology & Microbiology, and Physiology & Biophysics, Case Western Reserve University at Rainbow Babies and Children’s Hospital, Cleveland OH. Objectives After completing this article, readers should be able to: 1. Describe cystic fibrosis and outline its pathophysiology. 2. Interpret the “sweat test” as a diagnostic test and compare its value with other diagnostic tests. 3. Describe the relationship between cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel function and disease. 4. List the complications of cystic fibrosis. 5. Outline appropriate therapeutic modalities for the complications of cystic fibrosis. 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 …

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