Cystic fibrosis (CF) is a monogenic disorder that presents as a multisystem disease. The first signs and symptoms typically occur in childhood, but about 5% of patients in the United States are diagnosed as adults. Due to improvements in therapy, >46% of patients are now adults (≥18 years old) and 16.4% are past the age of 30. The median survival is >37.4 years for patients with CF; thus, CF is no longer only a pediatric disease, and internists must be prepared to recognize and treat its many complications. CF is characterized by chronic bacterial infection of the airways that leads to bronchiectasis and bronchiolectasis, exocrine pancreatic insufficiency and intestinal dysfunction, abnormal sweat gland function, and urogenital dysfunction.
CF is an autosomal recessive disease resulting from mutations in the CFTR gene located on chromosome 7. The mutations in the CFTR gene fall into five major classes, as depicted in Fig. 259-1. Classes I–III mutations are considered "severe," as indexed by pancreatic insufficiency and high sweat NaCl values (see below). Class IV and V mutations can be "mild," i.e., associated with pancreatic sufficiency and intermediate/normal sweat NaCl values.
Schema describing classes of genetic mutations in CFTR gene and effects on CFTR protein/function. Note the ΔF508 mutation is a class II mutation and, like class I mutations, would be predicted to produce no mature CFTR protein in the apical membrane. CFTR, cystic fibrosis transmembrane conductance regulator.
The prevalence of CF varies with the ethnic origin of a population. CF is detected in approximately 1 in 3000 live births in the Caucasian population of North America and northern Europe, 1 in 17,000 live births of African Americans, and 1 in 90,000 live births of the Asian population of Hawaii. The most common mutation in the CFTR gene (~70% of CF chromosomes) is a 3-bp deletion (a class II mutation) that results in an absence of phenylalanine at amino acid position 508 (ΔF508) of the CF gene protein product, known as cystic fibrosis transmembrane conductance regulator (CFTR). The large number (>1500) of relatively uncommon (<2% each) mutations identified in the CFTR gene makes genetic testing challenging.
The CFTR protein is a single polypeptide chain, containing 1480 amino acids, that functions both as a cyclic AMP–regulated Cl− channel and a regulator of other ion channels. The fully processed form of CFTR localizes to the plasma membrane in normal epithelia. Biochemical studies indicate that the ΔF508 mutation leads to improper maturation and intracellular degradation of the mutant CFTR protein. Thus, absence of CFTR in the plasma membrane is central to the molecular pathophysiology of the ΔF508 mutation and other classes I–II mutations. Classes III–IV mutations produce CFTR proteins that are fully processed but are nonfunctional or only partially functional in the plasma membrane. Class V mutations include splicing mutations that produce small amounts of functional CFTR.
The epithelia affected by CF exhibit different functions in their native state, i.e., some are volume-absorbing (airways and distal intestinal epithelia), and some are salt- but not volume-absorbing (sweat duct), whereas others are volume-secretory (proximal intestine and pancreas). Given this diversity of native activities, it is not surprising that CF produces organ-specific effects on electrolyte and water transport. However, the unifying concept is that all affected tissues express abnormal ion transport function.
The diagnostic biophysical hallmark of CF airway epithelia is the raised transepithelial electric potential difference (PD), which reflects both the rate of active ion transport and epithelial resistance to ion flow. CF airway epithelia exhibit abnormalities in both active Cl− secretion and Na+ absorption (Fig. 259-2). The Cl− secretory defect reflects the absence of cyclic AMP–dependent kinase and protein kinase C–regulated Cl− transport mediated by CFTR itself. An important observation is that there is also a molecularly distinct Ca2+-activated Cl− channel (CaCC, TMEM16a) expressed in the apical membrane. This channel can substitute for CFTR with regard to Cl− secretion and is a potential therapeutic target. The abnormal Na+ transport reflects a second function of CFTR, its function as a tonic inhibitor of the epithelial Na+ channel. The molecular mechanisms mediating this action of CFTR remain unknown.
Comparison of ion transport properties of normal (top) and CF (bottom) airway epithelia. The vectors describe routes and magnitudes of Na+ and Cl− transport that is accompanied by osmotically driven water flow. The normal basal pattern for ion transport is absorption of Na+ from the lumen via an amiloride-sensitive epithelial Na+ channel (ENaC) composed of α, β, and γ ENaC subunits. This process is accelerated in CF. The capacity to initiate cyclic AMP–mediated Cl− secretion is diminished in CF airway epithelia due to abnormal maturation/dysfunction of the CFTR Cl− channel. The accelerated Na+ absorption in CF reflects the absence of CFTR inhibitory effects on Na+ channels. A Ca2+-activated Cl− channel, likely a product of the TMEM16a gene, is expressed in normal and CF apical membranes and can be activated by extracellular ATP. Horizontal arrows depict velocity of mucociliary clearance (μm/sec).
Mucus clearance is the primary innate airways defense mechanism against infection by inhaled bacteria. Normal airways vary the rates of active Na+ absorption and Cl− secretion to adjust the volume of liquid (water), i.e., "hydration," on airway surfaces for efficient mucus clearance. The central hypothesis of CF airways pathophysiology is that the faulty regulation of Na+ absorption and inability to secrete Cl− via CFTR ...