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Cystic Fibrosis: Introduction
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, >41% of patients are now adults (18 years old) and 13% are past the age of 30. The median survival is >41 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. This disease is characterized by chronic bacterial infection of the airways that ultimately 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 gene that encodes the CF transmembrane conductance regulator (CFTR) protein located on chromosome 7. The mutations in the CFTR gene fall into four major classes, as depicted in Fig. 253-1. Classes I–III mutations are considered “severe,” as indexed by pancreatic insufficiency and high sweat NaCl values (see below). Class IV mutations can be “mild,” i.e., associated with pancreatic sufficiency and intermediate/normal sweat NaCl values. Of note, Class I mutations that encode for premature stop codons are important to identify, as they may in the future be treated with agents that promote “read-through” of the stop codon with production of functional CFTR.
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 CF gene (~70% of CF chromosomes) is a 3-bp deletion (a Class III mutation) that results in an absence of phenylalanine at amino acid position 508 (F508) of the CF gene protein product, known as CFTR. The large number (>1400) of relatively uncommon (<2% each) mutations identified in the CF gene makes it difficult to use DNA diagnostic technologies for identifying heterozygotes in populations at large.
The CFTR protein is a single polypeptide chain, containing 1480 amino acids, that appears to function both as a cyclic AMP–regulated Cl– channel and, as its name implies, a regulator of other ion channels. The fully processed form of CFTR is found in the plasma membrane in normal epithelia. Biochemical studies indicate that the F508 mutation leads to improper processing and intracellular degradation of the CFTR protein. Thus, absence of CFTR in the plasma membrane is central to the molecular pathophysiology of the F508 mutation and other Classes I–II mutations. However, Classes III–IV mutations produce CFTR proteins that are fully processed but are nonfunctional or only partially functional in the plasma membrane.
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.
Cystic Fibrosis: Treatment
The major objectives of therapy for CF are to promote clearance of secretions and control infection in the lung, provide adequate nutrition, and prevent intestinal obstruction. Ultimately, therapies that restore the processing of misfolded mutant CFTR or gene therapy may be the treatments of choice.
Cystic Fibrosis – Genetics
Cystic Fibrosis – Pre- Natal Screening
Cystic Fibrosis – Related Diabetes
Cystic Fibrosis – Pancreas
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