Cystic fibrosis (CF) is an autosomal recessive exocrinopathy affecting multiple epithelial tissues. The gene product responsible for CF (the cystic fibrosis transmembrane conductance regulator [CFTR]) serves as an anion channel in the apical (luminal) plasma membranes of epithelial cells and regulates volume and composition of exocrine secretion. An increasingly sophisticated understanding of CFTR molecular genetics and membrane protein biochemistry has facilitated CF drug discovery, with a number of new agents recently approved or advancing through the clinical testing phase.
The major morbidity and mortality associated with CF is attributable to respiratory compromise, characterized by copious hyperviscous and adherent pulmonary secretions that obstruct small and medium-sized airways. CF airway secretions are exceedingly difficult to clear, and a complex bacterial flora that includes Staphylococcus aureus, Haemophilus influenzae, and Pseudomonas aeruginosa (among other pathogens) is routinely cultured from CF sputum. Microbiome analysis has identified hundreds of other bacterial species in CF lungs, although their relationship to pulmonary failure remains to be determined. Robust pulmonary inflammation in the setting of inspissated mucus and chronic bacterial infection leads to collateral tissue injury and further aggravates respiratory decline. Organisms such as P. aeruginosa exhibit a stereotypic mode of pathogenesis; a sentinel and early colonization event often engenders lifelong pulmonary infection by the same genetic strain. Over a period of many years, P. aeruginosa evolves in CF lungs to adopt a mucoid phenotype (attributable to release of alginate exoproduct) that confers selective advantage for the pathogen and poor prognosis for the host. Strategies to eradicate P. aeruginosa early in the course of disease have been successful and are thought to improve prognosis significantly if sustained.
The complete name of the disease, cystic fibrosis of the pancreas, refers to profound tissue destruction of the exocrine pancreas, with fibrotic scarring and/or fatty replacement, cyst proliferation, loss of acinar tissue, and ablation of normal pancreatic architecture. As in the lung, tenacious exocrine secretions (sometimes termed concretions) obstruct pancreatic ducts and impair production and flow of digestive enzymes to the duodenum. The sequelae of exocrine pancreatic insufficiency include chronic malabsorption, poor growth, fat-soluble vitamin insufficiency, high levels of serum immunoreactive trypsinogen (a diagnostic test used in newborn screening), and loss of pancreatic islet cell mass. CF-related diabetes mellitus is a manifestation in over 30% of adults with the disease and is likely multifactorial in nature (attributable to progressive destruction of the endocrine pancreas, insulin resistance due to stress hormones, and additional factors).
Other Organ System Damage
As in CF lung and pancreas, thick and tenacious secretions compromise numerous other exocrine tissues. Obstruction of intrahepatic bile ducts and parenchymal fibrosis are commonly observed in pathologic specimens, with multilobular cirrhosis in 4–15% of patients with CF and significant hepatic insufficiency as a resulting manifestation among adults. Contents of the intestinal lumen are ...