CYSTIC FIBROSIS Pathophysiology (Lung-Specific)

Cystic fibrosis affects many parts of the body. The most notable manifestation is in the lungs and in the pancreas. Patients often suffer from multiple lung infections. The underlying issue is the lack of a crucial protein (the Cystic Fibrosis Transmembrane Conductance Regulator or CFTR) that allows the transport of ions, specifically chloride, between the cells lining the surface of the respiratory system and gastrointestinal tract and the liquid that coats the cells (Figure 2). Under normal conditions, the balance of transport of these ions maintains the hydration of the liquid. One of the components of this liquid is mucus. In people who have CF, chloride ions are not well transported across the cell membranes so the mucus becomes extremely dehydrated and sticks to the surface. What does this mean? If you put soap on your hands to wash off honey versus just trying to wipe your hands off, it makes sense to translate that to the lungs. Inside of the lungs, there are very small fingerlike projections called cilia that move gently to push mucus up and out of the lungs. Pushing very thin and watery mucus is much easier than pushing very thick mucus. Because of this thick and sticky mucus, large pockets start to collect in the lungs and become infected. These pockets of mucus expand and cause scarring inside of the lungs (Figure 3). Additionally, nearly all patients with this disease will have swelling, thickened mucus, and subsequent infection that develop inside of the sinuses. When swelling becomes severe, large bags of watery inflamed skin may form called polyps (Figure 4). This can create even more problems because now there are both mechanical barriers AND thick mucus. People with CF may develop significant sinus pain and infections. Also, the bacteria that grow inside of their sinuses can infect their lungs and worsen the lung disease that is already present.

Figure 2 A diagram representing the most prevalent theory of the biologic basis of airway disease in cystic fibrosis. Although overly simplified, transport of sodium and chloride across the cell membrane works to maintain the hydration of the airway surface liquid. Loss of CFTR chloride channel function results in increased sodium absorption with passive water absorption. The net result is dehydration of

mucus

and

poor

mucociliary

clearance.

Figure 3 Artistic rendering of normal (left of image) and cystic fibrosis (right of image) lungs.

Figure 4 Nasal polyps (big arrow) obstructing the sinuses of a cystic fibrosis patient. Note the green, sticky mucus indicative of cystic fibrosis sinusitis (small arrow).

Another Take on the Summary of Pathophysiology of Mucoviscidosis

Cystic fibrosis is caused by defects in the cystic fibrosis gene, which codes for a protein transmembrane conductance regulator (CFTR) that functions as a chloride channel and is regulated by cyclic adenosine monophosphate (cAMP). Mutations in the CFTR gene result in abnormalities of cAMP-regulated chloride transport across epithelial cells on mucosal surfaces. Six classes of defects resulting from CFTR mutations have been described and are as follows: Complete absence of CFTR protein synthesis Defective protein maturation and early degradation (caused by the most common mutation, F508) Disordered regulation (diminished ATP binding and hydrolysis) Defective chloride conductance or channel gating Diminished transcription due to promoter or splicing abnormality Accelerated channel turnover from the cell surface

CFTR mutations have poor penetrance. This means that the genotype does not predict the pattern or severity of disease. Defective CFTR results in decreased secretion of chloride and increased reabsorption of sodium and water across epithelial cells. The resultant reduced height of epithelial lining fluid and decreased hydration of mucus results in mucus that is stickier to bacteria, which promotes infection and inflammation. Secretions in the respiratory tract, pancreas, GI tract, sweat glands, and other exocrine tissues have increased viscosity, which makes them difficult to clear. Most patients with cystic fibrosis have severe chronic lung disease and exocrine pancreatic insufficiency. Additional manifestations include the following: Nasal polyposis Pansinusitis Rectal prolapsed Chronic diarrhea Pancreatitis Cholelithiasis Cirrhosis or other forms of hepatic dysfunction