Cystic Fibrosis - Pathophysiology

Pathophysiology

There are several mutations in the CFTR gene, and different mutations cause different defects in the CFTR protein, sometimes causing a milder or more severe disease. These protein defects are also targets for drugs which can sometimes restore their function. ΔF508-CFTR, which occurs in >90% of patients in the U.S., creates a protein that does not fold normally and is degraded by the cell. Other mutations result in proteins that are too short (truncated) because production is ended prematurely. Other mutations produce proteins that do not use energy normally, do not allow chloride, iodide and thiocyanate to cross the membrane appropriately, or are degraded at a faster rate than normal. Mutations may also lead to fewer copies of the CFTR protein being produced.

The protein created by this gene is anchored to the outer membrane of cells in the sweat glands, lungs, pancreas, and all other remaining exocrine glands in the body. The protein spans this membrane and acts as a channel connecting the inner part of the cell (cytoplasm) to the surrounding fluid. This channel is primarily responsible for controlling the movement of halogens from inside to outside of the cell; however, in the sweat ducts it facilitates the movement of chloride from the sweat into the cytoplasm. When the CFTR protein does not work, chloride and thiocyanate are trapped inside the cells in the airway and outside in the skin. Then hypothiocyanite, OSCN, cannot be produced by immune defense system. Because chloride is negatively charged, this creates a difference in the electrical potential inside and outside the cell causing cations to cross into the cell. Sodium is the most common cation in the extracellular space and the combination of sodium and chloride creates the salt, which is lost in high amounts in the sweat of individuals with CF. This lost salt forms the basis for the sweat test.

Most of the damage in CF is due to blockage of the narrow passages of affected organs with thickened secretions. These blockages lead to remodeling and infection in the lung, damage by accumulated digestive enzymes in the pancreas, blockage of the intestines by thick faeces, etc. There are several theories on how the defects in the protein and cellular function cause the clinical effects. One theory is that the lack of halogen and pseudohalogen (mainly, chloride, iodide and thiocyanate) exiting through the CFTR protein leads to the accumulation of more viscous, nutrient-rich mucus in the lungs that allows bacteria to hide from the body's immune system. Another theory is that the CFTR protein failure leads to a paradoxical increase in sodium and chloride uptake, which, by leading to increased water reabsorption, creates dehydrated and thick mucus. Yet another theory is that abnormal chloride movement out of the cell leads to dehydration of mucus, pancreatic secretions, biliary secretions, etc.