Pathophysiology

General considerations

• The CFTR gene encodes the CFTR protein, which is an important component of the ATP-gated chloride channel in cell membranes.

• Mutated CFTR gene → misfolded protein → retention for degradation of the defective protein in the rough endoplasmic reticulum (rER) → absence of ATP-gated chloride channel on the cell surface of epithelial cells throughout the body (e.g., intestinal and respiratory epithelia, sweat glands, exocrine pancreas, exocrine glands of reproductive organs) [6][7]

In sweat glands

• The chloride channel is responsible for transporting Cl- from the lumen into the cell (reabsorption).

• Defective ATP-gated chloride channel → inability to reabsorb Cl- from the lumen of the sweat glands → reduced reabsorption of Na+ and H2O → excessive loss of salt and elevated levels of NaCl in sweat

In all other exocrine glands (e.g., in the GI tract or lungs)

• The chloride channel is responsible for transporting Cl- from the cell into the lumen (secretion).

• Defective ATP-gated chloride channel → inability to transport intracellular Cl- across the cell membrane → reduced secretion of Cl- and H2O → accumulation of intracellular Cl- → ↑ Na+ reabsorption (via ENaC) → ↑ H2O reabsorption → formation of hyperviscous mucus → accumulation of secretions and blockage of small passages of affected organs → chronic inflammation and remodeling → organ damage (see “Clinical features” below)

• ↑ Na+ reabsorption → transepithelial potential difference between interstitial fluid and the epithelial surface increases (i.e., negative charge increases; e.g., from normal -13 mv to abnormal -25 mv)