Cystic Fibrosis

  • Genetics
    • Autosomal recessive; defect in CFTR gene on chromosome 7; commonly a deletion of ΔF508, causing impaired post-translational processing (improper folding and glycosylation of CFTR, which is detected by the endoplasmic reticulum. Certain drugs (eg, lumacraftor), can partially correct this folding defect, leading to expression of functional CFTR. Other less common mutations are:
      • Decreased production of functionally normal CFTR (reduced mRNA or protein stability) – milder
      • Impaired chloride conduction through CFTR
      • Premature termination of transmembrane protein (nonsense, frameshift) – common in Ashkenazi Jews
      • Reduced ability or the channel to open.
  • Most common lethal genetic disease in Caucasian population.
  • Pathophysiology
    • CFTR encodes an ATP-gated Cl− channel that:
      • Secretes ATP-dependent Cl− release into mucosal surfaces, establishing a membrane potential that encourages sodium & water secretion,  and inhibits epithelial sodium channel (decreases sodium reabsorption) in lungs and GI tract, forming well-hydrated mucus
      • Reabsorbs Cl− in sweat glands, stimulates epithelial sodium channel to increase sodium reabsorption from the lumen
    • Most common mutation → misfolded protein → protein retained in RER and not transported to cell membrane, causing ↓Cl− (and H2O) secretion; ↑intracellular Cl− results in compensatory ↑Na+ reabsorption via epithelial Na+ channels → ↑H2O reabsorption → abnormally thick mucus secreted into lungs and GI tract. ↑ Na+ reabsorption also causes more negative transepithelial potential difference.
  • Diagnosis
    • Cl− concentration in pilocarpine-induced sweat test is diagnostic.
    • Can present with contraction alkalosis and hypokalemia (ECF effects analogous to a patient taking a loop diuretic) because of ECF H2O/Na+ losses and concomitant renal K+/H+ wasting.
    • ↑ immunoreactive trypsinogen (newborn screening).
    • Nasal transepithelial potential difference test – Saline is applied to the nose. CF patients have increased sodium reabsorption via ENaC, but chloride is retained in the lumen. The higher relative amounts of negatively charged chloride on the epithelial surface result in a more negative transepithelial voltage difference.
  • Complications
    • Recurrent pulmonary infections (eg, S aureus [early infancy], P aeruginosa [adolescence]), chronic bronchitis and bronchiectasis → reticulonodular pattern on CXR, opacification of sinuses.
    • Pancreatic insufficiency (↓ bicarbonate secretion in the pancreatic ducts, promoting mucin precipitation & intraductal concretions → exocrine pancreatic Insufficiency), malabsorption with steatorrhea, fat-soluble vitamin deficiencies (A, D, E, K), biliary cirrhosis, liver disease.
    • Meconium ileus in newborns.
    • Infertility in men (absence of vas deferens, spermatogenesis may be unaffected) and subfertility in women (amenorrhea, abnormally thick cervical mucus).
    • Nasal polyps, clubbing of nails.
  • Treatment
    • Multifactorial: chest physiotherapy, albuterol, aerosolized dornase alfa (DNase), and hypertonic saline facilitate mucus clearance. Azithromycin used as anti-inflammatory agent. Ibuprofen slows disease progression.
    • In patients with ΔF508 deletion: combination of lumacaftor (corrects misfolded proteins and improves their transport to cell surface) and ivacaftor (opens Cl– channels → improved chloride transport).

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