Medical Archive

Clinical features

• Neonates
  • Meconium ileus (d/t thick meconium, 15% of cases)
• Under 1yrs old
  • Cough, wheezing, or recurrent respiratory infection.
  • Steatorrhea and/or FTT
• Most over 1yrs old
  • FTT or chronic sinopulmonary disease/sputum production.
  • COPD-like PFT and CXR. Hyperresonance to percusion.
  • Bronchiectasis – m/c cause of hemoptysis in the pediatric population.

Hyponatremia

Exposure to high temperature or exercise can lead to hyponatremia and hypochloremia d/t excessive NaCl loss through sweat. ? Salt supplementation is recommended.

Chloride-dependent metabolic alkalosis

Infection

• Recurrent sinopulmonary infections
  • S aureus [early infancy], P aeruginosa [adolescence]
  • Nasal polyps
  • Chronic bronchitis and bronchiectasis ?? reticulonodular pattern & upper lobe involvement on CXR, opacification of sinuses. 
• Digital clubbing.
  • Cf) Primary ciliary dyskinesia: has all 4 features, but no pancreatic Insufficiency.

GI tract

Pancreatic insufficiency – malabsorption with steatorrhea, fat-soluble vitamin deficiencies (A, D, E, K), biliary cirrhosis, liver disease – vitamin D deficiency and bruising
Meconium ileus in newborns, failure to thrive.

Fertility

Infertility in men (>95%, absence of vas deferens, spermatogenesis may be unaffected) 
Subfertility in women (~20%, amenorrhea, abnormally thick cervical mucus).

Common cause of mortality

Pneumonia, bronchiectasis, and cor pulmonale

Pathogenesis

1. Mutation ? misfolded protein ?? protein retained in RER and not transported to cell membrane
2. ?Cl (and H2O) secretion
3. ?intracellular Cl
4. Compensatory �Na reabsorption via ENAC
5. ?H2O reabsorption, more negative transepithelial potential difference.
6. Abnormally thick mucus secreted into lungs and GI tract. 

Decreased bicarbonate secretion, no effect on potassium

Molecular genetics

Defect in CFTR gene on chromosome 7; commonly a deletion of Phe508.

CFTR encodes an ATP-gated Cl channel

• The channel pore opens after binding of 2 ATP
  • Secretes Cl in lungs and GI tract
  • Reabsorbs Cl in sweat glands.
• Mutant CFTR channel
  • Impaired ATP binding blocks chloride ions, creating sticky mucus buildup.

3-base pair deletion of F508 (70%) ? impaired post-translational processing
Nonsense or frameshift – more common in Ashkenazi Jewish.

Diagnosis

Sweat test

• Pilocarpine iontophoresis test
  • At least 50mg of sweat must be collected within a 45-minute period.
  • Sweat with high sodium and chloride levels.
• If mutation is mild, can be normal

Nasal transepithelial potential difference

Respiratory, intestinal epithelium: decreased CFTR ? increased ENAC ? more negative transcellular potential 
Cf) Sweat gland: decreased CFTR ? decreased ENAC

Treatment

Salt supplementation

Multifactorial

• To facilitate mucus clearance
  • Chest physiotherapy, albuterol, aerosolized dornase alfa (DNase), and hypertonic saline.
• Antibiotics
  • Should cover Psuedomonas and S.aureus
  • IV regimen
    • When severe exacerbation (SaO2 <88%), failure of oral antibiotic therapy
    • Tobramycin + antipseudomonal/extended 3rd-gen cefa/carbapenem
• Pancreatic enzymes for malabsorption
• High-calorie and high-protein diet
• To slow disease progression
  • Ibuprofen
• Lung or pancreas transplant

In patients with Phe508 deletion

Combination of lumacaftor (corrects misfolded proteins and improves their transport to cell surface) and ivacaftor (opens Cl channels ?? improved chloride transport).

Pancreatic enzyme supplementation.