I. CYSTIC FIBROSIS (CF)
Cystic Fibrosis (CF) is a multisystem autosomal recessive disease caused by mutations in the CFTR gene, leading to defective chloride and bicarbonate transport across epithelial membranes. This results in viscous secretions in the lungs, pancreas, intestine, biliary tract, and reproductive organs, causing chronic respiratory and digestive dysfunction.
Genetic and Molecular Basis
- Gene: CFTR (Cystic Fibrosis Transmembrane Conductance Regulator), located on chromosome 7q31.2.
- Inheritance: Autosomal recessive.
- Protein: CFTR is a chloride channel regulated by cAMP, present in epithelial cells of airways, pancreas, intestine, and sweat glands.
- Common mutation: ΔF508 (deletion of phenylalanine at position 508) → misfolded protein degraded before reaching the cell membrane (accounts for ~70% of cases).
Pathophysiology
- 1. Defective CFTR function → ↓ chloride secretion and ↑ sodium absorption via ENaC channels.
- 2. Leads to dehydration of mucus secretions → thick, sticky mucus in airways and ducts.
- 3. Airway obstruction traps bacteria → chronic infection and inflammation.
- 4. Recurrent infections (especially Pseudomonas aeruginosa, Staphylococcus aureus) → bronchiectasis and lung destruction.
- 5. In pancreas → obstruction of ducts → exocrine pancreatic insufficiency, malabsorption, and steatorrhea.
- 6. Sweat glands: inability to reabsorb Na⁺ and Cl⁻ → salty sweat (basis for sweat test).
- 7. Reproductive tract: congenital bilateral absence of vas deferens → infertility in males.
Major Affected Organs and Manifestations
Diagnosis
1. Screening
- Newborn screening: immunoreactive trypsinogen (IRT) test (↑ in CF).
2. Confirmatory Tests
- Sweat chloride test: gold standard
- Sweat [Cl⁻] > 60 mmol/L = diagnostic.
- Genetic testing: detects CFTR mutations (ΔF508 and others).
- Nasal potential difference test: abnormal ion transport pattern.
3. Additional findings
- Pancreatic enzyme deficiency (↓ elastase in stool).
- Chronic bacterial cultures: Pseudomonas aeruginosa, Burkholderia cepacia.
Treatment
- Airway clearance: chest physiotherapy, mucolytics (dornase alfa), hypertonic saline inhalation.
- Antibiotics: inhaled tobramycin, azithromycin for chronic Pseudomonas.
- CFTR modulators:
- Ivacaftor (for gating mutations – G551D).
- Lumacaftor / Ivacaftor or Elexacaftor / Tezacaftor / Ivacaftor (for ΔF508).
- Pancreatic enzyme replacement and fat-soluble vitamin supplementation.
- Lung transplantation in advanced disease.