Learning Objective: By the end of this lesson, the learner will be able to explain the genetic basis, pathophysiology, clinical features, diagnostic tests, complications, and management of cystic fibrosis, including how CFTR modulators work and the rationale for their use.

Genetics

• Inheritance: Autosomal recessive
• Gene: CFTR on chromosome 7; most common mutation: ΔF508
• Epidemiology: The most common lethal genetic disease in individuals of European ancestry

Pathophysiology

1. CFTR function: ATP-gated chloride channel
   • Lungs/GI tract: secretes Cl⁻ and HCO₃⁻
   • Sweat glands: reabsorb Cl⁻
   • ΔF508 mutation: misfolded protein → fails trafficking → absent from membrane
2. Resulting ion/water changes:
   • ↓ Cl⁻ & H₂O secretion in lungs/GI → thick, viscous mucus
   • ↑ Na⁺ reabsorption via ENaC → ↑ water reabsorption
   • More negative transepithelial potential difference
3. Clinical consequence: mucus obstruction → recurrent infections, pancreatic insufficiency, infertility

Clinical Features & Complications

1. Pulmonary:
   • Recurrent infections: S. aureus (infancy), P. aeruginosa (adulthood)
   • Chronic bronchitis, bronchiectasis → reticulonodular CXR pattern
   • Allergic bronchopulmonary aspergillosis (ABPA)
   • Nasal polyps, digital clubbing
2. Gastrointestinal / Pancreatic:
   • Pancreatic insufficiency → steatorrhea, fat-soluble vitamin deficiency (A, D, E, K)
   • CF-related diabetes
   • Meconium ileus in newborns
   • Biliary cirrhosis, liver disease
3. Reproductive:
   1. Males: congenital absence of vas deferens → infertility (spermatogenesis may be intact)
   2. Females: thick cervical mucus → subfertility

Diagnosis

1. Sweat chloride test (pilocarpine-induced)
2. Newborn screening: immunoreactive trypsinogen
3. Electrolyte effects: contraction alkalosis, hypokalemia (like loop diuretics) due to renal compensation for Na⁺/H₂O loss

Management

1. Airway clearance: chest physiotherapy, inhaled hypertonic saline, dornase alfa (DNase)
2. Infections: azithromycin (prevent exacerbations), antibiotics as needed
3. Anti-inflammatory: ibuprofen
4. Pancreatic insufficiency: enzyme replacement (pancrelipase)
5. CFTR modulators (pharmacogenomics-based):
   1. Potentiators: hold CFTR channel open → Cl⁻ flows (e.g., ivacaftor)
   2. Correctors: improve protein folding/trafficking to the membrane (e.g., lumacaftor, tezacaftor)

High-Yield Mnemonics / Tips

• “CFTR defect → Thick Mucus & Salt in sweat”
• Pulmonary infections evolve with age: S. aureus → Pseudomonas
• Remember ΔF508 → protein misfolding → absent at membrane

Activity: