U01.01.057 Cystic fibrosis

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Learning Objectives

  • Explain the genetics and pathophysiology of the CFTR protein defect.
  • Contrast the CFTR function in sweat glands vs. respiratory/GI epithelia.
  • Identify multisystem complications (Pulmonary, GI, Reproductive).
  • Describe diagnostic methods and modern CFTR modulator therapies.

1. Genetics & Pathophysiology

Genetics: Autosomal recessive; caused by a mutation in the CFTR gene on chromosome 7. The most common mutation is a 3-base pair deletion of phenylalanine at position 508 (ΔF508).

  • Mechanism: The ΔF508 mutation leads to a misfolded protein. It is trapped in the Rough ER and degraded, never reaching the cell membrane.
  • CFTR Function: An ATP-gated Cl^- channel.
    • Lungs/GI: Normally secretes Cl^-. In CF, decreased Cl^- secretion leads to increased ENaC activity → massive Na^+ and H_2O reabsorption → dehydrated, thick mucus.
    • Sweat Glands: Normally reabsorbs Cl^-. In CF, Cl^- stays in the duct, preventing Na^+ reabsorption → high salt content in sweat.

2. Clinical Manifestations

System Key Findings & Complications
Pulmonary Recurrent infections (S. aureus in kids, P. aeruginosa in adults). Bronchiectasis, nasal polyps, nail clubbing.
Gastrointestinal Meconium ileus in newborns. Pancreatic insufficiency (steatorrhea, ADEK vitamin deficiency), biliary cirrhosis.
Reproductive Males: Infertility due to congenital bilateral absence of vas deferens (CBAVD). Females: Subfertility (thick cervical mucus).

3. Diagnosis & Management

  1. Diagnosis: Increased Cl^- concentration in pilocarpine-induced sweat test. The newborn screen looks for increased immunoreactive trypsinogen.
  2. Treatment:
    1. Mucus Clearance: Chest physiotherapy, dornase alfa (DNase), hypertonic saline.
    2. Antibiotics: Azithromycin (prevention), Tobramycin (for Pseudomonas).
    3. CFTR Modulators:
      1. Potentiators (Ivacaftor): Keep the channel gate open.
      2. Correctors (Lumacaftor/Tezacafortor): Help the protein fold and reach the surface.

 

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