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CYSTIC FIBROSIS - MD Exam Answer (10 Marks)

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DEFINITION

• Murray & Nadel, Chapter 67

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GENETICS

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PATHOGENESIS FLOWCHART

CFTR Gene Mutation (Chromosome 7q31.2)
              |
              ▼
     Defective/Absent CFTR Protein
      (ABC Transporter, 27 exons, 2 MSDs, 2 NBDs, R domain)
              |
              ▼
     Defective Anion Transport
    (↓ Cl⁻ secretion + ↑ Na⁺ absorption via ENaC)
    (↓ HCO₃⁻ secretion)
         /         \
        ▼            ▼
Dehydrated ASL     Impaired Mucin Unfolding
(Airway Surface    (↓ HCO₃⁻ → acidic milieu →
 Liquid depleted)   mucins don't expand on exit
                    from submucosal glands)
         \         /
          ▼       ▼
     MUCUS ABNORMALITY
  (↑ MUC5B + MUC5AC expression driven by IL-1β)
  (+ DNA from necrotic neutrophils → ↑ viscosity)
  (Viscosity ∝ [mucin]³)
         |
    ┌────┴──────────────────────┐
    ▼                           ▼
ASL Decrement               Defective Bacterial
+ Delayed Mucociliary         Killing
Clearance                   (↓ thiocyanate → ↓
(Cilia compressed,           lactoperoxidase activity)
 motility impaired)         (↓ antimicrobial peptides)
    \                           /
     └──────────┬──────────────┘
                ▼
   ┌────────── VICIOUS CYCLE ──────────────┐
   │                                        │
   │  Bacterial Colonization                │
   │  (S. aureus early → P. aeruginosa      │
   │   mucoid late → B. cepacia complex)    │
   │         ↓                             │
   │  Neutrophil recruitment               │
   │  (IL-8, IL-1β, TNF-α)                │
   │         ↓                             │
   │  Exuberant Neutrophilic Inflammation  │
   │  (proteases, ROS, DNA release)        │
   │         ↓                             │
   │  Airway Wall Destruction              │
   │  + Bronchiectasis                     │
   │         ↓                             │
   │  ↑ Mucus obstruction                 │
   │  → more infection → ...              │
   └────────────────────────────────────────┘
                ▼
   END-STAGE LUNG DISEASE
   (Respiratory failure, Cor pulmonale)

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CFTR PROTEIN - STRUCTURE & FUNCTION

• Located on apical surface of epithelial cells and on novel ionocytes (a minority airway cell type discovered via single-cell sequencing - major site of CFTR expression)
• CFTR regulates Cl⁻ and HCO₃⁻ secretion, membrane potential, and indirectly modulates ENaC (Na⁺ channel)
• Acts as a PDZ-domain anchored membrane complex, regulating numerous apical ion transporters
• Murray & Nadel, Chapter 67

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DETAILED LUNG PATHOGENESIS (Fishman's Chapter 48)

Step 1 - Ion Transport Failure

• CFTR mutations → imbalance between ENaC-mediated Na⁺ absorption and CFTR-mediated Cl⁻ secretion
• Deficient HCO₃⁻ secretion → impaired mucin unfolding as mucus exits gland ducts
• Deficient thiocyanate secretion → reduced lactoperoxidase-derived isothiocyanate (antimicrobial)

Step 2 - Mucus Dysfunction

• Concentrated mucus layer draws water from periciliary liquid → cilia compressed → mucociliary clearance fails
• Biophysical properties scale with third power of mucin concentration (modest increase = dramatic viscosity increase)
• Increased MUC5B + MUC5AC (driven by IL-1β)
• DNA from necrotic neutrophils further increases mucus rigidity

Step 3 - Infection (Characteristic Organisms)

Step 4 - Inflammation

• Disproportionate neutrophilic inflammation (even before detectable infection in newborn pigs)
• IL-8, IL-1β, TNF-α, LTB4 dominate
• Neutrophil elastase, MMP, ROS destroy airway walls
• Protease-antiprotease imbalance

Step 5 - Structural Lung Disease

• Small airway obstruction → tree-in-bud opacities (early HRCT)
• Progressive bronchiectasis (upper lobe predominant)
• Hyperinflation, air trapping
• Eventually: respiratory failure, pulmonary hypertension, cor pulmonale

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EXTRAPULMONARY MANIFESTATIONS

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DIAGNOSIS

1. Newborn screening - immunoreactive trypsinogen (IRT)
2. Sweat chloride test (gold standard):

   • 60 mEq/L = positive (CF)

   • 30-59 mEq/L = intermediate (borderline)
   • <30 mEq/L = normal
3. CFTR mutation analysis (genetic testing - 2-allele identification)
4. Nasal potential difference (CFTR function when sweat test equivocal)
5. Clinical features: chronic sinopulmonary disease, exocrine pancreatic insufficiency, male infertility

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MANAGEMENT (Fishman's + Murray & Nadel + CFF Guidelines 2024)

A. CFTR Modulator Therapy (Disease-Modifying)

B. Airway Clearance

• Hypertonic saline (7%) - hydrates ASL, restores mucociliary clearance
• Dornase alfa (DNase) - cleaves extracellular DNA in mucus, reduces viscosity
• Chest physiotherapy / oscillating PEP devices (Flutter, Acapella)
• Inhaled mannitol - osmotic agent

C. Anti-infective Therapy

• Inhaled tobramycin (TOBI) - for chronic P. aeruginosa (28-day on/off cycle)
• Inhaled aztreonam - alternative for P. aeruginosa
• Inhaled colistin - for resistant gram-negatives
• Azithromycin - chronic anti-inflammatory use (reduces exacerbations via immunomodulatory effect)
• IV antibiotics for acute exacerbations (anti-pseudomonal combinations)

D. Nutritional Support

• High-calorie diet (120-150% of normal caloric requirement)
• Pancreatic enzyme replacement therapy (PERT)
• Fat-soluble vitamins (A, D, E, K)
• Salt supplementation (especially in hot weather)

E. Lung Transplantation

• FEV1 <25% predicted
• FEV1 <50% with 20% relative decline over 12 months
• Hypoxemia (PaO2 <60 mmHg) / Hypercapnia (PaCO2 >50 mmHg)
• Frequent hospitalizations, massive hemoptysis, rapid lung function decline
• CFF recommends early referral (before FEV1 <50%) to optimize medical/psychosocial status

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PROGNOSIS

• With ETI modulators, median predicted survival has improved dramatically (>50 years in current era)
• Pre-ETI era: median survival ~37 years
• Major causes of death: respiratory failure (~80%), lung transplant complications
• B. cepacia complex colonization: significantly worsened transplant outcomes

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SUMMARY TABLE FOR EXAM

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• Murray & Nadel's Textbook of Respiratory Medicine, Chapter 67 (CFTR and CF pathogenesis) and Chapter 68 (CFTR modulator therapy)
• Fishman's Pulmonary Diseases and Disorders, Chapters 6 and 48
• Mall MA et al. "Cystic fibrosis." Nat Rev Dis Primers. 2024 Aug 8. [PMID: 39117676]
• Terlizzi V & Lopes-Pacheco M. "Cystic fibrosis: new challenges and perspectives beyond elexacaftor/tezacaftor/ivacaftor." Ther Adv Respir Dis. 2025. [PMID: 40163448]
• Savant AP. "Cystic Fibrosis Year in Review 2024." Pediatr Pulmonol. 2025. [PMID: 40778614]