Cystic fibrosis in adults

Pathophysiology & Genetics - Salty Sweat & Sticky Stuff

• Genetics: Autosomal recessive mutation in the CFTR gene on chromosome 7.
  • Most common mutation: ΔF508, a Class II mutation leading to misfolded protein.
• Pathophysiology: A defective CFTR protein creates a dysfunctional chloride channel, disrupting ion transport across epithelial cells.

• Mechanism & Effect:
  • Sweat Ducts: Impaired NaCl reabsorption → high salt content in sweat (diagnostic).
  • Airways/Pancreas: Decreased Cl⁻ secretion → thick, dehydrated mucus → obstruction, infection, and inflammation.

⭐ The "salty sweat" paradox: In sweat glands, CFTR reabsorbs chloride. In respiratory/GI epithelia, it secretes chloride. The channel's function is tissue-specific.

Clinical Manifestations - The Multi-System Mayhem

• Pulmonary: The dominant cause of morbidity/mortality.
  • Persistent productive cough, wheezing, recurrent sinus/pulmonary infections (esp. Pseudomonas aeruginosa, S. aureus).
  • Leads to bronchiectasis, hemoptysis, and eventual respiratory failure.
• Gastrointestinal:
  • Exocrine pancreatic insufficiency (~85%): Steatorrhea, malabsorption of vitamins A, D, E, K.
  • Distal Intestinal Obstruction Syndrome (DIOS).
• Hepatobiliary: Focal biliary cirrhosis, cholestasis, portal hypertension.
• Endocrine: CF-Related Diabetes (CFRD) due to progressive pancreatic islet destruction.
• Reproductive:
  • Males: Infertility (>95%) from congenital bilateral absence of the vas deferens (CBAVD).
  • Females: Reduced fertility (thick, tenacious cervical mucus).
• Other: Digital clubbing, hypertrophic osteoarthropathy, high sweat chloride.

⭐ Recurrent pulmonary exacerbations, often with mucoid Pseudomonas aeruginosa, are a hallmark of adult CF, strongly linked to accelerated decline in lung function.

Diagnosis - Catching the Chloride Culprit

• Primary Test: Quantitative pilocarpine iontophoresis (Sweat Chloride Test).
• Thresholds (mmol/L):
  • < 30: CF unlikely.
  • 30-59: Intermediate; requires further testing.
  • ≥ 60: Diagnostic.
• Genetic Confirmation: CFTR gene analysis for inconclusive sweat tests or atypical presentations.

⭐ A diagnosis of CF generally requires clinical symptoms plus evidence of CFTR dysfunction (e.g., two positive sweat tests on different days, or identifying two CF-causing mutations).

Management & Treatment - The Modulator & Mop-Up Crew

• CFTR Modulators: Cornerstone therapy based on genotype.
  • Potentiators (e.g., Ivacaftor): Increase channel opening for gating mutations (e.g., G551D).
  • Correctors (e.g., Lumacaftor, Tezacaftor): Improve protein folding/trafficking for processing mutations (e.g., F508del).
  • Combination (e.g., Elexacaftor/Tezacaftor/Ivacaftor - Trikafta): Highly effective for patients with at least one F508del mutation.
• Airway Clearance ("Mop-Up"):
  • Dornase alfa (DNase) & hypertonic saline.
  • Chest physiotherapy (vest, percussion).
• Chronic Therapies:
  • Inhaled antibiotics for Pseudomonas (e.g., tobramycin, aztreonam).

⭐ Chronic azithromycin use is primarily for its anti-inflammatory and biofilm-disrupting effects, not its direct bactericidal action.

High‑Yield Points - ⚡ Biggest Takeaways

• Autosomal recessive CFTR gene mutation (ΔF508 is most common) causes defective chloride transport across epithelial cells.
• Suspect in adults with recurrent sinopulmonary infections (especially Pseudomonas), pancreatic insufficiency, and male infertility.
• Diagnosis is confirmed by an elevated sweat chloride test > 60 mEq/L.
• Pulmonary disease manifests as obstructive PFTs and bronchiectasis, the primary cause of mortality.
• Management includes airway clearance, pancreatic enzyme replacement, and antibiotics.
• CFTR modulators are a key emerging therapy.