Cystic Fibrosis Lecture Notes

Introduction

• Cystic fibrosis (CF): Inherited disorder caused by a defective CFTR gene
• Inheritance: Autosomal recessive pattern
• Carrier Statistics: 1 in 25 Caucasian people are carriers
• Survival Age: Median survival age in the US (2021): 33.9 years; Projections for those born 2018-2022: 56 years

Genetics

• CFTR Gene Location: Chromosome 7
• CFTR: Stands for Cystic Fibrosis Transmembrane Conductance Regulator
  • Forms a cyclic AMP chloride channel
  • Allows movement of chloride, bicarbonate, sodium, and water across epithelial membranes
• Exocrine Glands: Primary expression site of CFTR
• Variants: Over 2000 defective variants; 85% cases due to variant F508 deletion causing misfolding

Pathophysiology

• Normal Function: CFTR helps move chloride and bicarbonate out of cell, sodium remains out, causing water to move out forming normal secretions
• CF Dysfunction: Decreased chloride secretion, increased sodium resorption, more water in cells leading to thicker mucus, viscous secretions
  • Sweat Glands: Role reversed, chloride and sodium remain in sweat causing salty sweat, dehydration risk

Affected Organs and Systems

• Lungs: Sticky mucus, difficulty clearing, mucus plugging, recurrent infections
  • Common Infections: Staphylococcus aureus (early life), Pseudomonas aeruginosa (60% adults)
  • Inflammation: Proteases, cytokines release; interleukin-8 stimulates mucus secretion
  • Consequences: Exacerbations, bronchiectasis, worsening lung function, hypoxemia, pulmonary hypertension, right-sided heart failure
• Pancreas: Obstructed ducts, enzyme auto-destruction, insufficiency
  • Diabetes Mellitus: 2% children, 50% adults
• Hepatobiliary System: Bile stasis, hepatic fibrosis (1/3 patients), biliary cirrhosis (3% by age 12)
• Intestines: Viscous secretions, meconium ileus (neonates), intestinal obstruction (adults)
• Reproductive System: Impaired male fertility (98% infertile), impaired female fertility (15-30%)
• Symptoms: Failure to thrive, recurrent infections, respiratory issues, malabsorption, steatorrhea, malnutrition, vitamin deficiencies, intestinal obstruction, dehydration

Diagnosis

• Suspicion Triggers: Positive newborn screening, affected sibling, clinical manifestations, dysfunctional CFTR genes
• Screening: Newborn screening for immunoreactive trypsinogen, sweat test, CFTR gene analysis
  • Sweat Test: Chloride levels >60 mmol/L abnormal, 30-59 mmol/L intermediate
• Pancreatic Function: Evaluated via pancreatic elastase in stool
• Imaging: CT every 1-2 years, during exacerbations
• Pulmonary Function Tests: Spirometry (4 times/year for >5 years old) - Measures forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), FEV1/FVC ratio

Management

• Goals: Alleviate symptoms, prevent complications, improve quality of life
• Respiratory Care:
  • Vaccines: Annual influenza, COVID-19
  • Airway Clearance: Chest physiotherapy, vest therapy, aerobic exercise
  • CFTR Modulators: Potentiators (Ivacaftor), Correctors (Lumacaftor, Tezacaftor, Alexacaftor)
  • Antibiotics: Exacerbations, prophylactic - Inhaled tobramycin, oral azithromycin
  • Bronchodilators, mucolytics (Dornay's Alpha)
  • NSAIDs (Ibuprofen) - Not routine due to GI risks
• Functional Support: 50% excess calories, multivitamins
  • Pancreatic Insufficiency: Enzyme replacement therapy
  • Obstruction Management: Enemas, laxatives, stool softeners
• Surgery: Nasal polyps, atelectasis, bronchiectasis, lung transplantation (median survival ~9 years post-transplant), liver transplant in some cases