Cystic Fibrosis - CF

 

Clinical Background

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene; over 1,600 different CFTR mutations have been reported.

Epidemiology

  • Incidence
    • Classic CF affects 1/3,000 Caucasians and Ashkenazi Jews, 1/8,000 Hispanics, 1/15,000 African Americans, 1/32,000 Asians; incidence of nonclassic CF is unknown
    • 4% of Caucasians are carriers
  • Age – usually diagnosed in childhood
  • Ethnicity – >90% are Caucasian

Inheritance

  • Autosomal recessive 
    • 2 pathogenic CFTR mutations on different chromosomes 
      • Classic symptoms of CF – 2 severe mutations
      • Nonclassic symptoms of CF – 1 severe/moderate and 1 mild/moderate mutations
    • Penetrance – high for severe mutations, variable for mild/moderate mutations

Pathophysiology

  • CFTR codes for a cAMP-regulated chloride channel in the apical membrane of epithelial cells
    • Without enough functional CFTR, the salt concentration in sweat is elevated and the viscosity of the mucous in the lungs and pancreas is increased, leading to obstruction
    • Obstruction sets the stage for chronic infection, inflammation and eventual epithelial injury
  • Death typically results from obstructive airway disease in the 40s

Clinical Presentation

  • Classic – chronic sinopulmonary disease, gastrointestinal malabsorption, pancreatic insufficiency and obstructive azoospermia
  • Atypical – monosymptomatic disease such as chronic pancreatitis, bilateral absence of the vas deferens, nasal polyps or bronchiectasis
  • Sinopulmonary disease
    • Chronic lung infections – bronchiectasis, dyspnea, wheezing, chest pain, nasal polyps, clubbing
    • Infectious organisms
      • Pseudomonas aeruginosa
      • Staphylococcus aureus
      • Burkholderia cepacia
  • Pancreas/liver/gallbladder/gastrointestinal (GI) disease
    • Pancreas
      • 85% or more have pancreatic insufficiency
      • Absorption of lipids and fat soluble vitamins is reduced
      • Chronic or recurrent abdominal pain from pancreatitis
      • Steatorrhea and malnutrition result
      • 25% of adults develop diabetes
    • Liver
      • Clogging of biliary ducts leads to liver and biliary cirrhosis
      • Congestion of liver secondary to hypoxia-induced cor pulmonale
      • Gallbladder
      • Fecal loss of bile acids leads to reduction in bile-salt pool
      • Reduction may lead to gallstones
    • GI
      • Distal intestinal obstruction (meconium ileus equivalent)
      • Constipation, intussusception, colonic strictures, hypotonic colon
      • Meconium ileus in 15% of infants
  • Endocrine systems dysfunctions
    • Male – azoospermia due to congenital bilateral absence of vas deferens (CBAVD) in >95%
    • Female – modest reduction in fertility

Treatment

  • Respiratory therapy – chest physiotherapy
  • Antibiotic treatment of infections
  • Inhalant treatment – Dornase alfa
  • Pancreatic enzymes taken with meals to increase nutrient absorption
  • Lung transplantation
    • Improves quality of life but not survival