Cystic Fibrosis

Snapshot

• A 3-year-old boy with a history of recurrent pneumonia and chronic diarrhea. His mother states that he has 6-8 four smelling stools per day. PE reveals a low grade fever, scattered rhonchi over both lung fields, crepitant rales at the left lung base and dullness to percussion. 

Introduction

• Cystic fibrosis is a genetic disorder leading to excessive, viscous secretions that plug exocrine glands
  • autosomal recessive disorder
  • caused by mutations in CFTR gene (chloride channel) on chromosome 7
    • CFTR is a transmembrane cAMP-activated ion channel   
      • its normal function is to reabsorb chloride ions (lumen → cell) in sweat glands and to secrete chloride ions (cell → lumen) in other exocrine glands (e.g., pancreas and lungs)  
      • movement of chloride creates a charge gradient that induces movement of sodium ions in the same direction as chloride to mitigate the gradient
      • movement of these ions drags solvent (water) with them
    • 3 nucleotide deletion
      • most common mutation is 508 Phe del  
    • result is instability of CFTR protein and premature degradation by Golgi apparatus 
    • inability to alter ionic gradients of Cl- results in mucus dehydration 
• Affects multiple organ systems with widespread exocrine gland dysfunction
  • pancreatic exocrine insufficiency is responsible for most of them
• Epidemiology
  • most common genetic disease in the United States
  • mostly affects Caucasians
• Newborn screening now routine in all states

Presentation

• Symptoms
  • respiratory symptoms are more prominent in adulthood
    • recurrent pulmonary infections
      • Pseudomonal spp and S. aureus are most common
    • chronic sinusitis
    • chronic, productive cough
    • dyspnea on exertion
    • hemoptysis
  • gastrointestinal symptoms are more prominent in infancy
    • chronic, frequent diarrhea
      • greasy stool with flatulence from malabsorption secondary to pancreatic insufficiency
      • steatorrhea can cause deficiency in fat soluble vitamins
      • can lead to rectal prolapse
    • meconium ileus in infants (15%)
    • pancreatitis 
  • other symptoms
    • calcium oxalate kidney stones
      • secondary to fat malabosorption 
• Physical exam
  • failure to thrive (50%)
  • respiratory compromise (50%)
  • “salty taste”
  • cyanosis
  • digital clubbing
  • ronchi
  • rales
  • hyperresonance of chest to percussion
• nasal polyposis 

Evaluation

• CXR
  • hyperinflation
  • prominent bronchovascular markings
    • bronchiectasis with “tram tracks” and peribronchial cuffing
    • diffuse bronciectactic changes
• Sweat chloride test
  • historical diagnostic gold standard
  • >60 mEq/L in patients <20 years old
  • >80 mEq/L in adults
• Genetic testing
  • confirms disease by identification of specific genetic mutation
• Immunoreactive trypsinogen assay
• Nasal transepithelial potential difference 
• Pulmonary function testing
  • often abnormal before first birthday
  • obstructive pattern with increased lung volumes (TLC and RV) over time from air trapping and hyperinflation
  • reduced diffusing capacity (DLCO)
• reduced or normal FEV1:FVC ratio given obstructive pattern with possible late restrictive features (e.g., fibrosis, tissue destruction, and/or hyperinflation) 

Differential

• Inherited immunodeficiency (SCID, CVID)
• Primary ciliary dyskinesia

Treatment

• Lifestyle
  • health maintenance
    • nutritional counseling
    • psychiatric/psychologic support indicated in most patients with or without mental instability
    • up-to-date immunizations indicated in all patients
• Pharmacologic 
  • respiratory therapy
    • indicated in all patients
    • includes several components including
      • chest physiotherapy (percussion, positive pressure, nebulizers)
      • bronchodilators
      • inhaled corticosteriods 
        • if asthmatic component or ABPA
      • DNA-ase and hypertonic saline
      • antibiotics 
        • chronic macrolide therapy common
        • IV antibiotics for acute exacerbations
      • anti-inflammatory agents (ibuprofen)
  • pancreatic enzymes and fat-soluble vitamins
    • indicated for malabsorption
• Operative
  • lung and pancreas transplantation
• indicated for most severe, but only if patient can tolerate surgery

Prognosis, Prevention, and Complications

• Prognosis
  • while patients are living longer and more complete lives with modern medicine, rarely do CF patients live beyond 40 years of age without transplantation
• Prevention
  • immunization for influenza and pneumococcus can prevent infections
  • embryonic selection, although controversial, has been used by known carriers or affected couples to prevent transmission of the disease to their children
• Complications
  • chronic hypoxemia and hypercapnia lead to pulmonary hypertension
    • patients often develop cor pulmonale (RHF)
  • Recurrent, drug-resistent bacterial or fungal pneumonias 
    • classically Pseudomonas
  • idiopathic hyponatremia
  • CF-related diabetes mellitus
  • fat-soluble vitamin deficiency (low vitamin A, D, K, and E)   
  • esophageal varices
  • biliary cirrhosis and cholelithiasis
  • infertility (95%)    
    • absence/obliteration of the vas deferens 
  • heat exhaustion (poor sweating)