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Cystic Fibrosis. Paolo Aquino Internal Medicine-Pediatrics January 13, 2005. Outline. What is cystic fibrosis (CF)? What causes CF? What are the manifestations? How do you diagnose CF? How do you treat CF?. Cystic Fibrosis.

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cystic fibrosis

Cystic Fibrosis

Paolo Aquino

Internal Medicine-Pediatrics

January 13, 2005

  • What is cystic fibrosis (CF)?
  • What causes CF?
  • What are the manifestations?
  • How do you diagnose CF?
  • How do you treat CF?
cystic fibrosis1
Cystic Fibrosis
  • Inherited monogenic disorder presenting as a multisystem disease.
  • Typically presents in childhood
    • 7% of CF patients diagnosed as adults
  • Most common life limiting recessive trait among whites
cystic fibrosis2
Cystic Fibrosis
  • Prognosis improving
    • >38% of CF patients are older than 18
    • 13% of CF patients are older than 30
  • Median survival
    • Males: 32 years
    • Females: 29 years
genetics of cf
Genetics of CF
  • Autosomal recessive
  • Gene located on chromosome 7
  • Prevalence- varies with ethnic origin
    • 1 in 3000 live births in Caucasians in North America and Northern Europe
    • 1 in 17,000 live births of African Americans
    • 1 in 90,000 live births in Hawaiian Asians
genetics of cf1
Genetics of CF
  • Most common mutation
    • Occurs in 70% of CF chromosomes
    • 3 base pair deletion leading to absence of phenylalanine at position 508 (DF508) of the CF transmembrane conductance regulator (CFTR)
  • Large number (>1000) of relatively uncommon muations (~2%)
genetics of cf2
Genetics of CF
  • Difficult to use DNA diagnosis to screen for heterozygotes
  • No simple physiologic measurements yet available for heterozygote detection
genetics of cf3
Genetics of CF
  • The CFTR protein
    • Single polypeptide chain, 1480 amino acids
    • Cyclic AMP regulated chloride channel
    • Regulator of other ion channels
    • Found in the plasma membrane of normal epithelial cells
genetics of cf4
Genetics of CF
  • DF508 mutation leads to improper processing and intracellular degradation of the CFTR protein
  • Other mutations in the CF gene produce fully processed CFTR proteins that are either non-functional or partially functional
genetics of cf5
Genetics of CF
  • Epithelial dysfunction
    • Epithelia containing CFTR protein exhibit array of normal functions
      • Volume absorbing (airway, distal intestine)
      • Salt absorbing without volume (sweat ducts)
      • Volume secretory (proximal intestine, pancreas)
    • Dysfunction in CFTR gene leads to different effects on patterns of electrolyte and water transport
persistence of cf
Persistence of CF
  • Is there a reason why CF mutations are so prevalent?
  • Hypothetical resistance to morbidity and mortality associated with cholera
  • Evidence shows intestinal epithelial cells homozygous for the DF508 mutation are unresponsive to the secretory effects of cholera toxin
  • Lung
    • Raised trans-epithelial electric potential difference
    • Absence of cAMP-dependent kinase and PKC-regulated chloride transport
    • Raised sodium transport and decreased chloride transport
    • Alternative calcium-regulated chloride channel in airway epithelia which is a potential therapeutic target
Normal airway epithelia
  • CF altered airway epithelia
  • Lung
    • High rate of sodium absorption and low rate of chloride secretion reduces salt and water content in mucus, depletes peri-ciliary liquid
    • Mucus adheres to airway surface, leads to decreased mucus clearing
    • Predisposition to Staph and Pseudomonas infections
  • Gastrointestinal
    • Pancreas
      • Absence of CFTR limits function of chloride-bicarbonate exchanger to secrete bicarbonate
      • Leads to retention of enzymes in the pancreas, destruction of pancreatic tissue.
    • Intestine
      • Decrease in water secretion leads to thickened mucus and dessicated intraluminal contents
      • Obstruction of small and large intestines
  • Gastrointestinal
    • Biliary tree
      • Retention of biliary secretion
      • Focal biliary cirrhosis
      • Bile duct proliferation
      • Chronic cholecystitis, cholelithiasis
  • Sweat
    • Normal volume of sweat
    • Inability to reabsorb NaCl from sweat as it passes through sweat duct
  • Common presentations
    • Chronic cough
    • Recurrent pulmonary infiltrates
    • Failure to thrive
    • Meconium ileus
  • Respiratory tract
    • Chronic sinusitis
      • Nasal obstruction
      • Rhinorrhea
      • Nasal polyps in 25%; often requires surgery
    • Chronic cough
      • Persistent
      • Viscous, purulent, green sputum
  • Respiratory tract
    • Chronic cough
      • Exacerbations require aggressive therapy
        • Postural drainage
        • Antibiotics
        • Become more frequent with age
        • Progressive loss of lung function
    • Infection
      • Intially with H. influenzae and S. aureus
      • Subsequently P. aeruginosa
      • Occassionally, Xanthomonas xylosoxidans, Burkholderia gladioli, Proteus, E. coli, Klebsiella
  • Respiratory tract
    • Lung function
      • Small airway disease is first functional lung abnormality
      • Progresses to reversible as well as irreversible changes in FEV1
      • Chest x-ray may show hyperinflation, mucus impaction, bronchial cuffing, bronchiectasis
  • Respiratory tract
    • Complications
      • Pneumothorax ~10% of CF patients
      • Hemoptysis
      • Digital clubbing
      • Cor pulmonale
      • Respiratory failure
  • Gastrointestinal
    • Meconium ileus
      • Abdominal distention
      • Failure to pass stool
      • Emesis
    • Abdominal flat plate
      • Air-fluid levels
      • Granular appearancemeconium
      • Small colon
  • Gastrointestinal
    • Meconium ileus equivalent or distal intestinal obstruction syndrome
      • RLQ pain
      • Loss of appetite
      • Emesis
      • Palpable mass
      • May be confused with appendicitis
  • Gastrointestinal
    • Exocrine pancreatic insufficiency
      • Found in >90% of CF patients
      • Protein and fat malabsorption
      • Frequent bulky, foul-smelling stools
      • Vitamin A, D, E, K malabsorption
      • Sparing of pancreatic beta cells
        • Beta cell function decreases with age
    • Increased incidence of GI malignancy
  • Genitourinary
    • Late onset puberty
      • Due to chronic lung disease and inadequate nutrition
    • >95% of male patients with CF have azospermia due to obliteration of the vas deferens
    • 20% of female patients with CF are infertile
    • >90% of completed pregnancies produce viable infants
  • DNA analysis not useful due to large variety of CF mutations
  • Sweat chloride test >70 mEq/L
  • 1-2% of patients with clinical manifestations of CF have a normal sweat chloride test
    • Nasal transepithelial potential difference
  • Criteria
    • One of the following
      • Presence of typical clinical features
      • History of CF in a sibling
      • Positive newborn screening test
    • Plus laboratory evidence for CFTR dysfunction
      • Two elevated sweat chloride concentrations on two separate days
      • Identification of two CF mutations
      • Abnormal nasal potential difference measurement
  • Major objectives
    • Promote clearance of secretions
    • Control lung infection
    • Provide adequate nutrition
    • Prevent intestinal obstruction
  • Investigation into therapies to restore the processing of misfolded CFTR protein
  • Lung
    • >95% of CF patients die from complications of lung infection
    • Breathing exercises
    • Flutter valves
    • Chest percussion
    • ? Hypertonic saline aerosols
  • Lung
    • Antibiotics
      • Early intervention, long course, high dose
      • Staphylococcus- Penicillin or cephalosporin
      • Oral cipro for pseudomonas
        • Rapid emergence of resistance
        • Intermittent treatment (2-3 weeks), not chronic
      • IV antibiotics for severe infections or infections resistant to orals
  • Lung
    • Antibiotics
      • Pseudomonas treated with two drugs with different mechanisms to prevent resistance
        • e.g. cephalosporin + aminoglycoside
      • Use of aerosolized antibiotics
    • Increasing mucus clearance
      • N-acetylcysteine not clinically helpful
      • Long-term DNAse treatment increases time between pulmonary exacerbations
  • Lung
    • Inhaled b-adrenergic agonists to control airway constriction
      • No evidence of long-term benefit
    • Oral glucocoticoids for allergic bronchopulmonary aspergillosis
    • Studying benefits of high dose NSAID therapy for chronic inflammatory changes
  • Lung
    • Atelectasis
      • Chest PT + antibiotics
    • Respiratory failure and cor pulmonale
      • Vigorous medical management
      • Oxygen supplementation
      • Only effective treatment for respiratory failure is lung transplantation
        • 2 year survival >60% with lung transplatation
  • Gastrointestinal
    • Pancreatic enzyme replacement
    • Replacement of fat-soluble vitamins- especially vitamin E & K
    • Insulin for hyperglycemia
    • Intestinal obstruction
      • Pancreatic enzymes + osmotically active agents
      • Distal- hypertonic radiocontrast material via enema
  • Gastrointestinal
    • End-stage liver disease- transplantation
      • 2 year survival rate >50%
    • Hepatic and gallbladder complications treated as in patient without CF
  • CF is an inherited monogenic disorder presenting as a multisystem disease
  • Pathophysiology is related to abnormal ion transportation across epithelia
  • Respiratory, GI and GU manifestations
  • Treatment is currently preventative and supportive