Cystic Fibrosis

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Cystic Fibrosis

• Paolo Aquino
• Internal Medicine-Pediatrics
• January 13, 2005

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Outline

• What is cystic fibrosis (CF)?
• What causes CF?
• What are the manifestations?
• How do you diagnose CF?
• How do you treat CF?

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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

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Cystic Fibrosis

• Prognosis improving
• gt38 of CF patients are older than 18
• 13 of CF patients are older than 30
• Median survival
• Males 32 years
• Females 29 years

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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

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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 (gt1000) of relatively uncommon
  muations (2)

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Genetics of CF

• Difficult to use DNA diagnosis to screen for
  heterozygotes
• No simple physiologic measurements yet available
  for heterozygote detection

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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

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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

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Mutation of CFTR
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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

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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

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Pathophysiology

• 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

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• Normal airway epithelia
• CF altered airway epithelia

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Pathophysiology

• 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

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Pathophysiology

• 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

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Pathophysiology

• 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

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Manifestations

• Common presentations
• Chronic cough
• Recurrent pulmonary infiltrates
• Failure to thrive
• Meconium ileus

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Manifestations

• Respiratory tract
• Chronic sinusitis
• Nasal obstruction
• Rhinorrhea
• Nasal polyps in 25 often requires surgery
• Chronic cough
• Persistent
• Viscous, purulent, green sputum

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Manifestations

• 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

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Manifestations

• 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

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Manifestations

• Respiratory tract
• Complications
• Pneumothorax 10 of CF patients
• Hemoptysis
• Digital clubbing
• Cor pulmonale
• Respiratory failure

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Manifestations

• Gastrointestinal
• Meconium ileus
• Abdominal distention
• Failure to pass stool
• Emesis
• Abdominal flat plate
• Air-fluid levels
• Granular appearance?meconium
• Small colon

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Manifestations

• Gastrointestinal
• Meconium ileus equivalent or distal intestinal
  obstruction syndrome
• RLQ pain
• Loss of appetite
• Emesis
• Palpable mass
• May be confused with appendicitis

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Manifestations

• Gastrointestinal
• Exocrine pancreatic insufficiency
• Found in gt90 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

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Manifestations

• Genitourinary
• Late onset puberty
• Due to chronic lung disease and inadequate
  nutrition
• gt95 of male patients with CF have azospermia due
  to obliteration of the vas deferens
• 20 of female patients with CF are infertile
• gt90 of completed pregnancies produce viable
  infants

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Diagnosis

• DNA analysis not useful due to large variety of
  CF mutations
• Sweat chloride test gt70 mEq/L
• 1-2 of patients with clinical manifestations of
  CF have a normal sweat chloride test
• Nasal transepithelial potential difference

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Diagnosis

• 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

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Treatment

• 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

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Treatment

• Lung
• gt95 of CF patients die from complications of
  lung infection
• Breathing exercises
• Flutter valves
• Chest percussion
• ? Hypertonic saline aerosols

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Treatment

• 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

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Treatment

• 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

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Treatment

• 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

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Treatment

• 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 gt60 with lung transplatation

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Treatment

• 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

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Treatment

• Gastrointestinal
• End-stage liver disease- transplantation
• 2 year survival rate gt50
• Hepatic and gallbladder complications treated as
  in patient without CF

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Summary

• 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

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