Your SlideShare is downloading. ×
Cystic Fibrosis Paolo Aquino Internal Medicine-Pediatrics
Upcoming SlideShare
Loading in...5
×

Thanks for flagging this SlideShare!

Oops! An error has occurred.

×
Saving this for later? Get the SlideShare app to save on your phone or tablet. Read anywhere, anytime – even offline.
Text the download link to your phone
Standard text messaging rates apply

Cystic Fibrosis Paolo Aquino Internal Medicine-Pediatrics

1,045

Published on

0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total Views
1,045
On Slideshare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
44
Comments
0
Likes
0
Embeds 0
No embeds

Report content
Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
No notes for slide

Transcript

  • 1. Cystic Fibrosis Paolo Aquino Internal Medicine-Pediatrics January 13, 2005
  • 2. Outline
    • What is cystic fibrosis (CF)?
    • What causes CF?
    • What are the manifestations?
    • How do you diagnose CF?
    • How do you treat CF?
  • 3. 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
  • 4. 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
  • 5.  
  • 6. 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
  • 7. Genetics of CF
    • Most common mutation
      • Occurs in 70% of CF chromosomes
      • 3 base pair deletion leading to absence of phenylalanine at position 508 (  F 508 ) of the CF transmembrane conductance regulator (CFTR)
    • Large number (>1000) of relatively uncommon muations (~2%)
  • 8. Genetics of CF
    • Difficult to use DNA diagnosis to screen for heterozygotes
    • No simple physiologic measurements yet available for heterozygote detection
  • 9. 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
  • 10. Genetics of CF
    •  F 508 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
  • 11. Mutation of CFTR
  • 12. 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
  • 13. 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  F 508 mutation are unresponsive to the secretory effects of cholera toxin
  • 14.  
  • 15. 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
  • 16.
    • Normal airway epithelia
    • CF altered airway epithelia
  • 17. 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
  • 18. 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
  • 19. 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
  • 20.  
  • 21. Manifestations
    • Common presentations
      • Chronic cough
      • Recurrent pulmonary infiltrates
      • Failure to thrive
      • Meconium ileus
  • 22. Manifestations
    • Respiratory tract
      • Chronic sinusitis
        • Nasal obstruction
        • Rhinorrhea
        • Nasal polyps in 25%; often requires surgery
      • Chronic cough
        • Persistent
        • Viscous, purulent, green sputum
  • 23. 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
  • 24. 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
  • 25. Manifestations
    • Respiratory tract
      • Complications
        • Pneumothorax ~10% of CF patients
        • Hemoptysis
        • Digital clubbing
        • Cor pulmonale
        • Respiratory failure
  • 26. Manifestations
    • Gastrointestinal
      • Meconium ileus
        • Abdominal distention
        • Failure to pass stool
        • Emesis
      • Abdominal flat plate
        • Air-fluid levels
        • Granular appearance  meconium
        • Small colon
  • 27. Manifestations
    • Gastrointestinal
      • Meconium ileus equivalent or distal intestinal obstruction syndrome
        • RLQ pain
        • Loss of appetite
        • Emesis
        • Palpable mass
        • May be confused with appendicitis
  • 28. Manifestations
    • 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
  • 29. Manifestations
    • 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
  • 30.  
  • 31. Diagnosis
    • 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
  • 32. 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
  • 33. 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
  • 34. Treatment
    • Lung
      • >95% of CF patients die from complications of lung infection
      • Breathing exercises
      • Flutter valves
      • Chest percussion
      • ? Hypertonic saline aerosols
  • 35. 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
  • 36. 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
  • 37. Treatment
    • Lung
      • Inhaled  -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
  • 38. 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 >60% with lung transplatation
  • 39. 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
  • 40. Treatment
    • Gastrointestinal
      • End-stage liver disease- transplantation
        • 2 year survival rate >50%
      • Hepatic and gallbladder complications treated as in patient without CF
  • 41. 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
  • 42.  

×