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Cystic Fibrosis

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

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  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. 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

  6. 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%)

  7. Genetics of CF • Difficult to use DNA diagnosis to screen for heterozygotes • No simple physiologic measurements yet available for heterozygote detection

  8. 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

  9. 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

  10. Mutation of CFTR

  11. 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

  12. 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

  13. 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

  14. Normal airway epithelia • CF altered airway epithelia

  15. 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

  16. 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

  17. 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

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

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

  20. 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

  21. 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

  22. Manifestations • Respiratory tract • Complications • Pneumothorax ~10% of CF patients • Hemoptysis • Digital clubbing • Cor pulmonale • Respiratory failure

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

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

  25. 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

  26. 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

  27. 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

  28. 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

  29. 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

  30. Treatment • Lung • >95% of CF patients die from complications of lung infection • Breathing exercises • Flutter valves • Chest percussion • ? Hypertonic saline aerosols

  31. 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

  32. 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

  33. 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

  34. 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

  35. 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

  36. Treatment • Gastrointestinal • End-stage liver disease- transplantation • 2 year survival rate >50% • Hepatic and gallbladder complications treated as in patient without CF

  37. 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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