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

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

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

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

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