Cystic Fibrosis

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  • Many functions still under investigation----CFTR
  • Chronic sp disease---chronic cough, recurrent sp infection, bronchiolitis/asthma, nasal polyps Nutr---ftt, vit def Gi---mec ileus, DIOS, rectal prolapse, liver disease---biliary cirrhosis
  • Delta f508 causes loss of the amino acid phenylalanine located at position 508 in the protein
  • Age-specific prevalence of airway infections in patients with CF. Organisms reported to the U.S. Cystic Fibrosis Patient Registry, 2001 Early infections in CF airways are most frequently caused by S. aureus and H. influenzae. natural history study of patients with CF in the first 3 years of life, the mean age of detection of an antibody response to P. aeruginosa was approximately 15 months, whereas the mean ages of first positive upper and lower airway culture were approximately 21 and 23 months
  • Biofilms are sessile communities of bacteria that form in aggregates on surfaces using a hydrated polymeric matrix of their own synthesis ( Figures 6D and 6E ). Some common clinical characteristics of biofilm infections have been identified: slow growth of organisms, stimulation of production of antibodies that are ineffective in clearing bacteria, inherent resistance to antibiotics, and an inability to eradicate biofilm infections even in hosts with intact immune systems ( 134 – 137 ).
  • Nine recognized genomovars Most common are II, III, V
  • Ursodiol increases bile flow {02} . In chronic cholestatic liver disease, ursodiol appears to reduce the detergent properties of the bile salts, thus reducing their cytotoxicity. Also, ursodiol may protect liver cells from the damaging activity of toxic bile acids (e.g., lithocholate, deoxycholate, and chenodeoxycholate), which increase in concentration in patients with chronic liver disease

Transcript

  • 1. Cystic Fibrosis Esmeralda E. Morales, MD August 28, 2006
  • 2. Objectives
    • Know the clinical features of cystic fibrosis.
    • Know how CF is inherited.
    • Be familiar with criteria to diagnose CF.
    • Become aware of the myriad of treatments used in CF.
  • 3. What is cystic fibrosis (CF)?
    • A multisystem disease
    • Autosomal recessive inheritance
    • Cause: mutations in the cystic fibrosis transmembrane conductance regulator (CFTR)
      • chromosome 7
      • codes for a c-AMP regulated chloride channel
    Rosenstein, BJ and Zeitlin, PL. Cystic fibrosis. The Lancet. 351: 277-82.
  • 4. Diagnosis of cystic fibrosis
    • One or more clinical features of CF
    • PLUS
    • Two CF mutations
    • OR
    • Two positive quantative pilocarpine iontophoresis sweat chloride values
    • OR
    • An abnormal nasal transepithelial potential difference value
    Cystic Fibrosis Foundation. Clinical Practice Guidelines for Cystic fibrosis.1997.
  • 5. Clinical features of Cystic Fibrosis
    • Chronic Sino-Pulmonary Disease
    • Nutritional deficiency/GI abnormality
    • Obstructive Azoospermia
    • Electrolyte abnormality
    • CF in a first degree relative
    Cystic Fibrosis Foundation. Clinical Practice Guidelines for Cystic fibrosis.1997 .
  • 6. Welsh, MJ and Smith, AE. Cystic Fibrosis. Scientific American . 273 (6): 52, 1995.
  • 7. Burden of CF
    • Most common “life-shortening” recessive genetic disease in Caucasians
      • 1:3,500 newborns in the US
      • 1 in 10,500 Native Americans
      • 1 in 11,500 Hispanics
      • 1 in 14,000 to 17,000 African Americans
      • 1 in 25,500 Asians
      • http://www.cff.org
  • 8. Burden of CF (continued)
    • About 30,000 people affected in United States
    • >10,000,000 people carriers of mutant CFTR
    • 80% cases diagnosed by age 3
    • Almost 10% diagnosed ≥18 years
    http://www.cff.org
  • 9. CF Survival
    • Overall trend is improved survival
    • Female survival worse than male between 2-20 years of age 1
    • 35% of patients are older than 18 years of age 2
    • Median survival 36.8 years 3 compared to 1930s when life expectancy was about 6 months 2
    1.Goss, CH and Rosenfeld, M. Update on cystic fibrosis epidemiology. Current Opinion in Pulmonary Medicine. 10:510-514; 2004. 2. Davis, P. Cystic Fibrosis Since 1938. AJRCCM Articles in Press. Doi: 10.1164/rccm.200505-840OE; 2005. 3.www.cff.org/news/general_news
  • 10. Autosomal recessive inheritance in CF
    • Let C = normal CFTR
    • Let c = mutant CFTR
    • If mom and dad are both carriers then:
    • With mom and dad carriers, then:
      • 50% chance of having child who is a carrier
      • 25% chance of child being affected
      • 25% of child with no mutant copies of CFTR
    CC C c C c cc C c C c
  • 11. Cystic fibrosis transmembrane conductance regulator (CFTR) gene
    • The CFTR gene is located on the long arm of chromosome 7.
    • There are 1522 mutations in CFTR listed on the CFTR mutation database ( http://www.genet.sickkids.on.ca/cftr/ )
    • The most common mutation is Δ F508---70% CF alleles in caucasians. 1
    http://www.ornl.gov/sci/techresources/ Human_Genome/posters/chromosome/cftr.shtml 1. Gibson, RL, Burns, JL, and Ramsey, BW. Pathophysiology and Management of Pulmonary Infections in Cystic Fibrosis. AJRCCM 168 (918-951); 2003.
  • 12. Cell membrane diagram From: http://library.thinkquest.org/C004535/cell_membranes.html
  • 13. CFTR Gibson, RL, Burns, JL, and Ramsey, BW. Pathophysiology and Management of Pulmonary Infections in Cystic Fibrosis. AJRCCM 168 (918-951); 2003.
  • 14. Types of mutations in CFTR
    • Class I
      • Defective protein production
    • Class II
      • Defects in processing
        • Δ F508
    • Class III
      • CFTR reaches cell surface but regulation is defective (channel not activated)
    • Class IV
      • CFTR in membrane with defective conduction
    • Class V
      • Decreased synthesis of CFTR
    http://www.cysticfibrosismedicine.com/ htmldocs/CFText/genetics.htm
  • 15. CFTR and Airway Surface Liquid Donaldson,SH and Boucher,RC. Update on the pathogenesis of cystic fibrosis lung disease. Current Opinion in Pulmonary Medicine. 9: 486-491; 2003.
  • 16. Airway surface liquid low volume hypothesis
    • Mucus---helps clear airway of bacteria
    • Clearance of mucus depends on
      • Ciliary function
      • Mucin secretion
      • Volume of airway surface liquid (ASL)
        • Forms periciliary liquid layer
        • Dilutes mucus---facilates entrapment of bacteria and clearance
        • Optimal volume of ASL regulated by Na+ absorption and Cl- secretion
    Donaldson,SH and Boucher,RC. Update on the pathogenesis of cystic fibrosis lung disease. Current Opinion in Pulmonary Medicine. 9: 486-491; 2003.
  • 17. Airway surface liquid low volume hypothesis and CFTR
    • Normal CFTR inhibits a sodium channel (ENaC)
      • Mutant CFTR----ENaC not inhibited
        • Sodium absorption is increased
        • Water follows sodium
        • ASL volume decreases
    • Normal CFTR will cause Cl- ions to be secreted if the ASL fluid is low
      • Mutant CFTR Cl- ions not secreted
    Donaldson,SH and Boucher,RC. Update on the pathogenesis of cystic fibrosis lung disease. Current Opinion in Pulmonary Medicine. 9: 486-491; 2003.
  • 18. Airway surface liquid low volume hypothesis and consequences
    • Cilia do not beat well when PCL volume is depleted
    • Mucins are not diluted and cannot be easily swept up the airway
    • Mucus becomes concentrated
        • Results in increased adhesion to airway surface
        • Promotes chronic infection
    Donaldson,SH and Boucher,RC. Update on the pathogenesis of cystic fibrosis lung disease. Current Opinion in Pulmonary Medicine. 9: 486-491; 2003.
  • 19. CF Clinical Signs
  • 20. Chronic Sino-Pulmonary Disease
    • Chronic infection with CF pathogens
    • Endobronchial disease
      • Cough/sputum production
      • Air obstruction---wheezing; evidence of obstruction on PFTs
      • Chest x-ray anomalies
      • Digital Clubbing
    • Sinus disease
      • Nasal Polyps
      • CT or x-ray findings of sinus disease
    Cystic Fibrosis Foundation. Clinical Practice Guidelines for Cystic fibrosis.1997.
  • 21. Infection Gibson, RL, Burns, JL, and Ramsey, BW. Pathophysiology and Management of Pulmonary Infections in Cystic Fibrosis. AJRCCM 168 (918-951); 2003.
  • 22. CF Infections--- Pseudomonas aeruginosa
    • 80% CF patients eventually infected with pseudomonas
    • Association between acquiring pseudomonas and clinical status deterioration
    • Form biofilms
    • Relatively large genome
      • Pseudomonae collected from sputa of CF patients have been noted to have larger genomes than lab strains
    Gibson, RL, Burns, JL, and Ramsey, BW. AJRCCM 168 (918-951); 2003.
  • 23. Pseudomonas genome http://www.pseudomonas.com/
  • 24. Burkholderia cepacia complex
    • B. cepacia syndrome: fevers, rapidly progressive necrotizing pneumonia, death
    • Chronic cepacia infection—decreased lung function and increased mortality
    • Several closely related species termed genomovars 1
      • III has been associated with more severe disease
    Holmes, A, Govan, J, and Goldstein, R. Agricultural Use of Burkholderia (Pseudomonas) cepacia: A Threat to Human Health? Emerging Infectious Diseases. 4(2):221-227; 1998 1. Gibson, RL, Burns, JL, and Ramsey, BW. AJRCCM 168 (918-951); 2003.
  • 25. Endobronchial disease
    • Hyperinflation
    • Peribronchial cuffing
    • Bronchiectasis
    • Diffuse fibrosis
    • Atelectasis
    From: http://www.meddean.luc.edu/lumen/meded/elective/pulmonary/cf/cf_f.htm
  • 26. Nasal Polyps
    • Benign lesions in nasal airway
    • If large enough, can be associated with significant nasal obstruction, drainage, headaches, snoring
    • Likely associated with chronic inflammation
    • May need surgical intervention
    • High recurrence rate
    From: http://www.emedicine.com/ ped/topic1550.htm
  • 27. Digital Clubbing
    • Bulbous swelling at end of fingers
    • Normal angle between nail and nail bed lost---Schamroth sign
    • Can be associated with pulmonary disease, cardiac disease, ulcerative colitis, and malignancies
    From: Fawcett et al., 2004
  • 28. Nutritional deficiency
    • Pancreatic insufficiency
      • Autopsy of malnourished infants--1938--- “cystic fibrosis of the pancreas”---mucus plugging of glandular ducts 1
      • Chloride impermeability affects HCO3- secretion and fluid secretion in pancreatic ducts 2
        • Pancreatic enzymes stay in ducts and are activated intraductally
          • Autolysis of pancreas
          • Inflammation, calcification, plugging of ducts, fibrosis
      • Malabsorption
        • Failure to thrive
        • Fat soluble vitamin deficiency
    • Davis, P. Cystic Fibrosis Since 1938. AJRCCM Articles in Press.
    • Doi: 10.1164/rccm.200505-840OE; 2005.
    • 2. Quinton, P. Physiologic Basis of Cystic Fibrosis. Physiol Rev 79:3-22, 1999.
  • 29. GI disease
    • Intestinal abnormality
      • Meconium ileus
      • Distal intestinal obstruction syndrome (DIOS)
      • Rectal prolapse
    • Hepatobiliary disease
      • Focal biliary cirrhosis
      • Multilobular cirrhosis
    • Pancreatic endocrine dysfunction
      • Cystic fibrosis related diabetes
  • 30. Cystic fibrosis related liver disease
    • Focal inspissation of bile
      • Obstructs biliary ductules
    • Second leading cause of death in CF 1
    • Prevalence 9-37% 1
    • Spectrum of disease
      • increased liver enzymes
      • biliary cirrhosis
      • portal hypertension
    1. Efrati, O et al., Liver Cirrhosis and portal hypertension in CF. European Journal of Gastroenterology and Hepatology. 15(10): 1073-1078; 2003.
  • 31. Cystic fibrosis related diabetes mellitus
    • Screening
      • Oral glucose tolerance test (OGTT)
        • Every two years in patients 10-16 years
        • Any patient with random plasma glucose >180
    • Fasting>=140 mg/dl
      • initiate insulin treatment
    • Fasting<140 and OGTT at 2 hrs>200 mg/dl
      • Home glucose monitoring; consider insulin
    • Fasting <140 and 2 hour 140-200
      • Impaired glucose tolerance
        • OGTT annually
    • Fasting and 2 hour <140
      • Normal glucose tolerance
  • 32. Infertility
    • Men
      • Abnormal embryologic development of the epididymal duct and vas deferens---may be incomplete of absent 1
      • Congential bilateral absence of the vas deferens—97-98% of men with CF 1
    1. Lewis-Jones et al, Cystic fibrosis in infertility: screening before assisted reproduction: Opinion. Human Reproduction 15(11): 2415-2417.
  • 33. Infertility
    • Women
      • Lower fertility rate than non-CF women
      • Viscid mucoid cervical secretions of low volume in women with CF 1
    • Pregnancy and CF:
      • Goss et al, 2003---no significant difference in survival in women who became pregnant with CF compared to women who did not become pregnant (after adjusting for disease severity) 2
    1.Quinton, P. Physiologic Basis of Cystic Fibrosis. Physiol Rev 79:3-22, 1999 2.Goss, CH, Rubenfeld, GD, Otto, K and Aitken, ML. The effect of pregnancy on survival in women with cystic fibrosis. Chest 124(4):1460-68; 2003.
  • 34. Electrolyte abnormality---history
    • Dr. Paul di Sant’ Agnese
      • 1949 NYC heat wave----noted CF infants to have a higher rate of heat prostration than non-CF
        • Showed that sodium and chloride concentration in CF patients’ sweat was 5 times higher than in non-CF 1
          • Became basis for sweat chloride test
    • Davis, P. Cystic Fibrosis Since 1938. American Journal of Respiratory and Critical Care Medicine Vol 173. pp. 475-482, (2006)
  • 35. Electrolyte abnormality
    • Clinically---hypochloremic metabolic alkalosis
      • CFTR on luminal side of sweat duct
        • Chloride goes in from lumen via CFTR and out to blood by other transporters
        • Sodium goes in via ENaC
        • Defective CFTR---Na and Cl- movement and reabsoprtion into lumen impeded
    Goodman, B and Percy, WH..CFTR in Teaching Membrane Transport. Adv Physiol Educ. 29 (79-82); 2005
  • 36. CF: Diagnostic Methods
  • 37. Diagnosis---Sweat chloride
    • Technique first described by Gibson and Cooke in 1950s
      • Chemical that stimulates sweating placed under electrode pad; saline under other electrode pad on arm
      • Mild electric current is passed between electrodes
      • Sweat collected
    http://www.nucleusinc.com Illustration copyright 2003 Nucleus Communications, Inc.
  • 38. Sweat chloride
      • Positive Sweat chloride: 60-165 meq/L
      • Borderine sweat chloride: 40-60 meq/L
      • Normal sweat chloride: 0-40
    • False positives:
      • Hypothyroidism
      • Addison disease
      • Ectodermal dysplasia
      • Glycogen storage disease
      • Edema
      • Malnutrition
      • Lab error (evaporation or contamination of sample)
    • False negatives:
      • Edema
      • Malnutrition
      • Some CF mutations
      • Sample diluted
    Davis, P. Cystic Fibrosis Since 1938. AJRCCM Articles in Press. Doi: 10.1164/rccm.200505-840OE; 2005.
  • 39. Genetic testing
    • Mutation analysis available
      • Varies from screening for most common mutations to sequencing entire CFTR gene
  • 40. Prenatal screening
    • American College of Obstetricians and Gynecologists recommended offering patients option of prenatal screening for CF
      • Carrier testing of 23 most common mutations
      • Sensitivity of prenatal screening for CF among the white population < 78% 1
        • lower than that for newborn screening
        • sensitivity of prenatal testing in racial and ethnic minority populations is lower 1
    1. Grosse et al. Newborn Screening for Cystic Fibrosis. MMWR.53 (RR13):1-36; 2004.
  • 41. Newborn Screening for CF
    • Goal: diagnose early---evidence that early diagnosis may be associated with better nutritional outcome and chest radiographic scores 1
    • Several different protocols in different states
      • Immunoreactive trypsinogen usually first followed by either sweat or DNA testing
    • Mérelle ME, Nagelkerke AF, Lees CM, Dezateux C. Newborn screening for
    • cystic fibrosis. Cochrane Database of Systematic Reviews. Issue3; 2005.
  • 42. Cystic fibrosis---Treatment Multidisciplinary
    • Airway Clearance
    • Infection
    • Nutrition
    • Gastrointestinal
    • Inflammation
    • Infertility
    • Social Issues
  • 43. Treatment: Pulmonary toilet/Airway clearance
    • Chest physiotherapy
      • Postural drainage and percussion
      • P.E.P valve, Acapella valve, Flutter valve
      • High frequency chest wall oscillation
    • Albuterol
      • Bronchodilation
      • Increase ciliary efficiency
    • Dornase alpha/recombinant DNase
    • Hypertonic Saline by nebulization
  • 44. Treatment: Chronic infection
    • Inhaled antibiotics
      • Inhaled tobramycin in patients with pseudomonas
    • Sputum cultures
    • Treatment of pulmonary exacerbation
      • Pulmonary exacerbation---change in symptoms and signs from baseline (cough, sputum production, lung function, increased crackles on physical exam)
      • Requires hospitalization for antibiotics IV, as well as increased airway clearance
    Cystic Fibrosis Foundation. Clinical Practice Guidelines for Cystic fibrosis.1997.
  • 45. Treatment: Anti-inflammatory agents
    • Ibuprofen
      • Konstan et al., 2003
      • 85 patients 5-39 years of age with mild lung disease randomized to placebo or high dose ibuprofen over 4 years
        • Ibuprofen group:
          • Slower decrease in FEV1 annually than placebo group; better weight maintenance
          • No difference in frequency of hospitalization
          • Best effect seen in patients less than 13 years of age
    Konstan et al., Effect of High Dose Ibuprofen in Patients with Cystic Fibrosis. NEJM. 332:848-54; 2003.
  • 46. Treatment: Azithromycin
    • Saiman et al., 2003 double blind placebo controlled trial of azithromycin
      • 185 patients randomized to receive 3 times weekly azithromycin or placebo
      • Improvements in lung function, weight, and number of pulmonary exacerbations (decreased courses of antibiotics and days in hospital)
    Saiman et al., Azithromycin in Patinets with Cystic Fibrosis Chronically Infected with Pseudomonas Aeruginosa. JAMA 290(13):1749; 2003.
  • 47. Treatment: Nutrition
    • Follow nutrition parameters closely
    • Pancreatic enzymes
    • Vitamin supplementation
    • Other nutritional supplementation
      • Tube feedings
      • High calorie supplemental shakes, formulas
  • 48. Nutrition parameters
    • Percent ideal body weight (IBW%)
      • 90-110%: Normal
      • 85-89%: Underweight
      • 80-84%: Mild malnutrition
      • 75-79%: Moderate malnutrition
      • <75%: Severe malnutrition
    • Height as a percentage of 50 th percentile height for age (height/50 th percentile height for age )X100.
      • 95-100% normal
      • 90-94%: mildly stunted
      • 85-89%: moderately stunted
      • <85%: severely stunted
  • 49. Treatment: Pancreatic enzymes
    • Initiate if have malabsorption history
      • Fecal fat
      • Fecal elastase
    • May need H2 blocker or PPI to activate enteric coated enzyme
    • Fibrosing colonopathy
      • Strictures in the colon associated with high dose enzyme use (enzyme gets to colon and causes damage leading to scarring/stricture)
  • 50. Treatment: Cystic fibrosis related liver disease
    • Ursodiol
      • Increased bile flow
      • Decrease toxicity of bile acids
    • Sclerotherapy, portosystemic shunts
    • Liver transplantation---only curative treatment for portal hypertension
  • 51. Treatment: Infertility
    • Microsurgical epididymal sperm aspiration coupled plus in vitro technology
    • Percutaneous epididymal sperm aspiration
    • Testicular sperm extraction
    • Maternal genetic testing
    McCallum, TJ et al., Fertility in men with cystic fibrosis. Chest 118:1059-1062; 2000.
  • 52. Psychosocial issues
    • Quality of life
      • Frequent hospitalizations
      • Time spent on therapies
      • Morbidity from disease
      • Restrictions secondary to disease
    • Adherence to therapies
    • Family planning
    • End of life issues
  • 53. “ It is, in fact, nothing short of a miracle that the modern methods of instruction have not entirely strangled the holy curiosity of inquiry.” ----Albert Einstein