Cystic Fibrosis
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Transcript of Cystic Fibrosis
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Cystic Fibrosis
Roy Maynard, M.D. December 9, 2010
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Objectives for Cystic Fibrosis
• Understand the defect involving the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) in the pathogenesis of lung and pancreatic disease in cystic fibrosis patients.
• Describe laboratory testing used to confirm a diagnosis of cystic fibrosis.
• Recognize the association between nutritional status and lung function in patients with cystic fibrosis.
• Name 3 complications of cystic fibrosis.
• Understand the rationale for prescribed treatments for pulmonary exacerbations in patients with cystic fibrosis.
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Respiratory Disease in CF
• Clinical Pulmonary Manifestations – Chronic cough, often productive – Wheezing – Recurrent pneumonia – Nasal polyps – Chronic sinusitis – CF pathogen colonization
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Gastrointestinal Disease in CF
• Clinical Gastrointestinal Manifestations – Medonium ileus, DIOS, rectal prolapse – Pancreatic insufficiency, pancreatitis – Cirrhosis, portal hypertension – Speenomegaly – Failure to thrive, malabsorption
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Physical Feature of Cystic Fibrosis
http://en.wikipedia.org/wiki/File:ClubbingCF.JPG Accessed on 11/10/10
“Clubbing” of the fingers
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Genetics
• Northern European ancestry • Autosomal recessive • Most common lethal genetic disease in
Caucasians • 1/3,000 births • 30,000 individuals in USA • Chromosome 7 • Currently 1,820 known mutations
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Genetics (Autosomal Recessive)
www.cfnz.org.nz/about-cystic-fibrosis/ Accessed on 11/10/10
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Mutations
• Multiple types of mutations – Missense (most common 41%) – Frameshift – Splicing – Nonsense – Deletion
• Approximately 80% of mutations accounted for in 24 different mutations
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Newborn Screening for CF
• Newborn screening in Minnesota since March, 2006
• Screened for in all 50 states of the union
• IRT/DNA screen (immunoreactive trypsinogen)
• High false positive rate • Prenatal screening and carrier
screening available
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Laboratory
• Sweat chloride >60 mEq/liter confirmatory
• 40-60 mEq/liter indeterminate • <40 mEq/liter is normal • Other labs
– Hypoproteinemia – Decreased calcium levels – Hyponatremia – Increased stool fat
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Laboratory Diagnosis
• Elevated sweat chloride • Newborn screen • Genetic testing • Malabsorption
– 15% pancreatic sufficient – 85% pancreatic insufficient
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Cystic Fibrosis Transmembrane Regulator (CFTR)
• CF gene encodes a large single chain polypeptide of 1,480 amino acids (ATP-binding cassette proteins)
• Embedded in lipid membrane of epithelial cells, sweat glands, pancreas and lungs
• Mediates solute transport, mostly the chloride channel
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CFTR Protein
http://en.wikipedia.org/wiki/File:CFTR.jpg Accessed on 11/10/10
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Electrolyte Transport Activities of Submucosal Glands
Taussig-Landau, et al. Pediatric Respiratory Medicine. St. Louis: Mosby, Inc., 1999 Accessed on 11/10/10
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Pathophysiology
• Altered airway secretions – Periciliary fluid through which cilia beat – Overlying mucus gel phase
http://www.medscape.com/viewarticle/463495_4 (Figure 1B) Accessed on 11/10/10
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Pathophysiology (continued)
• Airway Secretions – Decreased water content – Increased solid content – Higher salt content – Increased submucosal glands and goblet cells
and their secretions – Increased amount of dehydrated, viscous
secretions that obstruct glands and airways
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Pathophysiology (continued)
• Dilatation of submucosal glands • Mucus plugging of airways • Hypertrophy and hyperplasia of secretory
elements • Chronic infections and inflammation • Chronic bronchiolitis • Squamous metaplasia of respiratory
epithelium impacts mucociliary clearance • Bronchiectasis • Loss of functional lung parenchyma
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Pathophysiology (continued)
• Airway inflammation – Documented to start in the infant lung despite
being normal at birth – Increased neutrophils – Increased neutrophil elastase and other cytokines – Imbalance in anti-inflammatory cytokines – Proteolytic enzymes destroy airway tissues
contributing to bronchiectasis
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Pathophysiology (continued)
• Respiratory Tract passengers and pathogens – Pseudomonas aeruginosa – Staphylococcus aureus – Haemophilus influenzae – Aspergillus – Stenotrophomonas maltophilia – Burkholderia cepacia
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Percent of Patients with Respiratory Infections (by age)
http://www.cff.org/UploadedFiles/research/ClinicalResearch/2008-Patient-Registry-Report.pdf Accessed on 11/10/10
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Complications of Cystic Fibrosis
• Hemoptysis • Pneumothorax • Respiratory failure • Cor pulmonale • Severe sinus disease/nasal polyps • Nutritional failure • Infertility • Allergic bronchopulmonary
aspergillosis
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Complications of Cystic Fibrosis (continued)
• Cirrhosis with portal hypertension
• Pancreatitis • Diabetes • Gallbladder disease • Fibrosing colonopathy • Peptic ulcer disease • Arthropathy/arthritis • Asthma
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Routine Management
• Quarterly visits CF center with pulmonary function testing and nutritional assessment
• Annual labs and chest x-rays • High protein diet • Titration of pancreatic enzymes • Fat soluble vitamin supplementation
ADEK • Exercise
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Routine Management (continued)
• Daily chest physiotherapy – Huff and cough – Flutter valve – Percussive therapy – High frequency chest wall oscillation
• Nebulizer treatments – Inhaled steroids – Beta-agonist – Recombinant DNase – Hypertonic saline – Inhaled antibiotics
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Main Method of Airway Clearance Therapy (ACT)
http://www.cff.org/UploadedFiles/research/ClinicalResearch/2008-Patient-Registry-Report.pdf Accessed on 11/10/10
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Routine Management (continued)
http://www.hill-rom.co.uk/PageFiles/10597/the_vest_w330.jpg Accessed on 11/10/10
Hill-Rom Vest
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Routine Management (continued)
• Anti-inflammatory therapies – Ibuprofen – Zithromax – Systemic steroids
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Cystic Fibrosis Exacerbations
• Diagnosis – 10% or more decline in pulmonary function
testing – Increased sputum production – New infiltrate on CXR – Fever/hypoxia – Weight loss
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Cystic Fibrosis Exacerbations (continued)
• Hospitalizations • Systemic antibiotics (culture directed) • Increased chest physiotherapy • Sinus surgery • Enhance nutrition • Psychosocial issues • End stage evaluate for lung/liver
transplantation
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Test Results of Cystic Fibrosis Patient (age 15)
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Test Results of Cystic Fibrosis Patient (age 16)
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Test Results of Cystic Fibrosis Patient (age 22)
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Cystic Fibrosis Exacerbation with Pneumonia
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Bronchiectasis
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Bronchiectasis
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Outcomes
• Decline in lung function associated with poorer nutritional status.
• Decline in lung function has improved with early diagnosis and new therapies over the past two decades.
• Median predicated survival has increased over the past two decades.
• Increase in lung transplants in patients with end-stage cystic fibrosis pulmonary disease.
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FEV1 Percent Predicted vs. BMI in Adults (20-40 years by gender)
http://www.cff.org/UploadedFiles/research/ClinicalResearch/2008-Patient-Registry-Report.pdf Accessed on 11/10/10
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Outcomes
• Decline in lung function associated with poorer nutritional status.
• Decline in lung function has improved with early diagnosis and new therapies over the past two decades.
• Median predicated survival has increased over the past two decades.
• Increase in lung transplants in patients with end-stage cystic fibrosis pulmonary disease.
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Median Percent Predicted FEV1 vs. Age (1990 and 2008)
http://www.cff.org/UploadedFiles/research/ClinicalResearch/2008-Patient-Registry-Report.pdf Accessed on 11/10/10
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Outcomes
• Decline in lung function associated with poorer nutritional status.
• Decline in lung function has improved with early diagnosis and new therapies over the past two decades.
• Median predicated survival has increased over the past two decades.
• Increase in lung transplants in patients with end-stage cystic fibrosis pulmonary disease.
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Median Predicted Survival
http://www.cff.org/UploadedFiles/research/ClinicalResearch/2008-Patient-Registry-Report.pdf Accessed on 11/10/10
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Outcomes
• Decline in lung function associated with poorer nutritional status.
• Decline in lung function has improved with early diagnosis and new therapies over the past two decades.
• Median predicated survival has increased over the past two decades.
• Increase in lung transplants in patients with end-stage cystic fibrosis pulmonary disease.
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Cystic Fibrosis Lung Transplants (1990 – 2008)
http://www.cff.org/UploadedFiles/research/ClinicalResearch/2008-Patient-Registry-Report.pdf Accessed on 11/10/10
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Research
• Gene therapy • CFTR modulation • Restore airway surface liquid • Mucus alteration • Anti-inflammatory • Anti-infective • Lung transplantation • Nutrition
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Conclusion
• Cystic fibrosis is the most common lethal genetic disease in Caucasians.
• Underlying problem uniquely associated with abnormal CFTR protein function.
• Increased viscosity of airway secretions causes progressive loss of lung parenchyma and function.
• Improved nutritional status associated with better lung function.
• Research has and will continue to provide new therapies and interventions to increase longevity.
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Q&A
Thank you for attending!