Cystic Fibrosis

Cystic Fibrosis

Roy Maynard, M.D. December 9, 2010

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.

Respiratory Disease in CF

• Clinical Pulmonary Manifestations – Chronic cough, often productive – Wheezing – Recurrent pneumonia – Nasal polyps – Chronic sinusitis – CF pathogen colonization

Gastrointestinal Disease in CF

• Clinical Gastrointestinal Manifestations – Medonium ileus, DIOS, rectal prolapse – Pancreatic insufficiency, pancreatitis – Cirrhosis, portal hypertension – Speenomegaly – Failure to thrive, malabsorption

Physical Feature of Cystic Fibrosis

http://en.wikipedia.org/wiki/File:ClubbingCF.JPG Accessed on 11/10/10

“Clubbing” of the fingers

http://upload.wikimedia.org/wikipedia/commons/4/4e/ClubbingCF.JPG

http://en.wikipedia.org/wiki/File:ClubbingCF.JPG

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

Genetics (Autosomal Recessive)

www.cfnz.org.nz/about-cystic-fibrosis/ Accessed on 11/10/10

http://www.cfnz.org.nz/about-cystic-fibrosis/





Mutations

• Multiple types of mutations – Missense (most common 41%) – Frameshift – Splicing – Nonsense – Deletion

• Approximately 80% of mutations accounted for in 24 different mutations

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

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

Laboratory Diagnosis

• Elevated sweat chloride • Newborn screen • Genetic testing • Malabsorption

– 15% pancreatic sufficient – 85% pancreatic insufficient

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

CFTR Protein

http://en.wikipedia.org/wiki/File:CFTR.jpg Accessed on 11/10/10

http://upload.wikimedia.org/wikipedia/commons/0/09/CFTR.jpg

Electrolyte Transport Activities of Submucosal Glands

Taussig-Landau, et al. Pediatric Respiratory Medicine. St. Louis: Mosby, Inc., 1999 Accessed on 11/10/10

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

http://www.medscape.com/viewarticle/463495_4

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


• 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


• 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


• Respiratory Tract passengers and pathogens – Pseudomonas aeruginosa – Staphylococcus aureus – Haemophilus influenzae – Aspergillus – Stenotrophomonas maltophilia – Burkholderia cepacia

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

Complications of Cystic Fibrosis

• Hemoptysis • Pneumothorax • Respiratory failure • Cor pulmonale • Severe sinus disease/nasal polyps • Nutritional failure • Infertility • Allergic bronchopulmonary

aspergillosis

Complications of Cystic Fibrosis (continued)

• Cirrhosis with portal hypertension

• Pancreatitis • Diabetes • Gallbladder disease • Fibrosing colonopathy • Peptic ulcer disease • Arthropathy/arthritis • Asthma

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

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

Main Method of Airway Clearance Therapy (ACT)



http://www.hill-rom.co.uk/PageFiles/10597/the_vest_w330.jpg Accessed on 11/10/10

Hill-Rom Vest

http://www.hill-rom.co.uk/PageFiles/10597/the_vest_w330.jpg




• Anti-inflammatory therapies – Ibuprofen – Zithromax – Systemic steroids

Cystic Fibrosis Exacerbations

• Diagnosis – 10% or more decline in pulmonary function

testing – Increased sputum production – New infiltrate on CXR – Fever/hypoxia – Weight loss

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

Test Results of Cystic Fibrosis Patient (age 15)



Cystic Fibrosis Exacerbation with Pneumonia

Bronchiectasis

Bronchiectasis

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.

FEV1 Percent Predicted vs. BMI in Adults (20-40 years by gender)


Outcomes





Median Percent Predicted FEV1 vs. Age (1990 and 2008)


Outcomes





Median Predicted Survival


Outcomes





Cystic Fibrosis Lung Transplants (1990 – 2008)


Research

• Gene therapy • CFTR modulation • Restore airway surface liquid • Mucus alteration • Anti-inflammatory • Anti-infective • Lung transplantation • Nutrition

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.

Q&A

Thank you for attending!

Health & Medicine

Cystic Fibrosis