CF

Question 1

Describe the genetic and protein defects in cystic fibrosis and how they relate to organ dysfunction

Answer 1

CF is most common inherited lethal disease in Caucasians
o Carrier frequency: 1 in 29
• Autosomal recessive

CF gene located on long arm of chromosome 7
o Encodes CFTR (cystic fibrosis transmembrane regulator protein)
o Structure: 12 transmembrane loops, 2 intracellular nucleotide binding folds, one regulatory domain with phosphorylation sites

Function: cAMP-dependent chloride channel in epithelial apical membrane
Normal salt transport
• Na+ out of lumen (into cells) via sodium channels
• Cl- passively follows via CFTR
• Result: dilute NaCl in sweat
CF-affected transport
• Can’t absorb Na+ without Cl-
• Result: high NaCl concentration in sweat

Mutation in CF gene → cystic fibrosis
o Most common mutation = ΔF508 (70% of all mutations)

Organ system involvement 
o	GI system
o	Sweat glands
o	Reproductive system
o	Respiratory system

Question 2

Describe the pathophysiology of cystic fibrosis in different organ systems and the resulting clinical manifestations.

Answer 2

GI system
Pancreatic insufficiency from blocked pancreatic ducts
• Clogged with thick, sticky secretions
Malabsorption of protein and fat, and fat-soluble vitamins
• Result: greasy, oily, smelly stools
• Failure to thrive
Increased incidence of gallstones and diabetes in older patients
• Fibrosis of pancreas over time → destroys insulin-producing cells

Sweat glands
o Decreased reabsorption of Na+ and Cl- → salty sweat
o Can leave behind salt crystals on skin → irritating rash
o If lose lots Na+ and Cl- → dehydration (hyponatremic, hypochloremic, metabolic alkalosis)

Reproductive system
Males: Wolffian duct does not develop
• Absence of vas deferens → sterile
Females: decreased fertility due to thick secretions blocking cervix

Respiratory system
o Respiratory infection = colonization with Staphlococcus aureus and pseudomonas aeruginosa
o Stimulates immune reaction = inflammation
o Cycles of inflammation, infection and mucous production → progressive airway obstruction, hyperinflation, increased incidence of reactive airway disease, and bronchiectasis
o Lung pathology → 95% CF deaths

Question 3

Describe and explain the pathologic changes and the changes in lung mechanics and gas exchange that occur in cystic fibrosis.

Answer 3

Born with normal lungs
o Shortly after birth = get lung infection → inflammatory response
o Ongoing response destroys airways, impairs gas exchange (V/Q mismatch) → death

Pulmonary function changes
Increased air trapping
• Increased RV/TLC
• Changes in maximal mid-expiratory flow rates
• Reduced FEV1 → obstructive ventilatory defect
• FEV1 declines throughout life
• Best predictor of mortality

Impaired gas exchange
• Hypoxemia
• Retention of CO2
• Secondary consequences = pulmonary HT and cor pulmonale
BUT: blunted erythrocyte response to hypoxia
• Not increase
• May be due to anemia of chronic disease

Question 4

Describe the clinical presentations of and illustrate how to make a diagnosis of cystic fibrosis.

Answer 4

Newborn screening

Respiratory CF presentations 
o	Chronic cough to clear thick secretions in airways
o	Wheezing
o	Recurrent pneumonia 
o	Sinusitis 
o	Nasal polyps 
o	Bronchiectasis (abnormal dilation of small airways → chronic cough and poor clearance of secretions)
o	Clubbing of fingernails and toenails

GI presentations
o	Prolonged jaundice of infancy 
o	Meconium ileus in utero; can sometimes lead to intestinal perforation 
o	Steatorrhea 
o	Rectal prolapse 
o	Failure to thrive
o	Recurrent abdominal pain 
o	Distal intestinal obstruction syndrome 
o	Edema, hypoproteinuria, anemia 
o	Portal HT

Diagnosis 
Newborn screening
Sweat test: 
•	Stimulate sweat glands with pilocarpine (cholinergic agonist)
•	Collect sweat on filter paper
•	Measure Cl- in sweat
Normal sweat Cl- < 40 mEq/L in older individual) 
Abnormal (positive for CF):  > 60 mEq/L

Question 5

Discuss the principles of management of cystic fibrosis.

Answer 5

•	Pancreatic enzymes 
•	Vitamins
•	High calorie diet
•	Airway clearance
•	Antibiotics
•	Bronchodilators as indicated 
•	Enzyme therapy:
--Neutrophils release DNA and F-actin = increases viscosity and adhesiveness of CF sputum 
--Give Dornase alfa (recombinant human DNAase I)
•	Breaks down extracellular DNA
•	Decreases viscosity of sputum

Question 6

Identify the basic gross and microscopic pathologic changes seen in CF

Answer 6

Gross findings:
•	Widespread bronchiectasis
•	Purulent mucus in airways
•	Lobar atelectasis (collapsed lung) or consolidation with abscesses
•	Pleura may have adhesions or fibrosis

Histologic findings
• Inflammatory infiltration in airways
• Luminal purulent mucous plugging
• Abnormally dilated airways (bronchiectatic)
• Epithelial sloughing with squamous and/or goblet cell metaplasia
• Evidence of pneumonia in distal/alveolar parenchyma
• Possible abscess formation
• Development of interstitial fibrosis and inflammation