Stephensons, CF

Question 1

Define Cystic fibrosis

Answer 1

Cystic fibrosis is an autosomal recessive disorder that occurs due to mutation in the CFTR gene on chromosome 7. The mutation causes defective chloride ion transport across epithelial cells, with subsequent disturbance in sodium/ water movement. This results in thick, dehydrated mucus accumulation in multiple organ systems including lungs, pancreas, intestines, liver and reproductive system.

Question 2

What is the most common type of mutation that occurs in CF?

Answer 2

Most common: Delta F508 mutation –> deletion of phenylalanine at position 508 on long arm of chromosome 7. This results in misfolding and premature intracellular degradation of the CFTR protein before it reaches the epithelial cell membrane.

Question 3

Explain the normal functioning of CFTR in luminal epithelium e.g. lungs

Answer 3

CFTR maintains hydrated mucous secretions/ airway surface liquid by transporting chloride (Cl⁻) into the lumen, ensuring adequate luminal chloride levels.

The negative charge from chloride helps limit excessive sodium (Na⁺) reabsorption by inhibiting ENaC. This keeps Na⁺ and Cl⁻ in the lumen, allowing water to remain there via osmosis, ensuring mucus / airways stay hydrated.

In cystic fibrosis, defective CFTR prevents chloride secretion, leading to unchecked ENaC activity and excessive sodium absorption. As a result, water is drawn from the lumen into epithelial cells, causing thick, dehydrated mucus.

Question 4

Explain how the CFTR protein functions in the pancreas

Answer 4

CFTR is essential for bicarbonate (HCO₃⁻) secretion in the pancreas. It facilitates chloride (Cl⁻) secretion into the ductal lumen, maintaining a high luminal chloride concentration.

This chloride is then used by the Cl⁻/HCO₃⁻ exchanger to exchange Cl⁻ for HCO₃⁻, allowing bicarbonate to be secreted into the bowel.

This process is crucial for neutralizing stomach acid and ensuring proper digestion.

In cystic fibrosis, defective CFTR impairs this chloride-bicarbonate exchange, leading to thickened pancreatic secretions, enzyme blockage, and pancreatic damage.

Question 5

List 4 respiratory manifestations of cystic fibrosis

Answer 5

1. Chronic productive cough with thick sputum.
2. Dyspnea.
3. Digital clubbing
4. Nasal polyposis
5. Sinusitis
6. Respiratory failure –> Cor pulmonale
7. Recurrent respiratory infections (pseudomonas aeruginosa, staph aureus, klebsiella pneumonaie, burkholderia cepacia)

Question 6

List 4 GI manifestations of cystic fibrosis

Answer 6

1. Intestinal obstruction
2. Meconium ileus
3. Peritonitis due to bowel rupture
4. malabsorption (anemia, vitamin ADEK deficiency, stunted growth)
5. Pancreatitis
6. Jaundice (hepatitis/ cholestasis)
7. Secondary DM due to pancreatic atrophy

Question 7

Describe the molecular events that occur to cause ion channel conductance through the CFTR

Answer 7

1. Binding of an agonist e.g. Ach to the extracellular domain of the GPCR leads to downstream activation of adenylate cyclase which increases cAMP levels.
2. Rising cAMP results in activation of protein kinase A.
3. PKA phosphorylates the R domain of CFTR which allows for ATP binding site to become accessible.
4. ATP then binds to the nucleotide binding domains causing opening of the channel