Cystic Fibrosis

Question 1

What is a typical clinical presentation of CF patient? (3)

Answer 1

Neonate
o Possible meconium ileus (bowel obstruction)

Childhood
o Pancreatitis (endocrine and digestive dysfunction, diabetes)
o Failure to thrive (poor absorption of nutrients)
o Persistent cough & chest infection

Adulthood
o Worsening airway/lung function (eventual effects on CVS)
o Digital clubbing

Question 2

CF patients do not all have the same CFTR mutation

Answer 2

various classes exist with varying levels of function

Question 3

What is the role of CFTR in tissues?

Answer 3

Hydration of lining fluid depends on osmotic balance (movement of
water to maintain equilibrium in the overall concentration of solutes)

Ion movement occurs via membrane channels. H2O moves to maintain
isotonicity. The presence of an ion gradient induces movement of H2O

Question 4

How/why does this affect the function of the respiratory system? (2)

Answer 4

Cilia and mucus function to trap and remove microorganisms and particles

Function of cilia relies on maintaining a minimum periciliary layer thickness

Question 5

What is the effect of CFTR dysfunction on the respiratory system?

Answer 5

Airway surface liquid diameter & mucus layer viscosity needs to be maintained to function correctly (via adequate hydration).

Alterations in ion balance due to CFTR dysfunction = movement of water = reduced periciliary thickness = disrupted mucociliary function

Question 6

What happens following CFTR mutation in terms of mucociliary clearance? (2)

Answer 6

CFTR mutation = ↓Cl- transport & ↑Na+ absorption (no ENaC
inhibition) into cell & beyond

=↑ absorption of H2O from airway surface liquid due to osmotic
pressure (ASL becomes hypotonic) = dehydration of ASL & mucus

Question 7

What effect will impaired mucociliary function have on the respiratory system? (4)

Answer 7

Loss of mucociliary function leads to lung infections and airway pathology:

CFTR mutation
↓
Mucus dehydration + ↓ airway surface fluid (& acidification due to ↓HCO3- secretion)
↓
Cilia dysfunction
↓
↓Mucus clearance
↓
o ↑ Respiratory infections
o Chronic airway inflammation
o Mucus hypersecretion + productive cough
o Airway dysfunction & obstruction
o Bronchiectasis & bronchomalacia
o Type II respiratory failure + pulmonary heart disease (cor pulmonale)

Question 8

CF pathology leads to recurrent & persistent infection of the lung

Question 9

Loss of mucociliary function leads to lung infections and airway pathology

Question 10

Why is bacterial infection and chronic inflammation damaging to the airways?

Answer 10

Airway inflammation in CF is:
* Neutrophilic
* Exaggerated
* Self-perpetuating
* Ineffective at clearing infection

1) Bacterial infection
2) Chemokine release (e.g. IL-8)
3) Neutrophil recruitment & degranulation

4a) Protease release (N’phil elastase)
4b) ↑ROS burden (Reactive oxygen species)

5) Cell and tissue injury

Question 11

Long term injury causes airway remodelling (4)

Answer 11

• Bronchiectasis
• Bronchomalacia
• Airway obstruction

1) Bacterial infection
2a) Bacterial elastase = Antiproteases
2b) Glutathione depletion = antioxidants

Question 12

Chronic CF airway pathology leads to obstruction and respiratory failure

Answer 12

graph

Question 13

Determine the correct order of these stages in the pathophysiology (8)

Answer 13

CFTR gene mutation
↓
CFTR protein dysfunction
↓
ASL depletion
↓
Mucus plugging
↓
Infection
↓
Inflammation
↓
Airway obstruction
↓
Respiratory failure

Question 14

What is the treatment strategy for CF?

Answer 14

Overall treatment strategy (to help patient breath and limit long term damage to the airways):
o Promote mucus removal
o Treat infections and inflammatory exacerbations as they arise
o Treat acute airway obstruction
o If suitable, use more recently developed CFTR modulators to limit pathology arising

Question 15

Current treatments for lung pathology in cystic fibrosis (8)

Answer 15

CFTR gene mutation - Gene therapy
↓
CFTR protein dysfunction - CFTR modulators
↓
ASL depletion - Hypertonic Saline
↓
Mucus plugging - Physiotherapy, N-acetylcysteine, dornase-alfa
↓
Infection - antibiotics
↓
Inflammation - Corticosteroids
↓
Airway obstruction - Bronchodilators
↓
Respiratory failure - Lung transplant

Question 16

The overall efficacy of CF treatment

Answer 16

treatment has improved greatly over the previous 50 years:
Median life expectancy of F patients has gone up

Question 17

Summary (4)

Answer 17

1. Cystic fibrosis is an genetic disorder caused by a mutation in the CFTR
   gene, which leads to protein dysfunction.
2. CFTR dysfunction results in disrupted epithelial ion transport,
   resulting in dehydration of airway lining fluid/mucus and impaired
   mucociliary clearance.
3. Failure to clear mucus effectively leads to infection and (primarily
   neutrophilic) inflammation of the airway. The excessive protease and
   ROS release causes cell and tissue injury, further impairing mucus
   clearance.
4. A vicious cycle is created resulting in progressively worsening airway
   obstruction (via accumulation of mucus), bronchiectasis,
   bronchomalacia. This eventually leads to type II respiratory failure
   (inadequate ventilation).