Cystic fibrosis

Question 1

What is cystic fibrosis?

Answer 1

Inheritable autosomal recessive disease
Mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene
Ion transport abnormalities dehydrates mucous becoming more viscous
Pulmonary and GI systems principally affected

Question 2

Epidemiology

Answer 2

Must common mutation is a three base-pair deletion that should code for a phenylalanine
Usually diagnosed in childhood, median survival is around 30 years
Prognosis is improving

Question 3

Body systems affected by CF

Answer 3

Lungs and sinuses
Sweat gland
Liver
Pancreas
Intestine
Male reproductive tract
Airway obstruction

Question 4

Cellular processing of CFTR

Answer 4

Activation by ATP binding and cAMP-dependent phosphorylation
Insertion into and retrieval from membrane
Glycosylation and vesicle packaging in the golgi
Translation and folding in the ER
Synthesis of mRNA

Question 5

Diagnosis of CF

Answer 5

Large number of CFTR mutations limits utility of DNA tests in diagnosis
Sweat test for chlorine levels (>60mM for adults)
Nasal transepithelial potential difference (same lining as lining of the lungs)

Question 6

Management of CF

Answer 6

Lifestyle and psychological support required
Poly-pharmacy is required
Maintenance to improve QoL and limit exacerbations
Treat exacerbations aggressively

Question 7

Treatment objectives

Answer 7

Promote clearance of secretions
Control lung infection
Provide adequate nutrition
Prevent intestinal obstruction

Question 8

Antibiotics: Tobramycin

Answer 8

Inhaled
Treats chronic pulmonary infection
Effective for all severities of CF

Question 9

Antibiotics: Macrolides

Answer 9

Inhaled
Treats chronic pulmonary infection
Use for up to 6 months safe and effective
Beyond 6 months can reduce exacerbations but concern over resistance
Mechanism of action unclear

Question 10

Pulmonary mucous clearance

Answer 10

Can’t move mucous as too thick for cilia

Enzymes/ immunity cells to kill bacteria cannot cross mucous so bacteria are free to grow

Question 11

Promoting mucous clearance: inhaled dornase alfa

Answer 11

DNA forma polymers thickening mucous, dornase alfa is a DNAse, reduces viscosity of mucous

Question 12

Promoting mucous clearance: inhaled hypertonic saline

Answer 12

Disrupts ionic bonds supporting entanglements, disassociates DNA from mucous proteins, improved access to endogenous proteolytics

Question 13

Promoting mucous clearance: inhaled mannitol

Answer 13

Hydrates mucous by pulling fluid from underlying tissue, osmotic mechanism

Question 14

Anti-inflammatories

Answer 14

Oral corticosteroids: not recommended, too many side effects
Inhaled corticosteroids: used in sub-set with asthma patients
Ibuprofen: reduce lung inflammation, little evidence of benefit in adults, beneficial in young patients

Question 15

Bronchodilators

Answer 15

Inhaled bronchodilators (salbutamol, ipratropium): commonly only used for acute relief of obstruction, no clinical studies on exacerbation

Question 16

Non-medical interventions

Answer 16

Chest physiotherapy: used to aid clearance of mucous from the lungs

Question 17

CF GI disease

Answer 17

Pancreatic enzyme supplements: contain protease, lipase and amylase, inactivated by stomach acid (take with food, enteric coating)
Diet: high calorie diet needed as digestion compromised

Question 18

Future developments

Answer 18

Modifiers of CFTR expression (mutation specific)
Gene therapy: non-viral delivery of plasmid encoding CFTR gene, phase 2b trial complete, only modest clinical outcome, proof gene therapy might work