MW L6 Cystic Fibrosis Flashcards
1 in …. people are carriers
25
Most common mutation?
Δf508 ( Δ- deletion f-phenylalanine)
Mutation is thought to be a survival advantage in…
cholera
Most common cause of morbidity? (2)
lung dysfunction and infection
Characterised by build up of…
neutrophils
CF is a defect in
ion transport
Secretory organs are affected, for example: (5)
- eccrine sweat glands
- digestive system (pancreas, meconium ileus)
- males usually infertile
- nasal polyps
- LUNG DISEASE
What is meconium?
The earliest stool of the infant, should be passed within the few days of birth but may not be in CF
What receptor is missing in CF
CFTR (cystic fibrosis transmembrane conductance receptor)
How is air-surface liquid formed?
CFTR pumps out Cl-, Na+ follows (paracellular), water follows (aquaporins).
ENaC pumps Na+ back out.
= balance
What happens to air-surface liquid in CF?
No CFTR so salt is no longer dragged through, lose water and airway surface is low volume.
Low volume of air-surface liquid results in…
sticky viscous mucus
difficult for cilia to clear
growth of bacteria
What can be used to partially correct the air-surface liquid?
Hypertonic saline
Why are lung infections harder to treat in CF?
Biofilms
Common lung infections: (4)
p aeruginosa
s aureus
h influenza
burkoholderia cepacia (rarer but harder to treat)
Early treatment (2)?
Proper nutrition and enzyme suppliments
Mucolysis therapy e.g.
DNAase (Dornase alpha)
N-acetyl cysteine is not effective
What does DNAase do?
breaks down viscous mucus containing large amounts of DNA from inflammatory cells and bacteria
Inhaled antibiotics are used e.g.
Tobramycin
Beta agonists are used to….
activate residual CFTR if they are present
3 types of defect causing CF
Premature stop codon - no CFTR
In-frame deletion - defective processing
Substitution - defective regulation
Potential therapy for class 1 CF
Ataluren - fires readthrough (ignore) of premature stop
What is class 1 CF caused by?
Premature stop codon (5% of pop)
What is class 2 CF caused by?
Defective channel processing
What is class 3 CF caused by?
Defective channel regualtion
Therapy for class 3 CF?
Ivacaftor - turns on channels that don’t work as well
Potential therapies for class 2? (2)
Lumacraftor and N6022 - stabilise CFTR on the membrane
Alternative approach to treating CF? (2)
ENAC antagonism
Actiativing Cl channels
What does ENAC transport?
Cl-
What does CFTR transport?
Na+
What are the risks of activating alternative Cl channels?
CaCC increase amount of mucus by activating goblet cells
What does CaCC stand for?
What does it transport?
Calcium activated chloride channel
e.g. of CaCC activator?
Denufosol (p2y2 agonist but not effective at maintain lung function)
e.g. of blocking ENAC
amiloride
risk of blocking the ENAC
hyperkalemia
Substantial improvement in life expectancy due to (4)
Early recognition
Nutrition
Aggressive antibiotics
Transplant
What anti-inflammatory therapies are used (2)?
High dose ibuprofen
Glucocorticoids
