Cystic Fibrosis Flashcards
What is cystic fibrosis
Genetic disorder
Affects the lungs, pancreas, liver, intestines and reproductive organs
Abnormal secretions from glands clogging them with sticky, thick mucus
Malabsorption due to pancreatic insufficiency
Single gene disease
Autosomal recessive disease
Symptoms
Chronic sinusitis, nasal polyps
Progressive COPD, Cough and sputum
Pancreatic insufficiency, pancreatis, poor growth and weight problems
Genitourinary problems, infertility
Clubbing (fingers swell and become rounded)
Salty tasting skin
Pathophysiology
Mutation on the CF gene on chromosome 7
The CF gene encodes a protein called CFTR (Cystic fibrosis transmembrane regulator)
- Leads to abnormalities in the Cl- channel causing excess Na+ and water reabsorption whereas normal Cl- channel moves Cl- out of the cell for Na+ to be reabsorbed back into the cell
- This causes production of thicker mucus and mucociliary clearance stops
- Causes dilation of secretary glans and cause damage to extreme tissues
- Cilia cannot work properly so bacteria gets trapped in the lungs causing recurrent infections
Delta F508 Mutation - Class 2 no traffic
- 3 base pair deletion - the phenylalanine at position 508
- The CFTR protein folds incorrectly causing a class 2 mutation
- Fails to reach cell membrane
Class 1A
No mRNA
No CFTR at all
Class 1B
No protein or stop codon
If the stop codon is produced too early there is a short CFTR leading to degradation by the cell
Class 3
Impaired gating
Glycine (G551D) replaced with aspartic acid
Makes it to cell membrane but doesn’t open correctly
Class 4
Decreased conductance
Protein is misshaped so only allows a small amount of Cl- to pass through
Makes is to cell membrane, reacts to cell signalling and opens gate
Class 5
Less protein
CFTR produced but not in a sufficient amount
Sometimes correct versions are made but often incorrect
Class 6
Less stable protein
Only some functional CFTR reaches the cell membrane
Mucolytics
Help expel the mucus
Dornase alfa is the first choice and if that is inadequate then give dornase alfa and hypertonic sodium chloride or hypertonic sodium chloride alone
Mannitol powder is given when everything else fails
Lumacaftor with ivacaftor is not considered due to its funding issues
CFTR modulators
Designed to correct the malfunctioning protein made by the CFTR gene
* Not recommended in patients with a lung transplant
Lumacaftor (Corrector) - Increase number and function of CFTR channels at the cell surface
Ivacaftor (Potentiator) - Increase gating and conductance of CFTR channels present at the cell surface
Amplifiers
- Enhance production of CFTR protein by the cell
Stabilisers
- Stabilise the CFTR protein at the cell membrane
- Cavonstat from Nivalis inhibit S-nitrosoglutathione decreasing CFTR degradation
Read through
Target premature termination of CFTR translation
Ataluren - induces ribosomal read through of premature but not normal termination codons
