PATHOPHYS: Cystic Fibrosis Flashcards
What portion of the population has CF?
Both children and adults (because treatment is allowing more CF patients to live into adulthood
What does the CF gene code for?
CFTR (cystic fibrosis transmembrane regulator)
Where is the CFTR gene located?
long arm of chromosome 7
How many mutations are found in CFTR?
over 1800
What is the most common mutaiton in CFTR in caucasians?
Delta F508
Where is CFTR located? What does it do?
located at the cell surface and acts as a regulated chloride channel
What does CFTR regulate?
increases airway surface liquid (ASL) via inhibiting Na+ absorption (along with water) and Cl- secretion
What does ASL do?
Forms periciliary liquid layer
Dilutes mucus—facilities entrapment of bacteria and clearance (helps clear airway secretions)
What does a mutant CFTR do to ASL?
Normal CFTR will cause Cl- ions to be secreted if the ASL fluid is low and in mutant CFTR, Cl- ions not secreted
Normal CFTR blocks an ENaC channel, mutant CFTR does not block this and sodium absorption is increased (water follows sodium and ASL volume decreases)
At what funcitonal level do mutations of the CFTR occur in the cell?
ALL OVER: membrane, vesicles, golgi, ER, and nucleus
this is why there are so many subtypes
What is the pathogenesis of CF?
Abnormal CFTR leads to defective ion and fluid transport which impairs mucociliary clearance. This leads to obstruction or mucus plugging that allows for CHRONIC infections, inflammation (with break-down of cartilage) and scarring of the lung.
What do people of CF die from?
end stage lung disease
What are the 5 classes of CFTR mutations?
NO CFTR I: No synthesis II: Block in processing (delta 508- CFTR does not reach surface!) SOME CFTR III: Block in regulation IV: Altered conductance V: Reduced synthesis
What is the clinical hallmark of CF?
chronic sinusitis
also see clubbing, airway obstruction, nasal polyps, etc.
If a CF patient has asthma symptoms with eosinophils, what should you think about?
ABPA (aspergillus)
An FEV1 <30% is predicted with a two year survival of what?
less than 50%
What are the stools of a CF patient like?
greasy, bulky stools
What liver problems may occur?
biliary cirrhosis (10%)
What feature is common in infants with CF?
meconium ileus
What does CF do to fertility?
95% of males are infertile
Most women are fertile (but may have difficulty due to thick cervical mucus and unovulatory cycles)
What is diagnostic for a positive sweat chloride test?
> 60 meq/L
What is the most popular medication for CF?
Tobi (300 mg twice daily)
What does pulmozyme (dornase alfa) do for CF?
cleaves extracellular DNA from the neutrophils in sputum to make it less viscous
What new medication is out to “fix” the G551D CF mutation?
Kalydeco (fixes the channel!)
IMPROVES FEV1 up to 18 points! Improves weight by 3 kg. Drops sweat chloride test by 50 points.
What is the new drug combination to treat homozygous deltaF508 mutation?
VX-809 and Ivacaftor
will change the fact of CF
What are the problems with CFTR in deltaF508?
1) Impaired cellular processing (improper folding, so degraded)
2) Small amounts of it lead to defective gating
3) Poor membrane halflife and increased turnover
