PATHOPHYS: Cystic Fibrosis

Question 1

What portion of the population has CF?

Answer 1

Both children and adults (because treatment is allowing more CF patients to live into adulthood

Question 2

What does the CF gene code for?

Answer 2

CFTR (cystic fibrosis transmembrane regulator)

Question 3

Where is the CFTR gene located?

Answer 3

long arm of chromosome 7

Question 4

How many mutations are found in CFTR?

Answer 4

over 1800

Question 5

What is the most common mutaiton in CFTR in caucasians?

Answer 5

Delta F508

Question 6

Where is CFTR located? What does it do?

Answer 6

located at the cell surface and acts as a regulated chloride channel

Question 7

What does CFTR regulate?

Answer 7

increases airway surface liquid (ASL) via inhibiting Na+ absorption (along with water) and Cl- secretion

Question 8

What does ASL do?

Answer 8

Forms periciliary liquid layer

Dilutes mucus—facilities entrapment of bacteria and clearance (helps clear airway secretions)

Question 9

What does a mutant CFTR do to ASL?

Answer 9

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)

Question 10

At what funcitonal level do mutations of the CFTR occur in the cell?

Answer 10

ALL OVER: membrane, vesicles, golgi, ER, and nucleus

this is why there are so many subtypes

Question 11

What is the pathogenesis of CF?

Answer 11

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.

Question 12

What do people of CF die from?

Answer 12

end stage lung disease

Question 13

What are the 5 classes of CFTR mutations?

Answer 13

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

Question 14

What is the clinical hallmark of CF?

Answer 14

chronic sinusitis

also see clubbing, airway obstruction, nasal polyps, etc.

Question 15

If a CF patient has asthma symptoms with eosinophils, what should you think about?

Answer 15

ABPA (aspergillus)

Question 16

An FEV1 <30% is predicted with a two year survival of what?

Answer 16

less than 50%

Question 17

What are the stools of a CF patient like?

Answer 17

greasy, bulky stools

Question 18

What liver problems may occur?

Answer 18

biliary cirrhosis (10%)

Question 19

What feature is common in infants with CF?

Answer 19

meconium ileus

Question 20

What does CF do to fertility?

Answer 20

95% of males are infertile

Most women are fertile (but may have difficulty due to thick cervical mucus and unovulatory cycles)

Question 21

What is diagnostic for a positive sweat chloride test?

Answer 21

> 60 meq/L

Question 22

What is the most popular medication for CF?

Answer 22

Tobi (300 mg twice daily)

Question 23

What does pulmozyme (dornase alfa) do for CF?

Answer 23

cleaves extracellular DNA from the neutrophils in sputum to make it less viscous

Question 24

What new medication is out to “fix” the G551D CF mutation?

Answer 24

Kalydeco (fixes the channel!)

IMPROVES FEV1 up to 18 points! Improves weight by 3 kg. Drops sweat chloride test by 50 points.

Question 25

What is the new drug combination to treat homozygous deltaF508 mutation?

Answer 25

VX-809 and Ivacaftor

will change the fact of CF

Question 26

What are the problems with CFTR in deltaF508?

Answer 26

1) Impaired cellular processing (improper folding, so degraded)
2) Small amounts of it lead to defective gating
3) Poor membrane halflife and increased turnover