Cystic Fibrosis

Question 1

Organs that CF affects?

Answer 1

Lots of them...
Lungs.
GI - ileus
Liver -biliary cholestasis.
Pancreas -pancreatic insufficiency, T1DM
Reproductive (male sterility).
Skin - sweat.

Question 2

3 main causes of death in CF?

Answer 2

Cardio/respiratory complications.
Transplant complications. (usu. lung or liver).
Liver disease.

Question 3

Why did CF patients formerly die as neonates/ before lung disease developed?

Answer 3

Pancreatic insufficiency - can’t get digestive enzymes out -> failure to thrive.

Question 4

What’s mutated in CF?

Answer 4

CFTR - an apical epithelial Cl- channel.

Question 5

Most common mutation in CF?

What does this cause?

Answer 5

deltaF508 - 70% allele frequency.

Missense mutation. Protein gets to ER, but gets targeted for destruction as a misfolded protein.

Question 6

Five classes of mutation in CFTR?

Which classes are more/less severe?

Answer 6

I: Null production.
II: Missense -> impaired trafficking.
III: Missense -> gets to membrane, but doesn’t work.
IV: Reduced function.
V: Reduced quantity, due to mRNA instability.

I-III have severe phenotypes, IV and V are more mild and there’s still pancreatic function.

Question 7

Things that bring CF to clinical attention?

Answer 7

Chronic sinopulmonary disease. (but this is common, and usu. not CF).
GI/nutritional abnormalities / failure to thrive.
CF in 1st degree relative.

Question 8

2+ ways to diagnose CF?

Answer 8

Clinical presentation plus one of following:

• ID of 2 disease-causing CF alleles.
• Sweat test (pilocarpine iontophoresis)

Question 9

What does CFTR have to do with sweat?

Answer 9

CFTR allows Cl- to be reabsorbed from sweat (and Na+ will follow it). Dysfunctional CFTR -> too much NaCl in sweat will impair evaporation.

(Note that CFTR is involved in Cl- reabsorption in the skin. In the lungs, CFTR does Cl- secretion. We think CFTR is oriented in opposite directions in the membrane in these 2 different organs.)

Question 10

What does the sweat test for CF actually do?

What are the diagnostic ranges?

Answer 10

Pilocarpine (Ach agonist, promotes sweating) iontophoresis.
Cl- concentration in skin is assessed.
>60 mEq/L suggests CF.
<40 mEq/L is normal.
40-60 mEq/L is ambiguous.

Question 11

Can you depend on genotyping for CF diagnosis?

Answer 11

No - there are too many different alleles, that genotyping has max sensitivity of 90% in caucasians, about 80% in African Americans / Hispanics.
(Full gene sequencing is better…)

Question 12

How are newborns screened for CF?
Why is this marker there?
What do you do with a positive result?

Answer 12

Immunoreactive trypsinogen (IRT).
If elevated, suggests pancreatic damage.
(can think of the enzyme building up when it can't be secreted until it spills into the blood)

Positive IRT: test for deltaF508, then do sweat test.

Question 13

Pros and cons of newborn screening?

Answer 13

Earlier diagnosis -> improved nutritional status and cognition (Vit E?)
Earlier exposure to more health care -> earlier colonization with Pseudomonas.

Question 14

Should your threshold for sweat testing be high?

Answer 14

nope.

Question 15

Why doesn’t mucus get cleared well in CF?

Answer 15

Not enough water is secreted into the mucus, the sol layer isn’t thicken enough. Cilia can’t beat effectively to clear mucus.

Question 16

Mouse model for CF?

Answer 16

Overexpression of ENaC on Clara cells - pulling Na+, and thus H2O, out of mucus produces similar effect.

Question 17

Vicious cycle of lung disease in CF? (4 steps)

Answer 17

Impaired airway clearance -> bacterial colonization -> inflammation -> tissue damage -> (further impaired airway clearance)

Question 18

Major pathogens that chronically colonize CF airways?

Answer 18

S. aureaus - earlier on
Pseudomonas - older (age 18+)
Lots of other bad stuff.

Question 19

How are children with tracheostomies similar to kids with CF?

Answer 19

Cough isn’t normal - the glottis doesn’t close, so cough can’t generate force.
(Ventilator associated pneumonia is similar)

Question 20

How is primary ciliary dyskinesia similar to CF?

Answer 20

Mucocilliary clearance is impaired - though cough is preserved.

Question 21

Is ABx sensitivity testing reliable in CF?

Answer 21

According to Dr. Rubenstein, no. Airway conditions with biofilms may alter the ABx sensitivity of pathogens…

Question 22

New drugs that target specific CFTR mutations?

Answer 22

Kalydeco (Ivacaftor) - targets G551D, which has non-functional CFTR at apical surface -> produces improvements.

Question 23

How would one target deltaF508 with a drug?

Answer 23

Would have to use 2 drugs - one (VX-809) to promote getting it to the apical membrane, and another (Kalydeco) to make it work once it’s there.

Phase III trials are in progress.