Cystic Fibrosis Flashcards
Describe the trafficking of CFTR
Under normal circumstances, the DNA is read and transcribed to messenger RNA, during which, the introns are spliced out. The messenger RNA strand exits the nucleus of the cell and travels to the ribosome, where it is translated to the immature CFTR protein product.
In the ER, chaperones help to fold the protein. CFTR is then transferred to the Golgi apparatus.
From the Golgi, transport vesicles are created and the CFTR protein is transported to the cell surface membrane.
CF is the most common inherence disease in _____.
Caucasians (30k patients in the US) and over 10million carriers
What is the most common genotype of CF?
D508- loss of the amino acid phenylalanine (other races are less likely to have this particular mutation)
What is the MOA of CF?
AR
The CFTR gene is located on the long arm of chromosome ___
7
Frequency of different CF mutations
48% F508del/F508del
39% F508del/other
13% other/other
Common ‘other’ mutations in CF?
-G542X and G551D
What is the normal function of ion/chloride channels in the airways?
Ion channels in the airway maintain the optimal height or volume of mucus (for cilia) by collectively moving salt out or in
So what is the function of CFTR?
moving chloride into the airways and down regulating ENACs, which resorb sodium
What happens when CFTR doesn’t work?
The airway surface liquid layer is reduced and the mucus dehydrated resulting impaired mucociliary clearance. The airways become obstructed with mucus and infection and inflammation soon follow resulting in lung destruction.
This occurs because CFTR is not secreting chloride and the sodium channel is absorbing too much sodium. Without salt secretion water does not move into the airway and ASL volume decreases
T or F. Mucocilliary clearance is reduced in CF
T. ASL is needed to allow cilia to beat normally and to hydrate the mucus above it for mucocilliary clearance
What is Class I CF?
result in CFTR not being synthesized at all
What mutations cause Class I CF?
1) mutation G542X: the codon for glycine (G) at position 542 is replaced with a STOP codon (X), resulting in premature termination of protein translation.
2) Frameshift mutation 394delTT: deletion of 2 T nucleotides from position 394, resulting in a frameshift during mRNA translation leading to premature termination of the protein
Can any other mutations cause Class I CF?
Splice junction mutation 1717-1GA: a nucleotide change from G to A at 1717-1, resulting in an mRNA splicing defect and failure to synthesize the protein.
What is Class II CF?
defective trafficking of CFTR to the surface.
What mutations can cause Class II CF?
Amino acid deletion ΔF508: this classic mutation involves deletion of 3 base pairs in exon 10, resulting in loss of phenylalanine (F) at position 508 (in the first nucleotide-binding domain) leading to defective processing of CFTR in the ER and, ultimately, to intracellular degradation.
What causes Class III CF?
Missense mutation G551D: glycine (G) at position 551 changes to aspartic acid (D) that block regulation of CFTR activity
What causes Class IV CF?
Missense mutation R117H: arginine (R) at position 482 changes to histidine (H) that alter conductance properties of CFTR
What causes Class V CF?
Missense mutation A455E: alanine (A) at position 455 changes to glutamic acid (E).
Alternative splicing mutation OR
3849+10kbCT: a nucleotide change from C to T in a fragment 10kB from exon 19, resulting in creation of a splice acceptor site leading to alternative mRNA splicing.
What is the result of Class V CF?
reduced synthesis of CFTR
Class I, II, and III mutations are associated with ____, whereas class IV to VI are not;
pancreatic insufficiency
class IV mutations are generally associated with a relatively mild phenotype.
What is ‘classic’ CF?
where there is no FUNCTIONAL CFTR
How does classic CF present?
- chronic sinusitis
- recurrent bacterial RT infections
- pancreatic insufficiency (hard to gain wgt without these enzymes!!)
- meconium ileus at birth
- obstructive azospermia
seen first in very young children
Sweat chloride values in classic CF?
90-110 mmol/liter
How does non classic CF differ?
- no pancreatic insufficiency
- sweat chloride values 60-90mmol/liter
older initial presentation
T or F. Digital clubbing is a sign of CF
T.
Nasal polyps occur in what percentage of CF patients?
30%
Most CF patients die of what?
pulmonary complications
How prevalent is pulmonary disease in CF?
98%
Most CF patients die of what?
pulmonary complications (scarring)
Do bronchodilators help with the persistent wheezing associated with CF?
less responsive with age due to decreased cartilage and inflammation damage
T or F. Early lung damage may not always be detectable on standard chest x-rays (CXRs).
T. Even though lung damage can precede a decline in lung function (and can be picked up on a HRCT)
If you see lower lobe bronchiectasis upon CT scan suspect what?
primary ciliary dyskinesia or immunoglobulin deficiency.
If you also see Non-Tuberculous mycobacteria or AAllergic bronchopulmonary aspergillosis suspect CF.
T or F. PFTs might not show decreased lung function in early CF
T. Monitoring lung health solely by lung function status may not accurately reflect progressive lung disease.
What is bronchiectasis?
damage to the airways causes them to widen and become flabby and scarred.
What causes bronchiectasis in CF?
mucus plugs/secretions and persistent inflammation
Infection with CF pathogens follows an age-related predictable course. Give a broad outline.
beginning mostly with nontypeable H influenzae and S aureus and progressing to P aeruginosa in adulthood
Change in P. aeruginosa infection with age
Approximately 30% of infants (aged 0-1 years) are infected with P aeruginosa (as early as 3-6 months based on antibody); this incidence increases with age, so that by 18 years of age, 80% are infected with this pathogen.
Most common infections in CF patients regardless of age?
P aeruginosa, 57.8% S aureus, 49.7% H influenzae, 16.3% S maltophilia, 9.4% B cepacia, 3.1% A xylosoxidans, 5.2%.
Lung deteriorates faster in what sex?
Female
How much lung function is lost per year in CF?
about 2% (an FEV1 less than 30% is associated with a 2-yr survival rate less than 50%)
Pancreatic insufficiency is manifested how?
- failure to thrive and gain wgt (malabsorption)
- greasy, bulky stools
- malabsorption of fat-soluble vitamins (A,D, E, and K)
- diabetes and glucose intolerance
What is a consequence of lack of vitamin K?
lack of coagulability
What is meconium ileus?
bulky, stickly stool blocks the ileum
Bowel obstruction in infants is likely to be meconium ileum and thus CF. What about obstruction presenting initially in adults?
distal intestinal obstruction syndrome (DIOS) due to inspissated mucus in the GI tract (chronic constipation)
Why is infertility a hallmark of CF in males?
bilateral absence of vas deferens. Note: Females are not infertile but may have difficulty conceiving due to thick cervical mucus and anovulatory cycles resulting from poor nutritional status.
How is sweat chloride tested to diagnose CF?
A chemical drug (pilocarpine) is used to stimulate sweating and a low current voltage is applied) NaCl is quantified and the test is repeated twice.
What is considered a positive sweat chloride?
60-165 meq/L
What is considered a normal sweat chloride?
0-40 meq/L (borderline in between 40-65)
What are some causes for a false positive SC test?
- hypothyroidism
- Addison disease
- edema
- malnutrition
- glycogen storage disease
- ectodermal dysplasia
T or F. CF patients with pancreatic sufficiency have lower SC levels
T. and better lung function
Low FEV1 is associated with what?
lower BMI. Thus, severity of lung function as measured by spirometry improves with increasing BMI from age 6-20
In boys with CF with a BMI greater than the 35th percentile for their age, FEV1 measurements show a normal level of lung function. In girls, this applies for those with a BMI at approximately the 60th percentile or greater.
Clinically, these data emphasize the importance of maintaining proper nutrition in patients with CF.
What is TOBI?
tobramycin given to CF 300 mg BID by inhaler alternating every 4 weeks vs. continue to decrease exacerbations of CF
What is Pulmozyme?
(aka Dornase alfa) hydrolyzes the DNA present in sputum/mucus of cystic fibrosis patients and reduces viscosity in the lungs, promoting improved clearance of secretions.
Decrease the frequency of CF exacerbations by 37%
What are some mechanisms for clearing airways in CF?
- postural drainage (free)
- hypertonic saline
- acapella/flutter valve
- VEST oscillations
- Pulmozyme
How does hypertonic saline help airway clearance?
re-hydration of airways
Treatment regimen for CF
Albuterol Q6/Xopenex 0.63 mg–1.25 mgQ6
Pulmozyme 2.5 mg daily
7% Hypertonic saline 4 ml BID/TID
Tobramycin nebs 300 mg twice daily
Colistin 150 mg twice daily
T or F. The therapies listed can help stop the progression of CF
F. Despite an aggressive AWCT, inh and IV ABX, the progression in lung function will continue to decline
T or F. Patients the same CF genotype have relatively similar disease presentations and progression
T.
What does Ivacaftor help?
- increased FEV1, weight gain,
- reduction in exacerbations
- decreased SC levels by 40-50 pts.
New medication for D508/D508 genotype?
Orkambi (lumacaftor/ivacaftor)
