SM 170a - Cystic Fibrosis Flashcards
Besides the respiratory tract, what other organ systems have primary effects due to cystic fibrosis?
- GI Tract
- Pancreatic insufficiency
- Malabsorption
- Constipation
- Obstruction
- Liver
- Obstructive jaundice
- Cirrhosis
- Galstones
- Reproductive tract
- Obliteration of the Vas Deferens (males)
- Increaesed viscocity of cervical and vaginal mucus (females)
- Increas frequency of anovulatory menstrual cycles (females)
- Sweat glands
- Metabolic alkalosis
- Dehydration
Class _____ CFTR mutations affect the channel itself; chloride conduction through the channel is decreased
Class IV CFTR mutations affect the channel itself; chloride conduction through the channel is decreased
A drug targeting the _____ mutation is likley to have the most profound overlal effect on the CF population.
Why?
A drug targeting the F508 deletion mutation is likley to have the most profound overlal effect on the CF population.
90% of patients with CF have at least one copy of this mutation, and this mutation is sever compared to other possible mutations
Genotype is most predictive of CF phenotype in which systems?
Genital tract > GI tract > Respiratory tract
Respiratory manifestations depend largely on the environment
Class _____ CFTR mutations are caused by retention of a misfolded protien in the ER, resulting in degradation of the protein in the proteasome. It never makes it to the plasma membrane
Class II CFTR mutations are caused by retention of a misfolded protien in the ER, resulting in degradation of the protein in the proteasome. It never makes it to the plasma membrane
Class II CFTR gene mutations result from…
Retention of misfolded protein in the ER, leading ot degradation in the proteasome
The protein does not make it to the plasma membrane.
Class II mutations include the ΔF508
List the available diagnostic tests for CF
Diagnostic for cystic fibrosis:
- Genetic
- Sweat test
- Nasal potential difference (rarely done)
Pancreatic insufficiency:
- Low fecal elastase
Class I CFTR gene mutations result from…
A premature stop codon -> no protein production
What is the most common CFTR mutation?
ΔF508 = deletion of phenylalanine 508
A class II mutation; results in a misfolded protein that is degraded in the proteasome
Describe the 3 components of the CFTR protein
- Transmembrane component
- Creates an anion channel
- Nucleotide binding fold
- Regulates the opening and closing of the channel
- R-domain
- Can be phosphorylated or dephosphorylated to regulate channel opening
Class V CFTR gene mutations result from…
A splicing abnormality
This causes decreased mRNA, CFTR protein, or both
Class _____ CFTR mutations are the result of a splicing abnormality, resulting in decreased mRNA, CFTR protein, or both.
Class V CFTR mutations are the result of a splicing abnormality, resulting in decreased mRNA, CFTR protein, or both.
What is the most commonly used newborn screening test for CF?
How are the results confirmed?
IRT (immunoreactive trypsin)
If IRT is elevated, repeat the test or run the genotype
If IRT is still elevated or a CFTR mutation is found, confirm with a sweat test
What is Ivacaftor?
Who should recieve it?
Ivacaftor is a potentiator drug used to treat CF
It increases Cl- movement through the CFTR channel
- Ivacaftor monotherapy
- Patients with class III, IV, and V mutations
- Includes G551D (class III)
- Ivacaftor + Tazacaftor + Elexacaftor
- Patients with F508 deletion
The _________ is the best initial diagnostic test for cystic fibrosis.
The sweat test is the best initial diagnostic test for cystic fibrosis
Run the test if CF is suspected;
Cl- ≥ 60 mmol/L => CF likely
Cl- 40-59 mmol/L => Additional testing needed
Cl- mmol/L => CF unlikely
Class IV CFTR gene mutations result from…
Changes in the channel itself
Result in decreased chloride conduction through the channel
F508 deletions can be rescued by therapeutic correctors elexacaftor and tezacaftor, and potentiator ivacaftor.
When rescued, what class of mutations does the F508 deletion fall into?
Class VI
There will be substantial plasma membrane insufficiency, even if the CFTR protein is pharmacologically rescued
Describe the “viscious cycle” of cystic fibrosis pathogenesis
Ion tranport abnormality results in…
- Changes in airway secretions
- Increased susceptibility to infection
- Increased inflammation
- Which further alters airway secretions
This all results in tissue damage (Bronchiectasis, sinusitis, nasal polyposis)
Hypothesis is that infection initiates the process; cannot be cleared due to altered airway secretions,
What is the recommended pharmacologic therapy for patients with the F508 deletion?
Elexacaftor + Tezacaftor + Ivacaftor
- Elexacaftor and Tezacaftor are correctors
- Ivacaftor is a potentiator
Shown to be highly effective at lowering sweat Cl- levels and increasing FEV1
What kinds of respiratory tissue damage are associated with cystic fibrosis?
Bronchiectasis
Sinusitis (upper airway)
Nasal polyposis (upper airway)
Class _____ CFTR mutations are caused by a premature stop cotdon, resulting in no protein production
Class I CFTR mutations are caused by a premature stop cotdon, resulting in no protein production
Class VI CFTR gene mutations result from…
Plasma membrane instability
There is faster turnover of the plasma membrane, so the channel does not remain in the membrane for as long
How does CFTR channel activity affect…
- Na+ channels?
- Alternative Cl- channels?
When Cl- moves through the CFTR channel normally
-
Na+ channels are negatively regulated. Na+ cannot get into the cell, which keeps enough Na+ (and therefore H2O) in the periciliary fluid layer
- LOF of CFTR results in increased Na+ flow into the cell
- H2O follows Na+, resulting in dehydration of airway secretions in teh periciliary fluid layer
-
Alternative Cl- channels are positively regulated
-
LOF of CFTR also results in decreased alternative Cl- channel activity
- Chloride remains in the secretions (ex: sweat)
-
LOF of CFTR also results in decreased alternative Cl- channel activity
Class _____ CFTR mutations result in plasma membrane stability; the CFTR protein doesn’t remain in the membrane for very long.
Class VI CFTR mutations result in plasma membrane stability; the CFTR protein doesn’t remain in the membrane for very long.
What is the difference between a corrector and a potentiator in CF pharmacologic therapy?
- Corrector
- Increases cellular processing and delivery of CFTR proteins to the cell surface
- Tezacaftor, Elexacaftor, Lamacaftor
- Potentiator
- Increase flow of ions through the CFTR protein
- Ivacaftor, VX-770
___________ are the strongest predictor of morbidity and mortality in patients with cystic fibrosis
Pulmonary manifesations are the strongest predictor of morbidity and mortality in patients with cystic fibrosis
Describe the standard therapy for cystic fibrosis
P-VACC
- Pancreas: Pancreatic enzyme supplementation
- Vitamins: Supplemental ADEC
- Antibiotics
-
Calories: Appropriate diet = increased calorie protein intake
- Nutritional supplements, nocturnal feeds
- Clearance: compounds/techniques for mucous clearance
**Main focus is on lung function and nutrition**
A sweat Cl- concentration of _______ indicates that cystic fibrosis is likely
A sweat Cl- concentration of 60 mmol/L indicates that cystic fibrosis is likely
Cl- ≥ 60 mmol/L => CF likely
Cl- 40-59 mmol/L => Additional testing needed
Cl- mmol/L => CF unlikely
____% of cystic fibrosis patients have pancreatic exocrine insufficiency and malabsorption
90 % of cystic fibrosis patients have pancreatic exocrine insufficiency and malabsorption
Compared to patients with pancreatic insufficiency, are CF patients with pancreatic sufficiency likely to have higher or lower sweat chloride values?
CF patients with pancreatic sufficiency are likely to have lower sweat Cl- levels
Class III CFTR gene mutations result from…
Abnormal channel gating (regulation)
The channel is not open as much/as often as it should be
How does increasing cAMP affect the activity of the CFTR channel?
More cAMP = more channel opening
Class _____ CFTR mutations affect channel regulation, resulting in impaired opening.
Class III CFTR mutations affect channel regulation, resulting in impaired opening.
How is bronchiectasis diagnosed?
If the airway is 1.5x bigger than its pulmonary artery
