SM_170a: Cystic Fibrosis Flashcards
Cystic fibrosis is most common in ______
Cystic fibrosis is most common in Caucasians
Cystic fibrosis inheritance is ________
Cystic fibrosis inheritance is autosomal recessive
Cystic fibrosis is caused by mutations in the _____ gene, which are associated with defective ion transport in ______ cells
Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene, which are associated with defective ion transport in epithelial cells
What are the functions of the CFTR protein?
- Chloride channel (cAMP regulated)
- Regulator of other ion channels
- HCO3- (pancreas, airway pH)
- Epithelial sodium channel (ENaC): increased activity in absence of CFTR
- Outward rectifying chloride channels (ORCC)
- Others
The most common mutation causing cystic fibrosis is _______, which is located in the ______
The most common mutation causing cystic fibrosis is F508del (phenylalanine deletion), which is located in the nucleotide binding domain
What are the clinical manifestations of cystic fibrosis?
- Lung disease
- Chronic sinopulmonary infections: bronchiectasis, chronic sinusitis / nasal polyps
- GI / nutritional abnormalities: pancreatic exocrine / endocrine insufficiency, liver cirrhosis around 2nd decade of life, small and large bowel (meconium ileus / distal intestinal obstruction, dysmotility / constipation)
- Male infertility (absence of vas deferens)
More recent CF patients have ______ FEV1% at birth and _____ expected survival age
More recent CF patients have higher FEV1% at birth and greater expected survival age
How is CF diagnosed?
- Sweat testing (pilocarpine iontophoresis)
- Nasal potential difference
- Genotyping: 2 mutations most common, >2000 mutations described, screen for virtually all mutations
Sweat of healthy patients is _______, while sweat of CF patients is _______
Sweat of healthy patients is hypotonic, while sweat of CF patients is hypertonic
(high [Cl-] in CF patients, which is a direct measure of CFTR activity)
Nasal potential differences in CF patients are more _______ at baseline, robustly ______ when amiloride is added, and ______ when Cl- is added
Nasal potential differences in CF patients are more negative at baseline, robustly increase when amiloride is added, and do not change when Cl- is added
______ is the best initial diagnostic test for CF
Sweat chloride test is the best initial diagnostic test for CF
Describe newborn screen for CF
- Mandated nationwide
- 66% of diagnoses made in first year of life
- Step-wise: measurement of IRT (marker of pancreatic inflammation) -> if elevated, repeat IRT or CFTR genotype -> if still elevated or mutation detected, then sweat chloride test
Describe the 6 classes of CF mutations
- Class I: premature stop codon -> severe phenotype
- Class II: mRNA transcribed but protein misfolds and is degraded (most common)
- Class III: diminished eletrical activity across cell membrane due to problem w/ CFTR gating function
- Class IV: diminished electrical activity due to problem w/ channel itself
- Class V: diminished CFTR function due to splicing abnormalities
- Class VI: faster towing through CFTR so less time for cell membrane to act properly
CF patients ________ for the ______ mutation have a more severe presentation
CF patients homozygous for the F508del (class II) mutation have a more severe presentation
(F508 deletion associated w/ severe decrement in CFTR function, class IV mutation R117H has some residual CFTR function)
Whether genetic testing can predict how severe the CF will be depends on the ______
Whether genetic testing can predict how severe the CF will be depends on the organ system
(most predictive for genital tract, somewhat predictive for GI tract, not very predicting for respiratory system)
The vicious cycle of CF results from ______, ______, and ______
The vicious cycle of CF results from altered airway secretions, infection, and inflammation
_____ in airway epithelial cells clear mucous by _____
Cilia in airway epithelial cells clear mucous by beating
Describe the CF pathophysiologic hypothesis
- ENaC channels are hyperactive
- Increased Na+ in airway
- Increased water in airway
- Squashes cilia
- Cilia cannot move mucous as efficiently
Proportion of bacteria is ______ in CF patients than non-CF patients
Proportion of bacteria is higher in CF patients than non-CF patients
(CF patients cannot clear bacteria as well)
_________ is the most common bacterium causing infection in adult CF patients, while _________ is the most common bacterium causing infection in CF patients less than 17 years old
Pseudomonas aeruginosa is the most common bacterium causing infection in adult CF patients, while Staphylococcus aureus is the most common bacterium causing infection in CF patients less than 17 years old
How is CF treated?
- Multi-disciplinary team (at accredited CF centers)
- Multi-organ drug therapies (end organ damage)
- Novel drugs
Describe the treatment of CF
- Mucolytics: DNAase (pulmozyme), hypertonic saline, mannitol
- CPT and postural drainage
- High frequency chest wall oscillation (HFCWO)
Others: PEP, Acapella, Flutter, Aerobika, Metaneb - Exercise
- Bronchodilators: short and long acting beta-2 agonists, anti-cholinergics, anti-leukotrienes
- Anti-inflammatory agents: corticosteroids, ibuprofen, macrolides
- Antibiotics
Mucolytics act by _______ to make expectorating mucus easier for CF patients
Mucolytics act by decreasing viscosity of mucus to make expectorating mucus easier for CF patients
[Non-medical therapy] allows for airway clearance
Exercise allows for airway clearance
Describe the nutritional treatment of CF
- Pancreatic enzyme replacement therapy
- Vitamins
- Nutritional supplements
- Nocturnal feeds (G-tube, nasogastric tubes)
Describe emerging therapy for CF
CFTR rescue
- Stop mutations: read through drugs
- Chemical chaperones (∆F508): Lumacaftor (corrector), Tezacaftor (corrector), Ivacaftor (potentiator, G551D), next generation correctors
- Amplifiers
- mRNA editing or replacement
- Gene therapy
In restoring CFTR function, potentiators _______
In restoring CFTR function, potentiators increase flow of ions through CFTR present at cell surface
In restoring CFTR function, correctors ________
In restoring CFTR function, correctors increase cellular processing and delivery of CFTR proteins to the cell surface
_______ (potentiator) increases FEV1 % by _____ % and ______ CFTR function in CF patients
Ivacaftor (potentiator) increases FEV1 % by 10 % and increases CFTR function in CF patients
(much less Cl-)
_______/Ivacaftor is more effective and safe for the treatment of CF than _______/Ivacaftor
Tezacaftor/Ivacaftor is more effective and safe for the treatment of CF than Lumacaftor/Ivacaftor
Triple CFTR modulator combination of Elexacaftor and Tezacaftor (both modulators) and Ivacaftor (potentiator) _______ FEV1 in CF patients
Triple CFTR modulator combination of Elexacaftor and Tezacaftor (both modulators) and Ivacaftor (potentiator) substantially improves FEV1 in CF patients
