SM_170a: Cystic Fibrosis

Question 1

Cystic fibrosis is most common in ______

Answer 1

Cystic fibrosis is most common in Caucasians

Question 2

Cystic fibrosis inheritance is ________

Answer 2

Cystic fibrosis inheritance is autosomal recessive

Question 4

Cystic fibrosis is caused by mutations in the _____ gene, which are associated with defective ion transport in ______ cells

Answer 4

Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene, which are associated with defective ion transport in epithelial cells

Question 5

What are the functions of the CFTR protein?

Answer 5

• 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

Question 6

The most common mutation causing cystic fibrosis is _______, which is located in the ______

Answer 6

The most common mutation causing cystic fibrosis is F508del (phenylalanine deletion), which is located in the nucleotide binding domain

Question 7

What are the clinical manifestations of cystic fibrosis?

Answer 7

• 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)

Question 8

More recent CF patients have ______ FEV1% at birth and _____ expected survival age

Answer 8

More recent CF patients have higher FEV1% at birth and greater expected survival age

Question 9

How is CF diagnosed?

Answer 9

• Sweat testing (pilocarpine iontophoresis)
• Nasal potential difference
• Genotyping: 2 mutations most common, >2000 mutations described, screen for virtually all mutations

Question 10

Sweat of healthy patients is _______, while sweat of CF patients is _______

Answer 10

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)

Question 11

Nasal potential differences in CF patients are more _______ at baseline, robustly ______ when amiloride is added, and ______ when Cl^- is added

Answer 11

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

Question 12

______ is the best initial diagnostic test for CF

Answer 12

Sweat chloride test is the best initial diagnostic test for CF

Question 13

Describe newborn screen for CF

Answer 13

• 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

Question 14

Describe the 6 classes of CF mutations

Answer 14

• 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

Question 15

CF patients ________ for the ______ mutation have a more severe presentation

Answer 15

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)

Question 16

Whether genetic testing can predict how severe the CF will be depends on the ______

Answer 16

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)

Question 17

The vicious cycle of CF results from ______, ______, and ______

Answer 17

The vicious cycle of CF results from altered airway secretions, infection, and inflammation

Question 18

_____ in airway epithelial cells clear mucous by _____

Answer 18

Cilia in airway epithelial cells clear mucous by beating

Question 19

Describe the CF pathophysiologic hypothesis

Answer 19

1. ENaC channels are hyperactive
2. Increased Na⁺ in airway
3. Increased water in airway
4. Squashes cilia
5. Cilia cannot move mucous as efficiently

Question 20

Proportion of bacteria is ______ in CF patients than non-CF patients

Answer 20

Proportion of bacteria is higher in CF patients than non-CF patients

(CF patients cannot clear bacteria as well)

Question 21

_________ 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

Answer 21

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

Question 22

How is CF treated?

Answer 22

• Multi-disciplinary team (at accredited CF centers)
• Multi-organ drug therapies (end organ damage)
• Novel drugs

Question 23

Describe the treatment of CF

Answer 23

• 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

Question 24

Mucolytics act by _______ to make expectorating mucus easier for CF patients

Answer 24

Mucolytics act by decreasing viscosity of mucus to make expectorating mucus easier for CF patients

Question 25

[Non-medical therapy] allows for airway clearance

Answer 25

Exercise allows for airway clearance

Question 26

Describe the nutritional treatment of CF

Answer 26

• Pancreatic enzyme replacement therapy
• Vitamins
• Nutritional supplements
• Nocturnal feeds (G-tube, nasogastric tubes)

Question 27

Describe emerging therapy for CF

Answer 27

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

Question 28

In restoring CFTR function, potentiators _______

Answer 28

In restoring CFTR function, potentiators increase flow of ions through CFTR present at cell surface

Question 29

In restoring CFTR function, correctors ________

Answer 29

In restoring CFTR function, correctors increase cellular processing and delivery of CFTR proteins to the cell surface

Question 30

_______ (potentiator) increases FEV₁ % by _____ % and ______ CFTR function in CF patients

Answer 30

Ivacaftor (potentiator) increases FEV₁ % by 10 % and increases CFTR function in CF patients

(much less Cl^-)

Question 31

_______/Ivacaftor is more effective and safe for the treatment of CF than _______/Ivacaftor

Answer 31

Tezacaftor/Ivacaftor is more effective and safe for the treatment of CF than Lumacaftor/Ivacaftor

Question 32

Triple CFTR modulator combination of Elexacaftor and Tezacaftor (both modulators) and Ivacaftor (potentiator) _______ FEV₁ in CF patients

Answer 32

Triple CFTR modulator combination of Elexacaftor and Tezacaftor (both modulators) and Ivacaftor (potentiator) substantially improves FEV₁ in CF patients