Cystic Fibrosis

Question 1

What is the root cause of cystic fibrosis?

Answer 1

Cystic Fibrosis Transmembrane Regulator mutation (CFTR)

Common areas of manifestations:
skin, lungs, pancreas

Question 2

What is CFTR?

Answer 2

Channel transport of chloride and water

-assists in cilia clearing debris

Question 3

Epidemiology of CF

Answer 3

Most common lethal genetically inherited disease affecting the caucasian population
- autosomal recessive genetic disease

Question 4

What is CF outcome dependent on?

Answer 4

Disease genotype/severity
Patient management
Compliance with therapies (adherence)

Question 5

Prevalence of CF Mutations

Answer 5

Class 2&raquo_space;> Class 1 > Class 3 ~ Class 4 > Class 5

• Class 4 + 5 = less severe
• Class 3 +4 +5 = result of dysfunctional proteins

Question 6

CFTR Mutation Classes

Answer 6

Normal: CFTR created, reaches cell surface and functions properly

Class 1: No functional CFTR created
-Nucleus

Class 2: CFTR protein created, but misfolded, but restricting it from reaching cell surface
-Golgi apparatus

Class 3: CFTR protein created and reaches cell surface, but gate does not function properly

Class 4: opening in CFTR protein ion channel is faulty

Class 5: CFTR created in insufficient quantities

Question 7

What is the most common CFTR mutation?

Answer 7

Homozygous and Heterozygous F508del

Question 8

CF Pulmonary Disease Pathophysiology

SHORT ANSWER Q

Answer 8

Mutated CFTR gene 
Loss of CFTR function 
Impaired bacterial eradication 
infection 
inflammation 
airway remodeling 
airway obstruction 
bronchiectasis 

result in buildup of mucus in lungs due to defective CFTR protein (no chloride transfer–> cilia cannot move debris)

Question 9

Obstruction

Answer 9

genetic defect of the CFTR results in dehydrated secretions

Question 10

Main bacterial infection in:

• children?
• adults?

Answer 10

children: S.aureus
adults: P. aeruginosa

Question 11

Inflammatory Triangle

Answer 11

Inflammatory - mediated tissue damage
-Anti-inflammatory: azithromycin and ibuprofen

Obstruction
-mucolytic/hydrating agents/ bronchodilators: dornase alfa, hypertonic saline, albuterol

Infection
-Antibiotics: inhaled tobramycin, inhaled aztreonam, systemic antibiotics

Question 12

Pulmonary Disease Signs and Symptoms

Answer 12

Symptoms: Cough

• Sputum production
• SOB/Difficulty of breath

Signs: Crackles/rales

• Rhonchi
• Wheezing
• Recurrent pneumonia
• Hyperinflation and atelectasis
• Late stage: pulmonary hypertension/ Cor pulmonale

> 75% patients with CF die from respiratory cause

Question 13

What does CF exocrine pathophysiology result in?

Answer 13

Results in:

• obstruction
• deficient pancreatic production of protease, amylase, lipase
• deficient pancreatic production of bicarbonate

Question 14

What does exocrine dysfunction acutely lead to?

Answer 14

Leads to poor absorption of:

• fat soluble vitamins (A,D,E, and K)
• Vit. B12
• Zinc

Question 15

What does LONG TERM exocrine dysfunction in CF result in?

Answer 15

acinar cell destruction –> fibrosis –> progressive adipose replacement of pancreatic tissue

Question 16

Exocrine Dysfunction Symptoms + Complications

Answer 16

Associated with poor digestion

• abdominal distention
• increased stool frequency with loose consistency / four odor
• increased fecal fat content

Complications

• malnutrition
• poor weight gain (predictor of mortality)

Question 17

Cystic Fibrosis Related Diabetes (CFRD)

Answer 17

Characterized by:

• diminished insulin and glucagon secretion
• increased insulin resistance: dynamic, variable, and progressive

More prevalent amongst adults

NOT PRONE to diabetic ketoacidosis

Question 18

What has Cystic Fibrosis Related Diabetes been associated with?
- Manifestations?

Answer 18

• Deterioration of pulmonary function
• Microvascular complications–> microalbumineruria; retinopathy; neuropathy
• increased mortality

Manifestations: asthma, acid reflux, CF related diabetes, sinus disease

Question 19

Ivacaftor (Kalydeco)

Answer 19

First approved for class 3 and 4 mutations (G551D)
MOA: facilitates opening of the chloride Chanel (CFTR Potentiator)
- indicated for patients > 4 months

Question 20

Lumcaftor + Ivacaftor (Orkambi)

Answer 20

MOA:

• Lumacaftor: fixes the defective CFTR protein so it can move to the proper place on the airway cell surface (CFTR corrector)
• Ivacaftor: CFTR potentiator

Indicated for patients aged > 2y/o that have two copies of the F508del homozygous

Question 21

Tezacaftor + Ivacaftor (Symdeko)

Answer 21

MOA:

• Tezacaftor: fixes the defective CFTR protein so it can move to the proper place on the airway cell surface (CFTR corrector)
• Ivacaftor: CFTR potentiator

Indicated for patients > 6y/o with 2 copies of the F508del CFTR mutation OR more than 1 mutation responsive to T-1

Question 22

Tezacaftor + Ivacaftor (Symdeko)

Answer 22

MOA:

• Tezacaftor: fixes the defective CFTR protein so it can move to the proper place on the airway cell surface (CFTR corrector)
• Ivacaftor: CFTR potentiator

Indicated: > 6 years who have 2 copies of the F508del CFTR

Question 23

Elexacaftor + Tezacaftor + Ivacaftor (Trikafta)

Answer 23

Triple Therapy

MOA: Elexacaftor + Tezacaftor: fix defective CFTR protein so it can move to the proper place on the airway cell surface (CFTR corrector)
- Ivacaftor: CFTR Potentiator