Cystic Fibrosis COPY Flashcards
What is the root cause of cystic fibrosis?
Cystic Fibrosis Transmembrane Regulator mutation (CFTR)
Common areas of manifestations:
skin, lungs, pancreas
What is CFTR?
Channel transport of chloride and water
-assists in cilia clearing debris
Epidemiology of CF
Most common lethal genetically inherited disease affecting the caucasian population
- autosomal recessive genetic disease
What is CF outcome dependent on?
Disease genotype/severity
Patient management
Compliance with therapies (adherence)
Prevalence of CF Mutations
Class 2»_space;> Class 1 > Class 3 ~ Class 4 > Class 5
- Class 4 + 5 = less severe
- Class 3 +4 +5 = result of dysfunctional proteins
CFTR Mutation Classes
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
What is the most common CFTR mutation?
Homozygous and Heterozygous F508del
CF Pulmonary Disease Pathophysiology
SHORT ANSWER Q
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)
Obstruction
genetic defect of the CFTR results in dehydrated secretions
Main bacterial infection in:
- children?
- adults?
children: S.aureus
adults: P. aeruginosa
Inflammatory Triangle
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
Pulmonary Disease Signs and Symptoms
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
What does CF exocrine pathophysiology result in?
Results in:
- obstruction
- deficient pancreatic production of protease, amylase, lipase
- deficient pancreatic production of bicarbonate
What does exocrine dysfunction acutely lead to?
Leads to poor absorption of:
- fat soluble vitamins (A,D,E, and K)
- Vit. B12
- Zinc
What does LONG TERM exocrine dysfunction in CF result in?
acinar cell destruction –> fibrosis –> progressive adipose replacement of pancreatic tissue
Exocrine Dysfunction Symptoms + Complications
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)
Cystic Fibrosis Related Diabetes (CFRD)
Characterized by:
- diminished insulin and glucagon secretion
- increased insulin resistance: dynamic, variable, and progressive
More prevalent amongst adults
NOT PRONE to diabetic ketoacidosis
What has Cystic Fibrosis Related Diabetes been associated with?
- Manifestations?
- Deterioration of pulmonary function
- Microvascular complications–> microalbumineruria; retinopathy; neuropathy
- increased mortality
Manifestations: asthma, acid reflux, CF related diabetes, sinus disease
Ivacaftor (Kalydeco)
First approved for class 3 and 4 mutations (G551D)
MOA: facilitates opening of the chloride Chanel (CFTR Potentiator)
- indicated for patients > 4y/o
Lumcaftor + Ivacaftor (Orkambi)
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
Tezacaftor + Ivacaftor (Symdeko)
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
Tezacaftor + Ivacaftor (Symdeko)
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
Elexacaftor + Tezacaftor + Ivacaftor (Trikafta)
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
