Day 8, Lecture 3 (Aug 31): Clinical Correlation 2: Cystic Fibrosis Flashcards
Mode of transmission of Cystic fibrosis
- Autosomal recessive
- mutations of a gene located on chromosome 7 called the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)
- CFTR protein is a cAMP-regulated chloride channel that usually resides within the apical portion of mucosal epithelial cells
- Most common mutations- DeltaF508, G542X, G551D, W1282X, W1303K, and R 553X
___ mortality in CF is a result of lung disease
85%
THe CFTR gene is on what chromosome
Chromosome 7
A normal-functioning CFTR channel moves ______ while a mutant CFTR channel does not, thus causing ______
chloride ions to the outside of the cell while a mutant CFTR channel does not, causing sticky mucus to build up on the outside of the cell
Classes of cystic fibrosis-causing mutations
Newborn screen for CF
- A few drops of blood from a heel prick are placed on a special card, called a Guthrie card.
- IRT level: >65ng/dl
What steps are taken if a newborn has a hellp prick IRT level: >65 ng/dl
Why does the sweat test help determine CF
- Malfunction of CFTR in sweat glands leads to the inability to reabsorb water and thus dehydration
- this leads to sweat having a higher than normal concentration of sodium and chloride
What are the primary goals of CF
- Maintain lung function
- Reduce pulmonary exacerbations
- Improve nutritional status
What is the most prevalent bacterial infections for CF patients
- P. aeruginosa
What are the most difficult/complex bacterial infections to eradicate in CF patients
-
Ps. aeruginosa and B. cepacia
-
True infection, not “colonization”
- difficulty in eradicating due too:
- intrinsic antibiotic resistance
- Acquired antibiotic resistance
- Poor antibiotic penetration into secretions
- Alginate produced by mucoid Ps. (biofilms)
- CF-related defects in mucosal (but not systemic) defenses
- difficulty in eradicating due too:
-
True infection, not “colonization”
What is the most reconized hallmark in CF disease
- progressive obstructive lung disease
- early thickening of progressive mucus
- subsequent colonization with pathogenic bacteria
- Ultimately diffuse airway inflammation that destroys conducting airways and lung parenchyma
- Combination of:
- Dessicated mucosal suface, infection, and host’s inflammatory response leads to inspissation of airway debris and progressive endobronchial destruction
Symptoms of CF
- Couch, sputum production
- Tachypnea
- use of accessory muscles
- Increased AP diameter of chest
- Hypoxemia
- Exercise intolerance
- Coarse crackles
- Decreased or absent breath sounds/air movement
- Decreased pulmonary function
- Weight loss
What is the strongest predictor of mortality in CF
- FEV1 (forced expiratory volume)
almost half of the CF patients are homozygous for
F508del-CFTR
F508del-CFTR
- Almost half of CF patients are homozygous for F508del-CFTR
- Severe phenotype
- early onset of progressive lung disease
- Shortened life expectancy compared to overall CF population
Pulmonary exacerbations in CF patients
- Serious life events for a CF patient
- Occur and increase throughout the life of a CF patient
- Characterized by worsening respiratory symptoms (cough, sputum, production, shortness of breath)
- Typically require treatment with antibiotics
- Often result in hospitalization (average of 19 days/year), absence from school or work
- Major clinical consequences
- Irreversible and progressive loss of lung function
- Increased risk for future exacerbations
- reduced health-related quality of life
- increased risk of deat
The underlying cause of CF is
- loss of CFTR protein activity
- Reduced CFTR activity results in a loss of chloride transport causing abnormalities in tissues where CFTR protein is present
Respiratory therapies in CF are directed at?
- Inflammation
- Infection
What causes infections in the airways of CF patients
What are some of the therapies that help combat the effects of neutrophils attacking bacterial infections in CF patients lungs
Why is Pulmozyme used to treat CF?
is is a Dnase and is used to breakdown the DNA matrixes of the white blood cells in the lung tissue. This is used becasue without the enzyme the DNA will incorporate into the mucus and make it thicker
What are some therapies of CF that help with mucus clearing?
- Clearance techniques and vests are also used
What is Kalydeco/Ivacaftor used for in treatment of CF
- Re-establish Chloride transport via the CFTR protein.
- IVacaftor is aCFTR potentiator that facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR protein at the cell at the surface
- thus resulting in more normal function of the cilia and mucus layer combined with physical removal of mucus form the airway relieves physical obstruction and helps clear bacteria form the airways
- Restoring CFTR function results in improved FEV
Therapies for the treatment of chronic airway infections in CF patients
*
do current therapies treat the underlying cause of CF
- No!
_____ treat the underlying cause of CF
- CFTR modulators
New CFTR modulator for homozygous F508del CF patients?
- Lumacaftor
- improves the conformational stability of F508del-CFTR, resulting in increased processing and trafficking of mature CFTR protein to the cell surface
- This drug is used with ivacaftor
Nutritional status is poor in CF patients because
- common due to pancreatic insufficiency and malabsorption
- Lower body mass index (BMI) is associated with reduced lung function
- Poor nutritional status is a predictor of reduced survival
GI issues in CF patients
- Protein and Fat malabsorption
- Malnutrition/failure ot thrive
- Meconium ileus
- Distal intestinal obstruction syndrome
- Obstructive jaundice
- Focal biliary cirrhosis
- Rectal prolapse
- Recurrent pancreatitis
Besides lung and GI issues other notable manifestations in CF include
- DM
- Digital clubbing
- Hyponatremic dehydration
- Hypochloremic alkalosis
- Vitamin A, D, E, and K deficiences
- Zinc deficiency dermatitis
- Male infertility
- Anxiety
- Depression
Recommended timing for transitioning CF patients to adult care
- 18-21 years old
What is the median number of therapies and mean time need to complete the therapies for adult CF patients?
- 7 therapies per day
- mean time: 108 minutes
Life expectancy for CF patients
41 years old
