Cystic Fibrosis Flashcards
Mutation of what gene causes cystic fibrosis?
cystic fibrosis transmembrane regulator (CFTR)
What is the inheritance pattern of cystic fibrosis?
autosomal recessive
structure and function of the CFTR protein
structure:
- resides in plasma membrane
- protein has 3 components
function:
- chloride channel
- HCO3 channel
- negatively regulates Epithelial Sodium Channel
- positively regulates alternative chloride channel
Class 1 CFTR mutation
premature stop codons
very little normal protein is made
Class 2 CFTR mutation
abnormal maturation
mutations in which mRNA is transcribed, protein is made, but folding is abnormal, degraded intracellularly
Class 3 CFTR mutation
defective activation
Class 4 CFTR mutation
decreased conductance
Class 5 CFTR mutation
decreased abundance
splice mutants, noncoding regions of the gene, diminished normal RNA transcript produced
clinical manifestations of CF
chronic sino-pulmonary infections
- bronchiectasis and chronis sinusitis/nasal polyposis
GI/nutritional abnormalities
- pancreatic exocrine/endocrine insufficiency
- liver cirrhosis
- small and large bowel obstructions, constipation
male infertility
methods of diagnosing CF
sweat testing (pilocarpine iontophoresis)
nasal potential difference
genotyping
How does a CF sweat gland differ from a normal one?
lack of chloride absorption due to mutant CFTR creates hypertonic sweat
How does nasal potentials differ in CF patients?
lower baseline resting potential
isuprel in the presence of amiloride gives a polarization response in normal and almost no response in CF patients
Class 6 CFTR mutation
turnover more rapid in the membrane
What is the most common CFTR mutation?
Delta F508
characteristics of bronchiectasis
effect of CFTR mutations in the mucosa of upper airways
obliteration of the airways as inflammatory cells and bacteria fill the lumen
severe obstruction and end stage emphysema
leads to respiratory failure and death in 85%-90% of affected individuals
features of a CF CT
signet ring sign
dilated distal bronchi
dilated bronchi in relation to adjoining vessel
signet ring signs
an indication in a CT where the airways are bigger than the adjoining pulmonary arteries
Describe the viscious cycle of infection in CF lungs.
begins with airway infection and impaired secretions impairs the immunity
out of proportion immune response
infections can last for decades and mutate frequently
biofilms form and make them very hard to treat
most common bacteria in airway infections
Staphylococcus aureus and Pseudomonas aeruginosa
How does CF affect the upper ariways?
Abnormal CFTR function, hyperabsorption of sodium and water across the cell
CF has a much thinner layer of mucous later - relative dessication of the mucous layer
Compression of the cilia, preventing them from working in a normal fashion
buildup of mucous and foreign debris
What are some predictive factors for outcomes in CF patients?
FEV1 and frequency of severe exacerbations of bronchiectasis
polymorphisms in transforming growth factor-beta 1
female gender
low socioeconomic status
CF treatment
mucolytics - DNAase (pulmozyme), hypertonic saline, mannitol (osmotic agent that introduces water secretions int he airway)
bronchodilators - beta2-agonists
anti-inflammatory agents - corticosteroids and ibuprofen
antibiotics
CPT and postural drainage
flutter
HFCWO - high frequency chest wall oscillatory device
exercise
CF nutritional supplements
pancreatic enzymes
vitamins
supplements
nocturnal feeds - G-tube and nasogastric tubes
gentamicin treatment
ongoing study that this drug may allow reading through a premature stop codon
modest success in clinical trials
VX-770 or Ivacaftor
augments chloride channel function for mutant and wild-type CFTR that sits in the plasma membrane
very effective for the G551D (class 3) mutation
F508del mutation
mutations that causes the CFTR protein to be trapped in the ER and then degraded in the cell
