Cystic Fibrosis Flashcards
What is cystic fibrosis (CF)?
Autosomal recessive genetic condition that results in a multisystem syndrome of chronic sinopulmonary infections; malabsorption; and nutritional abnormalities. Most common life-shortening genetic disease in Caucasians in the US (1:3000)
Which chromosome mutation causes CF?
Gene that encodes for the CF transmembrane conductance regulator (CFTR) protein. On Chr. 7. Causes a deft in the ATP-binding cassette transporter gene
What is the most common mutation?
F508del. But there are more than 1500 others identified
How are CF gene mutations categorized?
5 main classes (I-V). Grouped by molecular consequences.
What is a class I mutation?
No synthesis of CFTR. Often caused by nonsense G542X
What is a class II mutation?
Block in CFTR synthesis. Often caused by AA deletion (F508del)
What is a class III mutation?
Block in gating. Often caused by missense G551D
What is a class IV mutation?
Altered conductance of CFTR. Often caused by missense R117H
What is a class V mutation?
Reduced synthesis of CFTR. Often caused by missense mut or alternative splicing
What effects do defects/deficiences of CFTR proteins cause?
Problems in salt and water movement across cell membranes; resulting in abnormally thick secretions in various organ systems
Why are CFTR effects in lungs often major cause of morbidity and mortality?
Depleted periciliary layer in the lung leads to impaired mucociliary clearance and altered host defense; critical to the pathogenesis of CF lung disease. Chronic infections with CF-related pathogens and excessive inflammatory response progressively damage the airways and lung parenchyma. Results in widespread bronchiectasis; decline in lung function; early death from respiratory failure
What are typical clinical features in sinus?
Chronic sinus infections; nasal polyps
What are typical clinical features in lung?
Recurrent respiratory infections (endobronchitis) with opportunistic bacteria (e.g. Staphylococcus aureus; Pseudomonas aeruginosa and Burkholderia cepacia); Bronchiectasis
What are typical clinical features in pancreas?
Exocrine pancreatic insufficiency (85%) - greasy; bulky; malodorous stools; failure to thrive and malabsorption nutritional consequences; CF-related diabetes
What are typical clinical features in GI?
Meconium ileus; rectal prolapse; constipation; distal ileal obstructive syndrome (DIOS)
What are typical clinical features in liver?
Cholestasis; sclerosis; cirrhosis
What are other clinical presentations of CF?
Congenital absence of the vas deferens; digital clubbing on examination; sweat chloride > 60 mmol/L
How are most newborns with CF identified in the US?
Most are asymptomatic and identified through newborn screening. Some (10-15%) are identified with meconium ileus. Infants with meconium ileus should be treated presumptively as having CF until a sweat test or genotyping can be obtained.
In CO; what is our approach for newborn screening?
IRT/IRT/DNA. 1st screen for elevated immunoreactive trypsinogen (pancreatic enzyme). If ^ repeat IRT in 2 months. If still ^ do CF DNA panel
What is traditional treatment of CF?
Historically targeted “downstream affects;” tried to manage symptoms. Requires specialized/multidisciplinary team to focus on nutrition; lung disease; antibiotic therapy; anti-inflammatory treatments
How is nutrition in CF Pts usually treated?
Management of exocrine pancreatic insufficiency with enzyme supplementation; high calorie; high protein; and high fat diet; and fat soluble vitamin supplements. Also daily salt supplement due to salt loss in sweat
How is lung disease in CF Pts usually treated?
Try to target cycle of mucous obstruction; airway infection; inflammatory response. Do airway clearance treatment to loosen and remove thick mucus from airways. Daily percussive therapy (Chest PT; vest therapy). Recombinant human DNAse (Pulmozyme); an inhaled mucolytic agent. Inhaled hypertonic saline. Bronchodilators. Also antibiotic therapy and anti-inflammatory treatments
What kind of antibiotic therapy is done in CF?
Targets common CF related bacteria such as P. aeruginosa. Inhaled tobramycin; aztreonam. Oral or IV antibiotics
What kind of anti-inflammatory therapy is done in CF?
High dose ibuprofen. Chronic azithromycin
What new drugs are on the horizon for CF?
CFTR modulator. Target specific CFTR mutations.
What is ivacaftor (kalydeco)?
CFTR potentiator FDA approved for people age 2 years or older with at least one G551D mutation or another gating mutation (Class III); potentially will help in partial function (Class IV and V) mutations as well
What is Lumacaftor/ Ivacaftor (Orkambi)?
combination CFTR corrector and potentiator FDA approved for people ages 12 years or older with 2 copies of the F508del mutation (Class II)
