B4.076 Cystic Fibrosis Flashcards
what is meconium ileus
abdominal distension
failure to pass meconium (first stool after birth)
what is the CF gene?
spans 250 kilo bases on chromosome 7
encodes CFTR protein (1480 AAs)
more than 1800 CF causing mutations in CF gene have been identified
varying degrees of protein dysfunction
what is CFTR
cystic fibrosis transmembrane conductance regulator
conducts chloride and bicarbonate across the cell membrane
why do people with CF have salty sweat?
Cl cannot be transported out ductal lumen into the tissues, so more Cl binds to Na in the lumen and exits the sweat ducts
where are CFTRs found
widely throughout body in epithelial cells
what is the pathogenesis of CF
loss of CFTR function results in abnormal regulation of airway surface liquid which sets the stage for chronic infection and related inflammation
what type of disease is universal amongst CF patients?
chronic lung disease
why are mutations categorized into groups?
categories of mutations can have different effects on protein function
this can be used to provide targeted therapies
what are some examples of effects of mutations on protein function
- no functional protein made
- protein not trafficked to membrane
- defective channel regulation
- decreased channel conductance
- reduction of synthesis of CFTR
- decreased CFTR membrane stability
most common mutation
Phe508 del (86.4% of people) trafficking defect
different organ systems affected by CF
general (growth and vitamin deficiencies) nose and sinuses liver gallbladder bone intestines lungs heart spleen stomach pancreas reproductive
major lung manifestation of CF
bronchiectasis
why are many male CF patients infertile?
absence of vas deferens
80-85% of males with CF
screening algorithm for CF in newborns
immunoreactive trypsinogen/CFTR (IRT/DNA)
- look at IRT level IRT >60
-look at CFTR mutation panel
if unsure after results, check sweat chloride (>60 diagnostic)
what is immunoreactive trypsinogen (IRT)
pro enzyme for pancreatic enzyme trypsin
can accumulate in blood if not distributed appropriately due to pancreatic dysfunction
clinical symptoms consistent with CF
failure to thrive
pulmonary symptoms
meconium ileus
evidence of CFTR dysfunction
elevated IRT
sweat chloride
mutation analysis
inheritance of CF
autosomal recessive
30,000 pts in US
carrier frequency varies from 1/20 to 1/80
carrier frequency for Phe503del
1/30
most common
what is oily stool indicative of
pancreatic insufficiency
what is pancreatic insufficiency
defective CFTR function result in viscous exocrine fluids
fluid becomes inspissated in the pancreatic ducts
pancreatic duct obstruction reduced secretion o pancreatic enzymes
what is fecal elastase and what is it used for
pancreatic enzyme
will be low in pancreatic insufficiency bc not secreted correctly
used to diagnose pancreatic insufficiency
what portion of CF patients get pancreatic insufficiency
2/3
what digestion specific pancreatic enzymes are reduced in pancreatic insufficiency
amylase
lipase
phospholipases
treatment for pancreatic insufficiency
pancreatic enzyme replacement therapy (PERT)
fat soluble vitamin supplementation
-vitamins A, D, E, and K
describe PERT
extract of porcine pancreas containing lipase, protease, amylase
prepared in microspheres that protect from destruction by stomach acid
dissolve in alkaline duodenum releasing the enzymes
helps digest fat
what is bronchiectasis
daily chronic cough and sputum production
bronchial wall thickening, mucopurulent plugs or debris, airway dilation with lack of distal tapering
what indicated cylindrical bronchiectasis
airway diameter at least 1.5 times the adjacent vessel diameter
common lower resp pathogens in young CF patients
s. aureus most common
most common lower resp pathogen in older CF patients
p. aeruginosa
what populates the lower resp tract in normal lungs?
nothing
should be sterile
once a pathogen is there, it never really goes away
discuss the microbiome qualities of the airways of CF patients
DNA testing of sputum over time reveals colonies of multiple bacteria, differing from test to test
bacteria coexist in sputum
primary treatment goals of CF lung disease
mucociliary clearance
anti-infection
restore CFTR function
methods of airway clearance
postural drainage and chest percussion
high frequency chest wall oscillation
exercise
describe dornase alpha
selective cleaves DNA
reduces mucous viscosity to improve airflow and decrease risk of infection
how is hypertonic saline helpful for CF
brings moisture
helps cough
makes mucous less thick
anti infective agents used in CF
nebulized antibiotics primarily targeting pseudomonas (tobramycin, aztreonam)
MRSA - dry power vancomycin
typical CF patient treatment procedure
chest wall oscillation vest+ albuterol bronchidilator HTS dornase nebulized antibiotic
discuss the function of the endocrine pancreas
contain islets of Langerhans
healthy people have 1 mil islets
pancreatic beta cells within islets secrete insulin
pathogenesis of CF related diabetes
viscous secretions cause obstructive damage to the exocrine pancreas with progressive fibrosis and fatty infiltration
disruption and destruction of islet architecture leads to reduced insulin secretion
how is CF related diabetes diagnosed
screening at 10 years old
oral glucose tolerance test
treatment for CF related diabetes
insulin therapy
diet: increased calories but with lower glycemic load
what is personalized medicine
a form of medicine that uses information about a person’s genes, proteins, and environment to prevent, diagnose, and treat disease
what is an example of a personalized drug for CF patients?
small molecule drug can restore CFTR function in G551A mutation
CF medicine aimed to repair RNA
modified RNA oligonucleotide designed for inhalation
result in translation of wild type CFTR
CF medicine aimed to repair DNA
no DNA correction technique proven successful to date
CRISPR/Cas9 gene editing
