Cystic Fibrosis Flashcards
what is cystic fibrosis
Cystic fibrosis is an inherited disease caused by a mutation in the CFTR gene on chromsome 7, resulting in thick, viscous mucus that clogs the lungs and digestive system, causing breathing difficulties and digestion issues and leaves the person susceptible to infection
what pattern of inheritance does cystic fibrosis follow
cystic fibrosis is an autosomal recessive disorder, meaning both parents must be carriers (have one copy of mutated gene) to produce a child with cystic fibrosis
how many of UK pop are carriers
1 in 25 have one copy of the mutated CFTR gene
calculate the probability of a CF birth
probability 1 parent is a carrier= 1/25= 0.4
of 2 carriers= 0.4 x 0.4 = 1/625 families in situation
each parent has 50% chance of passing on defective copy (as have one bad, one good each) so 0.5 x 0.5= 0.25
probability of 2 carrier parents and both parents passing on defective copy instead of normal= 1/625 x 0.25= 1/2500
therefore 1 in 2500 children born with CF
what is the avg rate for CF births?
1 in 2500
CF is the most common genetic disease in what race
caucasians/ Eu descent. However, no race is exempt
being a carrier must have had a selective advantage at some point in history but we don’t know why
life expectancy CF
over 50% UK CF pop live past 41, a baby born today expected to live much longer
CF occurs when the baby inherits?
2 mutated, non functioning copies of CFTR gene
how many CFTR gene mutations are there, what is the main one
at least 2000, with 6 occurring more than 1%
F508del is the most common, 90% of CF population has
what is F508del
the deletion of a phenylaline at residue 508
what does CFTR stand for and what briefly is it
cystic fibrosis transmembrane conductance regulator
a membrane protein that functions as a chloride ion channel, found in apical epithelial cell membranes
structure of normal CFTR and how the CFTR protein works
normal CFTR has 5 conserved domains, with the 5th domain (R domain) regulating the activity of the protein.
when the 5th domain is phosphorylated, the channel can open. Phosphorylation regulates channel opening.
therefore requires binding of ATP to protein
how does CFTR normally function in the cell
CFTR allows chloride ions out of cell.
protein kinase A (eg activated by adrenaline) phosphorylates CFTR
ATP binds so channel opens
Chloride ions flow out cell, down cell conc gradient
Sodium ions follow (through different exit) to establish charge neutrality
water then diffuses out too to maintain osmoic potential
this water keeps the layer of mucus that surrounds organs hydrated
why do sodium ions follow chloride ions out
to establish charge neutrality
why does water follow sodium and chloride out
to maintain osmotic potential
how do mutations in CFTR affect its function
mutations either reduce the amount of CFTR made/available in membrance or prevent its channel activity (or both)
if chloride cannot leave the cell, sodium and water won’t follow
this means mucus layer is not hydrated
what is the effect of chloride, sodium , water being unable to leave cell (as much)
extracellular liquid layer volume is reduced so mucus becomes concentrated, its viscosity increases
as a result, mucus can’t be moved by cilia, becomes static and can obstruct airways, will be colonised by bacteria and fungi
why does F508 del affect the CFTR protein so much
F508 del destabilises the protein and it is misfolded. protein targeted for degradation by cell’s qaulity control machinery, this leads to modification of protein by ubiquitination (addition of another small protein), targets for destruction by proteosome
why is cystic fibrosis a multi organ disease
CFTR protein channels in apical membranes of epithelial cells, regulate fluid and electrolyte balance in epithelial tissues across body. therefore when dysfunction, see in:
lungs, sinuses, pancreas, intestine, repro system, sweat glands
what are the different classes of mutation in cystic fibrosis
class 1 to 5, class 1 sees no protein made, class 5 sees an unstable protein that is rapidly degraded
different classes require different treatment
why does cystic fibrosis see so much lung damage
mucus= infection
multiple infections trigger immune responses that slowly cause remodeling and fibrosis of lung tissue
why does viscous mucus in lungs cause inflammation and more infection
thick viscour mucus= cilia don’t beat mucus or trapped bacteria away
= goblet cells produce more mucus
= chronic inflammation
less sodium so more acidic, impairs bacterial killing= infection
cystic fibrosis is a state of
chronic airway inflammation
CFTR function is typically below what percent in CF patients
CFTR function below 10% in CF patients
healthy indivs and carriers 50-100%
how do we screen for CF
blood from heel prick (Guthrie Test)
ELISA on blood spot for immunoreactive trypsinogen (IRT)
high IRT indicates CF
why is high IRT an indicator of CF
mucus blocks pancreatic ducts. Trypsinogen unable to enter GI tract so leaks into bloodstream, CF babies have high circulating trypsinogen
why repeat the IRT test
at 3-4 weeks repeat if get a positive to reduce false positives other reasons to have high IRT include: pancreatic disease stressful delivery/ other hypoglycaemia human error
what test do you do if they screen positive?
if high trypsinogen, do DNA test for CFTR mutation
analyse for the 6 most common CFTR mutations, with sequencing or mass spectometry (weighing) or by checking its structure
how is CF diagnosed
if high trypsinogen, DNA test and high sweat test, = CF
sweat test is gold standard
what is the sweat test
chemical agent to induce sweating, collect in filter paper, chloride ion analysis
high chloride and sodium in CF sweat
chloride >60mmol/L = CF
repeat the test to reduce false positives (although hypothyroidism tests positive)
what are chloride and sodium so high in CF sweat
in CF, defective CFTR reduces chloride reapsorption from sweat, so sodium ions are also retained in sweat to maintain neutral charge
(CFTR channels would normally move chloride back into sweat duct to get the balance right, but CFTR defective so chloried and sodium have to stay in sweat)
what happens with regards to further screening after diagnosis of CF
cascade screening to relatives as family members of someone with CF at greater carrier frequency
what if the sweat test is above normal but below CF
put into inbetween category that we arent currently sure of, CRMS/CRSPID
clinical tests to measure CF disease progression
FEV1 (%pred) - force of expiratory volume in 1 second against a predicted value (below 30% need lung transplant)
sweat salinity
nasal potential difference
other tests offered to check disease progression
broncho-alveolar lavage which bacteria deep sequencing of microbiome wellbeing eight, bmi gas exchange
tell me about meconium ileus in CF
almost 1 in 5 CF patients have meconium ileus
meconium ileus= obstruction of bowel caused by thick, abnormal meconium
may lead to bowel perforation, twisted bowel, inflam/infection of abdominal cavity, may require gut resection
gut resection in babies== short gut syndrome
98% of babies with meconium ileus have CF so def test for CF
what cycle do the lungs go through in CF
viscous mucus secretion to microbial colonisation to inflammation with ant inflamm drugs comes destruction of bacteria released trapped in mucus to colonisation
how does CF affect the lungs
mucus clogs airways, traps bacteria, causes infections, inflamm, resp failure. lung function starts to decline from childhood, over time see permanent lung damage
how does CF affect liver
mucus can block bile duct, causing liver disease
how can CF affect sinuses
swollen lining to thick mucus to chronic rhinosinusitis
assoc with polyp formation
how do the CFTR channels usually work in the pancreas and what is the function of this
CFTR on pancreatic duct cells secrete chloride and sodium bicarbonate into lumen of pancreatic ducts
this maintains correct alkaline pH and so ensures stomach acid neutralised and optimal environment for pancreatic enzymes
what happens when defective CFTR channels in pancreas
altered transport of electrolyes sees abnormal production pancreatic enzymes
decreased production sodium bicarbonate means pancreatic secretions dehydrated and thick, this blocks pancreatic ducts
pancreas makes even more enzymes for digestion, now have large amount digestive enzymes trapped, damage pancreatic enzyme wby autodigestion
this leads to fibrosis of pancreas, unable to produce enough enzymes to properly digest food, this is pancreatic insufficiency
what does exocrine pancreatic insufficiency mean for person
pt unable to digest food properly, especially fats= malnutrition, malabsorption
impaired absorption of fats= diarrhoea, weight loss, malnutrition
males lack what? re fertility?
congenital absence of vas deferens
what types of medicines/ management for lungs
mucolytics
antibiotics
steroids and anti fungals if fungal infection
bronchodilators
ACT- airway cleaning therapy, manual physical therapy or device worn to shake mucus in airways, dislodge and cough up
mouthpiece that forces high pressure exhale
management CF re digestion
eat 1.5 to 2 times daily recommended, high calorie and high fat feeding tube may be necessary pancreatic enzymes to support digestion vitamins dietary supplements
why aim for higher weight (and what) CF
22 bmi female, 23 bmi male.
weight correlates with lung function (though obese has own set of issues)
recently developed treaments for CF?
CFTR modulators (correctors and potentiators)
CFTR correctors= increase quantity CFTR channels delivered to cell surface, therefore increase chloride transport
CFTR potentiators= increase channel opening probability
how have CFTR modulators changed the game?
CFTR modulators: bring sweat chloride to normal, lung function huge increase, reduce risk of exacerbation by 60%, increases quality life, raised weight. Less death, transplant, hospitalisation
in children have reversed pancreatic insufficiency
CFTR modulators are unable to help?
class 1 mutations that cause total inability to produce CFTR Gene therapy in future may be able to correct all CFTR mutations
the first organism to infect a baby/ child with CF is usually? usually followed by?
staph aureus
followed by pseudomonas aeruginosa
the most common organisms to infect in CF?
pseudomanas aeruginosa
haemophilus influenza
burkholderia cepacia
non tuberculus myobacteria
fungus- aspergillus
what special rule is there for CF patients
CF patients must not come into contact with one another as have different bacteria, can’t risk exposure
CF patients with differetn bacteria therefore attend different clinics
