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Semester 1 > Cystic Fibrosis > Flashcards

Cystic Fibrosis Flashcards

1
Q

what is cystic fibrosis

A

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

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2
Q

what pattern of inheritance does cystic fibrosis follow

A

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

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3
Q

how many of UK pop are carriers

A

1 in 25 have one copy of the mutated CFTR gene

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4
Q

calculate the probability of a CF birth

A

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

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5
Q

what is the avg rate for CF births?

A

1 in 2500

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6
Q

CF is the most common genetic disease in what race

A

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

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7
Q

life expectancy CF

A

over 50% UK CF pop live past 41, a baby born today expected to live much longer

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8
Q

CF occurs when the baby inherits?

A

2 mutated, non functioning copies of CFTR gene

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9
Q

how many CFTR gene mutations are there, what is the main one

A

at least 2000, with 6 occurring more than 1%

F508del is the most common, 90% of CF population has

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10
Q

what is F508del

A

the deletion of a phenylaline at residue 508

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11
Q

what does CFTR stand for and what briefly is it

A

cystic fibrosis transmembrane conductance regulator

a membrane protein that functions as a chloride ion channel, found in apical epithelial cell membranes

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12
Q

structure of normal CFTR and how the CFTR protein works

A

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

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13
Q

how does CFTR normally function in the cell

A

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

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14
Q

why do sodium ions follow chloride ions out

A

to establish charge neutrality

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15
Q

why does water follow sodium and chloride out

A

to maintain osmotic potential

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16
Q

how do mutations in CFTR affect its function

A

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

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17
Q

what is the effect of chloride, sodium , water being unable to leave cell (as much)

A

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

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18
Q

why does F508 del affect the CFTR protein so much

A

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

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19
Q

why is cystic fibrosis a multi organ disease

A

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

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20
Q

what are the different classes of mutation in cystic fibrosis

A

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

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21
Q

why does cystic fibrosis see so much lung damage

A

mucus= infection

multiple infections trigger immune responses that slowly cause remodeling and fibrosis of lung tissue

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22
Q

why does viscous mucus in lungs cause inflammation and more infection

A

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

23
Q

cystic fibrosis is a state of

A

chronic airway inflammation

24
Q

CFTR function is typically below what percent in CF patients

A

CFTR function below 10% in CF patients

healthy indivs and carriers 50-100%

25
Q

how do we screen for CF

A

blood from heel prick (Guthrie Test)
ELISA on blood spot for immunoreactive trypsinogen (IRT)
high IRT indicates CF

26
Q

why is high IRT an indicator of CF

A

mucus blocks pancreatic ducts. Trypsinogen unable to enter GI tract so leaks into bloodstream, CF babies have high circulating trypsinogen

27
Q

why repeat the IRT test

A 
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
28
Q

what test do you do if they screen positive?

A

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

29
Q

how is CF diagnosed

A

if high trypsinogen, DNA test and high sweat test, = CF

sweat test is gold standard

30
Q

what is the sweat test

A

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)

31
Q

what are chloride and sodium so high in CF sweat

A

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)

32
Q

what happens with regards to further screening after diagnosis of CF

A

cascade screening to relatives as family members of someone with CF at greater carrier frequency

33
Q

what if the sweat test is above normal but below CF

A

put into inbetween category that we arent currently sure of, CRMS/CRSPID

34
Q

clinical tests to measure CF disease progression

A

FEV1 (%pred) - force of expiratory volume in 1 second against a predicted value (below 30% need lung transplant)
sweat salinity
nasal potential difference

35
Q

other tests offered to check disease progression

A 
broncho-alveolar lavage
which bacteria
deep sequencing of microbiome
wellbeing
eight, bmi
gas exchange
36
Q

tell me about meconium ileus in CF

A

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

37
Q

what cycle do the lungs go through in CF

A 
viscous mucus secretion
to microbial colonisation
to inflammation
with ant inflamm drugs comes destruction of 
bacteria released
trapped in mucus
to colonisation
38
Q

how does CF affect the lungs

A

mucus clogs airways, traps bacteria, causes infections, inflamm, resp failure. lung function starts to decline from childhood, over time see permanent lung damage

39
Q

how does CF affect liver

A

mucus can block bile duct, causing liver disease

40
Q

how can CF affect sinuses

A

swollen lining to thick mucus to chronic rhinosinusitis

assoc with polyp formation

41
Q

how do the CFTR channels usually work in the pancreas and what is the function of this

A

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

42
Q

what happens when defective CFTR channels in pancreas

A

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

43
Q

what does exocrine pancreatic insufficiency mean for person

A

pt unable to digest food properly, especially fats= malnutrition, malabsorption
impaired absorption of fats= diarrhoea, weight loss, malnutrition

44
Q

males lack what? re fertility?

A

congenital absence of vas deferens

45
Q

what types of medicines/ management for lungs

A

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

46
Q

management CF re digestion

A 
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
47
Q

why aim for higher weight (and what) CF

A

22 bmi female, 23 bmi male.

weight correlates with lung function (though obese has own set of issues)

48
Q

recently developed treaments for CF?

A

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

49
Q

how have CFTR modulators changed the game?

A

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

50
Q

CFTR modulators are unable to help?

A 
class 1 mutations that cause total inability to produce CFTR
Gene therapy in future may be able to correct all CFTR mutations
51
Q

the first organism to infect a baby/ child with CF is usually? usually followed by?

A

staph aureus

followed by pseudomonas aeruginosa

52
Q

the most common organisms to infect in CF?

A

pseudomanas aeruginosa
haemophilus influenza
burkholderia cepacia
non tuberculus myobacteria

fungus- aspergillus

53
Q

what special rule is there for CF patients

A

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

Semester 1 (18 decks)

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