3- cystic fibrosis

Question 1

what is CFTR channel?

Answer 1

= one of most important chlorine channels
= the CFTR is an ATP-regulated chloride channel involved in the active transport of chloride out of cells into the lumen.

It reduces activity of ENAC, the major sodium transporter, and potentiates other chloride channels. Water follows sodium, from areas of low concentration to high concentration (osmosis) – the water flows through between the cell contacts. In the normal state, Chloride is pumped into the lumen, sodium stays in the lumen, and there are watery secretions.

Question 2

what happens if no CFTR channel?

Answer 2

= cystic fibrosis

• there is no pump of chloride out of the cell into the lumen, there is no attenuation (weakening) of ENAC, so there is unopposed flow of sodium into the cell, means increased sodium influx and decreased chloride efflux →increased osmotic gradient between the lumen and the cell (more solutes inside than outside because more Na+). The increased water flow into the cell and interstitium leads to dehydration of the lumen and thickening of secretions. This results in the production of sticky mucus in various organs, including the lungs, pancreas, and digestive tract - This is what happens in CF – sticky secretions, due to abnormal salt transport

Question 3

what are consequences of cystic fibrosis?

Answer 3

• Salty Sweat (test sweat)
• Intestinal Blockage (dios)
• Fibrotic Pancreas
• Failure to Thrive (detect in heel prick test now)
• Recurrent Bacterial Lung Infections
• Congenital Bilateral Absence of Vas Deferens in men (infertile not because they don’t make sperm but because when they ejaculate no sperm in it)
• Filled Sinuses
• Gallbladder and Liver disease

*remember CF is not the same in everyone

Question 4

what is class 1 of CFTR genetic abnormalities?

Answer 4

class 1 = no CFTR synthesis at all →usually don’t survive in utero

Question 5

what is class 2 of CFTR genetic abnormalities?

Answer 5

class 2 = amino acid deletion deltaF508 (typical gene, causes typical classic severe CF syndrome) →CFTR trafficking defect (make CFTR in ribosome goes to golgi and then get blocks because protein wrong shape so doesn’t make it to membrane, some gets to membrane and works to small degree)

Question 6

what is class 3 of CFTR genetic abnormalities?

Answer 6

class 3 = protein made, goes to golig, gets into membrane but missing key thing e.g. ATP binding site so won’t activate like won’t open or open partially

G551D = celtic gene

Question 7

what is class 4 of CFTR genetic abnormalities?

Answer 7

class 4 = gating problem = too narrow, only little passage of chlorine

Question 8

what is class 5 of CFTR genetic abnormalities?

Answer 8

class 5 = normal chloride production but not enough channels

Question 9

when should you test for cystic fibrosis in bronchiectasis clinic?

Answer 9

• under 40
• upper lobe bronchiectasis
• colonisation with staph
• infertility
• low weight

Question 10

how do people with cystic fibrosis get missed until adulthood?

Answer 10

• don’t present
• present out of hours - lots of respiratory present at night
• failure to think about it - just prescribe antibiotics or think asthma etc
• loss of continuity in care →young people move around a lot, if went to same person easier to realise weird having 4 infections this year already

Question 11

what is common presentation of cystic fibrosis?

Answer 11

• frequent chest infections all through life
• frequent courses of antibiotics
• occasional chest pains
• low weight
• moves around a lot - houses (why missed diagnosis)

Question 12

what are some important factors that help diagnosis of cystic fibrosis? (like test, people etc)

Answer 12

• have to be very suspicious of CF (not just in young people etc)
• screening programmes - screen at infancy + birth
• specialist bronchiectasis service - very thorough testing for CF if high NMT
• genetic department engagement

Question 13

what are some difficulties for cystic fibrosis patients?

Answer 13

• massive treatment burden - loads everyday (a lot of preventative which means doesn’t necessarily make feel better - just in case medicine)
• huge psychological illness with CF patients
• complications can be rapid in onset

Question 14

what are antibiotics for staph aureus colonised in cystic fibrosis?

Answer 14

• Oral Flucloxacillin
• Oral Septrin = co trimoxazole →sulfamethoxazole + trimethoprim

Question 15

what are antibiotics for pseudomonas colonised in cystic fibrosis?

Answer 15

• Oral Azithromycin (macrolide)
• Nebulised Colomycin

Question 16

what is exocrine pancreas function?

Answer 16

responsible for production of digestive enzymes that aid breakdown of food in small intestine

Question 17

what happens with exocrine failure?

Answer 17

= problem of CF

• Sludged up ducts due to abnormal secretions the ducts get blocked leading to DIOS (distal intestinal obstructive syndrome)
• Failure of secretion of lipases, amylase
• lack of enzyme secretion means digestive failure

Question 18

what is treatment of exocrine failure in CF?

Answer 18

Treatment = CREON, pancreatic enzyme replacement therapy (PERT)

• Patients hate taking it
• Without adequate enzyme replacement therapy they can’t absorb energy

Question 19

what happens in endocrine failure?

Answer 19

• Destruction of pancreatic islet cells which are responsible for producing insulin
• Fatty replacement of pancreatic tissue (as over time the tissue is damaged/destroyed)

Question 20

what is monitoring + management of endocrine failure?

Answer 20

• Annual OGTT (oral glucose tolerance tests) are done to screen for impaired glucose tolerance and other CF related illnesses
• CGMS (continuous glucose monitoring system) = like the white stickers that go on arm in diabetes
• Usually need insulin therapy as they have insulin production failure

Question 21

what is DIOS?

Answer 21

thick mucous blocks large + small intestine leading to symptoms similar to constipation

Question 22

what is treatment of DIOS?

Answer 22

• gastrografin = contrast agent to help clear thick mucous + alleviate blockages
• laxido = to help soften stools + promote bowel movement
• fluids

Question 23

what happens due to liver disease?

Answer 23

• common cause of death in CF
• can lead to sludging of hepatic ducts (can be intra or extra hepatic)
• can cause portal hypertension (increased blood pressure within portal vein + it’s tributaries)

Question 24

what occurs due to portal hypertension?

Answer 24

• can lead to Porto-systemic anastamoses between venous system + systemic veins bypassing the liver. these anastamoses can lead to Variceal Bleeding which is a serious complication
• also can lead to Hepatic encephalopathy since in liver disease there’s accumulation of toxic substances in blood stream →can affect brain function and lead to hepatic encephalopathy

Question 25

what is hepatic encephalopathy?

Answer 25

characterised by cognitive impairment, confusion + altered consciousness

Question 26

what is treatment of liver disease?

Answer 26

TIPSS (Transjugular Intrahepatic Portosystemic Shunt) = medical procedure, shunt in between portal vein and hepatic vein to reduce portal pressure and improve blood flow.

• Reduces anastamoses + Reduction in bleeding risk
• Can increase encephalopathy risk

Question 27

what is management of exacerbation in CF?

Answer 27

• IV antibiotic = a lot, need to give 2 at a time to reduce resistance
• physio 2x day
• hydrated
• extra food with fridge in their room
• some sort of video games for encouragement and happiness

Question 28

what are first line drugs for if they are colonised with staph aureus?

Answer 28

Oral Flucloxacillin or Oral Septrin = co trimoxazole →sulfamethoxazole + trimethoprim

Question 29

what are first line drugs for if they are colonised with pseudomonas?

Answer 29

Oral Azithromycin (macrolide) or Nebulised Colomycin = 1st choice

Question 30

what is OHPAT treatment?

Answer 30

when start in hospital then finish treatment at home
- 2 weeks at home
- only done when safe and well tolerated, depends on capability
- does save money

Question 31

what is life expectancy for CF patients?

Answer 31

life expectancy 37 if 22 today, if born today then 50 - got way better, used to be 25 ish

Question 32

what is ivacaftor drug?

Answer 32

for G551D celtic gene (type 3 mutation) which is when channel delivered to epithelium normally but the channel is non-functioning

= ivacaftor opens channel and improves chloride flow. one of first ones to be made

Question 33

what is the game changer drug for cystic fibrosis?

Answer 33

kaftrio (completely took over the earlier made drugs symkevi + orkambi)
= Elexacaftor + tezecaftor + ivacaftor = 1 tablet in morning (tezecaftor in evening)

Question 34

what is patients experience of kaftrio?

Answer 34

→think it’s amazing - miracle

• call it purge, make everything
• feel much better
• want to stop all other medicines

= will see benefits over next 15 years, now licensed from age 2 as will hopefully prevent most complications

Question 35

what are risks of kaftrio?

Answer 35

there is risk of worsening liver disease →people still die from taking it with liver disease already (2 people died when first tried)

acne also side effect of kaftrio (but can get treatment for that too so not too bad)

Question 36

is kaftrio affordable?

Answer 36

it’s very expensive but when getting kaftrio, less complications so ends up just being cost effective

Question 37

is lung transplantation option?

Answer 37

yes, less common now due kaftrio but still happens - usually bilateral lung transplant

• important to do psychological assessments

Question 38

what type of genetic condition is cystic fibrosis?

Answer 38

autosomal recessive

Question 39

what are some common colonisers that cystic fibrosis patients have to deal with?

Answer 39

staph aureus and pseudomonas aeruginosa

Question 40

what antibiotics are given for COPD exacerbation?

Answer 40

pick specific full dose antibiotics based on sputum results

*new drug kaftrio means some patients don’t need prophylactic antibiotics and have less exacerbations