Genetics and Treatment of CF Flashcards
What is the epidemiology of cystic fibrosis?
1 in 25 people carry the gene
What is the purpose of the cystic fibrosis transmembrane conductance regulator?
Moves chloride Cl- out of cell
What are the components that work in association with the cystic fibrosis conductance regulator?
- Cystic fibrosis conductance regulator (CFTR) - moves Cl- out of cell
- Epithelial sodium channel (ENAC) - flow of Na+ into cell
- Other chloride channels
What regulates CFTR, ENAC and chloride channels?
ATP
What happens if there is a failure of the CFTR?
- Cannot pump chloride out of cell
- More Na+ going in and less Cl- going out,
- Water flows into cell
What are consequences of CFTR failure? (8)
- Salty Sweat
- Intestinal Blockage
- Fibrotic Pancreas
- Failure to Thrive
- Recurrent bacterial lung Infections
- Congenital Bilateral absence of Vas Deferens
- Filled Sinuses
- Gallbladder and Liver disease
What are the stages of cystic fibrosis development?
- Mutation in CFTR DNA
- Altered CFTR protein
- Affects ion transport
- Alters secretions
- Blocked ducts, impaired mucosal defence
- Infection, inflammation
- Cystic fibrosis
What are kinds of CFTR defect?
- Class I - no CFTR synthesis, death
- Class II - CFTR trafficking defect, CFTR protein made but missense mutation so protein cannot pass through Golgi into membrane
- Class III - Deregulation of CFTR (diminished ATP binding and hydrolysis), CFTR embeds in membrane but channel cannot open so chloride cannot pass through it
- Class IV - defective chloride conductance/channel gating - channel does not open to the correct stimuli
- Class V - reduced CFTR transcription and synthesis, CFTR is correct shape etc but just not enough of it
Why is it important to study the genetic code?
Allows you to predict mutation effects
What are the 2 main mutations that affect the CFTR gene?
- F508del - most common (70%), deletion of phenylalanine
* G551D - (4-6%) substitution of glycine to asparagine
In recessive diseases, will the same mutation affect both genes?
No, you can have different mutations in each copy of the gene
Where are most CF patients transferred from?
Bronchiectasis clinic
In what circumstances would a patient in bronchiectasis clinic undergo CF genetic testing?
- Bronchiectasis under 40
- Upper lobe bronchiectasis
- Colonisation with Staph
- Infertility
- Low weight
All receive CF genetic testing
How do CF patients get missed?
- Don’t present
- Present out of hours
- Present sporadically
- Loss of continuity in care (different GPs)
What does genetic testing for CF include?
- Detection of F508del mutation
What are the difficulties of CF?
- Massive treatment burden
- Much treatment is ‘preventative’ (do not feel better after taking it, just prevent symptoms from worsening)
- Complications can be rapid in onset
What does prophylactic management of cystic fibrosis include?
- Antibiotics
* Regular Clinic Review
What do antibiotics used to treat cystic fibrosis include?
Staph Aureus Colonised
- Oral Fluclox
- Oral Septrin
Pseudomonas Colonised
- Oral Azithromycin
- Nebulised Colomycin
- Nebulised Tobramycin
- Nebulised Aztreonam
- Inhaled Tobramycin
What is the effect of exocrine failure of the pancreas?
- Ducts blocked with mucous
- Failure of secretion of lipase, amylase
- Digestive failure
What is the treatment for exocrine failure of the pancreas?
CREON
Why do patients often refuse total CREON?
Without it they can’t absorb energy – purposely don’t take it to lose weight
What are the effects of endocrine failure of the pancreas?
- Destruction of pancreatic islet cells
* Fatty replacement of pancreatic tissue
What is the treatment for endocrine failure of the pancreas?
- Annual oral glucose tolerance test (OGTT)
- Continuous glucose monitoring system (CGMs)
- Usually need insulin as they have insulin production failure
What are the effects of cystic fibrosis on the bowels?
- Distal Intestinal Obstruction Syndrome (DIOS)
- Thick mucus blocks up the large and small intestine
- Symptoms similar to constipation
What is Distal Intestinal Obstruction Syndrome (DIOS)?
- Thick mucus blocks up the large and small intestine
* Symptoms similar to constipation
What is the treatment for DIOS?
- Gastrograffin
- Laxido
- Fluids
What are the prevention methods for DIOS?
- Laxido
- Hydration
- Keep moving (exercise encouraged)
What are the effects of cystic fibrosis on the liver?
- Sludging up of intrahepatic/extrahepatic ducts
* Portal hypertension - port-systemic anastomoses, variceal bleeding, hepatic encephalopathy
What are the consequences of portal hypertension?
- Porto-systemic anastamoses
- Variceal Bleeding
- Hepatic encephalopathy
What procedure is used to reduce hypertension and its complications?
Transjugular intrahepatic portosystemic shunt (TIPSS)
What is the purpose of TIPSS procedure?
Reduce hypertension and its complications
- Reduces anastamoses
- Reduction in bleeding risk
- Can increase encephalopathy risk
How are exacerbations of cystic fibrosis managed?
- Antibiotics
- Physiotherapy -Autogenic Drainage, ACBT (breathing techniques)
- Adequate hydration
- Increased dietary input
Why are 2 antibiotics always given when treating cystic fibrosis?
Reduces resistance
What are oral antibiotics to treat cystic fibrosis?
- Augmentin
- Fluclox
- Minocycline
- Septrin
- Fusidin
- Ciprofloxacin
What are IV antibiotics to treat cystic fibrosis?
Pseudomonas
- Tazocin
- Ceftazidime
- Tobramicin
- Meropenem
- Colistin
Staph Aureus
- Flucloxacillin
- Tigecycline
Cepacia
* Temocillin
What is OHPAT?
- Antibiotics as an in-patient for 2 weeks out of 52
* Start antibiotics as an in-patient, finish at home
What are the advantages of OHPAT?
- Well tolerated
- Safe
- Saves money
- Keeps patients working
Why are CF survival rates increasing?
Due to advances in treatment - treatment starting to be directed towards specific genetic mutations
What is the G551D mutation?
- The Celtic Gene - class III mutation
- Normal CFTR
- Delivered to epithelium normally
- Non-functional channel
What is used to treat a G551D mutation?
Ivacaftor
What is ivacaftor?
CFTR potentiator - improves chloride flow through the CFTR
Why are patients instructed not to eat grapefruit when they use Ivacaftor?
Doubles activity of Ivacaftor
What percentage of patients is Ivacaftor appropriate for?
10%
What are other ways to target genes other than direct effect on the protein?
- Post-translational modification
- RNA editing
- Increased transcription
- Gene replacement
What is used to treat a F508del mutation?
Lumacaftor
What percentage of patients is lumacaftor appropriate for?
70% (F508del is most common mutation)
What is the effect of lumacaftor?
8.5% improvement in FEV1 at 56 days
How does lumacaftor work?
Lumacaftor binds onto CFTR and changes its shape so it can pass through Golgi and embed into membrane
Why must lumacaftor be coupled with ivacaftor?
The CFTR protein cannot otherwise open once embedded
