Cystic Fibrosis Flashcards
1
Q
What are the basic qualities of cystic fibrosis?
A
- Autosomal recessive
- Progressive multi-organ disease
- Affects all races and ethnicities - mainly people of European descent
2
Q
Describe the pathophysiology of cystic fibrosis.
A
- Caused by mutations of CFTR gene - involved in chloride transport in organs
- Leads to reduced functioning of chloride channels in epithelium
- Increased intracellular NaCl - water moves from mucus in airway lumen intracelullarly
3
Q
What are some symptoms of cystic fibrosis?
A
- Abnormally viscous secretions
- Inflammation and tissue damage of lungs and pancreatic duct
- Sweat glands (salty sweat - reduced influx of chloride as opposed to reduced efflux in airways)
- Intestine (DIOS), bile duct(liver cirrhosis) and male reproductive tract (infertility)
4
Q
What is the clinical presentation of cystic fibrosis?
A
- Recurrent respiratory tract infections and chronic cough
- Salty sweat
- Digital clubbing
- Nasal polyps
- DIOS
- Weight loss
- Meconium ileus in neonates
- Steatorrhoea
5
Q
How is cystic fibrosis diagnosed?
A
- Carrier testing and prenatal diagnosis- through CFTR gene sequencing
- Neonatal screening - heel prick test, IRT (immunoreactive trypsinogen testing - tests for pancreatic enzyme - raised in CF patients)
- Sweat test for newborns
6
Q
What are the treatments for cystic fibrosis?
A
- CF clinics/ MDT
- Chest physiotherapy - clear airways of thick mucus - reduce risk of infection
- Propylactic and PO/IV antibiotics
- Dieticians
- Inhalers/nebulisers e.g steroids, bronchodilators
- Annual review - CXR, bloods and USS abdominal exams
7
Q
What is the prognosis for cystic fibrosis?
A
- Obstructive lung disease - primary cause of morbidity
- Loss of pancreatic exocrine functions causes malnutrition and poor growth
- Prognosis has gradually improved
8
Q
Describe the genetics behind cystic fibrosis.
A
- Variant in CFTR gene - ΔF508 - most common genetic mutation causing CF
- CFTR encodes chloride channel - regulated by cAMP dependent phosphorylation (regulated by PKA)
9
Q
Describe the variants in CFTR.
A
- 40% cause substitution/deletion of single amino acid
- 36% cause nonsense/stop, frameshift and mis-splicing variants
- 3% - large rearrangements of CFTR
- 1% mutations in promoter region
- 14% neutral variants
- 6% unclear cause
10
Q
How does the ΔF508 variant lead to disease?
A
- Most common mutation (Class II) - deletion of 3 nucleotides (CTT/TCT)
- Loss phenylalanine at position 508 of CFTR protein
- Aberrant CFTR folding - degradation of majority of protein
- Protein trafficked to cell membrane functions abnormally
11
Q
CF patients show variable disease expression (some suffer from symptoms ‘more’ than others). Suggest why.
A
- Genotype
- Environment
- Genetic modifiers
12
Q
What is the current research into CF?
A
- On lung epithelia - available and short-lived cultures
- Recent advances in stem cell research - genetic editing in iPSCs to generate lung organoids for drug screening
- Animal models
13
Q
What are the function of small molecular therapies in cystic fibrosis?
A
- Increase CFTR function at protein level
- EXAMPLES: Ivacaftor, lumacaftor and tezacaftor
14
Q
Describe ivacaftor.
A
- Increase chloride transport up to 50% in class III/IV mutations
- Has been clinically trialled - improves lung function
15
Q
Describe lumacaftor.
A
- Reverse folding defect caused by ΔF508 - improved CFTR function
- Combination of Iumafactor and Ivafactor(orkambi) approved for patients homozygous for ΔF508 - orkambi funded by NHS
