PSC2002/L07 Cystic Fibrosis I Flashcards
What kind of disease is cystic fibrosis?
Autosomal recessive
What is cystic fibrosis caused by?
Loss-of-function mutations in Cystic Fibrosis Transmembrane Conductance regulator (CFTR) gene
What is regulated by the CFTR channel? (2)
Volume
pH
-of epithelial secretions
How does CF present?
Severe lung & pancreatic disease
Affects multiple organs including GI and reproductive tracts and sweat glands
What percentage of morbidity and mortality foes CF lung disease account for?
90%
Give 3 statistics about CF.
> 11,000 people with CF in UK
150,000 worldwide
In UK, 1/25 people are carriers
In 1964, median life expectancy was 5 years; is now >50
Females have lower life expectancy than males
CF screening started in 2007
How many mutations and disease-causing mutations have been identified for CF?
> 2000 mutations
720 disease-causing mutations
What are the most common CF mutations?
50% of pwCF homozygous F508del
35% pwCF compound heterozygous (F508del/G542X)
5 other mutations have >1% frequency
Describe type I CFTR mutations.
No protein produced
E.g., G542X
Describe type II CFTR mutations.
No traffic of protein to Golgi or apical membrane
E.g., F508del
Describe type III CFTR mutations.
Normal protein level but channels don’t function normally (gating)
E.g., G551D
Describe type IV CFTR mutations.
Single channel conductance reduced (less function)
E.g., R117H
Describe type V CFTR mutations.
Less protein produced
E.g., A455E
Describe type VI CFTR mutations.
Less stable protein
Lower half-life so channels broken down more quickly
No example required
Describe genotype-phenotype relationship.
Whether disease severity (phenotype) can be predicted from mutational analysis (genotype)
Describe normal pancreatic fluid secretion. (3)
NaCl-rich acidic fluid secretion (low rate) in acini
Enzyme secretion
NaHCO3-rich alkaline fluid secretion through duct (high rate)
What happens to the pancreas in CF? (2)
85% of people born with CF are pancreatic insufficient with <5% normal function
Acini destroyed and duct blocked
Require pancreatic enzyme replacement therapy (PERT) at every meal
Give the 4 cells with the highest CFTR expression.
Club cell
Goblet cell
Basal cell
Ionocyte
Describe the role of CFTR in the conducting airways. (3)
Maintains hydration & pH on airway surface liquid (inc. PCL and mucus layer)
Ensures efficient mucociliary clearance (MCC) removing pathogens in mucus layer
Surface cells & submucosal glands secrete antimicrobial peptides (AMPs) into ASL
Define mucociliary clearance.
Removes pathogens trapped in mucus layer
Describe failure in mucociliary clearance in CF. (3)
ASL dehydrated and more acidic
Leads to viscous mucus (mucus stasis), mucus accumulation and obstruction
Leads to chronic bacterial colonisation, airway inflammation and respiratory failure
How is ASl pH lowered in CF? (2)
Lack of CFTR function reduces HCO3- secretion into ASL
With active H+ secretion (via apical proton ATPase) from airway cells, more acidic ASL pH produced
Give 3 consequences of a more acidic ASL.
Increased fluid absorption due to enhances ENaC activity
Increased mucus stasis and viscosity
Decreased bacterial killing
Why is fluid absorption increased in CF?
Due to increased channel activating proteases (CAP) activity (cathepsin B & neutrophil elastase) and decreased SPLUNC function
Why is mucus stasis and viscosity increased in CF?
Due to increased mucin release and expansion (unfolding) on release from goblet cells and conformational changes in mucins making them more rigid
Why is there decreased bacterial killing in CF?
Due to reduced AMP activity
How does a defect in CFTR cause lung disease? (5)
Decreased Cl- and HCO3- transport
Decreased ASL volume and pH
Increased ENaC function, mucus obstruction, decreased MCC & microbial activity
Increased bacterial and viral infections and inflammation
Destruction of lung
How can symptoms of CF be treated?
Mucus clogging - physiotherapy and mucolytics
Restore airway surface liquid 0 nebulised hypertonic saline or mannitol
Draws water from body into airways improving hydration (transient)
Describe how pulmozyme works.
DNA interacts with mucus and makes it stickier so breaking down this DNA can reduce mucus viscosity
How can recurrent lung infections be treated?
Antibiotics
Esp. Pseudomonas aeruginosa
How can:
a) overactive immune response
b) destruction of lung
be treated?
a) NSAIDs
b) Lung transplant
Describe the NBD1 gene mutation that leads to CF.
Loss of phenylalanine at position 508
Impairs nomal trafficking of F508del-CFTR protein to cell surface
