Cystic Fibrosis Flashcards
What is Cystic Fibrosis?
- Autosomal recessive disorder caused by mutations in the CF transmembrane conductance regulator (CFTR) protein.
- Mutations within the CFTR gene result in changes in ion and water transport which leads to an accumulation of thick secretions that block mucus glands
- Reported to be the commonest AR life limiting disorder in the UK Caucasian population
Which systems are affected by Cystic Fibrosis?
Lungs and digestive systems are primarily affected.
- Presenting symptoms: frequent chest infections and failure to thrive
What is the CFTR (Cystic Fibrosis Transmembrane Regulator) protein?
- Transmembrane protein
- Present in all secretory cells that require mucus for normal function eg sweat, saliva, tears, digestive enzymes
- Member of the ATP binding cassette (ABC) family of proteins. Superfamily of proteins that covert energy from ATP into movement of substances or subtrates
- Transport chloride ions into and out of cells to regulate water movement
- Helps maintain free flowing, thin mucus essential for normal secretion within the cells
Why does mucus build up in Cystic Fibrosis?
Normal process is for Cl- ions to travel through the CFTR from the cell into the airway surface liquid (ASL).
If Defective CFTR
- Build-up of Cl- ions inside the cell
- Increased flow of sodium from the ASL into the cell for electroneutrality
- Water follows the sodium depleting the ASL and leaving the cilia stuck in the mucus layer and unable to clear the mucus
What are Clinical Manifestations of Cystic Fibrosis?
- Lungs: Mucus plugging leading to repeated infections
- Pancreas: Decreased exocrine function leading to malabsorption of fats and protein (endocrine function is less affected)
- Liver: Bile duct plugging leading to biliary stasis and hepatic fibrosis
- Intestine: Abnormally viscous secretion leading to meconium ileus (newborns) and constipation
- Reproductive System: Infertility in 98% of adult men due to obstruction or malformation (vas deferens)
How does cystic fibrosis present?
- Infants often presented during first 3 years of life with failure to thrive, malnutrition despite extreme hunger and repeated chest infections
- 15-20% of babies with CF present with meconium ileus (obstruction of terminal ileum due to retention of meconium)
- Pulmonary infections are a major cause of morbidity and mortality
How is Cystic Fibrosis Screened?
- Early protocols relied on the measurement of Immunoreactive Trypsinogen which was noted to be elevated in the bloodspot of CF babies
- UK newborn screening protocol introduced which involves IRT-DNA-IRT.
- IRT is a protease enzyme produced within the pancreas
- High levels observed in CF patients thought to be leakage of pancreatic enzymes from blocked pancreatic ducts
What are limitations of IRT as a sceening tool?
IRT cannot be used beyond 8 weeks of age
False positive caused by:
- Faecal contamination
- Multiple spotting
- Extreme prematurity (< 29 weeks)
- Renal disease
- Congenital abnormalities
- Bowel atresia
False negatives caused by:
- Meconium ileus
- Blood transfusions (within 72 hours)
- Viral infection leading to acute gastroenteritis or respiratory illness
How is DNA analysis conducted with Cystic Fibrosis?
Two-stage mutation analysis
- Must be carried out by an accredited molecular genetics laboratory
What are the stages of the DNA analysis of Cystic Fibrosis?
Step 1
- 4 mutation panel
- 4 commonest alleles in the Caucasian population associated with severe disease
- Will detect >80% of disease causing mutation in the UK population
Step 2
- Extended panel looking for 53 mutations
- This is performed if only one mutation is found on the 4-mutation panel
What is done with Positve tests?
All positive cases are referred to the CF centre for further investigations which include a sweat test, faecal elastase and confirmation of genetic testing with a whole blood sample
What is done following the referal?
Sweat test is generally accepted as the gold standard confirmatory test for Cystic Fibrosis
- Sweat chloride < 30nmol/l - Low probability of CF
- Sweat chloride 30-60mmol/l - Suggestive but not diagnostic of CF
- Sweat chloride > 60mmol/l - Supports a diagnosis of CF
How is the Sweat Test conducted?
- Sweat production in the arm or thigh (in newborns) is stimulated using pilocarpine and an electrical charge
- Sweat is collected either on filter paper or using a specialised collecting device
- Sweat is analysed for sodium and chloride
- Elevated levels confirm cystic fibrosis
- Problems is particularly with newborns due to inadequate sweat
What are the other tests for CFTR?
Faecal elastase
- Faecal Elastase <100 indicates severe exocrine pancreatic insufficiency
- Faecal Elastase >200 indicates normal exocrine pancreatic function
Cough swab
Chest X-Ray
Sweat Test on unscreened siblings
Mouth wash samples from parents to ascertain the cystic fibrosis gene mutations they carry
What is the treatment for Cystic Fibrosis?
- Dalivit
- Pancreatic enzyme supplements (Creon) if they have pancreatic insufficiency
- Children with CF have a higher calorie requirement. After weaning they are encouraged to consume calorie dense foods closely supervised by the paediatric dietitian.
- Routine immunisations. Children with CF older than 6 months should have the influenza vaccine each year
- Daily chest physiotherapy and regular physical activity (beyond infancy) to prevent airway obstruction
- Regular Flucloxacillin as prophylaxis against staphylococcus aureus infection
- Minimising lung damage by treating any infection early and vigorously. Take cough swabs for bacteriology & post to lab approximately every 2 weeks
