Genetic determinants of the lung function Flashcards
Is Asthma genetic?
- Transmission of the disease through generations does not follow simple inheritance
- New genotyping technologies has made it possible to sequence the human genome for asthma-associated variants
- It is identified on certain chromosomes
What is Cystic Fibrosis?
Chronic genetic disease
Multi-organ involvement
Who does CF affect?
- In UK >10,000 people affected
- Median age of death improving
- Most common lethal autosomal recessive genetic disorder in Caucasians
Where is the defect for cystic fibrosis?
- Long arm of chromosome 7 coding for the cystic fibrosis transmembrane regulator (CFTR) protein (anion channel)
- F508del is the most common mutation causing CF
What is the function of the CTFR protein?
Transport protein on membrane of epithelial cells
What would an abnormal CFTR protein lead to?
Abnormal CFTR protein leads to dysregulated epithelial fluid transport
- 80% Lung and gastrointestinal involvement
- 15% Lung alone
What is the vicious cycle?
Bronchitis - Bronchiectasis - Fibrosis
- More infection leads to more inflammation leads to more lung damage leads to more progressive lung disease
How is CF diagnosed?
- Genetic profile and neonatal screening (day 5 IRT)
- Clinical symptoms – frequent infections, malabsorption, failure to thrive
- Abnormal salt / chloride exchange – raised skin salt
At what age are most people diagnosed with CF?
50% diagnosed @ 6 months
90% diagnosed @ 8 years of age
What happens in the pancreas with CF?
- Blockage of exocrine ducts, early activation of pancreatic enzymes, and eventual auto-destruction of the exocrine pancreas
- Most patients require supplemental pancreatic enzymes
What happens in the intestines with CF?
Bulky stools can lead to intestinal blockage
What happens in the respiratory system with CF?
- Mucus retention, chronic infection, and inflammation that eventually destroy lung tissue
- There are multiple hypotheses regarding the pathogenesis of lung disease, each of which is supported by data in vitro and in vivo
- Lung disease is the most common cause of morbidity and mortality
What is the CF genotype classification? (6)
Class I: no functional CFTR protein is made (e.g. G542X)
Class II: CFTR protein is made but it is mis-folded (e.g. F508del) (MOST COMMON)
Class III: CFTR protein is formed into a channel but it does not open properly (e.g. G551D)
Class IV: CFTR protein is formed into a channel but chloride ions do not cross the channel properly (e.g. R347P)
Class V: CFTR protein is not made in sufficient quantities (e.g. A455E)
Class VI: CFTR protein with decreased cell surface stability (e.g. 120del123)
What are some CF prevention methods?
- Segregation (don’t put people with CF together in one room)
- Surveillance
- Airway clearance
- Nutrition (pancreatic enzymes, diet high calorie & fat, supplements including vitamins, percutaneous feeding)
- Psychosocial support
- Suppression of chronic infections – antibiotic nebulisation
- Bronchodilation – salbutamol nebulisation
- Anti inflammatory – azithromycin, corticosteroids
- Diabetes – insulin treatment
- Vaccinations – influenza, pneumococcal, SARS CoV 2
What do we give to CF patients?
2 week course IV antibiotics
