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Cystic Fibrosis - disease resulting from abnormality of CFTR gene - Cl…
Cystic Fibrosis - disease resulting from abnormality of CFTR gene - Cl channel in lungs/intestines/pancreatic ducts/sweat glands/reproductive organs
Epi/Risk factors
- Caucasians 1 in 25/1 in 2500 incidence
- UK's most lethal genetic disease
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Aetiology
- autosomal recessive gene inheritance
- chromosome 7
- defect in CF transmembrane conductive regulator gene
- defect in ion transport
- most common deletion at position 508 in amino acid sequence
I - prevents protein synthesis
II- deficienct processing - degradation within lysozyme - can not travel to cell membrane - most common DF508
III - fails to open in response to signal - most common G551 D
IV- deficient conductance - channel opening normal
V- deficient synthesis - reduced amount of protein produced
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Pathophysiology
Anion channel
- alters secondary/tertiary shape of protein
- failure of opening Cl --> decrease excretion + increased intracellular Cl + Na reabsorption (via Na channels)
- decreased excretion of H2O and increased viscosity + increased airway secretion
- abnormally thick/dry mucous into lungs and GI tract --> bronchial airway obstruction --> infection --> inflammation --> release of proteases --> thickened mucous --> progressive lung tissue destruction --> resp failure
- mucociliary clearance dysfunction
- mucous plugging
- increase Na reabsorption also causes more negative transepithelial potential difference
Signs and Symptoms
- meconium ileus after birth
- exocrine pancreatic insufficieny (malabsorption of protein and fat and increased fecal loss)
- malabsorption (large, foul smelling stools, abdominal distention, poor weight gain)
- faulty fat absorption - deficiency states (growth failure) + fat soluble vitamins ADEK
- biliary cirrhosis
- hypoproteinemia --> edema
- persistent diarrhea --> rectal prolapse
Cardioresp:
- chronic cough
- persistent pulmonary infection (S. aureus - early infancy, P aeruginosa- adolesnce), chronic bronchitis and bronchiectasis --> reticulonodular pattern on CXR
- sinusitis/nasal polyps
- RVH + cor pulmonale
- nail clubbing
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Diagnosis
- Antenatal testing
- chorionic vilus biopsy - 11w (12-14w) - parents who have child with/parents who are carriers/fetus --> echogenic bowel
- amniocentesis - 16w (16-24w)
- New born screening - Guthrie test - immunoreactive trysinogen assay (IRT)
- sweat test (>2m age) Cl > 60mmol/L
- DNA sequencing - gene defect
- blood immunoreactive trypsin levels
Management
- MDT - stop smoking/vaccination (influenza/pneumococcal vaccine/pul rehab)
- O2 therapy - as necessary
- antibiotic treatment (resp infection) - Tobramycin
- pseudomonas infection --> sputum
- nebulised anti-pseudomonal antibiotic therapy improves lung function
- decreased risk infective exacerbation/hospitilisation
- mucolytics- recombinant DNAse pre physiotherapy - pulmozyme
- beta 2 agonists --> inhaled corticosteroids
- airway clearance - inhale recombinant DNase (dornase alfa)
- amiloride - decrease Na transport - no overall benefit
- non invasive ventilation - increase symptoms of chronic resp failure
- treatment pancreatic insufficiency
- pancreatic supplements
- high calorie diet
- salt supplements
- fat soluble vitamins
Ivacaftor:
Rescues G551D mediated Cl trannsport
Normalises Sweat test
Improves FEV1 by 10%
Reduces Pulmonary Exacerbations
Proof that Mutation specific therapy –effective
A new era in personalised medicine for CF
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