CR - CF (i)
Intro
worst bronchiectatic disease
Beaumont = adult CF service
most common life-shortening disorder in western causasian pops
abnormal apical membrane chloride channel (CFTR) defect
defective epithelial ion transport
chloride not secreted into lumen of airway (hence no water either) - airway surface dehydration
undiluted thick mucus (reduced vol, increased hyperviscosity)
in all epithelial surfaces - multi system disorder (most commonly affects resp tract + GIT)
end-organ damage (e.g. panbronchiectasis)
non-functional mucociliary escalator allows for bacterial colonisation (NEUTROPHILIC INFLAMM, as opposed to lymphocytic/eosinophilic inflamm in asthma)
discovered in 1938
% reaching adulthood increasing (most now do)
majority of deaths now due to resp disease + failure (previously death @ birth from malnutrition)
gene mutation frequency high in Europe
highest in Ire (1 in 17) - hence highest incidence (1 in 1700, 35-40 born/yr
Genotypes
over 1500 CFTR mutations
most common = deltaF508
phenylalanine deletion
decreased lung function + survival in homozygotes (56% of Irish CF patients are)
carrier completely normal
G551D
R117H (mild)
on long arm (Q) of chromo 7
in different classes
1 = defective synthesis (most severe)
2 = defective processing (delF508)
3 = defective regulation (G551D)
4 = defective conductance (R117H)
5 = reduced quantity
6 = increased turnover (mildest)
Dx
clinical features OR sibling with it OR +ve newborn screening (check blood for raised immunoreactive trypsinogen-IRT, made by pancreas, in Ire since 2012)
AND
+ve sweat test (measure conc of chloride in sweat) OR +ve nasal potential difference (measure voltage across nasal epithelium) OR 2 identifiable CFTR mutations
Presentation
from birth/infancy
failure to thrive
meconium ileum (bowel obstruction that occurs because there's too much mucus in the meconium)
childhood
failure to reach growth milestones
recurrent chest infections
abdo cramps
diarrhoea
pancreatic insufficiency
DM (not type 1 or 2, insulin dependent)
risk increases with age (most are born with some endocrine pancreatic function which declines over time)
renal disease
made worse by DM + aminoglycoside use
risk increases with age + post-transplant
liver disease
focal biliary cirrhosis
fatty infiltration
cirrhosis with splenomegaly
varices (enlarged veins)
sometimes liver transplant required (often before 10 y/o)
distal intestinal obstruction syndrome (DIOS)
osteoporosis (low bone mineral density, asymptomatic - no pathological fractures, significance unknown)
Congenital bilat absence of vas deferens (CBAVD)
causes obstructive azoospermia - complete absence of sperm from ejaculate - functional sterility
nasal polyps
result of chronic inflamm
recurrent frontal headaches + nasal congestion
common in normal adults, but if in a child they have CF
sinusitis
growth retardation/delayed puberty
resp disease
decreased mucociliary clearance
recurrent pul exacerbations
diffuse panbronchiectasis (starts in upper + mid zones. goes everywhere)
mucus plugging (atelectasis)
obstructive airways disease
resp failure
may see a Portacath (implanted IV device) on an CXR of a CF patient
exacerbation symptoms
even more coughing + sputum (increased vol, purulence + viscidity)
SOB, wheeze, haemoptysis
nasal/sinus symptoms
often absence of febrile symptoms
over the course of a few days-wks
life expectancy = 39 (less in women)
lung transplant
refer when estimated survival < 5 yrs
used to be when FEV1<30%, but that's too late as takes v long to find a match
50% 5-yr survival post-transplant
benefits vs risks
future Tx
probably not gene tx
newer forms of existing drugs (antiinflamms, antibiotics, airway clearance meds)
small molecule potentiators/correctors/modulators
work @ CFTR to increase ion flow
10-15% lung function improvement (v big)
ivacaftor (kalydeco)
PO
potentiator for G551D
normalised sweat test, increased FEV1 + BMI
FDA-approved but v expensive
when combined with Lumacaftor = Orkambi (for those homozygous for delF508)