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)