Mixed Flashcards
Diagnostic test for CF
pilocarpine iontophoresis. High levels of Cl (>60) and high Na (>60) in 100mg sweat
CFTR protein
Part of ATP binding cassette. Transmembrane ion channel than lets Cl through (also bicarb) - movement draws water with it
It found in plasma membrane (apical membrane) of multiple tissues, including cells linins lungs, liver, pancreas, intestines, reproductive tract and skin.
Gene is carried on chromosome 7
CFTR mutation classes
Class 1 is protein loss (G542X) Class 2 is trafficking error (delta 508F) Class 3 is functional loss (G551D) class 4 is functional reduction class 5 is protein reduction class 6 is unstable (degraded easily)
Delta 508 F mutation
Phenylalanine deleted at 508, causes problem with trafficking protein to membrane. Severe mutation. Class II
G542 x CF mutation
Stop codon inserted at 542, premature end and no protein (class 1). Severe mutation
621 + 1G>T
mRNA splicing mutation in intron 4, results in loss of an exon. Class 1
CF modifier mutation increase bacterial infection risk
NOS1
CF modifier mutation increasing meconium ileus risk
CFM1
CF modifier mutation increasing GI phenotype risk
MUC1
CF modifier genes affecting pulmonary phenotype
TGF beta, HLAII, TNFA,MBL2
Gene therapy for CF
Could use viral vector (retrovirus or adenovirus) - but these had limited effects and increasing dose lead to inflammation
Adeno-associated viral vectors (AAVV)
being trialed, deemed safer in terms of immune response
Non-viral vectors include DNA fused to cationic liposome (encapsulates DNA, allows cell entry)
Barriers to gene therapy
Host immune response counters virus vectors
Resp epithelium has defences against infection (cilia, complement cellular and humoral immune)
Also get cytoplasmic degradation of non-viral vectors
These barriers limit the number of cells that can be affected by the therapy and therefore limit the response.
Which CF mutation classes cause no/not enough protein?
Class I, class II, class V (also class VI as degrades). So delta 508F (class II) and G542X / 621 + 1G>T(class I).
Which CF mutation classes cause no/reduced function
Class III and IV. G551D is Class III
Potentiators
e.g. ivacaftor
these increase the flow of Cl- through the CFTR bu binding in a non-conventional way
Improves lung function, reduce infective exacerbations, reduces sweat chloride and improves weight gain.(therefore fix theme III, V and VI)
Correctors:
e.g. VX809
these increase the synthesis, processing and/or delivery of CFTR proteins to the cell surface (these target theme I, II and IV)
Antenatal CF presentation
echogenic bowel, but not specific as can occur in CMV infection
Meconium ileus treatment
Gastrograffin enema (water soluble contrast)is diagnostic, and may also be therapeutic. Can also add N/G tubel acetylcysteine (mucolytic agent) that helps dissolve meconium plug. If these don't work, then surgery can be performed (defunctioning ileostomy)
CF screening
Heel prick checks IRT (immune reactive trypsin). If high, then screen for 4 common mutations.
If 2 mutations then CF
If 1 then screen for more. If find another then CF. If not then repeat IRT and see in clinic if raised.
If no mutations were found on initial mutation screen then repeat IRT and if raised then see in clinic.
CF resp infections
Viral risks include RSV, influenza (same as other babies)
Bacterial infections:
Early common infections:
- Haemophilus influenzae
- Staphylococcus aureus (particularly dangerous as destructive)
Late common infections:
- Pseudomonas aeroginosa
- Burkholderia cepacia
- Aspergilus, MRSA
Often, these infections become chronic.
Management is with antibiotics, guided by sputum culture (older patients) and cough swab (younger patients, unlikely to have sputum).
If no positive results, but symptomatic then cover them with antibiotics that are appropriate for their likely organisms.
High dose over long course (14 days ) - as difficult to penetrate the sputum.
If they don’t work orally then can use IV or inhaled antibiotics.
Babies born with CF now get put on antibiotic prophylaxis (flucloxacillin to prevent staph. Aureus). Used for first 3 years to prevent initial infection leading to chronic infection.
Although this reduces the risk of hospitalisation with S aureus later, there is concern that it may leave room for other organisms to take hold (currently under trial).
Other lung treatment
- Bronchodilators
- DNase (mucolytic) - nebulised drug used od. It cleaves DNA (DNA thick mucus secretions in CF). It improves expectoration, improves lung function, reduces infective exacerbations.
- Steroids (systemic)- can be useful acutely, and has effects when used long term (effects on growth). Inhaled steroids not useful.
- Oxygen supplementation (initially at night, but may progress to day use too)
Transplantation (big complication is obliterative bronchiolitis (seen in lung transplants in general, is overwhelming organ rejection and this is not CF specific))
CF - GI tract
Pancreatic insufficiency leads to malabsorption (fats + ADEK), and CF patients already have higher metabolic demand. Creon is given (pancreatic enzyme) with food (dose according to fat content). Sometimes NG needed to supplement.
Complications include DIOS - distal intestinal obstruction syndrome (equivalent of meconium ileus). Due to not enough pancreatic enzyme replacements, causes faecal retention. Present with RIF abdominal pain and RIF mass (could mimic an appendix problem/abcess).
Treatment is with Lactulose/acetylcystine/gastrograffin
