W6 Pathophysiology of Cystic Fibrosis Flashcards
aka Overview of Cystic Fibrosis
What is Cystic Fibrosis?
- Cystic fibrosis (CF), also known as mucoviscidosis
- Its an Inheritable autosomal recessive disease
- Mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene
- CFTR is involved in production of sweat, digestive fluids, and mucus
- Ion transport abnormalities dehydrates mucous (becomes more viscous – less fluid)
- Pulmonary and GI systems principal systems affected (Pancreas)
What are the long term issues of CF?
- Include difficulty breathing/coughing up sputum as a result of frequent lung
infections.
What are the other symptoms of CF? (minor)
- Other symptoms include
- sinus infections
- poor growth
- fatty stool
- clubbing of the finger and toes
- infertility in males among others.
- Different people have different degrees of symptoms.
Epidemiology of CF (for info)
- Although technically a rare disease, cystic fibrosis is ranked as one of the most widespread life-shortening genetic diseases.
-Prevalence varies with ethnicity, worse in Caucasians (1 in 3000 live births)
-Cystic fibrosis is diagnosed in males and females equally
-Until recently males tended to have longer life expectancy – reason unclear and gap now reducing
*Most common mutation (70% of cases) ΔF508 - a three base-pair deletion that should code for phenylalanine (position 508)
-There are 1000s of other relatively rare mutations
* CF usually diagnosed in childhood (93%)
* Median survival was around 30 years, now in the 40s/50s
-Prognosis is improving:
CF: What are the Main Signs and Symptoms? (4)
- salty-tasting skin
- poor growth and poor weight gain despite normal food intake
- accumulation of thick, sticky mucus
- frequent chest infections, and coughing or shortness of breath
What body systems are affected by CF?
Lungs and sinuses- infection, inflammation and obstruction
Sweat gland- elevated sweat chloride concentration
Liver- cirrhosis
Pancreas- exocrine dysfunction diabetes and pancreatitis
Intestine-neonatal obstruction (meconium ileum) and distal intestinal obstruction
Male reproductive tract- obstructive male infertility
What are the causes of CF?
What type of gene is CTFR?
- Autosomal recessive disease
- Structurally, CFTR is a type of gene known as an ABC gene / ABC transporter (transmembrane proteins and ATPases).
- The product of this gene (the CFTR) is a chloride ion channel important in creating sweat, digestive juices and mucus.
- The CFTR gene, found at the q31.2 locus of chromosome 7, is 230,000 base pairs long, and creates a protein that is 1,480 amino acids long
- Its location is 7q31.2 More specifically it is found on the long arm of chromosome 7, region 3, band 1, sub-band 2, represented as.
- (Won’t test you on the above)
Cellular processing of CFTR
How does it occur?
- Activation by ATP binding and cAMP-dependent phosphorylation
- Insertion into and retrieval from membrane
- Glycosylation and vesicle packaging in the Golgi
- Translation and folding in the ER
- Synthesis of mRNA
CFTR In Cystic Fibrosis
- CFTR Channel: Chloride ions aren’t transported through chloride channels in CF
- Chloride ions – reduced extracellularly (on the surface of epithelium)
- Affects constituency of mucus
- Na+ and Cl− on airway surfaces
- Coupled with reduced water flow to
the airway lumen - Dehydrating mucus
-Reduced HCO3− to the airway surface, acidifying layer
Difference between normal-functioning and abnormally functioning CFTR
- A normal functioning CFTR channel moves chloride ions to the outside of the cell while a mutant CFTR channel does not, causing sticky mucus to build up on the outside of the cell.
Diagnosis of CF
What tests can be done? (3)
- Large number of CFTR mutations limits utility of DNA tests in diagnosis but can be done
= The heel prick test blood test newborns – common variants - Sweat test for chlorine levels (>60mM for adults) (1-2% patients have normal sweat)
- Nasal transepithelial potential difference
(increased luminal Na+ absorption makes potential more negative in CF patients)
Management of CF
- Management of CF requires a diverse professional team
- Lifestyle and psychological support required
- Poly-pharmacy is common
- Stratification of treatment to disease severity:
- Maintenance to improve QoL and limit exacerbations
- Treat exacerbations aggressively
What are the treatment objectives in CF? (4)
- Promote clearance of secretions
- Control lung infection
- Provide adequate nutrition
- Prevent intestinal obstruction
- Excess mucous in the GI system reduces ability to get nutrients from the diet and can block intestine
What are the 3 most common
organisms causing lung
infections in CF patients?
- Staphylococcus aureus,
- Haemophilus influenzae,
- Pseudomonas aeruginosa
Pulmonary mucous clearance
Airway surface liquid (ASL) protects lung
* Periciliary layer (PCL) and mucus layer.
* PCL is a grafted brush of tethered
mucins (proteins)
* lubrication for ciliary beat
* Mucus - viscoelastic fluid
* ASL layers trap and clear inhaled pathogens
from the lung via mucociliary transport
* Mucus consistency affects this
* Acid (low pH may also affect this)
* Ciliary clearance becomes ineffective
* Colonised with bacteria
* Chronic inflammations, bronchiectasis and
obstruction
