Cystic Fibrosis

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Cystic fibrosis

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heterogenous recessive genetic disorder causing mutations in cystic fibrosis transmembrane conductance regulator gene

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Classic CF

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Chronic bacterial infection of airways/sinuses, fat maldigestion, infertility in males and elevated concentatrions of chloride in sweat

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Non classic CF

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Partial function of CFTR protein, no signs of maldigestion since some pancreatic function is reserved

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cftr gene is found on

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locus 7q31.2

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CFTR role

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Transports chloride ions across the membranes of cells in the lungs, liver, pancreas, digestive tract, reproductive tract and skin.

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classes of mutations

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Class 1: Mutations exemplifed by G542x contain premature stop mutations that create truncated mRNA

class 2: Mutations (∆508 most common) are misfolded and inable to escape the ER, where they are ubiquitinated and degraded

class 3:Mutations such as g551D reach the cell membrane but the channel is not properly activated.

class 4: mutations (r347p) reach the cell surface and the channel can be activated but have decreased chloride condutcance

class 5: mutations result in decreased abundance of CFTR

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cftr role further

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exerts an inhibitor effect on epitherlial sodium channels whilst influencing other chloride channels. as a result, an abundance of Cftr causes reduced net fluid secretion across affected epithelium

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mutant CFTR

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ENaC not inhibited

sodium absopriton is increased

water follows sodium into the cells

airways liquid volume decreases.

normal CFTR will secret CL- ions when aiway surface liquid volume is low. This doesnt happen in mutated gene.

Cilia doesnt beat well when PCL volume is depleted. Mucins are not diluted and cannot easily be swept away therefore mcuus becomes concetrated resulting in increased adhesion to aiway surface promoting chronic infection

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CF therapy.

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Airway clearance

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Bronchodilators

dornase alfa

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infection

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INHALED IV ORAL

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gastrointestinal/nutritional

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pancreatic supplements.

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inflammation

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ibuprofen

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difference in mucus in CF

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Not mucin derived, instead it is made up of polymerised DNA derived from degraded neutrophils therefore most mucolytics which tiarget mucin whill not be suitable. treatment requires further thought - dornase alfa has proven effectice and is current the only mucootyic with proven efficay in CF

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gastro complications

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Thickened secretions block pancraetic exocrine movement of the digestive ensymes in the duodenum - results in irreversible damage to the pancreas and inflammation (pancreatisi)

lack of digesting enzymes leads to malabsorption

thickened secretons can also cause liver problems, secreted bile may block bile ducts leading to liver damage, this can lead to scarring (cirrhosis) over time

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infections

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Bacterial lung infections are typical of CF.

Ineffective mucocilliary clearance system produces airway obstruction leading to progressive damage

infection triggers inappropriately robust and persisten inflamamtory response e.g excessive neutrophils that release mediators such as IL-8 that damage cells/thicken secretions

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inflammation -> sputum retention -> infection -> inflammation

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Perpetuates itself because inflammatory produxts realeased by neutorphils stimulate mucus secretion

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Treatment

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High dose tobramycin for chronic infection

oinly way to cure CF is with gene therapy to replace defective genes or give patient normal for of the protein before symptoms cause permanent damamge.

major goal in treating CF is to clear abnormal and excessive secretions and control infections in the lungs and to prevent obstructions in the intestines

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