22nd February 2024

Background

Cystic fibrosis (CF) is a genetic multi-organ disorder. It predominantly affects the lungs in the earlier stages, with subsequent involvement of further organs such as the spleen, pancreas, liver, and intestines. 

Cystic fibrosis is an autosomal recessive inherited disorder with a carrier frequency of 1:22 in the Caucasian population. There are more than >1900 genetic mutations for cyst transmembrane conductor regulator (CFTR) which is the critical culprit protein involved in the pathophysiology and subsequent sequalae of cystic fibrosis.

Pathophysiology

The genetic mutation for CFTR is located on the long arm of chromosome 7 in the region of 7q31.2.  The most common genetic abnormality is deletion of position 508 in the amino acid sequence which results in a defective CFTR protein. CFTR is a channel protein in membranes of cells which produce mucus, sweat, saliva, tears, and the digestive system. The channel is responsible for the transportation of chloride ions across cell membranes.  The mutation alters the secondary and tertiary structure of proteins, leading to a failure of the opening of chloride ion channels in response to elevated cyclic AMP in epithelial cells. This results in decreased excretion of chloride ions, increased absorption of sodium ions and subsequently increased water retention in epithelial cells. Thus, intraluminal secretions have increased viscosity and tenacity. This subsequently leads to chronic bacterial colonisation, causing more repeated episodes of infection. Each infection episode produces more inflammatory cytokines, causing organ parenchymal damage.

References

• Thibodeau PH, Richardson JM 3rd, Wang W, Millen L, Watson J, Mendoza JL, Du K, Fischman S, Senderowitz H, Lukacs GL, Kirk K, Thomas PJ. The cystic fibrosis-causing mutation deltaF508 affects multiple steps in cystic fibrosis transmembrane conductance regulator biogenesis. J Biol Chem. 2010 Nov 12;285(46):35825-35. doi: 10.1074/jbc.M110.131623. Epub 2010 Jul 28.
• Farrell PM, White TB, Ren CL, et al. Diagnosis of Cystic Fibrosis: Consensus Guidelines from the Cystic Fibrosis Foundation. J Pediatr 2017; 181S:S4.