Cystic Fibrosis (CF)


Cystic fibrosis (CF) is the most common life-shortening illness among whites in the United States. This disease affects more than 30,000 individuals in the United States1 and approximately 100,000 globally.2 Among people of northern European descent, the annual incidence of CF is 1 in 3500. Although multiple organs are affected, morbidity and mortality in persons with CF are caused primarily by pulmonary problems.1

The inheritance of CF is autosomal recessive.3 Mutations in the CFTR gene on chromosome 7 result in abnormalities of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which functions as a cyclic adenosine monophosphate (cAMP)-activated transmembrane chloride channel. Individuals with CF carry 2 mutant genes.4 

The CFTR gene encodes the CFTR protein, which is a channel protein found on the apical side of epithelial tissue. The protein is involved in the transport of chloride and bicarbonate across the apical surface of many secretory epithelial tissues, including those in the airways, sweat glands, gastrointestinal tract, pancreas, and vas deferens.2 Physiologically generated bicarbonate is involved in the activation of pancreatic enzyme activation and the correct unfolding of mucins in the airways, which is critical for protection against bacterial infection. In the lungs, chloride secretion and sodium absorption in the epithelial sodium channel, which are mediated by the CFTR protein, modulate airway surface hydration, which is necessary for ciliary function and antimicrobial protection.4 Defects in the CFTR protein result in surface dehydration and the formation of thick, viscous, mucopurulent secretions.2 

CFTR Mutations in Cystic Fibrosis

More than 2000 mutations in the CFTR gene have been identified; the F508del mutation is the most common. However, not all of these mutations are linked to the development of CF.5 Specific mutations in the CFTR gene have different effects on CFTR protein function and can cause various disease phenotypes.6 Data on the rarer mutations are insufficient to advise patients about their prognosis; however, some of them are associated with relatively mild manifestations of the disease.7 Mutations in the CFTR gene are now classified according to the type of dysfunction they cause, which can be defective protein translation, cell processing, or CFTR channel gating. Missense (single amino acid substitution) mutations comprise approximately 38.74%, frameshift (insertion or deletion) mutations 16.25%, splicing (incorrect intron splicing) mutations 10.93%, and nonsense (early codon termination) mutations 8.41% of all the CFTR mutations that have been identified globally. Mutations in the CFTR gene have been grouped into six main classes, each of which corresponds to a different type of CFTR protein dysfunction. The mutations in classes I through III are associated with more severe disease and those in classes IV through VI with milder disease.8 

Many individuals carry a gene associated with CF yet have no symptoms. CF is diagnosed in most children by the age of 2 years as a consequence of the widespread practice of newborn screening in the United States. In a small percentage of people, the illness is not discovered until they are 18 years of age or older. The condition is usually relatively mild in these individuals.9 

The “low volume” concept is the most widely recognized explanation for airway disease in CF. Mucociliary clearance, an innate defensive system of the lungs, fails when the volume of airway surface fluids is diminished. The failure of mucociliary clearance prevents the efficient removal of inhaled germs. In addition, the inflammatory response to infection is exaggerated. Abnormalities of the composition of mucus may also play a role. Although there is some debate regarding this observation, the airway is not infected and presumably not inflamed at birth. The abnormalities of CF previously described eventually result in permanent airway impairment, with bronchiectasis and respiratory failure, in most individuals. Other organs with an epithelial lining may also be affected by ion and water imbalances.7,10,11 

References

  1. Brown SD, White R, Tobin P. Keep them breathing: cystic fibrosis pathophysiology, diagnosis, and treatment. JAAPA. 2017;30(5):23-27. doi:10.1097/01.JAA.0000515540.36581.92
  2. Shteinberg M, Haq IJ, Polineni D, Davies JC. Cystic fibrosis. Lancet. 2021;397(10290):2195-2211. doi:10.1016/S0140-6736(20)32542-3
  3. Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med. 2005;352(19):1992- 2001. doi:10.1056/NEJMra043184
  4. Yu E, Sharma S. Cystic fibrosis. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2021. Accessed January 6, 2022.
  5. De Boeck K. Cystic fibrosis in the year 2020: a disease with a new face. Acta Paediatr. 2020;109(5):893-899. doi:10.1111/apa.15155
  6. Davies JC, Alton EW, Bush A. Cystic fibrosis | The BMJ. BMJ. 2007;335:1255-1259. doi:10.1136/bmj.39391.713229 AD 
  7. Naehrig S, Chao CM, Naehrlich L. Cystic fibrosis. Dtsch Arztebl Int. 2017;114(33-34):564-574. doi:10.3238/arztebl.2017.0564 
  8. Chen Q, Shen Y, Zheng J. A review of cystic fibrosis: basic and clinical aspects. Animal Model Exp Med. 2021;4(3):220-232. doi:10.1002/ame2.12180
  9. Hadjiliadis D, Harron Jr PF, Zieve D. Cystic fibrosis: MedlinePlus Medical Encyclopedia. Accessed January 6, 2022. 
  10. Gibson RL, Burns JL, Ramsey BW. Pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med. 2003;168(8):918-951. doi:10.1164/rccm.200304-505SO
  11. Matsui H, Grubb BR, Tarran R, et al. Evidence for periciliary liquid layer depletion, not abnormal ion composition, in the pathogenesis of cystic fibrosis airways disease – PubMed (nih.gov). Cell. 1998;95(7):1005-1015. doi:10.1016/s0092-8674(00)81724-9

Reviewed by Debjyoti Talukdar, MD, on 1/9/2022.

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