Cystic fibrosis pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shaghayegh Habibi, M.D.[2]

Overview

Cystic fibrosis is an autosomal recessive disease that caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Substitution of a single amino acid is the most common type of CFTR gene mutation. CFTR gene functions as a chloride channel (pumps chloride from the intracellular space to the extracellular space) found on the surface of the epithelial cells. The genetic mutations result in defective transport of chloride, and secondarily sodium and eventually abnormal viscous mucoid secretions mostly in lungs (results in airway surface liquid depletion, decreased mucociliary transport, inflammation and infection) and GI tract (results in reduced volume of pancreatic secretion, pancreatic tissue destruction and fibrosis, malnutrition and poor growth). Infertility due to atresia/absent vasa deferentia and abnormal/absent seminal vesicles is the associated condition of cystic fibrosis.

Pathophysiology

Pathogenesis

 
 
 
Lack of CFTR normal activity
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Less chloride secretion
 
More sodium absorption
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Less water transport into the epithelial surface layer
 
Excessive sodium and water absorption through the epithelial channel
 
 

Lung involvement in cystic fibrosis

  • In patients with cystic fibrosis abnormal chloride conductance of epithelial cells results in airway surface liquid depletion and decreased mucociliary transport (airway surface liquid is essential to support ciliary function).
  • The consequence of cystic fibrosis is a vicious circle of inflammation, tissue damage and infection.[3]
  • Also, exaggerated, generalized, and prolonged inflammatory response of lungs to bacterial and viral pathogen is observed.
  • The inflammatory response is characterized by neutrophilic dominated airway inflammation which is present even in clinically stable patients and in young infants diagnosed by neonatal screening.[3][4]
  • Breakdown of accumulated neutrophils in the infected lungs of patients with cystic fibrosis leads to the release of large amounts of DNA.
  • Accumulated DNA causes high viscosity of the infected sputum, followed by decreased ciliary transport and function.[5]

Gastrointestinal tract involvement in cystic fibrosis

Pancreatic disease:

Biliary disease:

Genetics

Cystic fibrosis is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. This gene codes for a chloride transporter regulated by cyclic AMP (cAMP)-dependent phosphorylation. There are almost 2,000 variants of CFTR gene mutations:[4]

CFTR protein - Molecular structure of the CFTR protein Source: Wikimedia Commons[8]


In Caucasian populations, the frequency of mutations is as follows:[9]

Mutation Frequency
worldwide
ΔF508 66.0%
G542X 2.4%
G551D 1.6%
N1303K 1.3%
W1282X 1.2%


Associated Conditions

Gross Pathology

Microscopic Pathology

References

  1. National Center for Biotechnology Information (US). Genes and Disease [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 1998-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK22183/
  2. Voter KZ, Ren CL (2008). "Diagnosis of cystic fibrosis". Clin Rev Allergy Immunol. 35 (3): 100–6. PMID 18506640. doi:10.1007/s12016-008-8078-x. 
  3. 3.0 3.1 3.2 Ratjen FA (2009). "Cystic fibrosis: pathogenesis and future treatment strategies". Respir Care. 54 (5): 595–605. PMID 19393104. 
  4. 4.0 4.1 4.2 Cutting GR (2015). "Cystic fibrosis genetics: from molecular understanding to clinical application". Nat. Rev. Genet. 16 (1): 45–56. PMC 4364438Freely accessible. PMID 25404111. doi:10.1038/nrg3849. 
  5. Konstan MW, Ratjen F (2012). "Effect of dornase alfa on inflammation and lung function: potential role in the early treatment of cystic fibrosis". J. Cyst. Fibros. 11 (2): 78–83. PMC 4090757Freely accessible. PMID 22093951. doi:10.1016/j.jcf.2011.10.003. 
  6. 6.0 6.1 Ratjen F, Döring G (2003). "Cystic fibrosis". Lancet. 361 (9358): 681–9. PMID 12606185. doi:10.1016/S0140-6736(03)12567-6. 
  7. "Cystic Fibrosis - National Library of Medicine - PubMed Health". 
  8. "File:CFTR.jpg - Wikimedia Commons". 
  9. Prevalence of ΔF508, G551D, G542X, R553X mutations among cystic fibrosis patients in the North of Brazil. Brazilian Journal of Medical and Biological Research 2005; 38:11–15. PMID 15665983
  10. Ratjen F, Döring G (2003). "Cystic fibrosis". Lancet. 361 (9358): 681–9. PMID 12606185. doi:10.1016/S0140-6736(03)12567-6. 

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