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CFTR Function & Sweat Chloride

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Role of CFTR Proteins CFTR in Sweat Glands

Cystic fibrosis (CF) is a rare genetic disease which can affect lung function, digestion, sweat production, and reproductive function. The disease is present in a person who inherits two copies of a cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation, resulting in a CF genotype. CF phenotypes can show variability, even among patients with the same mutations.1,2

What Do CFTR Proteins Do?

CFTR proteins are found on the surfaces of epithelial cells in various organs in the body. Normally, CFTR protein channels transport ions, such as chloride and bicarbonate, into and out of epithelial cells in these organs.1-3

Different CFTR mutations affect CFTR protein function in different ways. Level of CFTR protein function is largely determined by the quantity and the activity of the protein at the cell surface.1

CFTR protein channels transport ions, such as chloride and bicarbonate, into and out of epithelial cells1

Mutations in CFTR genes cause changes in the function of CFTR proteins at the cell surface. Mutations in CFTR genes cause changes in the function of CFTR proteins at the cell surface.
  • Characteristically, CFTR mutations cause problems that affect the reabsorption of chloride, and as a result, cause the sweat glands to secrete excessive amounts of chloride1
  • Thickened mucus leads to manifestations common to CF
    • CF can significantly impact the lung airways. If left untreated, mucus clogging of small airways can lead to repeated bacterial infection, inflammation, bronchiectasis, and ultimately an accelerated decline in lung function1
    • In the pancreas and gastrointestinal tract, the defective secretion of digestive enzymes and malabsorption of fat can lead to fatty stools. 85% to 90% of patients with CF have pancreatic insufficiency, which is common even at a young age1,4
    • CF also affects reproductive fertility, particularly in men. Approximately 98% of men with CF have a congenital bilateral absence of the vas deferens, blocking the transport of sperm and resulting in azoospermia. Infertility in women with CF is not as common, with up to 50% of women able to conceive5

Maintaining good water and salt balance at the epithelial cell surface requires both adequate quantity and adequate function of CFTR proteins.6

SwCl Concentration is an Indicator of CFTR Function in Sweat Glands

  • SwCl concentration is the standard test of CFTR function used in the diagnosis of CF7
  • SwCl concentration is a reliable measure of CFTR function7
    • SwCl concentration is standardized for both clinical diagnosis and clinical trial use7
    • Testing procedures may cause variability in SwCl concentration values8

SwCl concentration is measured on the skin, which is typically unaffected by chronic infection and inflammation9,10

In normal sweat glands, as sweat travels to the skin surface, chloride is absorbed from sweat in a CFTR-dependent manner. In CF sweat glands, defective or deficient CFTR proteins hinder chloride reabsorption resulting in higher-than-normal chloride concentrations in sweat reaching the skin surface. In normal sweat glands, as sweat travels to the skin surface, chloride is absorbed from sweat in a CFTR-dependent manner. In CF sweat glands, defective or deficient CFTR proteins hinder chloride reabsorption resulting in higher-than-normal chloride concentrations in sweat reaching the skin surface.

References: 1. Derichs N. Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis. Eur Respir Rev. 2013;22(127):58-65. doi:10.1183/09059180.00008412 2. Zielenski J. Genotype and phenotype in cystic fibrosis. Respiration. 2000;67(2):117-133. doi:10.1159/000029497 3. Boyle MP, De Boeck K. A new era in the treatment of cystic fibrosis: correction of the underlying CFTR defect. Lancet Respir Med. 2013;1(2):158-163. doi:10.1016/S2213-2600(12)70057-7 4. Orenstein DM, Spahr JE, Weiner DJ. Cystic fibrosis: a guide for patient and family. 4th ed. Lippincott Williams & Wilkins; 2011. 5. Ahmad A, Ahmed A, Patrizio P. Cystic fibrosis and fertility. Curr Opin Obstet Gynecol. 2013;25(3):167-172. doi:10.1097/GCO.0b013e32835f1745 6. Feng LB, Grosse SD, Green RF, Fink AK, Sawicki GS. Precision medicine in action: the impact of ivacaftor on cystic fibrosis–related hospitalizations. Health Aff (Millwood). 2018;37(5):773-779. doi:10.1377/hlthaff.2017.1554 7. Muhlebach MS, Clancy JP, Heltshe SL, et al. Biomarkers for cystic fibrosis drug development. J Cyst Fibros. 2016;15:714-723. 8. Collaco JM, Blackman SM, Raraigh KS, et al. Sources of variation in sweat chloride measurements in cystic fibrosis. Am J Crit Care Med. 2016;194(11):1375-1382. doi:10.1164/rccm.201603-0459OC 9. De Boeck K, Kent L, Davies J. CFTR biomarkers: time for promotion to surrogate end-point? Eur Respir J. 2013;41:203-216. doi:10.1183/09031936.00057512 10. Lyczak JB, Cannon CL, Pier GBl. Clin Microbiol Rev. 2002;15(2):194-222. doi:10.1128/CMR.15.2.194–222.2002