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Nasal potential difference measurements of our cystic fibrosis patients

Nasal potential difference measurements of our cystic fibrosis patients. Güzin Cinel, Dicle Balkancı, Meltem Sevgili, İsmail Karabulut Deniz Doğru, Ebru Yalçın, Nazan Çobanoğlu, Sevgi Pekcan, Uğur Özçelik, Meltem Kaplan, Nural Kiper Hacettepe University Pediatric Pulmonology and

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Nasal potential difference measurements of our cystic fibrosis patients

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  1. Nasal potential difference measurements of our cystic fibrosis patients Güzin Cinel, Dicle Balkancı, Meltem Sevgili, İsmail Karabulut Deniz Doğru, Ebru Yalçın, Nazan Çobanoğlu, Sevgi Pekcan, Uğur Özçelik, Meltem Kaplan, Nural Kiper Hacettepe University Pediatric Pulmonology and Physiology Departments

  2. American CF Foundation Diagnosis Criteria (1998) • Presence of one or more characteristic phenotypic features • or a history of CF in a sibling • or a positive newborn screening test result • And laboratory evidence of aCFTR abnormality as documented by *elevated sweat chloride concentration *or identification of mutations in each CFTR gene known to cause CF *or abnormal nasal potential difference

  3. CFTR • cAMP-regulated chloride channel on the apical membrane of epithelial cells • Regulates sodium and chloride flow on the cell surface • Disfunction leads to -impaired sodium and chloride reabsorbtion on sweat ducts -impaired chloride secretion on respiratory epithelia, increased Na absorbtion because of the effects on the epithelial Na channel -Chloride channel on the pancreatic duct; important activity on bicarbonate secretion

  4. Normal airway epithelial ion transport-1 • Active sodium (Na+) absorption is the dominant ion flow across airway epithelia under basal conditions • This provides the driving force for absorption of airway surface liquid • The transepithelial transport of Na+ involves two distinct steps; Na+ enters the cell down an electrochemical gradient through a Na+-selective channel on the apical membrane that can be inhibited by amiloride, and pumped from the cell by the energy-requiring Na+/K+/ATPase on the basolateral membrane

  5. Normal airway epithelial ion transport-2 • The accompanying absorptive flow of Cl- (and water) occurs through paracellular pathways • Net liquid (Cl-) secretion does not occur under basal conditions; however, airway epithelia can secrete Cl- (liquid) into the lumen under certain conditions, eg, if Na+ entry is inhibited with amiloride. The secretion of Cl- can occur via CFTR or another population of Cl-channels that are Ca2+-activated

  6. Normal airway ion transport

  7. Abnormal airway epithelial ion transport in CF-1 • CF airway epithelia exhibit excessive absorption of Na+ (and liquid) that is twofold to threefold greater than normal airway epithelia • There is also limited ability to secrete Cl-via the CFTR protein in response to cAMP-mediated stimulation

  8. Abnormal airway epithelial ion transport in CF-2 • The limited capacity to secrete Cl-, coupled to the excessive Na+ absorption, contributes to abnormal rheology of airway secretions and abnormal mucociliary clearance • The result is retention of thick secretions and chronic bacterial infection,usually with S. aureus and P. aeruginosa

  9. Airway ion tranport in CF

  10. Nasal potential difference • This active transport of ions across respiratory epithelia, including nasal epithelia, generates a transepithelial electrical potential difference (PD) which can be measuredin vivo on nasal epithelia • Abnormalities of ion transport in respiratory epithelia of patients with CF are associated with a different pattern of nasal PD compared with normal epithelia

  11. Specifically, three features distinguish CF • Higher (raised) basal PD, which reflects enhanced Na+ transport across a relatively Cl—impermeable barrier • Greater inhibition of PD after nasal perfusion with Na+ channel inhibitor, amiloride, which reflecs inhibition ofaccelerated Na+ transport • Little or no change in PD in response to perfusion of the nasal epithelial surface with Cl- free solution in conjunction with isoproterenol (a β-adrenerjik agonist), which reflects an absence of CFTR-mediated Cl- secretion

  12. CF and normal NPD records

  13. Nasal potential difference (NPD) measurement-1 • The general principle for recording transepithelial PD is that the subcutaneous space is isoelectric at all locations in the human body; thus, the transepithelial voltage can be quantified in magnitude and polarity, by referencing the PD to “zero” in submucosal space • In brief, a subcutaneous reference electrode located anywhere in the body would be equivalent to a reference electrode located in the submucosal space of the nasal epithelium

  14. Nasal potential difference (NPD) measurement-2 • The voltage between the reference electrode and the exploring electrode accurately reflects the transepithelial PD, assuming the system is appropriately established • Abrasion of the epithelium reduces the transepithelial potential to zero, which demonstrates that the development of transepithelial PD requires an intact epithelial surface • Local application of drugs, also provides clues to the nature of the active ion transport process across the epithelium

  15. Aims: • To determine the difference of NPD measurements between CF patients and non-CF subjects • To exclude CF diagnosis in patients with elevated sweat chloride concentration but without any symptoms of CF • To distinguish atypical CF patients

  16. Method-1 • Between June 2005 and February 2006, in Hacettepe University Pediatric Pulmonology Department • Patients known as CF with clinical and laboratory evidence • Control group from subjects followed in our department and known as not CF • NPDmeasurements carried out to these patients in HU Physiology Department when they were not receiving any antibiotic or steroid therapy

  17. Results-1

  18. NPD record of a patient in control group

  19. NPD record of a CF patient

  20. Results-2 ***Not direct measurements but response to amiloride, OCl and isoproterenol is important in evaluation ΔAmil=response to amiloride ΔOCl=response to OCl Δiso=response to isoproterenol

  21. Conclusion-1 • NPD measurement which shows CFTR disfunction in vivo is a reliable test for CF diagnosis • With NPD measurement, we confirmed our patients’ CF diagnosis • CF patients with atypical manifestations can be distinguished with this test

  22. Conclusion-2 • More than 1500 mutations defined that cause CF; so it’s impossible to show mutations in each CFTR gene in all of our patients • For patients • in whom sweat chloride concentrations are normal or borderline and • in whom two CF mutations are not identified, • an abnormal nasal PD measurement recorded ontwo seperate days can be used as evidence of CFTR disfunction

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