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Intestinal current measurement for diagnostic classification of patients with questionable cystic fibrosis: validation and reference data
  1. Nico Derichs1,
  2. Javier Sanz2,
  3. Thomas Von Kanel2,
  4. Cornelia Stolpe1,
  5. Antonia Zapf3,
  6. Burkhard Tümmler1,
  7. Sabina Gallati2,
  8. Manfred Ballmann1
  1. 1Cystic Fibrosis Centre, Department of Pediatric Pulmonology and Neonatology, Medizinische Hochschule Hannover, Germany
  2. 2Division of Human Genetics, Department of Pediatrics, Inselspital, University of Bern, Switzerland
  3. 3Institute for Biometry, Medizinische Hochschule Hannover, Germany
  1. Correspondence to Nico Derichs, Cystic Fibrosis Centre, Department of Pediatric Pulmonology and Neonatology, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany; derichs.nico{at}mh-hannover.de

Abstract

Background In questionable cystic fibrosis (CF), mild or monosymptomatic phenotypes frequently cause diagnostic difficulties despite detailed algorithms. CF transmembrane conductance regulator (CFTR)-mediated ion transport can be studied ex vivo in rectal biopsies by intestinal current measurement (ICM).

Objectives To describe reference values and validate ICM for the diagnostic classification of questionable CF at all patient ages.

Methods ICM was performed in 309 rectal biopsies from 130 infants, children and adults including patients with known pancreatic-insufficient (PI)-CF (n=34), pancreatic-sufficient (PS)-CF (n=7), patients with an unclear diagnosis with mild CF symptoms, intermediate sweat test and/or CFTR mutation screening (n=61) and healthy controls (n=28). ICM was correlated to sweat chloride, extensive CFTR genotype and transcript analysis in the diagnostic group. The results were compared with previous ICM data in subjects with CF, congenital bilateral absence of the vas deferens, heterozygotes and controls.

Results The cumulative chloride secretory response of ΔIsc,carbachol, ΔIsc,cAMP/forskolin and ΔIsc,histamine was the best diagnostic ICM parameter (cut-off 34 μA/cm2 between patients with known PS-CF and controls), differentiating patients with questionable CF into PS-CF (n=6) and ‘CF unlikely’ (n=55) groups. Extensive genotype analysis detected two mutations (40% disease-causing) in 100% of individuals classified as PS-CF compared with 1.8% in those classified as ‘CF unlikely’.

Conclusions This comprehensive investigation of CFTR function and genotype underlines the diagnostic value of ICM, especially for confirmation of CF in the absence of two disease-causing CFTR mutations, exclusion of CF despite intermediate sweat test and age groups unsuitable for nasal potential difference measurements. ICM is an important tool for functional assessment in CFTR mutations of unknown clinical relevance.

  • CFTR function
  • sweat chloride
  • diagnosis
  • genotype
  • algorithm
  • cystic fibrosis
  • paediatric lung disaese
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Footnotes

  • Funding Deutsche Forschungsgemeinschaft SFB 621, C7 and the Swiss National Foundation (3200-066767.01, 310000-112652).

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the local ethics committee, MH Hannover, Germany and all patients and/or parents and healthy controls gave their written informed consent.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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