Intestinal current measurement for diagnostic classification of patients with questionable cystic fibrosis: validation and reference data.
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).


OBJECTIVE
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 DeltaI(sc,carbachol), DeltaI(sc,cAMP/forskolin) and DeltaI(sc,histamine) was the best diagnostic ICM parameter (cut-off 34 muA/cm(2) 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.
Derichs
Nico
N
Cystic Fibrosis Centre, Department of Pediatric Pulmonology and Neonatology, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. derichs.nico@mh-hannover.de
Sanz
Javier
J
Von Kanel
Thomas
T
Stolpe
Cornelia
C
Zapf
Antonia
A
Tümmler
Burkhard
B
Gallati
Sabina
S
Ballmann
Manfred
M
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002712:Chlorides / Q000378:metabolism; D003550:Cystic Fibrosis / Q000175:diagnosis*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000502:physiology*; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D008875:Middle Aged; D009154:Mutation; D012007:Rectum / Q000503:physiopathology*; D012016:Reference Values; D015203:Reproducibility of Results; D013542:Sweat / Q000378:metabolism; D055815:Young Adult
C505032:CFTR protein, human; D002712:Chlorides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator