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

• Published in: Thorax Vol. 65; no. 7; pp. 594 - 599
• Main Authors: Derichs, Nico, Sanz, Javier, Von Kanel, Thomas, Stolpe, Cornelia, Zapf, Antonia, Tümmler, Burkhard, Gallati, Sabina, Ballmann, Manfred
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group 01.07.2010; BMJ Publishing Group LTD
• Subjects: Adolescent; Adult; Anesthesia; Biological and medical sciences; Biopsy; Cardiology. Vascular system; Child; Child, Preschool; Chlorides - metabolism; Cystic fibrosis; Cystic Fibrosis - diagnosis; Cystic Fibrosis Transmembrane Conductance Regulator - genetics; Cystic Fibrosis Transmembrane Conductance Regulator - physiology; Disease; Errors of metabolism; Female; Genotype; Humans; Infant; Male; Medical sciences; Membrane Potentials - physiology; Metabolic diseases; Middle Aged; Miscellaneous hereditary metabolic disorders; Mutation; Pneumology; Rectum - physiopathology; Reference Values; Reproducibility of Results; Suctioning; Sweat - metabolism; Young Adult; Germany; Human; Validation; Respiratory disease; Reference; Gut; Metabolic diseases; Patient; Cystic fibrosis; Data; Genetic disease; Current measurement; Classification; Digestive diseases; Anesthesia; Circulatory system; Diagnosis; Cardiology; Pancreatic disease
• ISSN: 0040-6376; 1468-3296; 1468-3296
• DOI: 10.1136/thx.2009.125088

BackgroundIn 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).ObjectivesTo describe reference values and validate ICM for the diagnostic classification of questionable CF at all patient ages.MethodsICM 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.ResultsThe 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’.ConclusionsThis 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.