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Diagnosing cystic fibrosis
  1. CHRISTOPHER J TAYLOR
  1. Department of Paediatrics, University of Sheffield
  2. Sheffield Children’s Hospital
  3. Western Bank, Sheffield S10 2TH
  4. Department of Human Genetics and Department of Biomedical Science*
  5. University of Sheffield
    1. ANN DALTON,
    2. JACKIE HARDCASTLE

      *

      ,
    3. PETER T HARDCASTLE

      *

      ,
    4. STEVEN EVANS
    1. Department of Paediatrics, University of Sheffield
    2. Sheffield Children’s Hospital
    3. Western Bank, Sheffield S10 2TH
    4. Department of Human Genetics and Department of Biomedical Science*
    5. University of Sheffield

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      Editor,—Colin Wallis’ review of diagnostic criteria for cystic fibrosis gave an excellent overview of an increasingly complex subject.1 No longer can cystic fibrosis be diagnosed on the basis of suggestive symptomatology confirmed by sweat testing. Mutation analysis has lead to the identification of many pancreatic sufficient ‘mild mutations’, some of which, including the 3849+1 Okb C-T splicing mutation at intron 192 and the A455E mutation,3 are associated with normal sweat electrolytes. In other cases the phenotype can vary with the length of the polypyrimidine tract in the splice acceptor site in intron 8 (poly T variant).4 In many of these mild mutations functional cystic fibrosis transmembrane conductance regulator (CFTR) is produced but with reduced single channel kinetics.5

      Quantitation of chloride channel dysfunction, derived from transepithelial current measurements,6 can provide a rapid and reliable method for confirming or excluding the diagnosis of cystic fibrosis.7 However, nasal potential difference measurements are far from straightforward, particularly in infants and young children. In such cases intestinal current measurements can prove helpful. Our own studies using jejunal biopsy tissue and similar work from Dutch colleagues using rectal biopsy tissue8 have shown abnormal intestinal chloride currents can be identified in patients with inconclusive sweat electrolyte concentrations or where genetic analysis has revealed only one CFTR mutation.

      The results of secretagogue challenge performed on duodenal or jejunal biopsy tissue in 10 patients with chronic lung disease with or without poor weight gain and two patients with meconium ileus but normal immunoreactive trypsin values are given below. Seven were known to be heterozygous for the ΔF508 mutation. Compared with 49 normal controls and four obligate heterozygotes, the secretory response induced by 10−3 M acetylcholine was significantly reduced in six patients supporting a diagnosis of cystic fibrosis (mean (SE) changes in short circuit current (ΔSCC): 4.3(1.4) μA/cm2, controls 37.0(4.0) μA/cm2; p <0.05), three of whom subsequently had the diagnosis confirmed by genetic analysis (ΔF508/L88S, ΔF508/3849+10kbC>T, 15251G>A/1525-1 G>A). Six patients had basal and secretory responses within the normal or heterozygote range (mean (SE) ΔSCC after acetylcholine: 26.7(6.8) μA/cm2, heterozygotes 17.4(4.9) μA/cm2); none of these patients has been found to have two identifiable cystic fibrosis mutations despite extended genetic analysis (2 × ΔF508/N, 4 × N/N).

      Neither Veeze’s group nor our own has found false positive intestinal current measurements in control subjects. Intestinal current measurement appears an accurate and reliable method of either confirming or excluding the diagnosis of cystic fibrosis, particularly in young children unsuitable for nasal potential difference measurements, symptomatic adults with negative sweat tests, and patients with false positive sweat tests and atypical sodium/chloride ratios.9

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