Increased prevalence of CFTR mutations and variants and decreased chloride secretion in primary sclerosing cholangitis

Hum Genet. 2003 Aug;113(3):286-92. doi: 10.1007/s00439-003-0963-z. Epub 2003 Jun 3.


Primary sclerosing cholangitis (PSC) and cystic fibrosis (CF) are both slowly progressive cholestatic liver diseases characterized by fibro-obliterative inflammation of the biliary tract. We hypothesized that dysfunction of the CF gene product, cystic fibrosis transmembrane conductance regulator (CFTR), may explain why a subset of patients with inflammatory bowel disease develop PSC. We prospectively evaluated CFTR genotype and phenotype in patients with PSC ( n=19) compared with patients with inflammatory bowel disease and no liver disease ( n=18), primary biliary cirrhosis ( n=17), CF ( n=81), and healthy controls ( n=51). Genetic analysis of the CFTR gene in PSC patients compared with disease controls (primary biliary cirrhosis and inflammatory bowel disease) demonstrated a significantly increased number of mutations/variants in the PSC group (37% vs 8.6% of disease controls, P=0.02). None of the PSC patients carried two mutations/variants. Of PSC patients, 89% carried the 1540G-variant-containing genotypes (resulting in decreased functional CFTR) compared with 57% of disease controls ( P=0.03). Only one of 19 PSC patients had neither a CFTR mutation nor the 1540G variant. CFTR chloride channel function assessed by nasal potential difference testing demonstrated a reduced median isoproterenol response of 14 mV in PSC patients compared with 19 mV in disease controls ( P=0.04) and 21 mV in healthy controls ( P=0.003). These data indicate that there is an increased prevalence of CFTR abnormalities in PSC as demonstrated by molecular and functional analyses and that these abnormalities may contribute to the development of PSC in a subset of patients with inflammatory bowel disease.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Action Potentials
  • Adult
  • Aged
  • Case-Control Studies
  • Chloride Channels / genetics*
  • Chlorides / metabolism*
  • Cholangitis, Sclerosing / genetics*
  • Cholangitis, Sclerosing / metabolism
  • Cystic Fibrosis / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics*
  • Female
  • Genetic Testing
  • Genetic Variation
  • Genotype
  • Humans
  • Inflammatory Bowel Diseases / genetics
  • Liver Cirrhosis, Biliary / genetics
  • Male
  • Middle Aged
  • Mutation*
  • Nasal Mucosa / physiopathology
  • Phenotype
  • Prevalence
  • Sweat / metabolism


  • CFTR protein, human
  • Chloride Channels
  • Chlorides
  • Cystic Fibrosis Transmembrane Conductance Regulator