The molecular pathogenesis of cystic fibrosis (CF) liver disease is unknown. This study investigates its earliest pathophysiological manifestations employing a mouse model carrying DeltaF508, the commonest human CF mutation. We hypothesized that, if increased bile salt spillage into the colon occurs as in the human disease, then this should lead to a hydrophobic bile salt profile and to "hyperbilirubinbilia" because of induced enterohepatic cycling of unconjugated bilirubin. Hyperbilirubinbilia may then lead to an increased bile salt-to-phospholipid ratio in bile and, following hydrolysis, precipitation of divalent metal salts of unconjugated bilirubin. We document in CF mice elevated fecal bile acid excretion and biliary secretion of more hydrophobic bile salts compared with control wild-type mice. Biliary secretion rates of bilirubin monoglucuronosides, bile salts, phospholipids, and cholesterol are increased significantly with an augmented bile salt-to-phospholipid ratio. Quantitative histopathology of CF livers displays mild early cholangiopathy in approximately 53% of mice and multifocal divalent metal salt deposition in cholangiocytes. We conclude that increased fecal bile acid loss leads to more hydrophobic bile salts in hepatic bile and to hyperbilirubinbilia, a major contributor in augmenting the bile salt-to-phospholipid ratio and endogenous beta-glucuronidase hydrolysis of bilirubin glucuronosides. The confluence of these perturbations damages intrahepatic bile ducts and facilitates entrance of unconjugated bilirubin into cholangiocytes. This study of the earliest stages of CF liver disease provides a framework for investigating the molecular pathophysiology of more advanced disease in murine models and in humans with CF.

Elevated C4 concentrations indicating BAM are common in children with CD. They are associated with ileal resection and non-bloody diarrhea in the absence of active disease or elevated inflammatory markers. The C4-test identifies a subgroup of CD patients with persistent diarrhea in spite of clinical remission which may benefit from bile acid binding therapy.

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CSA monotherapy is effective in SRNS. Discontinuation of CSA is possible in many patients with complete remission.

ObjectiveFaecal calprotectin is used as a sensitive marker for gastrointestinal mucosal inflammation. We compared the performance of three different assays in a large cohort of symptomatic paediatric patients.DesignRetrospective monocentric study.SettingInpatients and outpatients of a tertiary referral centre for paediatric gastroenterology.Participants304 symptomatic patients (163 males, aged 2–20 years) with active inflammatory bowel disease (IBD/A, n=130), IBD in clinical remission (IBD/R, n=62), other intestinal diseases (n=45) and controls without identified intestinal disease (n=67).InterventionsCalprotectin was measured in homogenised faecal samples with three tests (A: EliA Calprotectin, Phadia AB, Sweden; B: PhiCal, Calpro AS, Norway; C: EK-Cal, Bühlmann Laboratories, Switzerland).OutcomesConcordance between tests was calculated using Kendall's τ coefficient.ResultsIBD/A and controls were correctly classified as 97.7%/82.1% (A), 97.7%/85.1% (B) and 98.4%/62.7% (C; not significant). Test C tended to have higher calprotectin values with a lower specificity compared to tests A and B. The concordance between two tests was 0.835 for tests A and B, 0.782 for tests A and C and 0.765 for tests B and C.ConclusionsAll three tests are very sensitive for detecting mucosal inflammation, but major differences exist between specificity and absolute values. It is highly advisable to use the test of the same manufacturer for follow-up and to monitor for disease activity.