Citrulline: A Plasmatic Marker to Assess and Monitor Small Bowel Crohn's Disease Patients
Condition: Crohn's Disease; Short Bowel Syndrome; Malabsorption Syndromes; Celiac Disease
MeSH terms: Crohn Disease; Celiac Disease; Short Bowel Syndrome; Malabsorption Syndromes; Syndrome
Study type: Observational

Summary: 
      Citrulline is an amino acid produced in the intestine and in the liver, but the liver does
      not contribute significantly to circulating citrulline concentrations. The intestine is thus
      the only organ that normally releases significant amounts of citrulline into the blood. The
      investigators have designed a study looking at the value of measuring plasma citrulline
      concentration in patients with Crohn's disease and short bowel or normal intestinal length.
      Measuring the plasma citrulline concentration in short bowel patients may help to distinguish
      between patients who need permanent parenteral feeding from patients with just transient
      intestinal dysfunction. It may also help the investigators in understanding the small bowel
      intestinal length remaining and the absorptive integrity. In patients with normal intestinal
      length and Crohn's disease, it may be a reliable marker of small bowel damage and could be
      applied to establish therapeutic improvements. It has been demonstrated to strongly correlate
      (inversely) with severity on intestinal biopsies.

      The investigators hypothesise that the plasma citrulline concentration is a marker for small
      bowel absorptive integrity and an appropriate surrogate for functional length of the small
      intestine.

      Controlled data do not yet exist to establish the place of plasma citrulline in the
      assessment of small bowel function in man.
    

Detailed description: 
      Preliminary studies reported that plasma citrulline concentrations may be a reliable
      biochemical marker for intestinal dysfunction and absorptive enterocyte mass. The
      relationship between citrulline concentration and intestinal function has been supported in
      other studies including those examining rejection in small bowel allografts. Concentrations
      of citrulline are dramatically reduced in cases of mucosal damage (e.g. moderate graft
      rejection or viral enteritis) and strongly correlate (inversely) with severity on biopsy.
      Plasma citrulline concentration is lower also in patients with villous atrophy (24±13 μmol/L)
      than in healthy subjects (40±10 μmol/L) and patients with anorexia nervosa (39±9).

      A citrulline threshold of 20 µmol/L apparently permitted the classification of short bowel
      syndrome patients into either transient or permanent intestinal failure categories, with 92%
      sensitivity, 90% specificity, and 95% positive and 86% negative predictive values,
      respectively. Experimental studies have been carried out also in assessing the value of
      citrulline as a marker for severity of small bowel epithelial damage from radiation. The
      plasma citrulline was shown to be a simple, non-invasive and sensitive assay to monitor and
      quantify radiation-induced small bowel damage in mice and humans. Otherwise, the literature
      on citrulline as a potential marker of intestinal and nutritional integrity is young and data
      for specific conditions come only from single centres; there are limited data on normal
      ranges. More crucially, however, there has been no attempt to clarify the effect of
      inflammation on citrulline homeostasis. To date there is no information in respect of
      patients with intestinal failure in whom there has been no resection.

      We hypothesise that plasma citrulline concentration reflects small bowel absorptive capacity
      and correlates to the functional intestinal length independently from inflammation.

      Comparisons: To exclude the possibility that citrulline merely reflects inflammation, control
      groups (six subjects each) with short bowel syndrome without inflammation (mesenteric
      infarct) (negative control); and those with inflammation but no anatomical loss (active
      coeliac disease) (positive controls); will be studied as well as healthy volunteers.

      The study is designed to utilise patients from the positive and negative control groups to
      permit a correlation of plasma citrulline with intestinal length and with a "gold standard"
      assessment of intestinal function as judged from the patients need for nutritional
      intervention (from normal diet to dependence on home parenteral nutrition).

      Plasma citrulline will be determined by Reverse-phase High Performance Liquid Chromatography
      (RF-HPLC) after an overnight fast. Albumin and Routine biochemical assessment will also be
      performed. Gastrointestinal permeability will be determined from the double sugar test using
      rhamnose and lactulose, and functional absorptive capacity will be estimated by D-Xylose
      absorption rate.

      Analysis will allow for paired comparison between patients and between groups. Differences in
      the clinical performance of the various parameters will be determined. The study has adequate
      statistical power.
    

Observational model: Case-Control
Time perspective: Prospective
Keywords: Citrulline; Parenteral Nutrition; functioning intestinal mass; small bowel permeability and absorption; Granulomatous Enteritis