Another Measurement of the Elusive Entity Called “Intestinal Function”

Plasma Citrulline: A Marker of Enterocyte Mass in Villous Atrophy-Associated Small Bowel Disease. P Crenin, K Vahedi, A Lavergne-Slove, L Cynober, C Matuchansky, B Messing. Gastroenterology, 2003;124:1210–9 Summary: The authors of the study referenced above found that in adult humans, plasma citrulline concentration correlated well with the extent of villous atrophy as assessed by small bowel (and in some cases, ileal) biopsies. The comparison groups consisted of healthy controls, patients with anorexia nervosa, and patients with other enteropathies without villous atrophy. Using receiver-operator characteristic curves, the authors found that plasma citrulline could distinguish patients with total villous atrophy from those without total villous atrophy and that discrimination was best at a cut-off citrulline concentration of 20 micromol/L (sensitivity 0.95, specificity 0.90, positive predictive value 0.88, negative predictive value 0.96, and accuracy 0.92). Furthermore, in patients with celiac disease, citrulline levels normalized during treatment with gluten-free diet. Comment: Enterocytes convert glutamine and other amino acids into citrulline. The kidney then converts citrulline to arginine. In the rat, the responsible enzyme for this conversion, pyrroline-5-caroboxylate synthase, is expressed in the duodenum and jejunum and, to a lesser extent, in the ileum. Therefore, plasma citrulline should be a function of enterocyte mass. As a result of this study, do we now have a justification to use this measurement to identify patients with villous atrophy? I suspect that good clinical judgment and a stool examination for fat are still equally useful as non-specific indicators of mucosal malfunction. Like other similar non-specific markers, plasma citrulline does not reveal the cause of, nor suggest appropriate treatment for, small intestinal injury. A great number of human diseases produce small intestinal mucosal injury. These include inflammatory disorders such as Crohn disease, celiac disease, allergy, graft versus host disease, ischemic bowel disease, short bowel syndrome, toxins or drugs such as chemotherapy or radiation, and many more. Although new technologies such as video capsule and push enteroscopy allow visualization of the small bowel, small bowel functional capacity remains a vague general concept of uncertain clinical significance that is difficult to quantitate. Current tools include measurements of sugar digestion and absorption by breath tests and permeability assays, measurements of fecal fat content, and direct and indirect measurements of protein loss in stool. The potential value of plasma citrulline as I see it, is not to identify individuals with this poorly defined “intestinal insufficiency” but rather to aid in clinical management of selected small bowed disorders and as a research tool. If changes in this biochemical marker of small intestinal injury actually precede clinical features of disease, it may have even more uses. At the moment, however, the authors have studied only adults with established intestinal injury. Such a test might for example help guide the feeding of premature infants while providing an early signal of impending necrotizing enterocolitis. Citrulline levels might alert clinicians to modify therapy to avoid intestinal injury caused by cancer therapy (both radiation and chemotherapy). It might be possible to monitor recovery from inflammatory disorders such as Crohn disease, food allergy or celiac disease, and monitor compliance with a gluten-free diet. Repeated measurements could perhaps assist in defining the extent of deficiency in short bowel syndrome or monitor the intestinal status after small bowel transplantation. These ideas sound hopeful, but the present study does not allow such clinical applications yet. Currently, plasma citrulline is simply an interesting observation with the potential for becoming a clinical tool. It will remain on the sidelines until it can prove itself with reproducible age-related norms and predictable correlations with degree of intestinal injury. Stay tuned as citrulline undergoes further evaluation in the clinical proving ground. Edward J. Hoffenberg MD Section of Gastroenterology, Hepatology and Nutrition University of Colorado Health Sciences Center and the Children's Hospital Denver, Colorado

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