Imad Elkhatib1, Alan L Buchman. 1. Division of Gastroenterology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Abstract
BACKGROUND: Citrulline is a nitrogen end product produced from the intermediary metabolism of glutamine through the enzymatically mediated urea cycle, almost exclusively in the enterocytes of small intestinal epithelium, with some synthesis in colonocytes. Intestinal dysfunction resulting from intestinal diseases or injuries affects intermediary metabolism, which includes citrulline synthesis. We sought to determine whether plasma citrulline was a biomarker for disease activity in patients with Crohn's disease with the hypothesis that citrulline concentration would be reduced during active disease. METHODS: A total of 81 outpatients aged 18 to 65 years (mean, 40.6±15.4 y) with a known history of Crohn's disease were studied prospectively. Patients with prior small intestinal resection, or renal or hepatic insufficiency were excluded. Crohn's disease activity was measured by Harvey-Bradshaw Index (HBI) and was correlated to the plasma citrulline concentration measured simultaneously (ion chromatography). Spearman correlation coefficients were used to assess for an association between the 2 variables. Subgroup analyses of patients with isolated small intestinal disease and endoscopically or radiologic verified disease activity were also performed. RESULTS: Twenty-two patients had isolated colonic disease and 59 had small intestinal involvement. Twenty-six of these patients had concurrent endoscopy and/or computed tomography or magnetic resonance imaging. On the basis of HBI scores, 32 patients had active disease (HBI ≥5) and 49 patients had inactive disease. The mean HBI scores were 4.8±5.5. The mean plasma citrulline concentration was normal, although was below normal in some patients. However, it failed to distinguish between active and inactive patients based on the HBI (active 27.8±8.8 μmol/L, inactive 27.8±11.1 μmol/L, P=0.991). There was no significant linear association between the ranks of citrulline and ranks of HBI (rs=0.012, P=0.915). Of the 59 patients with isolated small intestinal disease, there was no association between plasma citrulline concentration and the HBI (Spearman correlation coefficient, 0.073; P=0.583). There was no difference in plasma citrulline concentrations among those with confirmed inflammation by imaging or endoscopy (confirmed, 26.2±11.8; negative, 28.0±10.0; independent t test P=0.583). CONCLUSIONS: Plasma citrulline concentration was not a marker of disease activity in patients with Crohn's disease. However, all patients studied were outpatients and it is possible that plasma citrulline concentration may be depressed only in patients with more severe disease or extensive small bowel involvement. In addition, plasma citrulline may be increased in the postabsorptional state, and for the most part, our patients were nonfasting. More studies are needed to further elucidate the role of citrulline as a marker of disease activity in patients with Crohn's disease. The possibility also exists that citrulline may be a better marker in patients with previous resection, and this group will require specific evaluation.
BACKGROUND:Citrulline is a nitrogen end product produced from the intermediary metabolism of glutamine through the enzymatically mediated urea cycle, almost exclusively in the enterocytes of small intestinal epithelium, with some synthesis in colonocytes. Intestinal dysfunction resulting from intestinal diseases or injuries affects intermediary metabolism, which includes citrulline synthesis. We sought to determine whether plasma citrulline was a biomarker for disease activity in patients with Crohn's disease with the hypothesis that citrulline concentration would be reduced during active disease. METHODS: A total of 81 outpatients aged 18 to 65 years (mean, 40.6±15.4 y) with a known history of Crohn's disease were studied prospectively. Patients with prior small intestinal resection, or renal or hepatic insufficiency were excluded. Crohn's disease activity was measured by Harvey-Bradshaw Index (HBI) and was correlated to the plasma citrulline concentration measured simultaneously (ion chromatography). Spearman correlation coefficients were used to assess for an association between the 2 variables. Subgroup analyses of patients with isolated small intestinal disease and endoscopically or radiologic verified disease activity were also performed. RESULTS: Twenty-two patients had isolated colonic disease and 59 had small intestinal involvement. Twenty-six of these patients had concurrent endoscopy and/or computed tomography or magnetic resonance imaging. On the basis of HBI scores, 32 patients had active disease (HBI ≥5) and 49 patients had inactive disease. The mean HBI scores were 4.8±5.5. The mean plasma citrulline concentration was normal, although was below normal in some patients. However, it failed to distinguish between active and inactive patients based on the HBI (active 27.8±8.8 μmol/L, inactive 27.8±11.1 μmol/L, P=0.991). There was no significant linear association between the ranks of citrulline and ranks of HBI (rs=0.012, P=0.915). Of the 59 patients with isolated small intestinal disease, there was no association between plasma citrulline concentration and the HBI (Spearman correlation coefficient, 0.073; P=0.583). There was no difference in plasma citrulline concentrations among those with confirmed inflammation by imaging or endoscopy (confirmed, 26.2±11.8; negative, 28.0±10.0; independent t test P=0.583). CONCLUSIONS: Plasma citrulline concentration was not a marker of disease activity in patients with Crohn's disease. However, all patients studied were outpatients and it is possible that plasma citrulline concentration may be depressed only in patients with more severe disease or extensive small bowel involvement. In addition, plasma citrulline may be increased in the postabsorptional state, and for the most part, our patients were nonfasting. More studies are needed to further elucidate the role of citrulline as a marker of disease activity in patients with Crohn's disease. The possibility also exists that citrulline may be a better marker in patients with previous resection, and this group will require specific evaluation.