Serum Citrulline as a Biomarker of Gastrointestinal Function During Hematopoietic Cell Transplantation in Children

Objectives:We sought to determine whether serum citrulline (CIT), an amino acid produced by small bowel enterocytes, was associated with clinical and biochemical markers of gastrointestinal function in children undergoing hematopoietic cell transplantation (HCT).Methods:We conducted a multicenter, prospective cohort study of 26 children to define time-related changes in serum CIT during the course of HCT. Markers of gastrointestinal function including oral energy intake, emesis, stool volume, presence of graft-versus-host disease (GVHD), oral mucositis severity, and cytokine and neurohormone levels were measured. Weekly serum CIT concentrations were obtained from 10 days prior until 30 days after HCT.Results:Mean baseline CIT concentration was 22.7mol/L (95% confidence interval [CI] 17.7-27.6) on day -10, which decreased to a nadir of 7.5mol/L (95% CI 3.1-18.0, P=0.017) on day 8 following HCT before returning to baseline by day 30. After adjustment for IL-6 level (1.0% lower CIT per 10% increase in interleukin-6, P=0.004), presence of acute GVHD (27% lower CIT, P=0.025), and oral energy intake (2.1% lower CIT per 10% decrease in energy intake, P=0.018), the nadir shifted to day 10, when mean CIT concentration was lower in patients with severe oral mucositis (6.7mol/L, 95% CI 3.4-13.1) than in those without severe mucositis (11.9mol/L, 95% CI 5.8-24.4, P=0.003). Change in CIT was not correlated with stool volume, C-reactive protein, tumor necrosis factor-, leptin, or ghrelin.Conclusions:In children undergoing HCT, serum CIT correlates with measures of gastrointestinal function (oral mucositis severity, dietary intake, acute GVHD) and may reflect mucosal injury to the gastrointestinal tract.