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

Gosselin, Kerri B.*; Feldman, Henry A.*; Sonis, Andrew L.*; Bechard, Lori J.*; Kellogg, Mark D.*; Gura, Kathleen*; Venick, Robert; Gordon, Catherine M.; Guinan, Eva C.§; Duggan, Christopher*

Journal of Pediatric Gastroenterology and Nutrition: June 2014 - Volume 58 - Issue 6 - p 709–714
doi: 10.1097/MPG.0000000000000335
Original Articles: Hepatology and Nutrition

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 22.7 μmol/L (95% confidence interval [CI] 17.7–27.6) on day −10, which decreased to a nadir of 7.5 μmol/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 (6.7 μmol/L, 95% CI 3.4–13.1) than in those without severe mucositis (11.9 μmol/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-α, 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.

*Boston Children's Hospital, Boston, MA

UCLA Mattel Children's Hospital, Los Angeles, CA

Brown University, Providence, RI

§Dana-Farber Cancer Institute, Boston, MA.

Address correspondence and reprint requests to Christopher Duggan, MD, MPH, Center for Nutrition, Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115 (e-mail:

Received 15 November, 2013

Accepted 31 January, 2014

The present study was supported by the Massachusetts Vitamin Litigation Grant, the Harvard Clinical and Translational Science Center UL1 RR-025758, and National Institutes of Health grants K24 HD 058795 and T32 DK 7477-30. C.D. was supported in part by Bill and Melinda Gates Foundation Award OPP1066203.

The authors report no conflicts of interest.

© 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,