Advertisement

World Journal of Pediatrics

, Volume 14, Issue 5, pp 448–453 | Cite as

Elevated serum neopterin levels in children with functional constipation: association with systemic proinflammatory cytokines

  • Ceren Cıralı
  • Emel Ulusoy
  • Tuncay Kume
  • Nur Arslan
Original Article

Abstract

Background

Functional constipation is a clinical problem with an incompletely understood etiology. Functional bowel diseases have been shown to be related to inflammation in many studies in adults. In this study, we aimed to evaluate leukocytes, C-reactive protein, proinflammatory and anti-inflammatory cytokines, and neopterin levels in children with functional constipation.

Methods

Seventy-six children with constipation and 71 healthy controls (mean age 7.12 ± 3.46 years and 7.32 ± 4.33 years, respectively, P = 0.991) were included in the study. Leukocytes, C-reactive protein, interleukin (IL)-1β, IL-6, IL-10, IL-12, tumor necrosis factor-alpha (TNF-α) and neopterin levels were assessed in patients and healthy controls. Parameters were measured in the serum using enzyme-linked immunosorbent assay methods.

Results

Mean IL-6 (20.31 ± 12.05 vs. 16.2 ± 10.25 pg/mL, respectively, P = 0.003), IL-12 (181.42 ± 133.45 vs. 135.6 ± 83.67 pg/mL, respectively, P = 0.018) and neopterin levels (2.08 ± 1.12 vs. 1.52 ± 1.02 pg/mL, respectively, P = 0.001) were significantly higher in constipated children than healthy controls. Leukocyte and thrombocyte counts, C-reactive protein, and IL-1β, IL-10 and TNF-α levels did not show any difference between the two groups.

Conclusions

In this study, IL-6, IL-12 and neopterin levels of constipated patients were found to be higher than those of controls. These results indicate the presence of subclinical inflammation in children with functional constipation.

Keywords

Children Constipation Cytokine Inflammation Neopterin 

Notes

Author contributions

CC contributed to concept and design, and acquisition of data. EU contributed to acquisition of data and drafting the article. TK contributed to acquisition of data, analysis and interpretation of data. NA contributed to concept and design, acquisition of data, analysis and interpretation of data, revising it critically for important intellectual content and final approval of the version to be published.

Funding

This study was funded by a grant (grant number: 2013.KB.SAG.001) from Dokuz Eylul University Funding Committee for Scientific Research, Izmir, Turkey.

Compliance with ethical standards

Ethical approval

All procedures performed in study involving the patients were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was started after the approval of the Ethics Committee of Dokuz Eylul University Faculty of Medicine (number of ethical approval: 2012/30-01). Written informed consent was obtained from parents of all patients included in the study.

Conflict of interest

All authors declared that they have no conflict of interest.

References

  1. 1.
    Hua MC, Lai MW, Kuo ML, Yao TC, Huang JL, Chen SM. Decreased interleukin-10 secretion by peripheral blood mononuclear cells in children with irritable bowel syndrome. J Pediatr Gastroenterol Nutr. 2011;52:376–81.CrossRefPubMedCentralGoogle Scholar
  2. 2.
    Sheikh Sajjadieh MR, Kuznetsova L, Bojenko V. Cytokine status in Ukrainian children with irritable bowel syndrome residing in a radioactive contaminated area. Iran J Immunol. 2012;9:248–53.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Vázquez-Frias R, Gutiérrez-Reyes G, Urbán-Reyes M, Velázquez-Guadarrama N, Fortoul-van der Goes TI, Reyes-López A, et al. Proinflammatory and anti-inflammatory cytokine profile in pediatric patients with irritable bowel syndrome. Rev Gastroenterol Mex. 2015;80:6–12 (in English, Spanish).PubMedPubMedCentralGoogle Scholar
  4. 4.
    Caini S, Bagnoli S, Palli D, Saieva C, Ceroti M, Bendinelli B, et al. Total and cancer mortality in a cohort of ulcerative colitis and Crohn’s disease patients: the Florence inflammatory bowel disease study, 1978-2010. Dig Liver Dis. 2016;48:1162–7.CrossRefPubMedCentralGoogle Scholar
  5. 5.
    van den Heuvel TR, Wintjens DS, Jeuring SF, Wassink MH, Romberg-Camps MJ, Oostenbrug LE, et al. Inflammatory bowel disease, cancer and medication: cancer risk in the Dutch population-based IBDSL cohort. Int J Cancer. 2016;139:1270–80.CrossRefPubMedCentralGoogle Scholar
  6. 6.
    Sinha R, Doval DC, Hussain S, Kumar K, Singh S, Basir SF, et al. Lifestyle and sporadic colorectal cancer in India. Asian Pac J Cancer Prev. 2015;16:7683–8.CrossRefPubMedCentralGoogle Scholar
  7. 7.
    Hu LY, Ku FC, Lu T, Shen CC, Hu YW, Yeh CM, et al. Risk of cancer in patients with irritable bowel syndrome: a nationwide population-based study. Ann Epidemiol. 2015;25:924–8.CrossRefPubMedCentralGoogle Scholar
  8. 8.
    Guérin A, Mody R, Fok B, Lasch KL, Zhou Z, Wu EQ, et al. Risk of developing colorectal cancer and benign colorectal neoplasm in patients with chronic constipation. Aliment Pharmacol Ther. 2014;40:83–92.CrossRefPubMedCentralGoogle Scholar
  9. 9.
    Berdowska A, Zwirska-Korczala K. Neopterin measurement in clinical diagnosis. J Clin Pharm Ther. 2001;26:319–29.CrossRefPubMedCentralGoogle Scholar
  10. 10.
    Skogmar S, Schön T, Balcha TT, Sturegård E, Jansson M, Björkman P. Plasma levels of neopterin and C-reactive protein (CRP) in tuberculosis (TB) with and without HIV coinfection in relation to CD4 cell count. PLoS One. 2015;10:e0144292.CrossRefPubMedCentralGoogle Scholar
  11. 11.
    Oweira H, Lahdou I, Daniel V, Hofer S, Mieth M, Schmidt J, et al. Early post-transplant neopterin associated with one year survival and bacteremia in liver transplant recipients. Hum Immunol. 2016;77:115–20.CrossRefPubMedCentralGoogle Scholar
  12. 12.
    Arslan N, Tokgoz Y, Kume T, Bulbul M, Sayın O, Harmancı D, et al. Evaluation of serum neopterin levels and its relationship with adipokines in pediatric obesity-related nonalcoholic fatty liver disease and healthy adolescents. J Pediatr Endocrinol Metab. 2013;26:1141–7.CrossRefPubMedCentralGoogle Scholar
  13. 13.
    van Dijk RA, Rijs K, Wezel A, Hamming JF, Kolodgie FD, Virmani R, et al. Systematic evaluation of the cellular innate immune response during the process of human atherosclerosis. J Am Heart Assoc. 2016;5:e002860.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Palabiyik SS, Keles S, Girgin G, Arpali-Tanas E, Topdagi E, Baydar T. Neopterin release and tryptophan degradation in patients with uveitis. Curr Eye Res. 2016;41:1513–7.CrossRefPubMedCentralGoogle Scholar
  15. 15.
    Volgger BM, Windbichler GH, Zeimet AG, Graf AH, Bogner G, Angleitner-Boubenizek L, et al. Long-term significance of urinary neopterin in ovarian cancer: a study by the Austrian Association for Gynecologic Oncology (AGO). Ann Oncol. 2016;27:1740–6.CrossRefPubMedCentralGoogle Scholar
  16. 16.
    Beksac K, Sonmez C, Cetin B, Kısmalı G, Sel T, Tuncer Y, et al. Evaluation of proinflammatory cytokine and neopterin levels in women with papillary thyroid carcinoma. Int J Biol Markers. 2016;31:e446–50. CrossRefPubMedCentralGoogle Scholar
  17. 17.
    Zezulová M, Bartoušková M, Hlídková E, Juráňová J, Červinková B, Kasalová E, et al. Prognostic significance of serum and urinary neopterin concentrations in patients with rectal carcinoma treated with chemoradiation. Anticancer Res. 2016;36:287–92.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Guerrant RL, Leite AM, Pinkerton R, Medeiros PH, Cavalcante PA, DeBoer M, et al. Biomarkers of environmental enteropathy, inflammation, stunting, and impaired growth in children in Northeast Brazil. PLoS One. 2016;11:e0158772.CrossRefPubMedCentralGoogle Scholar
  19. 19.
    Campbell DI, McPhail G, Lunn PG, Elia M, Jeffries DJ. Intestinal inflammation measured by fecal neopterin in Gambian children with enteropathy: association with growth failure, Giardia lamblia, and intestinal permeability. J Pediatr Gastroenterol Nutr. 2004;39:153–7.CrossRefPubMedCentralGoogle Scholar
  20. 20.
    Coşkun K, Menteş O, Atak A, Aral A, Eryılmaz M, Onguru O, et al. Is neopterin a diagnostic marker of acute appendicitis? Ulus Travma Acil Cerrahi Derg. 2012;18:1–4.CrossRefPubMedCentralGoogle Scholar
  21. 21.
    Nancey S, Boschetti G, Moussata D, Cotte E, Peyras J, Cuerq C, et al. Neopterin is a novel reliable fecal marker as accurate as calprotectin for predicting endoscopic disease activity in patients with inflammatory bowel diseases. Inflamm Bowel Dis. 2013;19:1043–52.CrossRefPubMedCentralGoogle Scholar
  22. 22.
    Frin AC, Filippi J, Boschetti G, Flourie B, Drai J, Ferrari P, et al. Accuracies of fecal calprotectin, lactoferrin, M2-pyruvate kinase, neopterin and zonulin to predict the response to infliximab in ulcerative colitis. Dig Liver Dis. 2017;49:11–6. CrossRefPubMedCentralGoogle Scholar
  23. 23.
    Clarke G, Fitzgerald P, Cryan JF, Cassidy EM, Quigley EM, Dinan TG. Tryptophan degradation in irritable bowel syndrome: evidence of indoleamine 2,3-dioxygenase activation in a male cohort. BMC Gastroenterol. 2009;9:6.CrossRefPubMedCentralGoogle Scholar
  24. 24.
    Hyman PE, Milla PJ, Benninga MA, Davidson GP, Fleisher DF, Taminiau J. Childhood functional gastrointestinal disorders: neonate/toddler. Gastroenterology. 2006;130:1519–26.CrossRefPubMedCentralGoogle Scholar
  25. 25.
    Rasquin A, Di Lorenzo C, Forbes D, Guiraldes E, Hyams JS, Staiano A, et al. Childhood functional gastrointestinal disorders: child/adolescent. Gastroenterology. 2006;130:1527–37.CrossRefGoogle Scholar
  26. 26.
    Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J Gastroenterol. 1997;32:920–4.CrossRefPubMedCentralGoogle Scholar
  27. 27.
    Bashashati M, Rezaei N, Shafieyoun A, McKernan DP, Chang L, Öhman L, et al. Cytokine imbalance in irritable bowel syndrome: a systematic review and meta-analysis. Neurogastroenterol Motil. 2014;26:1036–48.CrossRefPubMedCentralGoogle Scholar
  28. 28.
    Bashashati M, Rezaei N, Andrews CN, Chen CQ, Daryani NE, Sharkey KA, et al. Cytokines and irritable bowel syndrome: where do we stand? Cytokine. 2012;57:201–9.CrossRefPubMedCentralGoogle Scholar
  29. 29.
    Ortiz-Lucas M, Saz-Peiró P, Sebastián-Domingo JJ. Irritable bowel syndrome immune hypothesis. Part two: the role of cytokines. Rev Esp Enferm Dig. 2010;102:711–7.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Seyedmirzaee S, Hayatbakhsh MM, Ahmadi B, Baniasadi N, Bagheri Rafsanjani AM, Nikpoor AR, et al. Serum immune biomarkers in irritable bowel syndrome. Clin Res Hepatol Gastroenterol. 2016;40:631–7.CrossRefPubMedCentralGoogle Scholar
  31. 31.
    Hod K, Ringel-Kulka T, Martin CF, Maharshak N, Ringel Y. High-sensitive C-reactive protein as a marker for inflammation in irritable bowel syndrome. J Clin Gastroenterol. 2016;50:227–32.CrossRefPubMedCentralGoogle Scholar
  32. 32.
    Murr C, Widner B, Wirleitner B, Fuchs D. Neopterin as a marker for immune system activation. Curr Drug Metab. 2002;3:175–87.CrossRefPubMedCentralGoogle Scholar
  33. 33.
    Niederwieser D, Fuchs D, Hausen A, Judmaier G, Reibnegger G, Wachter H, et al. Neopterin as a new biochemical marker in the clinical assessment of ulcerative colitis. Immunobiology. 1985;170:320–6.CrossRefPubMedCentralGoogle Scholar
  34. 34.
    El-Salhy M, Gundersen D, Hatlebakk JG, Hausken T. Low-grade inflammation in the rectum of patients with sporadic irritable bowel syndrome. Mol Med Rep. 2013;7:1081–5.CrossRefPubMedCentralGoogle Scholar
  35. 35.
    Hughes PA, Moretta M, Lim A, Grasby DJ, Bird D, Brierley SM, et al. Immune derived opioidergic inhibition of viscerosensory afferents is decreased in irritable Bowel Syndrome patients. Brain Behav Immun. 2014;42:191–203.CrossRefPubMedCentralGoogle Scholar
  36. 36.
    Darkoh C, Comer L, Zewdie G, Harold S, Snyder N, Dupont HL. Chemotactic chemokines are important in the pathogenesis of irritable bowel syndrome. PLoS One. 2014;9:e93144.CrossRefPubMedCentralGoogle Scholar
  37. 37.
    Pike BL, Paden KA, Alcala AN, Jaep KM, Gormley RP, Maue AC, et al. Immunological biomarkers in postinfectious irritable bowel syndrome. J Travel Med. 2015;22:242–50.CrossRefPubMedCentralGoogle Scholar
  38. 38.
    Sinagra E, Pompei G, Tomasello G, Cappello F, Morreale GC, Amvrosiadis G, et al. Inflammation in irritable bowel syndrome: Myth or new treatment target? World J Gastroenterol. 2016;22:2242–55.CrossRefPubMedCentralGoogle Scholar
  39. 39.
    Schmulson M, Bielsa MV, Carmona-Sánchez R, Hernández A, López-Colombo A, López Vidal Y, et al. Microbiota, gastrointestinal infections, low-grade inflammation, and antibiotic therapy in irritable bowel syndrome: an evidence-based review. Rev Gastroenterol Mex. 2014;79:96–134 (in English, Spanish).PubMedPubMedCentralGoogle Scholar
  40. 40.
    Zhu L, Liu W, Alkhouri R, Baker RD, Bard JE, Quigley EM, et al. Structural changes in the gut microbiome of constipated patients. Physiol Genomics. 2014;46:679–86.CrossRefPubMedCentralGoogle Scholar
  41. 41.
    de Meij TG, de Groot EF, Eck A, Budding AE, Kneepkens CM, Benninga MA, et al. Characterization of microbiota in children with chronic functional constipation. PLoS One. 2016;11:e0164731.CrossRefPubMedCentralGoogle Scholar
  42. 42.
    Piche T, Barbara G, Aubert P, Bruley des Varannes S, Dainese R, Nano JL, et al. Impaired intestinal barrier integrity in the colon of patients with irritable bowel syndrome: involvement of soluble mediators. Gut. 2009;58:196–201.CrossRefPubMedCentralGoogle Scholar
  43. 43.
    Cremon C, Carini G, Wang B, Vasina V, Cogliandro RF, De Giorgio R, et al. Intestinal serotonin release, sensory neuron activation, and abdominal pain in irritable bowel syndrome. Am J Gastroenterol. 2011;106:1290–8.CrossRefPubMedCentralGoogle Scholar
  44. 44.
    Borrelli O, Barbara G, Di Nardo G, Cremon C, Lucarelli S, Frediani T, et al. Neuroimmune interaction and anorectal motility in children with food allergy-related chronic constipation. Am J Gastroenterol. 2009;104:454–63.CrossRefPubMedCentralGoogle Scholar
  45. 45.
    Irastorza I, Ibañez B, Delgado-Sanzonetti L, Maruri N, Vitoria JC. Cow’s-milk-free diet as a therapeutic option in childhood chronic constipation. J Pediatr Gastroenterol Nutr. 2010;51:171–6.CrossRefPubMedCentralGoogle Scholar
  46. 46.
    El-Hodhod MA, Younis NT, Zaitoun YA, Daoud SD. Cow’s milk allergy related pediatric constipation: appropriate time of milk tolerance. Pediatr Allergy Immunol. 2010;21:e407–12.CrossRefPubMedCentralGoogle Scholar
  47. 47.
    Syrigou EI, Pitsios C, Panagiotou I, Chouliaras G, Kitsiou S, Kanariou M, et al. Food allergy-related paediatric constipation: the usefulness of atopy patch test. Eur J Pediatr. 2011;170:1173–8.CrossRefPubMedCentralGoogle Scholar

Copyright information

© Children's Hospital, Zhejiang University School of Medicine 2018

Authors and Affiliations

  • Ceren Cıralı
    • 1
  • Emel Ulusoy
    • 1
  • Tuncay Kume
    • 2
  • Nur Arslan
    • 3
  1. 1.Department of PediatricsDokuz Eylul UniversityIzmirTurkey
  2. 2.Department of Medical BiochemistryDokuz Eylul UniversityIzmirTurkey
  3. 3.Division of Pediatric Gastroenterology, Metabolism and Nutrition, Department of PediatricsDokuz Eylul University Faculty of MedicineIzmirTurkey

Personalised recommendations