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Pediatric Inflammatory Bowel Disease pp 225–232Cite as

Fecal Biomarkers in Inflammatory Bowel Disease

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Abstract

Numerous fecal biomarkers have been shown to correlate with disease activity in Crohn disease (CD) and ulcerative colitis (UC). Fecal calprotectin (FC) and lactoferrin are the two most frequently studied. FC in particular has been extensively studied and shown to have sufficient sensitivity and specificity for detecting mucosal inflammation to aid in initial diagnosis prior to ileocolonoscopy. Emerging research in CD and UC shows acceptable correlation of FC with endoscopic activity, prediction of inflammatory bowel disease (IBD) relapse, and therapy responsiveness. Given their relative ease of collection and lower cost, fecal biomarkers appear promising as a noninvasive test to improve disease monitoring in standard of care.

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References

  1. Colombel JF, Rutgeerts P, Reinisch W, Esser D, Wang Y, et al. Early mucosal healing with infliximab is associated with improved long-term clinical outcomes in ulcerative colitis. Gastroenterology. 2011;141:1194–201.

    Article  CAS  PubMed  Google Scholar 

  2. KF F, Jahnsen J, BA M, MH V, Group I. Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort. Gastroenterol. 2007;133:412–22.

    Article  Google Scholar 

  3. Meucci G, Fasoli R, Saibeni S, Valpiani D, Gullotta R, et al. Prognostic significance of endoscopic remission in patients with active ulcerative colitis treated with oral and topical mesalazine: a prospective, multicenter study. Inflamm Bowel Dis. 2012;18:1006–10.

    Article  PubMed  Google Scholar 

  4. Stange EF, Travis SP, Vermeire S, Beglinger C, Kupcinkas L, et al. European evidence based consensus on the diagnosis and management of Crohn’s disease: definitions and diagnosis. Gut. 2006;55(Suppl 1):i1–15.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Vogl T, Gharibyan AL, Morozova-Roche LA. Pro-inflammatory S100A8 and S100A9 proteins: self-assembly into multifunctional native and amyloid complexes. Int J Mol Sci. 2012;13:2893–917.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Abraham BP, Kane S. Fecal markers: calprotectin and lactoferrin. Gastroenterol Clin N Am. 2012;41:483–95.

    Article  Google Scholar 

  7. Schoepfer AM, Lewis JD. Serial fecal calprotectin measurements to detect endoscopic recurrence in postoperative Crohn’s disease: is colonoscopic surveillance no longer needed? Gastroenterology. 2015;148:889–92.

    Article  CAS  PubMed  Google Scholar 

  8. Sandborn WJ, Panes J, Zhang H, Yu D, Niezychowski W, Su C. Correlation between concentrations of fecal calprotectin and outcomes of patients with ulcerative colitis in a phase 2 trial. Gastroenterology. 2016;150:96–102.

    Article  CAS  PubMed  Google Scholar 

  9. Schoepfer AM, Beglinger C, Straumann A, Trummler M, Vavricka SR, et al. Fecal calprotectin correlates more closely with the simple endoscopic score for Crohn’s disease (SES-CD) than CRP, blood leukocytes, and the CDAI. Am J Gastroenterol. 2010;105:162–9.

    Article  CAS  PubMed  Google Scholar 

  10. Tibble J, Teahon K, Thjodleifsson B, Roseth A, Sigthorsson G, et al. A simple method for assessing intestinal inflammation in Crohn’s disease. Gut. 2000;47:506–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. van Rheenen PF, Van de Vijver E, Fidler V. Faecal calprotectin for screening of patients with suspected inflammatory bowel disease: diagnostic meta-analysis. BMJ. 2010;341:c3369.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Wright EK, Kamm MA, De Cruz P, Hamilton AL, Ritchie KJ, et al. Measurement of fecal calprotectin improves monitoring and detection of recurrence of Crohn’s disease after surgery. Gastroenterology. 2015;148:938–47.e1.

    Google Scholar 

  13. Yang Z, Clark N, Park KT. Effectiveness and cost-effectiveness of measuring fecal calprotectin in diagnosis of inflammatory bowel disease in adults and children. Clin Gastroenterol Hepatol. 2014;12:253–62.e2.

    Google Scholar 

  14. Henderson P, Anderson NH, Wilson DC. The diagnostic accuracy of fecal calprotectin during the investigation of suspected pediatric inflammatory bowel disease: a systematic review and meta-analysis. Am J Gastroenterol. 2014;109:637–45.

    Article  CAS  PubMed  Google Scholar 

  15. Tibble JA, Sigthorsson G, Foster R, Forgacs I, Bjarnason I. Use of surrogate markers of inflammation and Rome criteria to distinguish organic from nonorganic intestinal disease. Gastroenterology. 2002;123:450–60.

    Article  PubMed  Google Scholar 

  16. Van de Vijver E, Schreuder AB, Cnossen WR, Muller Kobold AC, van Rheenen PF, North Netherlands Pediatric IBDC. Safely ruling out inflammatory bowel disease in children and teenagers without referral for endoscopy. Arch Dis Child. 2012;97:1014–8.

    Article  PubMed  Google Scholar 

  17. Wright EK, Kamm MA, De Cruz P, Hamilton AL, Ritchie KJ, et al. Comparison of fecal inflammatory markers in Crohn’s disease. Inflamm Bowel Dis. 2016;22(5):1086–94.

    Article  PubMed  Google Scholar 

  18. Kopylov U, Rosenfeld G, Bressler B, Seidman E. Clinical utility of fecal biomarkers for the diagnosis and management of inflammatory bowel disease. Inflamm Bowel Dis. 2014;20:742–56.

    Article  PubMed  Google Scholar 

  19. RØseth AG, Fagerhol MK, Aadland E, Schjønsby H. Assessment of the neutrophil dominating protein calprotectin in feces: a Methodologic Study. Scand J Gastroenterol. 1992;27:793–8.

    Article  PubMed  Google Scholar 

  20. Klimczak K, Lykowska-Szuber L, Eder P, Krela-Kazmierczak I, Stawczyk-Eder K, et al. The diagnostic usefulness of fecal lactoferrin in the assessment of Crohn’s disease activity. Eur J Intern Med. 2015;26:623–7.

    Article  CAS  PubMed  Google Scholar 

  21. Roszak D, Galecka M, Cichy W, Szachta P. Determination of faecal inflammatory marker concentration as a noninvasive method of evaluation of pathological activity in children with inflammatory bowel diseases. Adv Med Sci. 2015;60:246–52.

    Article  PubMed  Google Scholar 

  22. Chung-Faye G, Hayee B, Maestranzi S, Donaldson N, Forgacs I, Sherwood R. Fecal M2-pyruvate kinase (M2-PK): a novel marker of intestinal inflammation. Inflamm Bowel Dis. 2007;13:1374–8.

    Article  PubMed  Google Scholar 

  23. Ghisoni K, Martins Rde P, Barbeito L, Latini A. Neopterin as a potential cytoprotective brain molecule. J Psychiatr Res. 2015;71:134–9.

    Article  PubMed  Google Scholar 

  24. Parker DC, Mielke MM, Yu Q, Rosenberg PB, Jain A, et al. Plasma neopterin level as a marker of peripheral immune activation in amnestic mild cognitive impairment and Alzheimer’s disease. Int J Geriatr Psychiatry. 2013;28:149–54.

    Article  PubMed  Google Scholar 

  25. Widner B, Leblhuber F, Fuchs D. Increased neopterin production and tryptophan degradation in advanced Parkinson’s disease. J Neural Transm (Vienna). 2002;109:181–9.

    Article  CAS  Google Scholar 

  26. Wirleitner B, Reider D, Ebner S, Bock G, Widner B, et al. Monocyte-derived dendritic cells release neopterin. J Leukoc Biol. 2002;72:1148–53.

    CAS  PubMed  Google Scholar 

  27. O’Sullivan S, Gilmer JF, Medina C. Matrix metalloproteinases in inflammatory bowel disease: an update. Mediat Inflamm. 2015;2015:964131.

    Google Scholar 

  28. Rodriguez D, Morrison CJ, Overall CM. Matrix metalloproteinases: what do they not do? New substrates and biological roles identified by murine models and proteomics. Biochim Biophys Acta. 2010;1803:39–54.

    Article  CAS  PubMed  Google Scholar 

  29. Sternlicht MD, Werb Z. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol. 2001;17:463–516.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Annahazi A, Molnar T, Farkas K, Rosztoczy A, Izbeki F, et al. Fecal MMP-9: a new noninvasive differential diagnostic and activity marker in ulcerative colitis. Inflamm Bowel Dis. 2013;19:316–20.

    Article  PubMed  Google Scholar 

  31. Matusiewicz M, Neubauer K, Mierzchala-Pasierb M, Gamian A, Krzystek-Korpacka M. Matrix metalloproteinase-9: its interplay with angiogenic factors in inflammatory bowel diseases. Dis Markers. 2014;2014:643645.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Klebanoff SJ. Myeloperoxidase: friend and foe. J Leukoc Biol. 2005;77:598–625.

    Article  CAS  PubMed  Google Scholar 

  33. Chua F, Laurent GJ. Neutrophil elastase: mediator of extracellular matrix destruction and accumulation. Proc Am Thorac Soc. 2006;3:424–7.

    Article  CAS  PubMed  Google Scholar 

  34. Doring G. The role of neutrophil elastase in chronic inflammation. Am J Respir Crit Care Med. 1994;150:S114–7.

    Article  CAS  PubMed  Google Scholar 

  35. Hara T, Ogawa F, Yanaba K, Iwata Y, Muroi E, et al. Elevated serum concentrations of polymorphonuclear neutrophilic leukocyte elastase in systemic sclerosis: association with pulmonary fibrosis. J Rheumatol. 2009;36:99–105.

    PubMed  Google Scholar 

  36. Janoff A. Elastase in tissue injury. Annu Rev Med. 1985;36:207–16.

    Article  CAS  PubMed  Google Scholar 

  37. Inokuchi T, Kato J, Hiraoka S, Takashima S, Nakarai A, et al. Fecal immunochemical test versus fecal calprotectin for prediction of mucosal healing in Crohn’s disease. Inflamm Bowel Dis. 2016;22(5):1078–85.

    Article  PubMed  Google Scholar 

  38. Saito YA, Schoenfeld P, Locke 3rd GR. The epidemiology of irritable bowel syndrome in North America: a systematic review. Am J Gastroenterol. 2002;97:1910–5.

    PubMed  Google Scholar 

  39. Harvey RF, Salih SY, Read AE. Organic and functional disorders in 2000 gastroenterology outpatients. Lancet. 1983;1:632–4.

    Article  CAS  PubMed  Google Scholar 

  40. Russo MW, Wei JT, Thiny MT, Gangarosa LM, Brown A, et al. Digestive and liver diseases statistics, 2004. Gastroenterology. 2004;126:1448–53.

    Article  PubMed  Google Scholar 

  41. Nyrop KA, Palsson OS, Levy RL, Von Korff M, Feld AD, et al. Costs of health care for irritable bowel syndrome, chronic constipation, functional diarrhoea and functional abdominal pain. Aliment Pharmacol Ther. 2007;26:237–48.

    Article  CAS  PubMed  Google Scholar 

  42. Halpin SJ, Ford AC. Prevalence of symptoms meeting criteria for irritable bowel syndrome in inflammatory bowel disease: systematic review and meta-analysis. Am J Gastroenterol. 2012;107:1474–82.

    Article  PubMed  Google Scholar 

  43. Lasson A, Kilander A, Stotzer PO. Diagnostic yield of colonoscopy based on symptoms. Scand J Gastroenterol. 2008;43:356–62.

    Article  PubMed  Google Scholar 

  44. von Roon AC, Karamountzos L, Purkayastha S, Reese GE, Darzi AW, et al. Diagnostic precision of fecal calprotectin for inflammatory bowel disease and colorectal malignancy. Am J Gastroenterol. 2007;102:803–13.

    Article  Google Scholar 

  45. Park KT, Colletti RB, Rubin DT, Sharma BK, Thompson A, Krueger A. Health insurance paid costs and drivers of costs for patients with Crohn’s disease in the United States. Am J Gastroenterol. 2016;111:15–23.

    Article  CAS  PubMed  Google Scholar 

  46. D’Haens G, Ferrante M, Vermeire S, Baert F, Noman M, et al. Fecal calprotectin is a surrogate marker for endoscopic lesions in inflammatory bowel disease. Inflamm Bowel Dis. 2012;18:2218–24.

    Article  PubMed  Google Scholar 

  47. Bitton A, Peppercorn MA, Antonioli DA, Niles JL, Shah S, et al. Clinical, biological, and histologic parameters as predictors of relapse in ulcerative colitis. Gastroenterology. 2001;120:13–20.

    Article  CAS  PubMed  Google Scholar 

  48. Schnitzler F, Fidder H, Ferrante M, Noman M, Arijs I, et al. Mucosal healing predicts long-term outcome of maintenance therapy with infliximab in Crohn’s disease. Inflamm Bowel Dis. 2009;15:1295–301.

    Article  PubMed  Google Scholar 

  49. Peyrin-Biroulet L, Bressenot A, Kampman W. Histologic remission: the ultimate therapeutic goal in ulcerative colitis? Clin Gastroenterol Hepatol. 2014;12:929–34.e2.

    Google Scholar 

  50. Gheorghe C, Cotruta B, Iacob R, Becheanu G, Dumbrava M, Gheorghe L. Endomicroscopy for assessing mucosal healing in patients with ulcerative colitis. J Gastrointestin Liver Dis. 2011;20:423–6.

    PubMed  Google Scholar 

  51. Boirivant M, Leoni M, Tariciotti D, Fais S, Squarcia O, Pallone F. The clinical significance of serum C reactive protein levels in Crohn’s disease. Results of a prospective longitudinal study. J Clin Gastroenterol. 1988;10:401–5.

    Article  CAS  PubMed  Google Scholar 

  52. Fagan EA, Dyck RF, Maton PN, Hodgson HJ, Chadwick VS, et al. Serum levels of C-reactive protein in Crohn’s disease and ulcerative colitis. Eur J Clin Investig. 1982;12:351–9.

    Article  CAS  Google Scholar 

  53. Linskens RK, van Bodegraven AA, Schoorl M, Tuynman HA, Bartels P. Predictive value of inflammatory and coagulation parameters in the course of severe ulcerative colitis. Dig Dis Sci. 2001;46:644–8.

    Article  CAS  PubMed  Google Scholar 

  54. Moran A, Jones A, Asquith P. Laboratory markers of colonoscopic activity in ulcerative colitis and Crohn’s colitis. Scand J Gastroenterol. 1995;30:356–60.

    Article  CAS  PubMed  Google Scholar 

  55. Niederau C, Backmerhoff F, Schumacher B, Niederau C. Inflammatory mediators and acute phase proteins in patients with Crohn’s disease and ulcerative colitis. Hepato-Gastroenterology. 1997;44:90–107.

    CAS  PubMed  Google Scholar 

  56. Nielsen OH, Vainer B, Madsen SM, Seidelin JB, Heegaard NH. Established and emerging biological activity markers of inflammatory bowel disease. Am J Gastroenterol. 2000;95:359–67.

    CAS  PubMed  Google Scholar 

  57. Vermeire S, Van Assche G, Rutgeerts P. C-reactive protein as a marker for inflammatory bowel disease. Inflamm Bowel Dis. 2004;10:661–5.

    Article  PubMed  Google Scholar 

  58. Schoepfer AM, Trummler M, Seeholzer P, Seibold-Schmid B, Seibold F. Discriminating IBD from IBS: comparison of the test performance of fecal markers, blood leukocytes, CRP, and IBD antibodies. Inflamm Bowel Dis. 2008;14:32–9.

    Article  PubMed  Google Scholar 

  59. Gomes P, du Boulay C, Smith CL, Holdstock G. Relationship between disease activity indices and colonoscopic findings in patients with colonic inflammatory bowel disease. Gut. 1986;27:92–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Schunk K, Kern A, Oberholzer K, Kalden P, Mayer I, et al. Hydro-MRI in Crohn’s disease: appraisal of disease activity. Investig Radiol. 2000;35:431–7.

    Article  CAS  Google Scholar 

  61. Costa F, Mumolo MG, Ceccarelli L, Bellini M, Romano MR, et al. Calprotectin is a stronger predictive marker of relapse in ulcerative colitis than in Crohn’s disease. Gut. 2005;54:364–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Solem CA, Loftus Jr EV, Tremaine WJ, Harmsen WS, Zinsmeister AR, Sandborn WJ. Correlation of C-reactive protein with clinical, endoscopic, histologic, and radiographic activity in inflammatory bowel disease. Inflamm Bowel Dis. 2005;11:707–12.

    Article  PubMed  Google Scholar 

  63. Lewis JD. The utility of biomarkers in the diagnosis and therapy of inflammatory bowel disease. Gastroenterology. 2011;140:1817–26.e2.

    Google Scholar 

  64. Lobaton T, Rodriguez-Moranta F, Lopez A, Sanchez E, Rodriguez-Alonso L, Guardiola J. A new rapid quantitative test for fecal calprotectin predicts endoscopic activity in ulcerative colitis. Inflamm Bowel Dis. 2013;19:1034–42.

    Article  PubMed  Google Scholar 

  65. Zittan E, Kelly OB, Kirsch R, Milgrom R, Burns J, et al. Low fecal calprotectin correlates with histological remission and mucosal healing in ulcerative colitis and colonic Crohn’s disease. Inflamm Bowel Dis. 2016;22(3):623–30.

    Article  PubMed  Google Scholar 

  66. Langhorst J, Boone J, Lauche R, Rueffer A, Dobos G. Fecal lactoferrin, calprotectin, PMN-elastase, CRP and white blood cell count as an indicator for mucosal healing and clinical course of disease in patients with mild to moderate ulcerative colitis: post HOC analysis of a prospective clinical trial. J Crohns Colitis. 2016;10(7):786–94.

    Article  PubMed  Google Scholar 

  67. Langholz E, Munkholm P, Davidsen M, Binder V. Course of ulcerative colitis: analysis of changes in disease activity over years. Gastroenterology. 1994;107:3–11.

    Article  CAS  PubMed  Google Scholar 

  68. Riley SA, Mani V, Goodman MJ, Dutt S, Herd ME. Microscopic activity in ulcerative colitis: what does it mean? Gut. 1991;32:174–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Limburg PJ, Ahlquist DA, Sandborn WJ, Mahoney DW, Devens ME, et al. Fecal calprotectin levels predict colorectal inflammation among patients with chronic diarrhea referred for colonoscopy. Am J Gastroenterol. 2000;95:2831–7.

    Article  CAS  PubMed  Google Scholar 

  70. Roseth AG, Aadland E, Jahnsen J, Raknerud N. Assessment of disease activity in ulcerative colitis by faecal calprotectin, a novel granulocyte marker protein. Digestion. 1997;58:176–80.

    Article  CAS  PubMed  Google Scholar 

  71. Roseth AG, Schmidt PN, Fagerhol MK. Correlation between faecal excretion of indium-111-labelled granulocytes and calprotectin, a granulocyte marker protein, in patients with inflammatory bowel disease. Scand J Gastroenterol. 1999;34:50–4.

    Article  CAS  PubMed  Google Scholar 

  72. Tibble JA, Sigthorsson G, Bridger S, Fagerhol MK, Bjarnason I. Surrogate markers of intestinal inflammation are predictive of relapse in patients with inflammatory bowel disease. Gastroenterology. 2000;119:15–22.

    Article  CAS  PubMed  Google Scholar 

  73. D’Inca R, Dal Pont E, Di Leo V, Benazzato L, Martinato M, et al. Can calprotectin predict relapse risk in inflammatory bowel disease? Am J Gastroenterol. 2008;103:2007–14.

    Article  PubMed  Google Scholar 

  74. Gisbert JP, Bermejo F, Perez-Calle JL, Taxonera C, Vera I, et al. Fecal calprotectin and lactoferrin for the prediction of inflammatory bowel disease relapse. Inflamm Bowel Dis. 2009;15:1190–8.

    Article  PubMed  Google Scholar 

  75. Garcia-Sanchez V, Iglesias-Flores E, Gonzalez R, Gisbert JP, Gallardo-Valverde JM, et al. Does fecal calprotectin predict relapse in patients with Crohn’s disease and ulcerative colitis? J Crohns Colitis. 2010;4:144–52.

    Article  PubMed  Google Scholar 

  76. Kallel L, Ayadi I, Matri S, Fekih M, Mahmoud NB, et al. Fecal calprotectin is a predictive marker of relapse in Crohn’s disease involving the colon: a prospective study. Eur J Gastroenterol Hepatol. 2010;22:340–5.

    Article  CAS  PubMed  Google Scholar 

  77. De Vos M, Dewit O, D’Haens G, Baert F, Fontaine F, et al. Fast and sharp decrease in calprotectin predicts remission by infliximab in anti-TNF naive patients with ulcerative colitis. J Crohns Colitis. 2012;6:557–62.

    Article  CAS  PubMed  Google Scholar 

  78. Glasziou P, Irwig L, Mant D. Monitoring in chronic disease: a rational approach. BMJ. 2005;330:644–8.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Yamamoto T, Shimoyama T. Can fecal biomarkers detect ileal inflammation in inflammatory bowel disease? Am J Gastroenterol. 2015;110:1370.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Stanford Children’s Inflammatory Bowel Disease Center, Department of Pediatrics, Stanford, CA, USA

    Jennifer Damman MD & K. T. Park MD, MS

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  1. Jennifer Damman MD
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  2. K. T. Park MD, MS
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Correspondence to K. T. Park MD, MS .

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Editors and Affiliations

  1. Division of GI, Hepatology & Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

    Petar Mamula

  2. Division of GI, Hepatology & Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

    Andrew B. Grossman

  3. Division of GI, Hepatology & Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

    Robert N. Baldassano

  4. Division of GI, Hepatology & Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

    Judith R. Kelsen

  5. Division of Pediatric Gastroenterology & Nutrition, University of South Carolina School of Medicine - Greenville, Greenville, South Carolina, USA

    Jonathan E. Markowitz

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Damman, J., Park, K.T. (2017). Fecal Biomarkers in Inflammatory Bowel Disease. In: Mamula, P., Grossman, A., Baldassano, R., Kelsen, J., Markowitz, J. (eds) Pediatric Inflammatory Bowel Disease. Springer, Cham. https://doi.org/10.1007/978-3-319-49215-5_19

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