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Fecal Biomarkers in Inflammatory Bowel Disease

Chapter

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.

Keywords

Inflammatory bowel disease Ulcerative colitis Crohn disease Fecal biomarkers Calprotectin Lactoferrin Mucosal healing Monitoring 

References

  1. 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.CrossRefPubMedGoogle Scholar
  2. 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.CrossRefGoogle Scholar
  3. 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.CrossRefPubMedGoogle Scholar
  4. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Abraham BP, Kane S. Fecal markers: calprotectin and lactoferrin. Gastroenterol Clin N Am. 2012;41:483–95.CrossRefGoogle Scholar
  7. 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.CrossRefPubMedGoogle Scholar
  8. 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.CrossRefPubMedGoogle Scholar
  9. 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.CrossRefPubMedGoogle Scholar
  10. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 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. 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. 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.CrossRefPubMedGoogle Scholar
  15. 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.CrossRefPubMedGoogle Scholar
  16. 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.CrossRefPubMedGoogle Scholar
  17. 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.CrossRefPubMedGoogle Scholar
  18. 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.CrossRefPubMedGoogle Scholar
  19. 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.CrossRefPubMedGoogle Scholar
  20. 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.CrossRefPubMedGoogle Scholar
  21. 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.CrossRefPubMedGoogle Scholar
  22. 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.CrossRefPubMedGoogle Scholar
  23. 23.
    Ghisoni K, Martins Rde P, Barbeito L, Latini A. Neopterin as a potential cytoprotective brain molecule. J Psychiatr Res. 2015;71:134–9.CrossRefPubMedGoogle Scholar
  24. 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.CrossRefPubMedGoogle Scholar
  25. 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.CrossRefGoogle Scholar
  26. 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.PubMedGoogle Scholar
  27. 27.
    O’Sullivan S, Gilmer JF, Medina C. Matrix metalloproteinases in inflammatory bowel disease: an update. Mediat Inflamm. 2015;2015:964131.Google Scholar
  28. 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.CrossRefPubMedGoogle Scholar
  29. 29.
    Sternlicht MD, Werb Z. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol. 2001;17:463–516.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 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.CrossRefPubMedGoogle Scholar
  31. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Klebanoff SJ. Myeloperoxidase: friend and foe. J Leukoc Biol. 2005;77:598–625.CrossRefPubMedGoogle Scholar
  33. 33.
    Chua F, Laurent GJ. Neutrophil elastase: mediator of extracellular matrix destruction and accumulation. Proc Am Thorac Soc. 2006;3:424–7.CrossRefPubMedGoogle Scholar
  34. 34.
    Doring G. The role of neutrophil elastase in chronic inflammation. Am J Respir Crit Care Med. 1994;150:S114–7.CrossRefPubMedGoogle Scholar
  35. 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.PubMedGoogle Scholar
  36. 36.
    Janoff A. Elastase in tissue injury. Annu Rev Med. 1985;36:207–16.CrossRefPubMedGoogle Scholar
  37. 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.CrossRefPubMedGoogle Scholar
  38. 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.PubMedGoogle Scholar
  39. 39.
    Harvey RF, Salih SY, Read AE. Organic and functional disorders in 2000 gastroenterology outpatients. Lancet. 1983;1:632–4.CrossRefPubMedGoogle Scholar
  40. 40.
    Russo MW, Wei JT, Thiny MT, Gangarosa LM, Brown A, et al. Digestive and liver diseases statistics, 2004. Gastroenterology. 2004;126:1448–53.CrossRefPubMedGoogle Scholar
  41. 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.CrossRefPubMedGoogle Scholar
  42. 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.CrossRefPubMedGoogle Scholar
  43. 43.
    Lasson A, Kilander A, Stotzer PO. Diagnostic yield of colonoscopy based on symptoms. Scand J Gastroenterol. 2008;43:356–62.CrossRefPubMedGoogle Scholar
  44. 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.CrossRefGoogle Scholar
  45. 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.CrossRefPubMedGoogle Scholar
  46. 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.CrossRefPubMedGoogle Scholar
  47. 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.CrossRefPubMedGoogle Scholar
  48. 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.CrossRefPubMedGoogle Scholar
  49. 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. 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.PubMedGoogle Scholar
  51. 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.CrossRefPubMedGoogle Scholar
  52. 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.CrossRefGoogle Scholar
  53. 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.CrossRefPubMedGoogle Scholar
  54. 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.CrossRefPubMedGoogle Scholar
  55. 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.PubMedGoogle Scholar
  56. 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.PubMedGoogle Scholar
  57. 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.CrossRefPubMedGoogle Scholar
  58. 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.CrossRefPubMedGoogle Scholar
  59. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 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.CrossRefGoogle Scholar
  61. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 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.CrossRefPubMedGoogle Scholar
  63. 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. 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.CrossRefPubMedGoogle Scholar
  65. 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.CrossRefPubMedGoogle Scholar
  66. 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.CrossRefPubMedGoogle Scholar
  67. 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.CrossRefPubMedGoogle Scholar
  68. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 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.CrossRefPubMedGoogle Scholar
  70. 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.CrossRefPubMedGoogle Scholar
  71. 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.CrossRefPubMedGoogle Scholar
  72. 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.CrossRefPubMedGoogle Scholar
  73. 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.CrossRefPubMedGoogle Scholar
  74. 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.CrossRefPubMedGoogle Scholar
  75. 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.CrossRefPubMedGoogle Scholar
  76. 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.CrossRefPubMedGoogle Scholar
  77. 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.CrossRefPubMedGoogle Scholar
  78. 78.
    Glasziou P, Irwig L, Mant D. Monitoring in chronic disease: a rational approach. BMJ. 2005;330:644–8.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Yamamoto T, Shimoyama T. Can fecal biomarkers detect ileal inflammation in inflammatory bowel disease? Am J Gastroenterol. 2015;110:1370.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Stanford Children’s Inflammatory Bowel Disease Center, Department of PediatricsStanfordUSA

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