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Subclinical Intestinal Inflammation in Siblings of Children with Crohn’s Disease

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Abstract

Background

Intestinal permeability and altered inflammatory responses, along with genetic and environmental factors, likely contribute to the pathogenesis of Crohn’s disease.

Aims

This study aimed to assess the presence and prevalence of subclinical intestinal inflammation among apparently healthy, first-degree relatives of pediatric patients with Crohn’s disease, using non-invasive fecal markers.

Methods

Stool samples were collected from 13 patients with Crohn’s disease, 36 siblings and 41 parents. S100A12 levels were measured using an in-house ELISA assay and calprotectin levels were determined using the PhiCal test, with levels compared to normal healthy population controls.

Results

Fecal S100A12 levels in siblings (median, 14 mg/kg; 95% confidence interval [CI], 9–32 mg/kg) and patients (71 mg/kg; CI 4–286 mg/kg) differed significantly from pediatric controls (1 mg/kg; CI 1–5 mg/kg; p < 0.001). In contrast, fecal calprotectin levels in siblings (22 mg/kg; CI 15–31 mg/kg) were lower than that of pediatric controls (31 mg/kg; CI 19–52 mg/kg; p = 0.03). Fecal markers were not elevated in parents compared to adult controls.

Conclusions

This study provides further evidence of subclinical intestinal inflammation amongst first-degree relatives of patients with Crohn’s disease. The presence of sub-clinical gut inflammation may be a risk factor for the subsequent development of Crohn’s disease.

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References

  1. Langhorst J, Elsenbruch S, Mueller T, et al. Comparison of 4 neutrophil-derived proteins in feces as indicators of disease activity in ulcerative colitis. Inflamm Bowel Dis. 2005;11:1085–1091.

    Article  PubMed  Google Scholar 

  2. Brandtzaeg P, Haraldsen G, Rugtveit J. Immunopathology of human inflammatory bowel disease. Springer Sem Immunopathol. 1997;18:555–589.

    Article  CAS  Google Scholar 

  3. Krugliak P, Hollander D, Ma TY, et al. Mechanisms of polyethylene glycol 400 permeability of perfused rat intestine. Gastroenterology. 1989;97:1164–1170.

    CAS  PubMed  Google Scholar 

  4. Hollander D. The intestinal permeability barrier. A hypothesis as to its regulation and involvement in Crohn’s disease. Scand J Gastroenterol. 1992;27:721–726.

    Article  CAS  PubMed  Google Scholar 

  5. Bjarnason I, MacPherson A, Hollander D. Intestinal permeability: an overview. Gastroenterology. 1995;108:1566–1581.

    Article  CAS  PubMed  Google Scholar 

  6. Katz KD, Hollander D, Vadheim CM, et al. Intestinal permeability in patients with Crohn’s disease and their healthy relatives. Gastroenterology. 1989;97:927–931.

    CAS  PubMed  Google Scholar 

  7. Teahon K, Smethurst P, Levi AJ, Menzies IS, Bjarnason I. Intestinal permeability in patients with Crohn’s disease and their first-degree relatives. Gut. 1992;33:320–323.

    Article  CAS  PubMed  Google Scholar 

  8. Peeters M, Geypens B, Claus D, et al. Clustering of increased small intestinal permeability in families with Crohn’s disease. Gastroenterology. 1997;113:802–807.

    Article  CAS  PubMed  Google Scholar 

  9. Soderholm JD, Olaison G, Lindberg E, et al. Different intestinal permeability patterns in relatives and spouses of patients with Crohn’s disease: an inherited defect in mucosal defence? Gut. 1999;44:96–100.

    Article  CAS  PubMed  Google Scholar 

  10. Thjodleifsson B, Sigthorsson G, Cariglia N, et al. Subclinical intestinal inflammation: an inherited abnormality in Crohn’s disease relatives? Gastroenterology. 2003;124:1728–1737.

    Article  PubMed  Google Scholar 

  11. Roth J, Goebeler M, Sorg C. S100A8 and S100A9 in inflammatory diseases. Lancet. 2001;357:1041.

    Article  CAS  PubMed  Google Scholar 

  12. Roth J, Vogl T, Sorg C, et al. Phagocyte-specific S100 proteins: a novel group of proinflammatory molecules. Trends Immunol. 2003;24:155–158.

    Article  CAS  PubMed  Google Scholar 

  13. Poullis A, Foster R, Mendall MA, et al. Emerging role of calprotectin in gastroenterology. J Gastroenterol Hepatol. 2003;18:756–762.

    Article  CAS  PubMed  Google Scholar 

  14. Olafsdottir E, Aksnes L, Fluge G, Berstad A. Faecal calprotectin levels in infants with infantile colic, healthy infants, children with inflammatory bowel disease, children with recurrent abdominal pain and healthy children. Acta Paediatr. 2002;91:45–50.

    Article  CAS  PubMed  Google Scholar 

  15. 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 

  16. Tibble JA, Sigthorsson G, Foster R, et al. Use of surrogate markers of inflammation and Rome criteria to distinguish organic from nonorganic intestinal disease. Gastroenterology. 2002;123:450–460.

    Article  PubMed  Google Scholar 

  17. Canani RB, Terrin G, Rapacciuolo L, et al. Faecal calprotectin as reliable non-invasive marker to assess the severity of mucosal inflammation in children with inflammatory bowel disease. Dig Liver Dis. 2008;40:547–553.

    Article  PubMed  Google Scholar 

  18. Frosch M, Metze D, Foell D, et al. Early activation of cutaneous vessels and epithelial cells is characteristic of acute systemic onset juvenile idiopathic arthritis. Exp Dermatol. 2005;14:259–265.

    Article  PubMed  Google Scholar 

  19. Foell D, Kucharzik T, Kraft M, et al. Neutrophil derived human S100A12 (EN-RAGE) is strongly expressed during chronic active inflammatory bowel disease. Gut. 2003;52:847–853.

    Article  CAS  PubMed  Google Scholar 

  20. Vogl T, Propper C, Hartmann M, et al. S100A12 is expressed exclusively by granulocytes and acts independently from MRP8 and MRP14. J Biol Chem. 1999;274:25291–25296.

    Article  CAS  PubMed  Google Scholar 

  21. Kaiser T, Langhorst J, Wittkowski H, et al. Faecal S100A12 as a non-invasive marker distinguishing inflammatory bowel disease from irritable bowel syndrome. Gut. 2007;56:1706–1713.

    Article  CAS  PubMed  Google Scholar 

  22. de Jong NSH, Leach ST, Day AS. Fecal S100A12: a novel noninvasive marker in children with Crohn’s disease. Inflamm Bowel Dis. 2006;12:566–572.

    Article  PubMed  Google Scholar 

  23. Sidler MA, Leach ST, Day AS. Fecal S100A12 and fecal calprotectin as noninvasive markers for inflammatory bowel disease in children. Inflamm Bowel Dis. 2008;14:359–366.

    Article  PubMed  Google Scholar 

  24. Griffiths AM, Buller HB. Inflammatory bowel diseases. In: Walker WA, Hamilton JR, et al. eds. Pediatric Gastrointestinal Disease. Hamilton Ontario: BC Decker; 2000: 613–52, Chap. 41.

  25. Silverberg M, Satsangi J, Ahmad T, et al. Toward an integral clinical, molecular and serological classification of inflammatory bowel disease: report of a Working Party of the 2005 Montreal World Congress of Gastroenterology. Can J Gastroenterol. 2005;19(Suppl A):5A–36A.

    Google Scholar 

  26. Hyams JS, Ferry GD, Mandel FS, et al. Development and validation of a pediatric Crohn’s disease activity index. J Pediatr Gastroenterol Nutr. 1991;12:439–447.

    CAS  PubMed  Google Scholar 

  27. Pardi DS, Sandborn WJ. Predicting relapse in patients with inflammatory bowel disease: what is the role of biomarkers? Gut. 2005;54:321–322.

    Article  CAS  PubMed  Google Scholar 

  28. Hofmann MA, Drury S, Fu C, et al. RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell. 1999;97:889–901.

    Article  CAS  PubMed  Google Scholar 

  29. Olaison G, Sjodahl R, Tagesson C. Abnormal intestinal permeability in Crohn’s disease. A possible pathogenic factor. Scand J Gastroenterol. 1990;25:321–328.

    Article  CAS  PubMed  Google Scholar 

  30. Hollander D. Permeability in Crohn’s disease: altered barrier functions in healthy relatives? Gastroenterology. 1993;104:1848–1851.

    CAS  PubMed  Google Scholar 

  31. Munkholm P, Langholz E, Hollander D, et al. Intestinal permeability in patients with Crohn’s disease and ulcerative colitis and their first degree relatives. Gut. 1994;35:68–72.

    Article  CAS  PubMed  Google Scholar 

  32. Ruttenberg D, Young GO, Wright JP, Isaacs S. PEG-400 excretion in patients with Crohn’s disease, their first-degree relatives, and healthy volunteers. Dig Dis Sci. 1992;37:705–708.

    Article  CAS  PubMed  Google Scholar 

  33. Ainsworth M, Eriksen J, Rasmussen JW, Schaffalitzky de Muckadell OB. Intestinal permeability of 51Cr-labelled ethylenediaminetetraacetic acid in patients with Crohn’s disease and their healthy relatives. Scand J Gastroenterol. 1989;24:993–998.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Funding for this study was received in part from the Sydney Children’s Hospital Foundation.

Conflict of interest

The authors have no conflicts to declare.

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Correspondence to Andrew S. Day.

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Pham, M., Leach, S.T., Lemberg, D.A. et al. Subclinical Intestinal Inflammation in Siblings of Children with Crohn’s Disease. Dig Dis Sci 55, 3502–3507 (2010). https://doi.org/10.1007/s10620-010-1434-8

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  • DOI: https://doi.org/10.1007/s10620-010-1434-8

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