Evidence for Mast Cell Activation in Patients with Therapy-Resistant Irritable Bowel Syndrome

Zusammenfassung

Neuere Untersuchungen legen eine wesentliche Rolle von Mastzellen in der Pathogenese des Reizdarmsyndroms nahe. Ziel der vorliegenden Pilotstudie war es, die mögliche pathophysiologische Rolle von Mastzellen in Reizdarmpatienten mit einem neuartigen Untersuchungsansatz näher zu beleuchten. An 20 Patienten mit therapierefraktärem Reizdarmsyndrom wurde mit einer validierten Checkliste, die die Identifizierung von Mastzellmediator-vermittelten Symptomen erlaubt, und mit ausgesuchten Surrogatparametern das Vorliegen einer pathologisch gesteigerten Aktivität von Mastzellen mit gesteigerter Mediatorfreisetzung untersucht. Bei 19 der 20 untersuchten Patienten konnten Mastzellmediator-induzierte Symptome festgestellt werden. In Abhängigkeit von der Mastzellaktivität pathologisch veränderte Koagulation- und Finbrinolyseparameter wurden bei 11 von 12 dahingehend untersuchten Patienten gefunden. Ein weiterer Patient hatte einen pathologisch erhöhten Methylhistamingehalt im Urin. Die vorliegenden Befunde geben einen Hinweis auf eine hohe Prävalenz für eine pathologisch gesteigerte systemische Mastzellaktivität bei Patienten mit einem therapierefraktärem Reizdarmsyndrom. Diese Beobachtung passt zu der Vorstellung, dass aktivierte Mastzellen in die Pathophysiologie des Reizdarmsyndroms eingebunden sind. Reizdarmpatienten mit therapierefraktärer Symptomatik könnten demnach therapeutisch von der Gabe mastzellstabilisierender Medikamente oder von Wirkstoffen, die die Mediatorwirkung an den Erfolgsorganen antagonisieren, profitieren.

Abstract

Previous findings suggested an involvement of mast cells in the pathogenesis of irritable bowel syndrome (IBS). The pathophysiological significance of mast cells is defined both by their number in tissue and by their activity. In the present pilot study activity of mast cells in patients with therapy-resistant IBS was investigated for the first time systematically. Twenty patients with therapy-resistant IBS were investigated for the presence of a pathologically increased mast cell mediator release by means of a validated structured interview suitable to identify mast cell mediator-related symptoms and by determing selected surrogate parameters for mast cell activity. Nineteen of the 20 patients presented mast cell mediator-related symptoms. Pathologically increased mast cell activity-related coagulation and fibrinolysis parameters were detected in 11 of 12 patients investigated in that regard. One patient had an elevated level of methylhistamine in urine. The present data provide evidence that in patients with therapy-resistant IBS a pathologically increased systemic mast cell activity may occur with high prevalence. This finding fits to the idea of an assumed contribution of activated mast cells in the pathophysiology of IBS.

Colon irritabile - Reizdarm - Mastzellen - Mastzellmediator-vermittelte Symptome - c-kit

irritable bowel syndrome - IBS - mast cell - c-kit - mast cell mediator release syndrome

References

• 1 Vanner S J, Depew W T, Paterson W G et al. Predictive value of the Rome criteria for diagnosing the irritable bowel syndrome.  Am J Gastroenterol. 1999;  94 2912-2917
• 2 Ohman L, Simrén M. Pathogenesis of IBS: role of inflammation, immunity and neuroimmune interactions.  Nat Rev Gastroenterol Hepatol. 2010;  7 163-173
• 3 Santos J, Guilarte M, Alonso C et al. Pathogenesis of irritable bowel syndrome: The mast cell connection.  Scand J Gastroenterol. 2005;  40 129-140
• 4 Walker M M, Talley N J, Prabhakar M et al. Duodenal mastocytosis, eosinophilia and intra-epithelial lymphocytosis as possible disease markers in the irritable bowel syndrome and functional dyspepsia.  Aliment Pharmacol Ther. 2009;  29 765-773
• 5 Barbara G, Stanghellini V, De Giorgio R et al. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome.  Gastroenterology. 2004;  126 693-702
• 6 Barbara G, Wang B, Stanghellini V et al. Mast cell-dependent excitation of visceral-nociceptive sensory neurons in irritable bowel syndrome.  Gastroenterology. 2007;  132 26-37
• 7 Frieling T, Weber E, Schemann M. Inflammatory mediators influencing submucosal secretory reflexes.  Ann New York Acad Sci. 2000;  915 98-101
• 8 Barbara G, Stanghellini V, De Giorgio R et al. Functional gastrointestinal disorders and mast cells: implications for therapy.  Neurogastroenterol Motil. 2006;  18 6-17
• 9 Klooker T K, Braak B, Koopman K E et al. The mast cell stabiliser ketotifen decreases visceral hypersensitivity and improves intestinal symptoms in patients with irritable bowel syndrome.  Gut. 2010;  in press DOI: 10.1136 /gut.2010.213108
• 10 Castells M, Austen K F. Mastocytosis: mediator related signs and symptoms.  Int Arch Allergy Immunol. 2002;  127 147-152
• 11 Molderings G J, Kolck U, Scheurlen C et al. Systemic mast cell disease with gastrointestinal symptoms – a diagnostic questionnaire.  Dtsch Med Wochenschr. 2006;  131 2095-2100
• 12 Hermine O, Lortholary O, Leventhal P S et al. Case-control cohort study of patients’ perceptions of disability in mastocytosis.  PLoS ONE. 2008;  3 e2266
• 13 Alfter K, Kügelgen von I, Haenisch B et al. New aspects of liver abnormalities as part of the systemic mast cell activation syndrome.  Liver Int. 2009;  29 181-186
• 14 Bankl H C, Valent P. Mast cells, thrombosis, and fibrinolysis. The emerging concept.  Thrombosis Res. 2002;  105 359-365
• 15 Seidel H, Hertfelder H J, Alfter K et al. Activation of fibrinolysis and bleeding history in patients with systemic mastocytosis (abstract).  J Thromb Hemost. 2009;  7 (Suppl) PP-Mo-252
• 16 Winterkamp S, Weidenhiller M, Otte P et al. Urinary excretion of N-methylhistamine as a marker of disease activity in inflammatory bowel disease.  Am J Gastroenterol. 2002;  97 3071-3077
• 17 Guilarte M, Santos J, Torres de I et al. Diarrhoea-predominant IBS patients show mast cell activation and hyperplasia in the jejunum.  Gut. 2007;  56 203-209
• 18 Rossi T M, Krauss de N, Wilken V et al. Mast cell tryptase in sera of patients with Crohn’s disease and mastocytosis.  Eur J Gastroenterol Hepatol. 2009;  21 273-277
• 19 Hallgren J, Estrada S, Karlson U et al. Heparin antagonists are potent inhibitors of mast cell tryptase.  Biochemistry. 2001;  40 7342-7349
• 20 Theoharides T C, Kempuraj D, Tagen M et al. Differential release of mast cell mediators and the pathogenesis of inflammation.  Immunol Rev. 2007;  217 65-78
• 21 Qi J C, Li L, Li Y et al. An antibody raised against in vitro- derived human mast cells identifies mature mast cells and population of cells that are FcεRI + , tryptase –, and chymase – in a variety of human tissues.  J Histochem Cytochem. 2003;  51 643-653
• 22 Molderings G J, Kolck U W, Scheurlen C et al. Multiple novel alterations in Kit tyrosine kinase in patients with gastrointestinally pronounced systemic mast cell activation disorder.  Scand J Gastroenterol. 2007;  42 1045-1053
• 23 Kolck U W. Investigations on the pathogenesis of the systemic mast cell activation syndrome and its impact on heart function. University, medical thesis, Bonn; 2009 URN:nbn:de:hbz:5N-19064, http://hss.ulb.uni-bonn.de/ 2009 / 1906 / 1906.htm (in German)
• 24 Santos J, Alonso C, Guilarte M et al. Targeting mast cells in the treatment of functional gastrointestinal disorders.  Curr Opin Pharmacol. 2006;  6 541-546