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Clinical and Experimental Studies on Inflammatory Bowel Disease with special emphasis on Collagenous Colitis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Gastroenterology research group)
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis describes studies in patients with inflammatory bowel disease (IBD) and collagenous colitis (CC). We investigated mucosal eosinophil and neutrophil granulocytes and T-cells involved in the inflammatory processes and aimed at determining whether these processes are reflected in the faecal (F) contents of specific proteins secreted by cells in the intestinal mucosa. Thus, we measured eosinophil cationic protein (ECP) and eosinophil protein X (EPX) and the neutrophil derived myeloperoxidase (MPO) and calprotectin (C); and in addition, chromogranin A (CgA), Chromogranin B (CgB) and secretoneurin (SN), derived from EEC cells and cells in the enteric nervous system.

We found that a normalised FC level can serve as a surrogate marker for successful treatment in patients with IBD, but persistently high FC levels need further evaluation (study I). Furthermore, FC and F-MPO appear to relate better than F-EPX to treatment outcome in IBD. We evaluated F-ECP, F-EPX, F-MPO and FC as markers of disease activity and treatment outcome in patients with CC (study III) and concluded that F-ECP was the best discriminator of detecting active CC. Normalised F-ECP and F-EPX could serve as markers of successful treatment. We showed that the inflammation in CC is characterised by activated eosinophils, but that there is no neutrophil activity (study II). T-cells have a lower grade of activity in active CC than in control subjects. During budesonide treatment the normal activation of eosinophils and T-cells is restored, with concomitant clinical remission. The findings in studies II and III indicate that the eosinophils have an essential role in the pathophysiology of CC. Markedly higher values of F-CgA, F-CgB and F-SN were found in patients with CC than in those with IBD and controls (study IV) indicating a crucial role for the intestinal neuro-endocrine system in the pathogenesis of collagenous colitis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2010. , p. 75
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 565
Keywords [en]
Collagenous colitis, inflammatory bowel disease, ulcerative colitis, Crohn´s disease, faecal markers, eosinophil, T-cells, ECP, EPX, MPO, calprotectin, flowcytometry, chromogranin A, chromogranin B, secretoneurin, budesonide
National Category
Gastroenterology and Hepatology
Research subject
Medicine
Identifiers
URN: urn:nbn:se:uu:diva-123053ISBN: 978-91-554-7817-9 (print)OAI: oai:DiVA.org:uu-123053DiVA, id: diva2:311806
Public defence
2010-05-29, Robergsalen, ingång 40, plan 4, Akademiska sjukhuset, UPPSALA, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2010-05-07 Created: 2010-04-22 Last updated: 2010-05-18Bibliographically approved
List of papers
1. Fecal markers of inflammation used as surrogate markers for treatment outcome in relapsing inflammatory bowel disease
Open this publication in new window or tab >>Fecal markers of inflammation used as surrogate markers for treatment outcome in relapsing inflammatory bowel disease
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2008 (English)In: World Journal of Gastroenterology, ISSN 1007-9327, E-ISSN 2219-2840, Vol. 14, no 36, p. 5584-5589Article in journal (Refereed) Published
Abstract [en]

Aims: To evaluate fecal calprotectin (FC) as a surrogate marker for treatment outcome of a relapse of inflammatory bowel disease (IBD) and, secondly, to compare FC to fecal myeloperoxidase (MPO) and fecal eosinophil protein X (EPX).

Methods: Thirty-eight patients with IBD, whereof twenty-seven with ulcerative colitis (UC) and 11 with Crohn´s disease (CD) were studied before treatment (inclusion), and after four and eight weeks of treatment. Treatment outcome, based on clinical activity and endoscopy in UC patients, and clinical activity in CD patients, were evaluated together with fecal samples analysed for FC with ELISA and MPO and EPX with RIA.

Results: At inclusion 37/38 (97%) patients had elevated FC levels (>94.7 µg/g). At the end of the study 31/38 (82%) patients fulfilled predefined criteria of a complete response [UC 21/27 (78%); CD 10/11 (91%)].  Overall, a normalised FC level at the end of the study predicted a complete response in 100% whereas elevated FC level predicted noncomplete response in 30%. Normalised MPO or EPX levels predicted a complete response in 100% and 90%, respectively. However, elevated MPO or EPX levels predicted noncomplete response in 23% and 22%, respectively.

Conclusion: A normalised FC level poses the potential to be used as a surrogate marker for successful treatment outcome in IBD patients, but cases with persistent elevated FC levels needs further evaluation. FC and MPO appears to discriminate better than EPX to treatment outcome in IBD.

Place, publisher, year, edition, pages
WJG Press, 2008
Keywords
Fecal markers, calprotectin, myeloperoxidase, eosinophil protein X treatment, inflammatory bowel disease, ulcerative colitis, Crohn´s disease
National Category
Gastroenterology and Hepatology
Research subject
Medicine
Identifiers
urn:nbn:se:uu:diva-123028 (URN)10.3748/wjg.14.5584 (DOI)000259574400016 ()18810778 (PubMedID)
Available from: 2010-04-22 Created: 2010-04-22 Last updated: 2017-12-12Bibliographically approved
2. Budesonide Treatment of Patients With Collagenous Colitis Restores Normal Eosinophil and T-cell Activity in the Colon
Open this publication in new window or tab >>Budesonide Treatment of Patients With Collagenous Colitis Restores Normal Eosinophil and T-cell Activity in the Colon
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2010 (English)In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 16, no 7, p. 1118-1126Article in journal (Refereed) Published
Abstract [en]

Objective: The aim of this study was to assess the activity of eosinophils, neutrophils and CD4+ as well as CD8+ T-cells in eleven patients with active collagenous colitis (CC) before and after eight weeks of budesonide treatment (9 mg once daily) compared to ten healthy individuals.

Methods: Clinical symptoms were recorded and intestinal biopsy samples were taken and analysed by flow cytometry. Eosinophils with a high surface expression of CD44 and low CD9 expression were classified as activated. Neutrophil activity was assessed by their expression of CD66b and CD69 was used as an activation marker for T cells.

Results: All patients responded to the treatment. The eosinophils in active CC showed increased activity compared to controls. The activity was back to control levels after treatment. Neutrophils were not activated in CC patients before or after treatment.

CD8+ T cells from untreated CC patients had a lower activity than controls, and a tendency of lower activity was observed on CD4+ T cells. After treatment, the activity was increased on both types of T cells and was not different from controls.

Conclusions: In the present study we demonstrated that the inflammation in CC is characterized by activated eosinophils but there is no neutrophil activity. CD4+ and CD8+ T cells are increased in numbers in active CC but, surprisingly, they had a lower grade of activity than in control subjects. The major finding in this study is that budesonide treatment restores the normal activation of eosinophils and T-cells, accompanied by clinical remission.

Keywords
Eosinophil, T-lymphocyte, collagenous colitis, budesonide, flow cytometry
National Category
Gastroenterology and Hepatology
Research subject
Medicine
Identifiers
urn:nbn:se:uu:diva-123037 (URN)10.1002/ibd.21188 (DOI)000279718800009 ()20027654 (PubMedID)
Available from: 2010-04-22 Created: 2010-04-22 Last updated: 2017-12-12Bibliographically approved
3. Fecal eosinophil cationic protein as a marker of active disease and treatment outcome in collagenous colitis: A pilot study
Open this publication in new window or tab >>Fecal eosinophil cationic protein as a marker of active disease and treatment outcome in collagenous colitis: A pilot study
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2011 (English)In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 46, no 7-8, p. 849-854Article in journal (Refereed) Published
Abstract [en]

Background and aims. Fecal calprotectin (FC) is used as a marker for intestinal inflammation in inflammatory bowel disease (IBD) but there is no reliable marker for collagenous colitis (CC). We have previously demonstrated that the mucosal inflammation in CC is characterized by eosinophil activation, which is restored during budesonide treatment, but there is no enhanced neutrophil activity. The aim of this study was to evaluate the use of fecal eosinophil cationic protein (F-ECP) and eosinophil protein X (F-EPX) compared with the neutrophil-derived myeloperoxidase (F-MPO) and FC in patients treated for active CC. Methods. Patients with active CC (n = 12) were studied before and after 3, 7, 28 and 56 days of budesonide treatment. Clinical symptoms and stool frequency were recorded, fecal samples were collected, and F-ECP, F-EPX, F-MPO and FC were measured at each occasion. Results. All but one patient achieved remission. On inclusion 92%, 67%, 67% and 75% of the patients had elevated F-ECP, F-EPX, F-MPO and FC levels, respectively. All markers decreased during the treatment, particularly F-ECP and F-EPX, which decreased after only 3 days. At the end of the study 100%, 92%, 83% and 75% of the patients had normal F-ECP, F-EPX, F-MPO and FC values, respectively. Conclusion. F-ECP demonstrated the best discriminating capacity in detecting active CC. A normalized F-ECP and F-EPX may further be studied as a marker for successful treatment. During budesonide treatment there is a rapid fall in F-ECP and F-EPX, accompanied by clinical improvement, indicating an essential role for the eosinophil participating in the pathophysiology of CC.

Keywords
Budesonide, collagenous colitis, ECP, eosinophil, fecal markers
National Category
Gastroenterology and Hepatology
Research subject
Medicine
Identifiers
urn:nbn:se:uu:diva-123051 (URN)10.3109/00365521.2011.571707 (DOI)000292646800012 ()
Available from: 2010-04-22 Created: 2010-04-22 Last updated: 2017-12-12Bibliographically approved
4. Increased Fecal Levels of Chromogranin A, Chromogranin B and Secretoneurine in Collagenous Colitis
Open this publication in new window or tab >>Increased Fecal Levels of Chromogranin A, Chromogranin B and Secretoneurine in Collagenous Colitis
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2013 (English)In: Inflammation, ISSN 0360-3997, E-ISSN 1573-2576, Vol. 36, no 4, p. 855-861Article in journal (Refereed) Published
Abstract [en]

Interactions between the enteric nervous system and the immune system are suggested to play an important role in the pathophysiology of inflammatory bowel disease (IBD). This study aims to determine if chromogranin A (CgA), chromogranin B (CgB), and secretoneurin (SN) are detectable in feces (F) from patients with collagenous colitis (CC) and to compare the levels found in patients with ulcerative colitis (UC) and Crohn’s disease (CD) before and during treatment. Patients with CC (n = 12) were studied before and after 3, 7, 28, and 56 days of treatment. Patients with IBD (UC, n = 21; CD, n = 11) were studied before and after 28 and 56 days of treatment. Clinical data were recorded, and fecal samples were collected at each occasion. F-CgA, F-CgB, and F-SN were measured by RIA. Eleven patients with CC, 21 with UC, and 10 with CD achieved remission. On inclusion, CC patients had higher levels of F-CgA, F-CgB, and F-SN than patients with IBD and controls. Patients with IBD expressed markedly lower levels of F-SN than controls. During treatment, F-SN in CC patients decreased to control levels but remained low in IBD patients. No change was found in F-CgA or F-CgB in any of the groups. In conclusion, CgA, CgB, and SN are detectable in feces, and CC patients express higher values than patients with IBD and controls. During treatment, F-SN decreased to control levels in CC. These findings suggest that the enteric nervous system is clearly involved in the pathophysiology of CC.

Keywords
collagenous colitis, inflammatory bowel disease, chromogranin A, chromogranin B, secretoneurin, fecal samples
National Category
Gastroenterology and Hepatology
Research subject
Medicine
Identifiers
urn:nbn:se:uu:diva-123041 (URN)10.1007/s10753-013-9612-4 (DOI)
Available from: 2010-04-22 Created: 2010-04-22 Last updated: 2017-12-12Bibliographically approved

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