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The significance of low-grade inflammation in the gastrointestinal tract
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
2021 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background

Gastrointestinal (GI) symptoms are commonly reported in a normal population. Mostly, the symptoms are of benign cause but occasionally the symptoms can be signs of a more harmful disease. In general, it is difficult to distinguish whether the reported symptoms are caused by a benign (functional) or organic (i.e., inflammatory) disease. To make this distinction, the tools available in clinical practice are medical history, blood and faecal tests, radiology, endoscopy and histological evaluation. Mucosal inflammation usually separates organic from functional disease and, in patients with inflammatory bowel disease (IBD), mucosal inflammation correlates with disease activity. Faecal calprotectin (FC) corresponds well with mucosal inflammation and is in clinical practice often used as the first line non-invasive test for gut inflammation. Although the sensitivity of the FC test to detect gut inflammation is good, there are uncertainties in how to interpret a modestly elevated FC level (i.e., in the span of 50-200µg/g) and in patients with IBD, there is a disagreement into which degree of inflammatory remission it is sufficient to reach.

Aim

The overall aim of this thesis was to study factors associated with low-grade inflammation based on biochemical markers, and to study the clinical significance of low-grade inflammation in patients with IBD and other patients with elevated FC levels. Is low-grade inflammation associated with reported gastrointestinal symptoms in patients with IBD and could low-grade inflammation be detected in the pre-clinical phase of IBD? How should an elevated FC level in patients with a normal colonoscopy be interpreted and could it be a risk factor for gastrointestinal disease or associated with other factors? Could low-grade inflammation cause IBS-like symptoms in patients with IBD?

Methods and results

Three of the manuscripts on which this thesis is based are from the Faecal and Endoscopic Colorectal Study in Umeå Sweden (FECSU) which consists of 1263 patients that underwent colonoscopy during the period of May 2007 to February 2013. The patients that accepted to participate in the FECSU study performed a FC test the day before the bowel preparation for the colonoscopy and simultaneously filled in questionnaires of gastrointestinal symptoms (GSRS), symptoms of anxiety and depression (HADS) and current medications. A thorough medical chart review that focused on endoscopic evaluations, histological judgements and medical history was performed. The included patients with IBD (n=157) in the FECSU study were analysed separately. Patients with ulcerative colitis (UC) in endoscopic remission reported lower total scores on GSRS-irritable bowel syndrome (GSRS-IBS) than controls (6 vs 10.5; p=0.062). However there was a moderate, yet significant association between GSRS-diarrhoea score and FC levels in the span £ 200 µg/g (rho 0.38;p=0.004) in patients with UC. To investigate pre-clinical biomarkers of IBD we identified 96 patients with IBD in the “Västerbotten Intervention Program (VIP)” and the “Mammography screening project” (MA). In the pre-clinical study in patients with IBD we found that patients who later developed UC had lower plasma albumin levels and patients who later developed Crohn’s disease (CD) had higher levels of CRP in plasma, reflecting signs of a low-grade systemic inflammation years before diagnosis. Plasma calprotectin levels were not elevated before IBD-diagnosis. In the FECSU study, all non-IBD patients with a normal colonoscopy were studied for factors associated with an elevated FC level. Patients with a FC > 50 µg/g more often used Proton-pump inhibitors (PPI) (multivariate OR: 3.843; CI: 2.338-6.316), Non-steroidal anti-ivinflammatory drugs (NSAID) (multivariate OR: 2.411; CI: 1.162-5.002) and acetylsalicylic acid (ASA) (multivariate OR: 2.934; CI: 1.085-3.448). One third of the patients with a normal colonoscopy had elevated FC levels (> 50 µg/g) and these patients were observed three years after the colonoscopy. There was no increased risk for developing gastrointestinal disease in the patients with an increased baseline FC level and a normal colonoscopy during the observation period.

Conclusion

Patients with longstanding UC in remission did not experience more IBS-like symptoms than controls. In patients with UC in remission, the FC levels in the lower span were moderately associated with symptoms of diarrhoea. Patients with IBD had elevated inflammatory biochemical markers in blood in the pre-clinical phase. P- CRP and P-albumin were more sensitive to detect a low grade systemic inflammation than P-calprotectin in the pre-clinical phase of IBD. More than one-third of the patients with a normal colonoscopy had a slightly elevated FC. In patients with a normal colonoscopy, the use of PPI, NSAID and ASA was associated with an increased FC level. No significant gastrointestinal disease developed in the patients with an increased FC level together with a normal colonoscopy during the three-year period following colonoscopy. 

Place, publisher, year, edition, pages
Umeå: Umeå Universitet , 2021. , p. 53
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2147
Keywords [en]
Low-grade inflammation, gastrointestinal tract, faecal calprotectin, inflammatory bowel disease, Ulcerative colitis, irritable bowel syndrome, biomarkers, colonoscopy, proton pump inhibitors, albumin, C-reactive protein
National Category
Gastroenterology and Hepatology
Research subject
Medicine
Identifiers
URN: urn:nbn:se:umu:diva-186649ISBN: 978-91-7855-590-1 (print)ISBN: 978-91-7855-591-8 (electronic)OAI: oai:DiVA.org:umu-186649DiVA, id: diva2:1585177
Public defence
2021-09-10, Triple Helix, Universitetsledningshuset, Umeå, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2021-08-20 Created: 2021-08-16 Last updated: 2025-02-11Bibliographically approved
List of papers
1. Patients with longstanding ulcerative colitis in remission do not have more irritable bowel syndrome-like symptoms than controls
Open this publication in new window or tab >>Patients with longstanding ulcerative colitis in remission do not have more irritable bowel syndrome-like symptoms than controls
Show others...
2016 (English)In: BMC Gastroenterology, E-ISSN 1471-230X, Vol. 16, article id 139Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Irritable bowel syndrome (IBS) is more common in patients with ulcerative colitis (UC) than expected. The prevalence of IBS in patients with UC with longstanding disease is not known. We investigated the prevalence of IBS-like symptoms in patients with UC in remission and longstanding disease in comparison to control subjects.

METHODS: Sixty-eight patients with UC and 33 patients with hereditary familiar colon cancer and who underwent colonoscopy surveillance were included. Faecal calprotectin (FC), Gastrointestinal Symptoms Rating Scale-Irritable Bowel Syndrome (GSRS-IBS) and Hospital Anxiety and Depression scale were fulfilled prior to endoscopy. UC in remission was define by steroid-free clinical remission, a Mayo Score ≤ 1 on endoscopy, a FC ≤ 200 μg/g and no significant active inflammation on colon biopsies.

RESULTS: Fifty-five UC patients met the criteria for being in remission. The median disease duration was 17 years. The patients with UC in remission tended to have lower scores on total GSRS-IBS score (6 vs 10.5; p = 0.062) and lower or equal scores on all specific IBS symptoms in comparison to controls. There was a moderate but significant correlation between diarrhoea scores and FC levels (in the span ≤ 200 μg/g) (rs 0.38; p = 0.004) in the UC in remission group.

CONCLUSION: Patients with UC with longstanding disease and in remission do not have more IBS symptoms than controls. In UC patients in remission the FC level in the lower span showed a moderate correlation to symptoms of diarrhoea.

Keywords
Irritable bowel syndrome, Inflammatory bowel disorder, Ulcerative Colitis
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:umu:diva-128590 (URN)10.1186/s12876-016-0553-x (DOI)000388415600001 ()27881072 (PubMedID)2-s2.0-84997107116 (Scopus ID)
Available from: 2016-12-07 Created: 2016-12-07 Last updated: 2025-02-11Bibliographically approved
2. Proton pump inhibitor use is associated with elevated faecal calprotectin levels. A cross-sectional study on subjects referred for colonoscopy
Open this publication in new window or tab >>Proton pump inhibitor use is associated with elevated faecal calprotectin levels. A cross-sectional study on subjects referred for colonoscopy
Show others...
2019 (English)In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 54, no 2, p. 152-157Article in journal (Refereed) Published
Abstract [en]

Objectives: Faecal Calprotectin (FC) is a sensitive marker for gut inflammation. However, slightly elevated FC levels are also common in subjects without inflammation. We investigated the association between FC and clinical factors including concomitant use of medical therapy in patients with a normal colonoscopy.Material and methods: Out-patients (n=1263) referred for colonoscopy, performed FC test (CALPRO) the day before the start of bowel preparation. All subjects answered questionnaires that included questions on the present and past health history, concomitant medical treatment and gastrointestinal symptoms (GSRS). A medical record chart review was performed to check for concomitant disease, cause of referral and the result of the colonoscopy including biopsies. Inclusion criteria were a normal colonoscopy. Exclusion criteria were inflammatory bowel disease, colon cancer and high-grade dysplasia.Results: Five hundred ninety subjects fulfilled the inclusion criteria and completed the study. Thirty-six per cent of the subjects had a FC >50 mu g/g. In a logistic regression analysis, age (adjusted OR: 1.051; CI: 1.032-1.071), and the use of proton pump inhibitors (adjusted OR: 3.843; CI: 2.338-6.316), non-steroid anti-inflammatory drugs (adjusted OR: 2.411; CI: 1.162-5.002) and acetylsalicylic acid (adjusted OR: 2.934; CI: 1.085-3.448) were significantly associated with an elevated FC (>50 mu g/g).Conclusions: More than one-third of the patients with a normal colonoscopy performed in clinical routine had a slightly elevated FC level. Our results emphasise the need for attention to age, the use of proton pump inhibitors, non-steroid anti-inflammatory drugs and acetylsalicylic acid in the interpretation of FC tests in clinical practice.

Place, publisher, year, edition, pages
Taylor & Francis, 2019
Keywords
Faecal calprotectin, colonoscopy, non-steroidal inflammatory drugs, proton pump inhibitors
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:umu:diva-160629 (URN)10.1080/00365521.2019.1566493 (DOI)000468463000004 ()30676120 (PubMedID)2-s2.0-85060644775 (Scopus ID)
Funder
Västerbotten County Council
Available from: 2019-06-20 Created: 2019-06-20 Last updated: 2025-02-11Bibliographically approved
3. Elevated Faecal Calprotectin in Patients with a Normal Colonoscopy: Does It Matter in Clinical Practice? A Retrospective Observational Study
Open this publication in new window or tab >>Elevated Faecal Calprotectin in Patients with a Normal Colonoscopy: Does It Matter in Clinical Practice? A Retrospective Observational Study
2021 (English)In: Inflammatory Intestinal Diseases, ISSN 2296-9403, Vol. 6, p. 101-108Article in journal (Refereed) Published
Abstract [en]

Introduction: Faecal calprotectin (FC) is commonly used as a diagnostic tool for patients with gastrointestinal (GI) symptoms. However, there is uncertainty in daily clinical practice how to interpret an elevated FC in patients with a normal colonoscopy. We investigated if patients with a normal colonoscopy but with an elevated FC more often were diagnosed with a GI disease in a 3-year follow-up period.

Methods: Patients referred for colonoscopy (n = 1,263) to the Umeå University Hospital endoscopy unit between 2007 and 2013 performed a FC test (CALPRO®) on the day before bowel preparation. A medical chart review was performed on all patients who had normal findings on their colonoscopy (n = 585, median age 64 years).

Results: Thirty-four percent of the patients (n = 202) with normal colonoscopy had elevated FC (>50 μg/g), and these patients were more frequently diagnosed with upper GI disease during the follow-up period than patients with normal FC levels (9.9 vs. 4.7%; p = 0.015). The upper GI diseases were mainly benign (i.e., gastritis). In a binary logistic regression analysis controlling for age, gender, nonsteroid anti-inflammatory drug use, and proton-pump inhibitor use, there was no difference for a new diagnosis of upper GI disease in the follow-up period (multivariate OR 1.70; 95% CI: 0.77–3.74). There was no difference in a new diagnosis of lower GI disease (6.4 vs. 5.2%; p = 0.545) or cardiovascular disease/death (multivariate OR 1.68; 95% CI: 0.83–3.42) in the follow-up period between patients with elevated versus normal FC levels.

Conclusions: In patients with a normal colonoscopy, a simultaneously measured increased FC level was not associated with an increased risk for significant GI disease during a follow-up period of 3 years.

Place, publisher, year, edition, pages
S. Karger, 2021
Keywords
Faecal calprotectin, Colonoscopy, Cardiovascular disease, Colorectal cancer, Diverticular disease, Esophagitis, Gastritis, Inflammatory bowel disease
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:umu:diva-186650 (URN)10.1159/000513473 (DOI)2-s2.0-85114030310 (Scopus ID)
Available from: 2021-08-16 Created: 2021-08-16 Last updated: 2025-02-11Bibliographically approved
4. Pre-diagnostic markers in inflammatory bowel disease: A nested case-control study
Open this publication in new window or tab >>Pre-diagnostic markers in inflammatory bowel disease: A nested case-control study
(English)Manuscript (preprint) (Other academic)
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:umu:diva-186653 (URN)
Available from: 2021-08-16 Created: 2021-08-16 Last updated: 2025-02-11

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