The significance of low-grade inflammation in the gastrointestinal tract

Abstract: BackgroundGastrointestinal (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.AimThe 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 resultsThree 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.ConclusionPatients 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.