Martin Olesen

Microscopic colitis: a common diarrhoeal disease. An epidemiological study in Örebro, Sweden, 1993–1998

Background: Microscopic colitis, including collagenous colitis and lymphocytic colitis, mainly affects middle aged and older subjects, with a female predominance in collagenous colitis. The diseases have previously been regarded as rare. We present an epidemiological study of microscopic colitis in a well defined Swedish population. Methods: Patients were retrospectively searched for in colonoscopy reports of those who had a colonoscopy in the period 1993–1998 for non-bloody diarrhoea. All colonic mucosal biopsies were reassessed using strict diagnostic criteria. Results: Biopsies from 1018 patients were reassessed. Fifty one (45 female) collagenous colitis patients and 46 (31 female) lymphocytic colitis patients were diagnosed. Median age at diagnosis was 64 years in collagenous colitis and 59 years in lymphocytic colitis. The mean annual incidence of collagenous colitis was 4.9/105 inhabitants (95% confidence interval (CI) 3.6–6.2/105) and of lymphocytic colitis 4.4/105 inhabitants (95% CI 3.1–5.7/105). The annual incidence of collagenous colitis increased from 3.7/105 in 1993–1995 to 6.1/105 in 1996–1998 (difference 2.4/105 (95% CI −0.3–5.1/105)) whereas the incidence of lymphocytic colitis increased from 3.1/105 to 5.7/105 (difference 2.6/105 (95% CI 0.1–5.2/105)). Conclusions: The annual incidences of collagenous colitis and lymphocytic colitis are higher than considered previously and are now equal to the incidence of Crohn’s disease in Sweden, and combined rates approach the incidence of ulcerative colitis. Microscopic colitis was diagnosed in 10% of all patients with non-bloody diarrhoea referred for colonoscopy and in almost 20% of those older than 70 years.

Lymphocytic colitis: a retrospective clinical study of 199 Swedish patients

Background: Lymphocytic colitis is characterised by chronic diarrhoea and specific microscopic changes in a macroscopically normal colonic mucosa. We report clinical features and treatment outcome in a large patient cohort. Methods: Patients were searched for in 24 Swedish gastroenterology clinics. The biopsy material was reassessed using strict histopathological criteria. Clinical data were obtained from medical notes. Results: Lymphocytic colitis was diagnosed in 199 cases. The female:male ratio was 2.4:1. Median age at diagnosis was 59 (48–70) years. The most frequent symptoms were diarrhoea (96%), abdominal pain (47%), and weight loss (41%). The course was chronic intermittent in 30% of patients, chronic continuous in 7%, and a single attack in 63%, and in these cases the disease duration was 6 (4–11) months. Seventy nine (40%) patients reported associated diseases, of which thyroid disorders, coeliac disease, and diabetes mellitus were the most common. In 34 first or second degree relatives of 24 (12%) patients, a family history of ulcerative colitis, Crohn’s disease, collagenous colitis, or coeliac disease was reported. Drug induced disease was suspected in 19 (10%) patients. A non-significant peak of disease onset was seen in December-January. More than 80% of treated patients improved on corticosteroids, including budesonide. Conclusions: A family history of other bowel disorders is a new finding. The sudden onset and single attack of limited duration may support a possible infectious cause in some cases. Drugs may cause lymphocytic colitis.

Familial occurrence of microscopic colitis: a report on five families.

BACKGROUND The etiology and pathogenesis of microscopic colitis is unknown. Whether genetic predisposition is of importance, as in many other gastrointestinal diseases, is unknown. Familial occurrence of collagenous colitis has earlier been reported only in two families. METHODS Familial occurrence of microscopic colitis was searched for in a Swedish national microscopic colitis register. RESULTS Familial occurrence of microscopic colitis was identified in five families. In all families a sister-sister relationship was found. Two sisters with collagenous colitis had been living apart in different Nordic countries for many years before developing the disease. In one pair, the smoking sister had collagenous colitis and the never smoking sister had lymphocytic colitis. CONCLUSIONS Considering the relative rarity of microscopic colitis, these findings indicate that a genetic predisposition may be of importance.Background: The etiology and pathogenesis of microscopic colitis is unknown. Whether genetic predisposition is of importance, as in many other gastrointestinal diseases, is unknown. Familial occurrence of collagenous colitis has earlier been reported only in two families. Methods: Familial occurrence of microscopic colitis was searched for in a Swedish national microscopic colitis register. Results: Familial occurrence of microscopic colitis was identified in five families. In all families a sister- sister relationship was found. Two sisters with collagenous colitis had been living apart in different Nordic countries for many years before developing the disease. In one pair, the smoking sister had collagenous colitis and the never smoking sister had lymphocytic colitis. Conclusions: Considering the relative rarity of microscopic colitis, these findings indicate that a genetic predisposition may be of importance.

Luminal nitric oxide and epithelial expression of inducible and endothelial nitric oxide synthase in collagenous and lymphocytic colitis

BACKGROUND Colonic nitric oxide (NO) production in collagenous colitis (CC) has been studied in a small number of patients and found increased. The cellular source of NO is believed to be the colonic epithelial cells. The aim of this study was to investigate colonic NO levels in patients with CC and lymphocytic colitis (LC), to compare with the histopathological status and with the clinical activity, and to assess the epithelial expression of inducible and endothelial nitric oxide synthase (iNOS and eNOS). METHODS We included 19 patients with CC, 8 patients with LC and 15 controls. During colonoscopy, luminal gas was sampled and NO levels were measured using the chemiluminescence technique. Mucosal biopsies were obtained for routine histopathologic examination and immunohistochemical studies of iNOS and eNOS. Clinical activity, as measured by the mean frequency of daily bowel movements during the week prior to colonoscopy, was assessed. RESULTS Luminal NO levels, median (25-75 percentiles), in the patients with CC and LC were greatly increased compared to the controls, 1673 (145-8143) parts per billion (ppb) and 1838 (1065-2694) ppb versus 28 (20-46) ppb (P < 0.005, both). A positive association was seen between NO levels and histopathological status as well as clinical activity. Strong expression of iNOS was seen in the surface epithelium in 5 of 6 patients with CC and in 2 of 5 patients with LC. CONCLUSIONS The fact that luminal NO levels are related to histopathological status and correlate with clinical activity indicates that NO is involved in the pathophysiology of CC and LC. The epithelial cells are the most likely source of luminal NO.

An epidemiological study of collagenous colitis in southern Sweden from 2001-2010.

AIM To estimate the incidence of collagenous colitis (CC) in southern Sweden during 2001-2010. METHODS Cases were identified by searching for CC in the diagnostic registers at the Pathology Departments in the county of Skåne. The catchment area comprised the south-west part of the county (394 307 inhabitants in 2010) and is a mixed urban and rural type with limited migration. CC patients that had undergone colonoscopy during the defined period and were living in this area were included in the study regardless of where in Skåne they had been diagnosed. Medical records were scrutinized and uncertain cases were reassessed to ensure that only newly diagnosed CC cases were included. The diagnosis of CC was based on both clinical and histopathological criteria. The clinical criterion was non-bloody watery diarrhoea. The histopathological criteria were a chronic inflammatory infiltrate in the lamina propria, a thickened subepithelial collagen layer ≥ 10 micrometers (μm) and epithelial damage such as flattening and detachment. RESULTS During the ten year period from 2001-2010, 198 CC patients in the south-west part of the county of Skåne in southern Sweden were newly diagnosed. Of these, 146 were women and 52 were men, i.e., a female: male ratio of 2.8:1. The median age at diagnosis was 71 years (range 28-95/inter-quartile range 59-81); for women median age was 71 (range 28-95) years and was 73 (range 48-92) years for men. The mean annual incidence was 5.4/10(5) inhabitants. During the time periods 2001-2005 and 2006-2010, the mean annual incidence rates were 5.4/10(5) for both periods [95% confidence interval (CI): 4.3-6.5 in 2001-2005 and 4.4-6.4 in 2006-2010, respectively, and 4.7-6.2 for the whole period]. Although the incidence varied over the years (minimum 3.7 to maximum 6.7/10(5)) no increase or decrease in the incidence could be identified. The odds ratio (OR) for CC in women compared to men was estimated to be 2.8 (95% CI: 2.0-3.7). The OR for women 65 years of age or above compared to below 65 years of age was 6.9 (95% CI: 5.0-9.7), and for women 65 years of age or above compared to the whole group the OR was 4.7 (95% CI: 3.6-6.0). The OR for age in general, i.e., above or 65 years of age compared to those younger than 65 was 8.3 (95% CI: 6.2-11.1). During the last decade incidence figures for CC have also been reported from Calgary, Canada during 2002-2004 (4.6/10(5)) and from Terrassa, Spain during 2004-2008 (2.6/10(5)). Our incidence figures from southern Sweden during 2001-2010 (5.4/10(5)) as well as the incidence figures presented in the studies during the 1990s (Terrassa, Spain during 1993-1997 (2.3/10(5)), Olmsted, United States during 1985-2001 (3.1/10(5)), Örebro, Sweden during 1993-1998 (4.9/10(5)), and Iceland during 1995-1999 (5.2/10(5)) are all in line with a north-south gradient, something that has been suggested before both for CC and inflammatory bowel disease. CONCLUSION The observed incidence of CC is comparable with previous reports from northern Europe and America. The incidence is stable but the female: male ratio seems to be decreasing.

Low-dose budesonide for maintenance of clinical remission in collagenous colitis: a randomised, placebo-controlled, 12-month trial

Objective This 1-year study aimed to assess low-dose budesonide therapy for maintenance of clinical remission in patients with collagenous colitis. Design A prospective, randomised, placebo-controlled study beginning with an 8-week open-label induction phase in which patients with histologically confirmed active collagenous colitis received budesonide (Budenofalk, 9 mg/day initially, tapered to 4.5 mg/day), after which 92 patients in clinical remission were randomised to budesonide (mean dose 4.5 mg/day; Budenofalk 3 mg capsules, two or one capsule on alternate days) or placebo in a 12-month double-blind phase with 6 months treatment-free follow-up. Primary endpoint was clinical remission throughout the double-blind phase. Results Clinical remission during open-label treatment was achieved by 84.5% (93/110 patients). The median time to remission was 10.5 days (95% CI (9.0 to 14.0 days)). The maintenance of clinical remission at 1 year was achieved by 61.4% (27/44 patients) in the budesonide group versus 16.7% (8/48 patients) receiving placebo (treatment difference 44.5% in favour of budesonide; 95% CI (26.9% to 62.7%), p<0.001). Health-related quality of life was maintained during the 12-month double-blind phase in budesonide-treated patients. During treatment-free follow-up, 82.1% (23/28 patients) formerly receiving budesonide relapsed after study drug discontinuation. Low-dose budesonide over 1 year resulted in few suspected adverse drug reactions (7/44 patients), all non-serious. Conclusions Budesonide at a mean dose of 4.5 mg/day maintained clinical remission for at least 1 year in the majority of patients with collagenous colitis and preserved health-related quality of life without safety concerns. Treatment extension with low-dose budesonide beyond 1 year may be beneficial given the high relapse rate after budesonide discontinuation. Trial registration numbers http://www.clinicaltrials.gov (NCT01278082) and http://www.clinicaltrialsregister.eu (EudraCT: 2007-001315-31).

Altered microbiota in microscopic colitis

Recently, Shin et al 1 reported that Akkermansia spp had a beneficial effect on glucose homeostasis in obese mice. Mucin degrading Akkermansia —promoting mucin degradation and turnover—is associated with a healthy mucosa. In IBD, a deranged microbiota is reported while findings in microscopic colitis (MC) are lacking. MC is a disorder characterised by chronic non-bloody diarrhoea, predominantly affecting elderly smoking women. Despite frequent diarrhoea, laboratory anomalies are seldom seen. Since an altered microbiota is reported in several immune mediated diseases and since MC affects the gut, our hypothesis was that the microbiota would be altered in patients with MC. A group of 10 female patients (mean age 48 years, range 43–68 years) with onset of MC collected as previously described2 donated faecal samples that were compared with samples from seven healthy control women (mean age 50 years, range 45–65 years) with respect to their faecal microbiota. The bacterial microbiome was analysed by DNA sequencing (Illumina Hiseq 2000) and sequences were aligned to a …

Are collagenous and lymphocytic colitis different aspects of the same disease

Abstract Objective. Collagenous colitis (CC) and lymphocytic colitis (LC) are two subtypes of microscopic colitis (MC). Even though they most often are described as different entities they share many clinical and histological features. The aim of this study was to investigate the occurrence of conversion between CC and LC in a larger cohort of patients. Materials and methods. All 664 patients in our Pathology register with a diagnosis of CC and LC were scrutinized and those where additional endoscopies had been carried out were included, and their biopsies were re-examined. Results. Sixty-five patients (55 women, 10 men, median age 58 years; range 29–86) fulfilled our criteria for inclusion. The primary diagnosis was CC in 47 patients (39 women, 8 men, median age 58 years; range 29–86) and LC in 18 patients (16 women, 2 men, median age 58 years; range 33–74). Conversion occurred in nine of the 65 patients (14%, all women, median age 59 years; range 41–72), three from CC to LC and six from LC to CC. Conclusion. This study has found that patients can show histological features consistent with both CC and LC over time. These patients could represent a subgroup with a true conversion between two separate entities. Alternatively, MC could be a spectral disease where the varying histological features are manifestations of the natural fluctuation. A third possibility could be that the histological changes reflect different manifestations during the disease course and consequently, the diagnostic criteria could be too vague.

Elevated fecal levels of eosinophil granule proteins predict collagenous colitis in patients referred to colonoscopy due to chronic non-bloody diarrhea

Abstract Objective: Colonoscopy with biopsy sampling is often performed to detect collagenous colitis (CC) and lymphocytic colitis (LC) in patients with chronic non-bloody diarrhea. However, the diagnostic yield is low and incurs high costs. Fecal calprotectin (FC) and myeloperoxidase (MPO) indicate intestinal inflammation in ulcerative colitis (UC) and Crohn’s disease (CD). In CC, elevated fecal levels of eosinophil protein X (EPX) and eosinophil cationic protein (ECP) have been reported. We aimed to evaluate if F-EPX, F-ECP, FC, and F-MPO could predict the diagnostic outcome in patients with chronic non-bloody diarrhea referred to colonoscopy. We also evaluated serum (S) EPX and ECP in this regard. Methods: Of 67 included patients, 63 (94%) underwent colonoscopy with biopsy sampling. Fecal EPX, F-ECP, FC, F-MPO, S-EPX, and S-ECP were analyzed. Results: Diagnostic outcome: normal: n = 46 (73%), CC: n = 9 (14%), LC: n = 4 (6%), UC: n = 2 (3%), CD: n = 2 (3%). Higher levels of F-EPX and F-ECP were found in CC compared to a normal diagnostic outcome (p = 0.01). No change was noted in any of the fecal markers in LC. When all of the fecal markers were normal the probability of a normal diagnostic outcome was 92%. We found no differences in S-EPX and S-ECP between the groups. Conclusion: Elevated F-EPX and F-ECP could predict CC. None of the fecal markers predicted LC. Serum-EPX and S-ECP are not useful for the diagnosis of CC, LC, UC, or CD. With normal levels in all of the analyzed fecal markers, there is a low probability of a pathologic diagnostic outcome.