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

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.

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).

Chronic non-bloody diarrhoea: a prospective study in Malmö, Sweden, with focus on microscopic colitis.

BACKGROUND: Chronic non-bloody diarrhoea affects up to 5% of the population. Microscopic colitis is one of the most common causes, encompassing the subtypes collagenous colitis and lymphocytic colitis. The diagnosis of microscopic colitis is made by histological examination of colonic mucosal biopsy specimens. The aim of this investigation was to determine whether laboratory parameters or questions about disease history or concomitant disease could be helpful in discriminating patients with MC from those with a histologically normal colonic mucosa. FINDINGS: Patients admitted for colonoscopy because of chronic non-bloody diarrhoea (>2 loose stools for >3 weeks) at endoscopy units in Malmö during 2007 and 2009, were enrolled. A total number of 78 patients were included (60 women, 18 men, median age 59, IQR 45-69 years). Out of these 78, 15 patients (19%) had microscopic colitis (CC; n = 10, LC; n = 5). MC was especially prevalent in patients above the age of 50 (25%). No differences were found between those with normal histology and MC in laboratory analyses (inflammatory and liver parameters). Neither were differences shown in questions regarding symptoms, environmental factors or concomitant diseases except for an association with celiac disease (p = 0.019) and a trend maybe indicating an inverse association with appendectomy (p = 0.057). CONCLUSIONS: Microscopic colitis is associated with female gender, celiac disease and consumption of NSAIDs. Trends were observed indicating that age above 50 years, acute onset and absence of appendectomy may be associated with MC. No associations were observed with other symptoms, calprotectin levels or liver parameters.

Celiac disease and other autoimmune diseases in patients with collagenous colitis.

BACKGROUND AND AIMS: Collagenous colitis (CC) is associated with autoimmune disorders. The aim of the present study was to investigate the relationship between CC and autoimmune disorders in a Swedish multicenter study. METHODS: Patients with CC answered questionnaires about demographic data and disease activity. The patient's files were scrutinized for information about autoimmune diseases. RESULTS: A total number of 116 CC patients were included; 92 women, 24 men, median age 62 years (IQR 55-73). In total, 30.2% had one or more autoimmune disorder. Most common were celiac disease (CeD; 12.9%) and autoimmune thyroid disease (ATD, 10.3%), but they also had Sjögren's syndrome (3.4%), diabetes mellitus (1.7%) and conditions in skin and joints (6.0%). Patients with associated autoimmune disease had more often nocturnal stools. The majority of the patients with associated CeD or ATD got these diagnoses before the colitis diagnosis. CONCLUSION: Autoimmune disorders occurred in one-third of these patients, especially CeD. In classic inflammatory bowel disease (IBD), liver disease is described in contrast to CC where no cases occurred. Instead, CeD was prevalent, a condition not reported in classic IBD. Patients with an associated autoimmune disease had more symptoms. Patients with CC and CeD had an earlier onset of their colitis. The majority of the patients with both CC and CeD were smokers. Associated autoimmune disease should be contemplated in the follow-up of these patients.

Are collagenous and lymphocytic colitis different aspects of the same disease?

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.

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.

Mucosa-associated bacteria in two middle-aged women diagnosed with collagenous colitis.

AIM: To characterize the colon microbiota in two women histologically diagnosed with collagenous colitis using a culture-independent method. METHODS: Biopsies were taken from the ascending colon and the total DNA was extracted. Universal bacterial primers were used to amplify the bacterial 16S rRNA genes. The amplicons were then cloned into competent Escherichia coli cells. The clones were sequenced and identified by comparison to known sequences. RESULTS: The clones could be divided into 44 different phylotypes. The microbiota was dominated by Firmicutes and Bacteroidetes. Seven phylotypes were found in both patients and constituted 47.5% of the total number of clones. Of these, the most dominating were clones similar to Bacteroides cellulosilyticus, Bacteroides caccae, Bacteroides thetaiotaomicron, Bacteroides uniformis and Bacteroides dorei within Bacteroidetes. Sequences similar to Faecalibacterium prausnitzii and Clostridium citroniae were also found in both patients. CONCLUSION: A predominance of potentially pathogenic Bacteroides spp., and the presence of clones showing similarity to Clostridium clostridioforme were found but the overall colon microbiota showed similarities to a healthy one. Etiologies for collagenous colitis other than an adverse bacterial flora must also be considered.

Is smoking a risk factor for collagenous colitis?

OBJECTIVE: The association between smoking and idiopathic inflammatory bowel disease is well known; smoking seems to have a diverse effect. Crohn's disease is associated with smoking, while ulcerative colitis is associated with non-smoking. Data on smoking in microscopic colitis of the collagenous type (CC) are lacking. The aim of this investigation was to study smoking habits in CC and to observe whether smoking had any impact on the course of the disease. MATERIALS AND METHODS: 116 patients (92 women) with median age of 62 years (interquartile range 55-73) answered questionnaires covering demographic data, smoking habits and disease activity. As control group we used data from the general population in Sweden retrieved from Statistics Sweden, the central bureau for national socioeconomic information. RESULTS: Of the 116 CC patients, 37% were smokers compared with 17% of controls (p < 0.001, odds ratio (OR) 2.95). In the age group 16-44 years, 75% of CC patients were smokers compared with 15% of controls (p < 0.001, OR 16.54). All CC smoker patients started smoking before the onset of disease. Furthermore, smokers developed the disease earlier than non-smokers--at 42 years of age (median) compared with 56 years in non-smokers (p < 0.003). Although the proportion with active disease did not differ between smokers and non-smokers, there was a trend indicating that more smokers received active treatment (42% vs. 17%, p = 0.078). CONCLUSIONS: Smoking is a risk factor for CC. Smokers develop their disease more than 10 years earlier than non-smokers.

The Lactobacillus flora in vagina and rectum of fertile and postmenopausal healthy Swedish women.

BACKGROUND: Lactobacillus species are the most often found inhabitants of vaginal ecosystem of fertile women. In postmenopausal women with low oestrogen levels, Lactobacillus flora is diminishing or absent. However, no studies have been performed to investigate the correlation between oestrogen levels and the lactobacilli in the gut. The aim of the present study was to investigate the relation in healthy women between vaginal and rectal microbial flora as well as possible variations with hormone levels. METHODS: Vaginal and rectal smears were taken from 20 healthy fertile women, average 40 years (range 28-49 years), in two different phases of the menstrual cycle, and from 20 postmenopausal women, average 60 years (range 52-85 years). Serum sex hormone levels were analyzed. Bacteria from the smears isolated on Rogosa Agar were grouped by Randomly Amplified Polymorphic DNA and identified by multiplex PCR and partial 16S rRNA gene sequencing. RESULTS: Lactobacillus crispatus was more often found in the vaginal flora of fertile women than in that of postmenopausal (p = 0.036). Fifteen of 20 fertile women had lactobacilli in their rectal smears compared to 10 postmenopausal women (p = 0.071). There was no correlation between the number of bacteria in vagina and rectum, or between the number of bacteria and hormonal levels. Neither could any association between the presence of rectal lactobacilli and hormonal levels be found. CONCLUSION: Lactobacillus crispatus was more prevalent in the vaginal flora of fertile women, whereas the Lactobacillus flora of rectum did not correlate to the vaginal flora nor to hormonal levels.

Health-related quality of life is impaired in active collagenous colitis.

OBJECTIVES: The characteristic clinical symptoms of collagenous colitis are non-bloody diarrhoea, urgency and abdominal pain. Treatment is aimed at reducing the symptom burden and the disease impact on patients' health-related quality of life. The objective of this study was to analyse health-related quality of life in patients with collagenous colitis. METHODS: In a cross-sectional, postal HRQL survey, 116 patients with collagenous colitis at four Swedish hospitals completed four health-related quality of life questionnaires, two disease-specific (Inflammatory Bowel Disease Questionnaire and Rating Form of IBD Patient Concerns), and two generic (Short Form 36, SF-36, and Psychological General Well-Being, PGWB), and a one-week symptom diary. Demographic and disease-related data were collected. Results for the collagenous colitis population were compared with a background population controlled for age and gender (n = 8931). RESULTS: Compared with a Swedish background population, patients with collagenous colitis scored significantly worse in all Short Form 36 dimensions (p < 0.01), except physical function. Patients with active disease scored worse health-related quality of life than patients in remission. Co-existing disease had an impact on health-related quality of life measured with the generic measures. Lower education level and shorter disease duration were associated with decreased well-being. CONCLUSION: Health-related quality of life was impaired in patients with collagenous colitis compared with a background population. Disease activity is the most important factor associated with impairment of health-related quality of life. Patients in remission have a health-related quality of life similar to a background population.

Defining clinical criteria for clinical remission and disease activity in collagenous colitis.

BACKGROUND: Collagenous colitis is a chronic inflammatory bowel disease accompanied mainly by nonbloody diarrhea. The objectives of treatment are to alleviate the symptoms and minimize the deleterious effects on health-related quality of life (HRQOL). There is still no generally accepted clinical definition of remission or relapse. The purpose of this study was to analyze the impact of bowel symptoms on HRQOL and accordingly suggest criteria for remission and disease activity based on impact of patient symptoms on HRQOL. METHODS: The design was a cross-sectional postal survey of 116 patients with collagenous colitis. The main outcome measures were 4 HRQOL questionnaires: the Short Health Scale, the Inflammatory Bowel Disease Questionnaire, the Rating Form of IBD Patient Concerns, and the Psychological General Well-Being Index, and a 1-week symptom diary recording number of stools/day and number of watery stools/day. RESULTS: Severity of bowel symptoms had a deleterious impact on patients' HRQOL. Patients with a mean of ≥3 stools/day or a mean of ≥1 watery stool/day had a significantly impaired HRQOL compared to those with <3 stools/day and <1 watery stool/day. CONCLUSIONS: We propose that clinical remission in collagenous colitis is defined as a mean of <3 stools/day and a mean of <1 watery stool per day and disease activity to be a daily mean of ≥3 stools or a mean of ≥1 watery stool.

Does smoking influence the risk of pouchitis following ileal pouch anal anastomosis for ulcerative colitis?

OBJECTIVE: According to epidemiological studies, smoking habit is strongly associated with inflammatory bowel disease. Non-smokers, and especially recent ex-smokers, have an increased risk of ulcerative colitis (UC). Conversely, concerning Crohn's disease, the risk is increased among smokers. Pouchitis is the major long-term complication of restorative proctocolectomy for UC, and seems to be pathogenetically related to this condition. The aims of this study were to test the hypothesis that smoking reduces the risk of pouchitis, and to investigate whether cessation of smoking precedes the onset of the inflammation. MATERIAL AND METHODS: All living patients operated on for UC with proctocolectomy and ileal pouch anal anastomosis (IPAA) between November 1982 and November 1996 at Sahlgren's University Hospital were included in the study (n=410). Data concerning smoking habits and pouchitis were obtained from questionnaires and from medical records. The correlation between smoking habits and incidence of pouchitis was statistically evaluated by means of a survival test and a multivariate analysis, i.e. a Poisson model. RESULTS: In all, 327 patients (80%) completed the questionnaires. Ninety-six (29%) of these patients had had at least one episode of pouchitis. Smoking habits during follow-up did not significantly influence the risk of pouchitis (p=0.29). Nor did smoking habits before and at the time of IPAA correlate with the incidence of pouchitis. Women had a decreased risk of pouchitis, compared to men (p=0.014). There was a non-significant tendency for smoking to increase the risk, which was more pronounced in women. CONCLUSIONS: Smoking does not decrease the risk of pouchitis following IPAA for UC, and in this respect the pathogenetic model of pouchitis, suggested to be a manifestation of UC, is not supported.

Multiple displacement amplification of DNA from human colon and rectum biopsies: bacterial profiling and identification of Helicobacter pylori-DNA by means of 16S rDNA-based TTGE and pyrosequencing analysis.

Amplifying bacterial DNA by PCR from human biopsy specimens has sometimes proved to be difficult, mainly due to the low amount of bacterial DNA present. Therefore, nested or semi-nested 16S rDNA PCR amplification has been the method of choice. In this study, we evaluate the potential use of whole genome amplification of total DNA isolated from human colon and rectum biopsy specimens, followed by 16S rDNA PCR amplification of multiple displacement amplified (MDA)-DNA. Subsequently, a H. pylori-specific 16S rDNA variable V3 region PCR assay was applied directly on MDA-DNA and, combined with pyrosequencing analysis; the presence of H. pylori in some biopsies from colon in patients with microscopic colitis was confirmed. Furthermore, temporal temperature gradient gel electrophoresis (TTGE) of 16S rDNA amplicons using primers flanking variable regions V3, V4, and V9, was used to establish bacterial profiles from individual biopsies. A variation of the bacterial profiles in the colonic mucosa in microscopic colitis and in normal rectal mucosa was observed. In conclusion we find the MDA technique to be a useful method to overcome the problem of insufficient bacterial DNA in human biopsy specimens.

[The enteroscopy capsule--a swallowable instrument for video examination of the small bowel]. / Enteroskopikapseln--sväljbart engångsinstrument för videoundersökning av tunntarmen.

Since 1.5 years wireless enteroscopy with the GivenM2A-capsule has been tested clinically. Wireless capsule-enteroscopy (WCE) has already contributed significantly to the understanding of patients with obscure intestinal symptoms. Series of occult bleeders show that WCE detects lesions in 60%, whereas enterography only in 15%, and push-enteroscopy in 25%. Lesions detected are angiodysplasia in 55%, ulcerations in 14%, apthoid lesions and erosions in 11%, tumours in 8%. Active bleeding was seen in 43%. In patients with Crohn's disease further information on extent of disease and type of lesions is gained, mainly seen as erosions in 64%. WCE in hereditary polyposis disclosed more and bigger lesions, and in celiac enteropathy villous atrophy and scalloping of the mucous membrane is readily identified. Software to locate the capsule in the gastrointestinal tract is recently launched together with a graphic display of capsule track and transit times. Soon displays for motility and pressure will follow. Capsule adaptation for screening for Barrett's esophagus and colon cancer might come true.