Microscopic colitis:A large retrospective analysis from a health maintenance organization experience

AIM： To examine the demographic data on a large multi-ethnic population of patients with microscopic colitis （MC） in Southern California and to determine the association of MC with inflammatory bowel disease （IBD） and colorectal cancer. METHODS： All patients diagnosed with MC by co- Ionic biopsy from 1996-2005 were identified utilizing a pathology database. All biopsies were reviewed by experienced pathologists utilizing standard histologic criteria. Patients＇ medical records were reviewed and data regarding patient age, co-morbidities, sex, ethnic- ity, and medications were analyzed. An age- and sex- matched standard control group was also generated. Chi-square test was used to evaluate the associations of co-morbidities between lymphocytic colitis （LC）, col- lagenous colitis （CC） and the control group. RESULTS： A total of 547 cases of MC were identified, 376 patients with LC and 171 patients with CC. The fe- male/male ratio was 3：1 in CC and 2.7：1 in LC patients. Celiac disease （P 〈 0.001）, irritable bowel syndrome （IBS） （P 〈 0.001）, and thyroid diseases （P 〈 0.001） were found to have a higher occurrence in MC com- pared to the control group. No statistical differences in the occurrence of colorectal cancer, diabetes and IBD were found between the MC group and the control group. CONCLUSION： This is the largest group of patients with MC known to the authors that has been studied to date. Conditions such as celiac disease, IBS, and thyroid diseases were found to be related to MC. Fur- thermore, neither an increased risk of colorectal cancer nor IBD was associated with MC in this study.

Is there an association of microscopic colitis and irritable bowel syndrome-A subgroup analysis of placebo-controlled trials

With great interest we read the recent retrospectice study by Barta et al （1） dealing with the clinical presentation of patients with microscopic colitis. They investigated in a cohort of 53 patients with microscopic colitis （46 with collagenous colitis, 7 with lymphocytic colitis） the relationship between microscopic colitis and both constipation and diarrhea. One of their mean finding was that abdominal pain, diarrhea and constipation was a common symptom complex of patients with microscopic colitis, thus the face of microcopic colitis resembles the subgroups of irritable bowel syndrome （IBS）.

Microscopic colitis: A retrospective study of clinical presentation in 53 patients

AIM: To evaluate the relationship between symptoms and microscopic colitis (MC) subtypes: to test whether collagenous colitis (CC) and/or lymphocytic colitis (LC)might be related to both constipation and diarrhea.METHODS: A cohort of patients with independently confirmed typical histopathological changes was investigated. Fifty-three patients with histologically proved MC (46 with CC, 7 with LC) were included. The existence of diarrhea or constipation and the co-existence of autoimmune diseases were also investigated and all data were retrospectively analyzed.RESULTS: Twenty-three (43.39%) of MC patients had chronic constipation (20 in CC, 3 in LC patients). Twentyfour(45.28%) of MC patients had autoimmune disease and the diagnosis of autoimmune disease was always prior to MC. Sjogren's syndrome was associated only with the constipation subgroup.CONCLUSION: The Janus face of MC resembles the subgroups of irritable bowel syndrome. The co-existence of autoimmune diseases and MC is confirmed in both the constipation and diarrhea subgroups.

Microscopic colitis as a missed cause of chronic diarrhea

AIM: To determine the prevalence of increased intraepithelial lymphocytes, using immunohistochemistry in patients with normal colonoscopy and near normal biopsy. METHODS: We retrospectively reviewed all non-malignant colon mucosal biopsies between 2005 and 2007, reported as normal, chronic inflammation or melanosis coli in patients who were undergoing routine colonoscopy. Immunohistochemistry using CD3 was performed on all mucosal biopsies and an intraepithelial lymphocyte count (IEL) was determined. Cases with an IEL count of ≥ 20 IELs per 100 surface epithelial cells were correlated with demographic, clinical and follow-up data. A further subgroup was evaluated for lymphocytic colitis.RESULTS: Twenty (8.3%) of 241 cases revealed an IEL count ≥ 20. Six (2.5%) patients were identified as having lymphocytic colitis (P < 0.001), of whom, five were missed on initial evaluation (P = 0.01). Four of these five patients were labeled with diarrhea-predominant irritable bowel syndrome (IBS). On follow-up, three of the remaining 20 cases were diagnosed with malignancy (renal cell carcinoma and myelodysplastic syndrome) and one had an unknown primary tumor with multiple liver metastases. Two cases of collagenous colitis with an IEL count < 10 were included in this study. Increased IELs were not confined to patients with diarrhea as a primary presenting symptom, but were also present in patients with abdominal pain (n = 7), constipation (n = 3) and loss of weight (n = 1). CONCLUSION: Immunohistochemistry using CD3 is of value in identifying and quantifying IELs for the presence of microscopic colitis in patients with diarrheapredominant IBS.

Clear cell colitis: A form of microscopic colitis in children

AIM: To describe a new clinical and pathological subtype of microscopic colitis in children. METHODS: A selected group of children with abdominal pain, constipation and/or diarrhoea showing discrete or no macroscopic abnormalities on endoscopy was described. RESULTS: Multiple biopsies of colon showed large mononuclear clear cells in lamina propria of mucous membrane provided that good quality histological sections were performed and observed under a higher magnification. Otherwise, they could be misinterpreted as artefacts. Their presence in routine histology might suggest a systemic storage disease (Whipple’s disease), and neuronal intestine dysplasia. Using immunohistochemical staining and electron microscopy we confirmed their origin from CD68 positive mononuclear macrophages. CONCLUSION: The presence of large clear cells is a constant microscopic feature. Failure of transient large bowel stationary macrophages plays a role in the pathogenesis of this benign microscopic clear cell colitis, sometimes coexisting with allergy.

Distinct colonoscopy findings of microscopic colitis:Not so microscopic after all?

Microscopic colitis(MC) is considered an "umbrella term",comprising two subtypes,i.e.,collagenous colitis(CC) and lymphocytic colitis(LC).They are classically associated with normal or unremarkable colonoscopy.In the last few years,reports have been published revealing findings that are thought to be characteristic or pathognomonic of MC,especially CC.A systematic electronic and manual search of PubMed and EMBASE(to December 2010),for publications on distinct endoscopic findings in MC,resulted in 42 relevant reports for inclusion in this review.Eighty eight patients with collagenous colitis were presented.Only one publication describing a distinct endoscopic pattern in LC was found.Typical findings in CC are alteration of the vascular mucosal pattern,mucosal nodularity,a sequence of change from mucosal defects to mucosal cicatricial lesions,and perhaps(although of doubtful relevance) mucosal pseudomembranes.A causal connection of mucosal defects with the use of lansoprazole seems to exist.Adoption of the proposed lesion description herein is recommended in order to improve homogeneity of future reports.

Diagnosis and management of microscopic colitis

Microscopic colitis, comprising collagenous and lymphocytic colitis, is characterized clinically by chronic watery diarrhea, and a macroscopically normal colonic mucosa where diagnostic histopathological features are seen on microscoplc incidence of each disorder examination. The annual is 4-6/100000 inhabitants, with a peak incidence in 60-70-year-old individuals and a noticeable female predominance for collagenous colitis. The etiology is unknown. Chronic diarrhea, abdominal pain, weight loss, fatigue and fecal incontinence are common symptoms, which impair the health-related quality of life of the patient. There is an association with other autoimmune disorders such as celiac disease, diabetes mellitus, thyroid disorders and arthritis. Budesonide is the best-documented shortterm treatment, but the optimal long-term strategy needs further study. The long-term prognosis is good and the risk of complications including colonic cancer is low.

Microscopic colitis

Microscopic colitis may be defined as a clinical syndrome, of unknown etiology, consisting of chronic watery diarrhea, with no alterations in the large bowel at the endoscopic and radiologic evaluation. Therefore, a definitive diagnosis is only possible by histological analysis. The epidemiological impact of this disease has become increasingly clear in the last years, with most data coming from Western countries. Microscopic colitis includes two histological subtypes [collagenous colitis (CC) and lymphocytic colitis (LC)] with no differences in clinical presentation and management. Collagenous colitis is characterized by a thickening of the subepithelial collagen layer that is absent in LC. The main feature of LC is an increase of the density of intra-epithelial lymphocytes in the surface epithelium. A number of pathogenetic theories have been proposed over the years, involving the role of luminal agents, autoimmunity, eosinophils, genetics (human leukocyte antigen), biliary acids, infections, alterations of pericryptal fibroblasts, and drug intake; drugs like ticlopidine, carbamazepine or ranitidine are especially associated with the development of LC, while CC is more frequently linked to cimetidine, non-steroidal antiinflammatory drugs and lansoprazole. Microscopic colitis typically presents as chronic or intermittent watery diarrhea, that may be accompanied by symptoms such as abdominal pain, weight loss and incontinence. Recent evidence has added new pharmacological options for the treatment of microscopic colitis:the role of steroidal therapy, especially oral budesonide, has gained relevance, as well as immunosuppressive agents such as azathioprine and 6-mercaptopurine. The use of anti-tumor necrosis factoragents, infliximab and adalimumab, constitutes a new, interesting tool for the treatment of microscopic colitis, but larger, adequately designed studies are needed to confirm existing data.

Irritable bowel syndrome-like symptoms in treated microscopic colitis patients compared with controls:a cross-sectional study

Background:The prevalence of irritable bowel syndrome(IBS)-like symptoms is high in untreated patients with microscopic colitis(MC),but there is uncertainty of the prevalence of IBS-like symptoms in treated patients.We assessed the degree of IBS-like symptoms in patients with MC in comparison to control subjects,and investigated the association between IBS-like symptoms and faecal calprotectin(FC)in MC patients.Methods:Patients with an established MC diagnosis(n=57)were compared to sex-and age-matched controls(n=138)for scores in the GSRS-IBS(Gastrointestinal Symptom Rating Scale for Irritable Bowel Syndrome)and HADS(Hospital Anxiety Depression Scale).In MC patients,an FC level was simultaneously analysed.Results:The median interval from MC diagnoses to the time the subjects participated in the study was 5.5 years(25th-75th percentiles;4.5-9.5 years).The total GSRS-IBS score,subscores for abdominal pain,bloating,and diarrhoea were significantly higher in MC patients compared to controls(all P<0.001).There was a significant correlation between FC levels and reported bowel frequency(P=0.023),but there was no correlation between FC levels and GSRS-IBS scores.Patients with MC had significantly higher scores on anxiety(HADS-A)(P<0.001)and used more selective serotonin-reuptake-inhibitor drugs(P=0.016)than the control subjects.However,only the control subjects(not the patients with MC)showed significant correlations between GSRS-IBS scores and HADS scores.Conclusions:Patients with MC reported more IBS-like symptoms and anxiety than control subjects but neither FC levels nor symptoms of affectivity were significantly correlated with IBS-like symptoms.

Insights into the underlying mechanisms and clinical management of microscopic colitis in relation to other gastrointestinal disorders

Microscopic colitis(MC)is a chronic inflammatory disease of the large intestine and as a relatively late recognized condition,its relationship with other disorders of the gastrointestinal tract is gradually being understood and investigated.As a multifactorial disease,MC interacts with inflammatory bowel disease,celiac disease,and irritable bowel syndrome through genetic overlap,immunological factors,and gut microflora.The risk of colorectal cancer was significantly lower in MC,gastrointestinal infections increased the risk of developing MC,and there was an inverse association between Helicobacter pylori infection and MC.A variety of associations are found between MC and other gastrointestinal disorders,where aspects such as genetic effects,resemblance of immunological profiles,and intestinal microecology are potential mechanisms behind the relationships.Clinicians should be aware of these connections to achieve a better understanding and management of MC.

Lansoprazole-associated collagenous colitis:Diffuse mucosal cloudiness mimicking ulcerative colitis

There have only been a few reports on lansoprazole-associated collagenous colitis. Colonic mucosa of collagenous colitis is known to be endoscopically normal. We present a case of collagenous colitis where the mucosa showed diffuse cloudiness mimicking ulcerative colitis. A 70-year-old woman developed watery diarrhea four to nine times a day. She had interstitial pneumonia at 67 and reflux esophagitis at 70 years. Lansoprazole 30 mg/d had been prescribed for reflux esophagitis for nearly 6 mo. Lansoprazole was withdrawn due to its possible side effect of diarrhea. Colonoscopy disclosed diffuse cloudiness of the mucosa which suggested ulcerative colitis. Consequently sulfasalazine 2 g/d was started. The patient's diarrhea dramatically disappeared on the following day. However, biopsy specimens showed subepithelial collagenous thickening and infi ltration of inflammatory cells in the lamina propria, confirming the diagnosis of collagenous colitis. One month after sulfasalazine therapy was initiated, colonoscopic and histological abnormalities resolved completely. Five months later the diarrhea recurred. The findings on colonoscopy and histology were the same as before, confirming a diagnosis of collagenous colitis relapse. We found that the patient had begun to take lansoprazole again 3 mo ahead of the recent diarrhea. Withdrawal of lansoprazole promptly resolved the diarrhea. Endoscopic and histological abnormalities were also completely resolved, similar to the first episode. Retrospectively, the date of commencement of sulfasalazine and discontinuation of lansoprazole in the first episode was found to be the same. We conclude that this patient had lansoprazole-associated collagenous colitis.

Spectrum of non-inflammatory bowel disease and non-infectious colitis

A variety of inflammatory diseases of the colon, which can be differentiated from inflammatory bowel disease (IBD) and infectious colitis by their clinical, endoscopic and histological characteristics, are reported as non- IBD and non-infectious colitis. These diseases include microscopic colitis, ischemic colitis, segmental colitis associated with diverticula, radiation colitis, diversion colitis, eosinophilic colitis and Behcet's colitis. The etiopathogenesis of most of these diseases remains obscure and the epidemiological data are rather limited. These conditions are often troublesome for the patient and are associated with diagnostic difficulties for the physician. In many cases the treatment is empirical and there is a need for future research using randomized controlled trials.

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 werefound 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.

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 Skane. 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 under- gone colonoscopy during the defined period and were living in this area were included in the study regardless of where in Skane they had been diagnosed. Medical records were scrutinized and uncertain cases were re- assessed to ensure that only newly diagnosed CC cases were included. The diagnosis of CC was based on both clinical and histopathological criteria. The clinical crite-rion was non-bloody watery diarrhoea. The histopatho- logical criteria were a chronic inflammatory infiltrate in the lamina propria, a thickened subepithelial collagen layer ≥10 micrometers （um） 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 Skane 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 diag- nosis 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 5.4/105 inhabitants. During the time periods 2001-2005 and 2006-2010, the mean annual incidence rates were 5.4/105 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 6.7/105） no increase or decrease in the incidence could be identi- fied. 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 dur- ing 2002-2004 （4.6/105） and from Terrassa, Spain dur- ing 2004-2008 （2.6/105）. Our incidence figures from southern Sweden during 2001-2010 （5.4/10s） as well as the incidence figures presented in the studies during the 1990s （Terrassa, Spain during 1993-1997 （2.3/10s）, OI- msted, United States during 1985-2001 （3.1/10s）, Orebro, Sweden during 1993-1998 （4.9/10s）, and Iceland during 1995-1999 （5.2/10s） are all in line with a north- south gradient, something that has been suggested be- fore both for CC and inflammatory bowel disease.CONCLUSION： The observed incidence of CC is com- parable with previous reports from northern Europe and America. The incidence is stable but the female： male ratio seems to be decreasing.

Complications of collagenous colitis

Microscopic forms of colitis have been described, including collagenous colitis. This disorder generally has an apparently benign clinical course. However, a number of gastric and intestinal complications, possibly coincidental, may develop with collagenous colitis. Distinctive inflammatory disorders of the gastric mucosa have been described, including lymphocytic gastritis and collagenous gastritis. Celiac disease and collagenous sprue （or collagenous enteritis） may occur. Colonic ulceration has been associated with use of nonsteroidal anti-inflammatory drugs, while other forms of inflammatory bowel disease, including ulcerative colitis and Crohn＇s disease, may evolve from coUagenous colitis. Submucosal ＂dissection＂, colonic fractures or mucosal tears and perforation from air insufflation during colonoscopy may occur and has been hypothesized to be due to compromise of the colonic wall from submucosal collagen deposition. Similar changes may result from increased intraluminal pressure during barium enema contrast studies. Finally, malignant disorders have also been reported, including carcinoma and lymphoproliferative disease.

Obesity is associated with colitis in women but not necessarily causal relationship

The relationship between obesity and female risk of microscopic colitis remains to be discussed.