Proton pump inhibitor induced collagen expression in colonocytes is associated with collagenous colitis

To elucidate the role of proton pump inhibitors (PPIs) in collagenous disease, direct effect of PPI on colonocytes was examined.METHODSCollagenous colitis is a common cause of non-bloody, watery diarrhea. Recently, there has been increasing focus on the use of proton PPIs as a risk factor for developing collagenous colitis. Mouse CT26 colonic cells were treated with PPI and/or PPI-induced alkaline media. Expression of fibrosis-associated genes was examined by RT-PCR. In human materials, collagen expression was examined by immunohistochemistry.RESULTSCT26 cells expressed a Na+-H+ exchanger gene (solute carrier family 9, member A2). Treatment with PPI and/or PPI-induced alkaline media caused growth inhibition and oxidative stress in CT26 cells. The treatment increased expression of fibrosis inducing factors, transforming growth factor β and fibroblast growth factor 2. The treatment also decreased expression of a negative regulator of collagen production, replication factor C1, resulting in increased expression of collagen types III and IV in association with lipid peroxide. In biopsy specimens from patients with collagenous colitis, type III and IV collagen were increased. Increase of type III collagen was more pronounced in PPI-associated collagenous colitis than in non-PPI-associated disease.CONCLUSIONFrom these findings, the reaction of colonocytes to PPI might participate in pathogenesis of collagenous colitis.

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 Lansoprazole was withdrawn due to its possible side effect of diarrhea.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.

Clinical and immunologic effects of faecal microbiota transplantation in a patient with collagenous colitis

One to six percent of patients with microscopic colitis are refractory to medical treatment. The effect of faecal microbiota transplantation(FMT) in active collagenous colitis(CC) has, to the best of our knowledge, never been reported before. Here, we report the effect of repeated FMT in a patient with CC. The patient presented with severe symptoms including profuse diarrhea and profound weight loss. Although she responded to budesonide in the beginning, she became gradually refractory to medical treatment, and was therefore treated with FMT. The patient remained in remission for 11 mo after the third faecal transplantation. The immunomodulatory effect of the therapy was evaluated using flow cytometry, which showed alterations in the profile of intraepithelial and lamina propria lymphocyte subsets after the second transplantation. Our observations indicate that FMT can have an effect in CC, which support the hypothesis that luminal factors, influencing the intestinal microbiota, are involved in the pathogenesis of CC.

A unique case of collagenous colitis presenting as protein-losing enteropathy successfully treated with prednisolone

A 76-year-old woman with a 5-mo history of recurrent diarrhea and generalized edema was admitted to our hospital. Colonoscopy revealed edematous mucosa,and histopathological examination was compatible with collagenous colitis. Protein leakage from the colon,particularly in the ascending portion,was identified on 99mTc-human serum albumin scintigraphy. Collagenous colitis associated with protein-losing enteropathy (PLE) without small bowel disease was diagnosed. Prednisolone treatment ameliorated diarrhea and hypoproteinemia. Collagenous colitis should be included in the differential diagnosis of chronic diarrhea with hypoproteinemia for appropriate management.

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.

Steroids reduce local inflammatory mediator secretion and mucosal permeability in collagenous colitis patients

AIM：. To study the effect of oral steroids upon clinical response and rectal mucosa secretion of eosinophil cationic protein （ECP）, myeloperoxidase （NPO）, basic fibroblast growth factor （bFGF）, vascular endothelial growth factor （VEGF） and albumin in patients with collagenous colitis （CC）. METHODS： A segmental perfusion technique was used to collect perfusates from rectum of CC patients once before and twice （one and four weeks） after the start of steroid treatment. Clinical data was monitored and ECP, MPO, bFGF, VEGF and albumin concentrations were analyzed by immunochemical methods in perfusates and in serum. RESULTS： Steroids reduced the number of bowel movements by more than five times within one week and all patients reported improved subjective wellbeing at wk 1 and 4. At the same time, the median concentrations of ECP, bFGF, VEGF and albumin in rectal perfusates decreased significantly. MPO values were above the detection limit in only 3 patients before treatment and in none during treatment. VEGF, bFGF, ECP and albumin concentrations correlated with each other with the exception of ECP and albumin. A decrease of serum ECP and VEGF concentrations was also seen even if the overtime reduction was not significant.CONCLUSION： Oral steroid treatment in CC patients induced a simultaneous reduction of bowel movements and rectal release of ECP, bFGF, VEGF and albumin, suggesting that these polypeptides and increased mucosal permeability are important components of the pathophysiology in collagenous colitis.

Celiac disease and microscopic colitis:A report of 4 cases

Celiac disease (CD) is an autoimmune disorder of the small intestine that occurs in genetically predisposed people at all ages.However,it can be associated also to other immunopathological disorders,and may be associated with abnormal histology in segments of the gut other than the small bowel including colonic inflammation.While guidelines for endoscopic investigation of the jejunum are well defined,no indication is defined for colonic investigation.We describe four cases of concurrent CD and microscopic colitis (MC) diagnosed at our department over a 10-year period and analyzed the main features and outcomes of CD in this setting.The symptoms of these patients were improved initially by a gluten-free diet before the onset of MC symptoms.Two of the patients were siblings and had an atypical form of CD.The other two patients with CD and MC also presented with fibrosing alveolitis and were anti-Saccharomyces cerevisiae antibody positive.The co-existence of immune-mediated small bowel and colonic inflammatory and pulmonary diseases are not well-known,and no systematic approach has been used to identify the lifelong patterns of these immune-based diseases.Patients can develop,or present with CD at any stage in life,which can co-exist with other gastrointestinal diseases of (auto-) immune origin.In addition,the fa-milial co-existence and prevalence of MC in patients with a prior diagnosis of CD are unclear.Clinicians managing celiac disease should be aware of these associations and understand when to consider colon investigation.

Differential expression of interleukin-1/Toll-like receptor signaling regulators in microscopic and ulcerative colitis

AIM:To investigate Toll-like receptor(TLR)signaling regulators in microscopic and ulcerative colitis patients.METHODS:Total RNA and microRNA were isolated from fresh frozen colonic biopsies of non-inflamed controls and patients with active or in-remission collagenous colitis(CC),lymphocytic colitis(LC),or ulcerative colitis(UC).We compared expressions of interleukin-1receptor-associated kinase(IRAK)-2,IRAK-M,interleukin(IL)-37,microRNA(miR)-146a,miR-155,and miR-21 using quantitative real time reverse transcription polymerase chain reaction.RESULTS:IRAK-M expression was increased in LC patients with active disease in histopathological remission(LC-HR;P=0.02)and UC patients(P=0.01),but no differences in IRAK-2 expression were detected compared to controls.miR-146a,-155 and-21 expressions were increased in LC-HR(P=0.04,0.07,and 0.004)and UC(P=0.02,0.04 and 0.03)patients.miR-146a and miR-21 expressions were significantly enhanced in UC patients compared to UC remission(UC-R;P=0.01and 0.04).Likewise,active CC patients showed significantly increased expression of miR-155(P=0.003)and miR-21(P=0.006).IL-37 expression was decreased in both CC(P=0.03)and LC(P=0.04)patients with a similar trend in UC patients but not statistically significant,whilst it was increased in UC-R patients compared to controls(P=0.02)and active UC(P=0.001).CONCLUSION:The identification of differentially expressed miRNAs,IL-37,and IRAK-M suggests different pathophysiologic mechanisms in various disease stages in LC,CC,and UC.

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）.

Mechanism of diarrhea in microscopic colitis

AIM： To search the pathophysiological mechanism of diarrhea based on daily stool weights, fecal electrolytes, osmotic gap and pH. METHODS： Seventy-six patients were included： 51 with microscopic colitis （MC） [40 with lymphocytic colitis （LC）; 11 with collagenous colitis （CC）], 7 with MC without diarrhea and 18 as a control group （CG）. They collected stool for 3 d. Sodium and potassium concentration were determined by flame photometry and chloride concentration by titration method of Schales. Fecal osmotic gap was calculated from the difference of osmolarity of fecal fluid and double sum of sodium and potassium concentration. RESULTS： Fecal fluid sodium concentration was significantly increased in LC 58.11±5.38 mmol/L （P〈0.01） and CC 54.14±8.42 mmol/L （P〈0.05） than in CG 34.28±2.98 mmol/L. Potassium concentration in LC 74.65±5.29 mmol/L （P〈0.01） and CC 75.53±8.78 mmol/L （P〈0.05） was significantly less compared to CG 92.67±2.99 mmol/L. Chloride concentration in CC 36.07±7.29 mmol/L was significantly higher than in CG 24.11±2.05 mmol/L（P〈0.05）. Forty-four （86.7%） patients had a secretory diarrhea compared to fecal osmotic gap. Seven （13.3%） patients had osmotic diarrhea. CONCLUSION： Diarrhea in MC mostly belongs to thesecretory type. The major pathophysiological mechanism in LC could be explained by a decrease of active sodium absorption. In CC, decreased CI/HCO3 exchange rate and increased chloride secretion are coexistent pathways.

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.

Prevalence of microscopic colitis in patients with diarrhea of unknown etiology in Turkey

AIM: To investigate the prevalence and demography of microscopic colitis in patients with diarrhea of unknown etiology and normal colonoscopy in Turkey. METHODS: Between March, 1998 to July, 2005, 129 patients with chronic non-bloody diarrhea of unexplained etiology who had undergone full colonoscopy with no obvious abnormalities were included in the study. Two biopsies were obtained from all colonic segments and terminal ileum for diagnosis of microscopic colitis. On histopathologic examination, criteria for lymphocytic colitis (intraepithelial lymphocyte ≥ 20 per 100 intercryptal epithelial cells, change in surface epithelium, mononuclear infiltration of the lamina propria) and collagenous colitis (subepithelial collagen band thickness ≥ 10 μm) were explored. RESULTS: Lymphocytic colitis was diagnosed in 12 (9%) patients (Female/Male: 7/5, mean age: 45 year, range: 27-63) and collagenous colitis was diagnosed in only 3 (2.5%) patients (all female, mean age: 60 years, range: 54-65).CONCLUSION: Biopsy of Turkish patients with the diagnosis of chronic non-bloody diarrhea of unexplained etiology and normal colonoscopic findings will reveal microscopic colitis in approximately 10% of the patients. Lymphocytic colitis is 4 times more frequent than collagenous colitis in these patients.

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.

Development of collagenous colitis in inflammatory bowel disease:two case reports and a review of the literature

The occurrence of collagenous colitis(CC)in patients with pre-existing inflammatory bowel diseases(IBD)is rare,with only seven cases reported in the past.Herein,we report two IBD cases who developed CC after successful treatment of their IBD with two different tumor necrosis factor(TNF)-a inhibitors,which have been previously reported to successfully treat refractory CC.This report highlights the need to do random biopsies of the colon for CC diagnosis in IBD patients with symptoms of diarrhea after complete mucosal healing.The report also reviews plausible mechanisms as to how CC may develop,including the role of multiple medications.