Microscopic colitis: A review of etiology, treatment and refractory disease

Microscopic colitis is a common cause of chronic,nonbloody diarrhea. Microscopic colitis is more common in women than men and usually affects patients in their sixth and seventh decade. This article reviews the etiology and medical management of microscopic colitis. The etiology of microscopic colitis is unknown, but it is associated with autoimmune disorders, such as celiac disease, polyarthritis, and thyroid disorders. Smoking has been identified as a risk factor of mi-croscopic colitis. Exposure to medications, such as non-steroidal anti-inflammatory drugs, proton pump inhibitors, and selective serotonin reuptake inhibitors, is suspected to play a role in microscopic colitis, although their direct causal relationship has not been proven. Multiple medications, including corticosteroids, anti-diarrheals, cholestyramine, bismuth, 5-aminosalicylates, and immunomodulators, have been used to treat microscopic colitis with variable response rates. Budesonide is effective in inducing and maintaining clinical remission but relapse rate is as high as 82% when budesonide is discontinued. There is limited data on management of steroid-dependent microscopic colitis or refractory microscopic colitis. Immunomodulators seem to have low response rate 0%-56% for patients with refractory microscopic colitis. Response rate 66%-100% was observed for use of anti-tumor necrosis factor(TNF) therapy for refractory microscopic colitis. Anti-TNF and diverting ileostomy may be an option in severe or refractory microscopic colitis.

Microscopic colitis: A therapeutic challenge

The treatment of microscopic colitis is mainly based on the use of budesonide, the only drug found effective in controlled clinical trials. After an initial course at a dose of 9 mg daily, however, most patients relapse when the drug is discontinued, hence a maintenance therapy at doses of 6 mg daily or lower is necessary. In order to avoid steroid dependence and drug toxicity different pharmacological agents should be considered as an alternative to indefinite long-term budesonide treatment. Evidence-based guidelines are currently lacking due to the lack of conclusive data concerning the use of either immunosuppressive or anti-tumor necrosis factor agents. For the time being in clinical practice the skilled physician should therefore tailor long term management of microscopic colitis on the single patient.

Triggers of histologically suspected drug-induced colitis

BACKGROUND Drug toxicity is a common and even serious problem in the gastrointestinal tract that is thought to be caused by a broad spectrum of agents.Although withdrawal of the causative agent would cure the disease knowledge is scarce and mostly derives from case reports and series.AIM To investigate potential triggers of drug-induced colitis(DiC).METHODS We conducted a retrospective,observational case control study.Patients were assigned to DiC or one of two age-and gender-matched control groups(noninflammatory controls and inflammatory colitis of another cause)based on histopathological findings.Histopathology was reassessed in a subset of patients(28 DiC with atherosclerosis,DiC without atherosclerosis and ischaemic colitis each)for validation purposes.Medical history was collected from the electronic database and patient records.Statistical analysis included chi-squared test,t-test,logistic and multivariate regression models.RESULTS Drug-induced colitis was detected in 211 endoscopically sampled biopsy specimens of the colon mucosa(7%of all screened colonoscopic biopsy samples);a total of 633 patients were included equally matched throughout the three groups(291 males,mean age:62.1±16.1 years).In the univariate analysis,DiC was associated with diuretics,dihydropyridines,glycosides,ASS,platelet aggregation inhibitors,nonsteroidal anti-inflammatory drugs(NSAIDs),statins and fibrates,and with atherosclerosis,particularly coronary heart disease,and hyperlipoproteinaemia.Echocardiographic parameters did not show substantial differences.In the multivariate analysis only fibrates[odds ratio(OR)=9.1],NSAIDs(OR=6.7)and atherosclerosis(OR=2.1)proved to be associated with DiC.Both DiC reassessment groups presented milder inflammation than ischaemic colitis.The DiC patients with atherosclerosis exhibited histological features from both DiC without atherosclerosis and ischaemic colitis.CONCLUSION Several drugs indicated for the treatment of cardiovascular and related diseases are associated with DiC.Atherosclerosis and microcirculatory disturbances seem to play an important pathogenetic role.

Microscopic colitis: Common cause of unexplained nonbloody diarrhea

Microscopic colitis(MC) is characterized by chronic, watery, secretory diarrhea, with a normal or near normal gross appearance of the colonic mucosa. Biopsy is diagnostic and usually reveals either lymphocytic colitis or collagenous colitis. The symptoms of collagenous colitis appear most commonly in the sixth decade. Patients report watery, nonbloody diarrhea of a chronic, intermittent or chronic recurrent course. With collagenous colitis, the major microscopic characteristic is a thickened collagen layer beneath the colonic mucosa, and with lymphocytic colitis, an increased number of intraepithelial lymphocytes. Histological workup can confirm a diagnosis of MC and distinguish the two distinct histological forms, namely, collagenous and lymphocytic colitis. Presently, both forms are diagnosed and treated in the same way; thus, the description of the two forms is not of clinical value although this may change in the future. Since microscopic colitis was first described in 1976 and only recently recognized as a common cause of diarrhea, many practicing physicians may not be aware of this entity. In this review, we outline the epidemiology, risk factors associated with MC, its etiopathogenesis, the approach to diagnosis and the management of these individuals.

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

TO THE EDITOR 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 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 colonic 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, ethnicity, and medications were analyzed. An age-and sexmatched standard control group was also generated. Chi-square test was used to evaluate the associations of co-morbidities between lymphocytic colitis (LC), collagenous colitis (CC) and the control group.RESULTS: A total of 547 cases of MC were identif ied,376 patients with LC and 171 patients with CC. The female/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 compared 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. Furthermore, neither an increased risk of colorectal cancer nor IBD was associated with MC in this study.

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.

Obesity is associated with decreased risk of microscopic colitis in women

BACKGROUND Microscopic colitis is a leading cause of diarrhea in the older adults.There is limited information about risk factors.We hypothesized that obesity would be associated with microscopic colitis.AIM To examine the association between obesity and microscopic colitis in men and women undergoing colonoscopy.METHODS We conducted a case-control study at the University of North Carolina Hospitals.We identified and enrolled men and women referred for elective,outpatient colonoscopy for chronic diarrhea.We excluded patients with a past diagnosis of Crohn’s disease or ulcerative colitis.A research pathologist reviewed biopsies on every patient and classified them as microscopic colitis cases or non-microscopic colitis controls.Patients provided information on body weight,height and exposure to medications via structured interviews or Internet based forms.The analysis included 110 patients with microscopic colitis(cases)and 252 nonmicroscopic colitis controls.Multivariable analyses were performed using logistic regression to estimate odds ratios and 95%confidence intervals.RESULTS Cases were older and more likely than controls to be white race.Study subjects were well educated,but cases were better educated than controls.Cases with microscopic colitis had lower body mass index than controls and reported more weight loss after the onset of diarrhea.Compared to patients who were normal or under-weight,obese(BMI>30 kg/m2)patients were substantially less likely to have microscopic colitis after adjusting for age and education,adjusted OR(aOR)0.35,95%confidence interval(CI)0.18-0.66).When stratified by sex,the association was limited to obese women,aOR 0.21,95%CI:0.10-0.45.Patients with microscopic colitis were more likely to report weight loss after the onset of diarrhea.After stratifying by weight loss,there remained a strong inverse association between obesity and microscopic colitis,aOR 0.33,95%CI:0.10-1.11 among the patients who did not lose weight.Ever use of birth control pills was associated with lower risk of microscopic colitis after adjusting for age,education and BMI,aOR 0.38,95%CI:0.17-0.84.CONCLUSION Compared to controls also seen for diarrhea,microscopic colitis cases were less likely to be obese.Mechanisms are unknown but could involve hormonal effects of obesity or the gut microbiome.

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.

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 microscopic examination. The annual incidence of each disorder is 4-6/100 000 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 short-term 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.

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.

Microscopic colitis: Is it a spectrum of inflammatory bowel disease?

Lymphocytic and collagenous colitis are forms of microscopic colitis which typically presents in elderly patients as chronic watery diarrhea. The association between microscopic colitis and inflammatory bowel disease is weak and unclear. Lymphocytic colitis progressing to ulcerative colitis has been previously reported; however there is limited data on ulcerative colitis evolving into microscopic (lymphocytic or collagenous) colitis. We report a series of six patients with documented ulcerative colitis who subsequently were diagnosed with collagenous colitis or lymphocytic colitis suggesting microscopic colitis could be a part of the spectrum of inflammatory bowel disease. The median duration of ulcerative colitis prior to being diagnosed with microscopic colitis was 15 years. We noted complete histological and/or symptomatic remission in three out of six cases while the other three patients reverted back into ulcerative colitis suggesting lymphocytic or collagenous colitis could present as a continuum of ulcerative colitis. The exact molecular mechanism of this histological transformation or the prognostic implications is still unclear. Till then it might be prudent to follow up these patients to assess for the relapse of inflammatory bowel disease as well as for dysplasia surveillance.

Towards a new paradigm of microscopic colitis: Incomplete and variant forms

Microscopic colitis(MC) is a chronic inflammatory bowel disease that has emerged in the last three decades as a leading cause of chronic watery diarrhoea. MC classically includes two main subtypes: lymphocytic colitis(LC) and collagenous colitis(CC). Other types of histopathological changes in the colonic mucosa have been described in patients with chronic diarrhoea, without fulfilling the conventional histopathological criteria for MC diagnosis. Whereas those unclassified alterations remained orphan for a long time, the use of the term incomplete MC(MCi) is nowadays universally accepted. However, it is still unresolved whether CC, LC and MCi should be considered as one clinical entity or if they represent three related conditions. In contrast to classical MC, the real epidemiological impact of MCi remains unknown, because only few epidemiological studies and case reports have been described. MCi presents clinical characteristics indistinguishable from complete MC with a good response to budesonide and cholestiramine. Although a number of medical treatments have been assayed in MC patients, currently, there is no causal treatment approach for MC and MCi, and only empirical strategies have been performed. Further studies are needed in order to identify their etiopathogenic mechanisms, and to better classify and treat MC.

Microscopic colitis in patients with mild duodenal damage:A new clinical and pathological entity(“lymphocytic enterocolitis”)?

AIM To evaluate the potential association between mild duodenal damage and microscopic colitis(MC).METHODS We retrospectively included 105 consecutive patients with type I Marsh-Oberhuber duodenal damage and negativity for immunoglobulin A anti-endomysium and anti-tissue transglutaminase.The following parameters were analyzed:Sex,age at execution of esophagogastroduodenoscopy,duodenal damage,and number of intraepithelial lymphocytes at biopsies,prevalenceof Helicobacter pylori infection,age at execution of colonoscopy,macroscopic and microscopic features of colonoscopy,family history of gastrointestinal and autoimmune diseases,smoking habits,biochemical parameters of inflammation and autoimmunity,use of proton pump inhibitors or nonsteroidal anti-inflammatory drugs,adverse reactions to drugs or foods,pathologies known to be associated with celiac disease or MC,living on a gluten-free diet or on a gluten-low diet for at least 1 mo.RESULTS Colonoscopy was performed in 59 patients,but only in 48 of them biopsies were taken in the entire colon.Considering the latter cohort,the diagnosis of MC was met in 25(52.1%) patients while in 18 patients other pathologic findings were reported:13(27%) cases of nonspecific inflammatory bowel disease,2(4.2%) cases of Crohn's disease,2(4.2%) cases of eosinophilic gastroenteritis,and 1(2.1%) case of autoimmune enteritis.Five(10.4%) patients had a normal colonoscopic result.Matching the groups by age,and considering only patients who underwent colonoscopy(42.7 ± 15.5 years) vs those who did not undergo colonoscopy(36.9 ± 10.6 years),a statistical difference was found(P = 0.039).Focusing on symptoms,diarrhea was statistically more prevalent in MC group than in patients who did not undergo colonoscopy(P = 0.03).CONCLUSION Mild duodenal damage is associated with MC in more than half of the cases.This association supports the hypothesis of a link between these two entities.

Mucosal lesions of the upper gastrointestinal tract in patients with ulcerative colitis:A review

Ulcerative colitis(UC)is a chronic,nonspecific,relapsing inflammatory bowel disease.The colorectum is considered the chief target organ of UC,whereas upper gastrointestinal(UGI)tract manifestations are infrequent.Recently,emerging evidence has suggested that UC presents complications in esophageal,stomachic,and duodenal mucosal injuries.However,UC-related UGI tract manifestations are varied and frequently silenced or concealed.Moreover,the endoscopic and microscopic characteristics of UGI tract complicated with UC are nonspecific.Therefore,UGI involvement may be ignored by many clinicians.In addition,no standard criteria have been established for patients with UC who should undergo fibrogastroduodenoscopy.Furthermore,specific treatment recommendations may be needed for patients with UC-associated UGI lesions.Herein,we review the esophageal,gastric,and duodenal mucosal lesions of the UC-associated UGI tract,as well as the potential pathogenesis and therapy.

Fecal stream diversion and mucosal cytokine levels in collagenous colitis:A case report

In this case report, we examined the levels of cytokines expressed before and during fecal stream diversion and after intestinal continuity was restored in a patient with collagenous colitis. We report the case of a46-year-old woman with chronic, active collagenous colitis who either failed to achieve clinical remission or experienced adverse effects with the following drugs:loperamide, cholestyramine, budesonide, methotrexate and adalimumab. Due to the intractable nature of the disease and because the patient was having up to 15 watery bowel movements per day, she underwent a temporary ileostomy. Colonic biopsies were analyzed for mucosal cytokine protein levels before and during fecal stream diversion and after intestinal continuity was restored. Mucosal protein levels of interleukin(IL)-1β,IL-2, IL-6, IL-12, IL-17 A, IL-23, TNF, IFN-γ, IL-4, IL-5,IL-10 and IL-13 were all higher during active disease and decreased to non-detectable or considerably lower levels during fecal stream diversion. One month after the restoration of bowel continuity, when the patient experienced a relapse of symptoms, IL-2, IL-23 and IL-21 levels were again increased. Our results indicate that fecal stream diversion in this patient suppressed the levels of all cytokines analyzed in colonic biopsies. With the recurrence of clinical symptoms and histological changes after bowel reconstruction,the levels of primarily proinflammatory cytokines increased. Our findings support the hypothesis that a luminal factor triggers the inflammation observed in 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.

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.