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.

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 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.

New strategies in the diagnosis and treatment of immune-checkpoint inhibitor-mediated colitis

Immune-checkpoint inhibitor-mediated colitis(IMC)is an increasingly recognized adverse event in cancer immunotherapy,particularly associated with immune checkpoint inhibitors(ICIs)such as anti-cytotoxic T-lymphocyte antigen-4 and anti-programmed cell death protein-1 antibodies.As this revolutionary immunotherapy gains prominence in cancer treatment,understanding,diagnosing,and effectively managing IMC becomes paramount.IMC represents a unique challenge due to its immune-mediated nature and potential for severe complications.However,a precise picture of IMC pathophysiology is currently unavailable.Therefore,we aimed to summarize the existing data while acknowledging the need for further research.This comprehensive review explores the mechanisms underlying ICIs,gastrointestinal adverse effects,and,in particular,IMC’s incidence,prevalence,and features.Our review also emphasizes the importance of recognizing IMC’s distinct clinical and histopathological features to differentiate it from other forms of colitis.Furthermore,this paper highlights the urgentneed for evolving diagnostic methods,therapeutic strategies,and a multidisciplinary approach to effectively manage IMC.

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.

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.

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: 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.

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.

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.

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 the secretory type. The major pathophysiological mechanism in LC could be explained by a decrease of active sodium absorption. In CC, decreased Cl/HCO3 exchange rate and increased chloride secretion are coexistent pathways.

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.

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.

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.