Microscopic Colitis: Epidemiology, Pathophysiology, Diagnosis and Current Management—An Update 2013

Chronic diarrhea

In recent years, microscopic colitis has been increasingly diagnosed. This review was carried out to evaluate demographic factors for microscopic colitis and to perform a systematic assessment of available treatment options. Relevant publications up to December 2013 were identified following searches of PubMed and Google Scholar using the key words 'microscopic colitis', 'collagenous colitis' and 'lymphocytic colitis'. Two-hundred and forty-eight articles were identified. The term microscopic colitis includes lymphocytic colitis and collagenous colitis. Both have common clinical symptoms but are well defined histopathologically. The clinical course is usually benign, but serious complications, including death, may occur. A peak incidence from 60 to 70years of age with a female preponderance is observed. Although most cases are idiopathic, associations with autoimmune disorders, such as coeliac disease and hypothyroidism, as well as with exposure to nonsteroidal anti-inflammatory drugs and proton-pump inhibitors, have been observed. The incidence and prevalence of microscopic colitis is rising and good-quality epidemiological research is needed. Treatment is currently largely based on anecdotal evidence and on results from limited clinical trials of budesonide. Long-term follow-up of these patients is not well established. The review synthesizes work on the definition of microscopic colitis and the relationship between collagenous and lymphocytic colitis. It reviews the international epidemiology and work on aetiology. In addition, it critically considers the efficacy of a range of treatments.

Microscopic colitis (MC) encompasses the two morphologically distinct entities of collagenous colitis (CC) and lymphocytic colitis (LC). MC was first described less than 30 years ago but is presently recognized as a relatively common cause of chronic diarrhea in the adult population. Remarkably, up to 10% of adults who have a colonoscopy for the investigation of chronic diarrhea, and have endoscopically normal appearing mucosa, may have MC. Patients with MC generally present with chronic diarrhea, which can be associated with cramping and bloating. Endoscopic and radiological examinations are usually normal. Histological assessment reveals inflammation consisting predominantly of lymphocytic infiltration, and a thickened subepithelial collagen band is diagnostic of CC. Both LC and CC can be associated with autoimmune diseases such as celiac disease, diabetes, arthritis and thyroiditis, yet the mechanisms involved in the pathogenesis remain unclear. Emerging studies suggest that a stepwise approach be taken in the medical management of MC. This approach includes antidiarrheal agents and stopping of any offending agents; budesonide or bismuth subsalicylate; and cholestyramine or 5-acetylsalicylic acid agents. In resistant cases, oral corticosteroids and other immune modulatory therapy have been used.

Collagenous colitis and lymphocytic colitis, together constituting microscopic colitis, are common causes of chronic diarrhea. They are characterized clinically by chronic nonbloody diarrhea and a macroscopically normal colonic mucosa where characteristic histopathological findings are seen. Previously considered rare, they now have emerged as common disorders that need to be considered in the investigation of the patient with chronic diarrhea. The annual incidence of each disorder is five to ten per 100,000 inhabitants, with a peak incidence in 60- to 70-year-old individuals and a predominance of female patients in collagenous colitis. The etiology and pathophysiology are not well understood, and the current view suggests an uncontrolled mucosal immune reaction to various luminal agents in predisposed individuals. Clinical symptoms comprise chronic diarrhea, abdominal pain, fatigue, weight loss, and fecal incontinence that may impair the patient’s health-related quality of life. An association is reported with other autoimmune disorders, such as celiac disease, thyroid disorders, diabetes mellitus, and arthritis. The best-documented treatment, both short-term and long-term, is budesonide, which induces clinical remission in up to 80% of patients after 8 weeks’ treatment. However, after successful budesonide therapy is ended, recurrence of clinical symptoms is common, and the best possible long-term management deserves further study. The long-term prognosis is good, and the risk of complications, including colonic cancer, is low. We present an update of the epidemiology, pathogenesis, diagnosis, and management of microscopic colitis.

Global Incidence, Prevalence, and Risk Factors of Microscopic Colitis, 1984-2020: A Systematic Review and Meta-Analysis.

Microscopic Colitis: A Concise Review for Clinicians

Background: Diarrhea predominant irritable bowel syndrome (IBS-D) is a common functional disorder of the gastrointestinal tract shares similar symptoms and endoscopic findings with microscopic colitis (MC) with a major difference in treatment. IBS-D is diagnosed using criteria based on clinical symptoms, while histological evidence is mandatory for MC diagnosis. There is a continuous debate about the value of endoscopically normal colonic mucosa biopsies in IBS-D patient investigation. Objective: To determine the prevalence of MC in patients meeting Rome IV criteria of IBS-D. Patients and methods: A cross-sectional survey was performed in the Department of Hepatogastroenterology and Infectious Diseases, Al-Azhar University Hospitals. One hundred patients attended the outpatient clinics from January 2020 to April 2020 fulfilling Rome IV criteria for diagnosis of IBS-D was prospectively enrolled. Patients aged from 18 to 65 years old. Patients with other causes of chronic diarrhea were excluded. The studied patients were subjected to full history taking, extensive clinical examination, thorough laboratory investigations and complete colonoscopy with multiple biopsies were taken from endoscopically normal looking mucosa at different parts of the colon, and processed for histopathological examination. Results: The mean age of participants was 40.7 ± 11.01 years. Fifty three cases were males (53%) and 47 were females (47%). Twenty out of 100 patients were diagnosed as MC, 18 (90%) of them were lymphocytic colitis (LC) and 2 patients (10%) were collagenous colitis (CC). The mean age in MC patients was 50.8 ± 7.3 years. Nocturnal diarrhea and weight loss were only seen in cases diagnosed as MC (15 out of 20 patients 75%) and 15 out of 20 patients (75%) respectively. There was a significant difference between normal biopsy & MC patients as regard inflammatory markers C-reactive protein(CRP) and Erythrocyte sedimentation rate (ESR), but their levels were still within normal range. Conclusion: MC is not an uncommon disease that is often diagnosed in elderly people. It can be easily confused with IBS-D and histopathological examination of colonoscpic biopsies obtained from the normally appearing mucosa is the only way for differentiation. In cases with IBS-D, nocturnal diarrhea and weight loss increase the possibility of MC and require colonoscopic biopsy evaluation. In patients with IBS-D criteria mild increase in inflammatory markers (CRP and ESR) may occur, but these markers are non-specific and don't direct us for MC diagnosis.

INTRODUCTION: Microscopic Colitis (MC) is a chronic inflammatory disease of the colon that presents with chronic, non-bloody, watery diarrhea and is diagnosed with colonoscopy (CSPY). Literature is mixed on the association of Anti-Depressant (AD) use and their association with MC. We investigated the association of AD's with MC among patients with clinically significant diarrhea. METHODS: We performed a retrospective case-control study of all patients with clinically significant chronic diarrhea whom underwent CSPY to rule out MC from 1/2012–12/2016 at the University of Virginia Hospital. 127 patients diagnosed with MC were propensity score matched to 127 patients with normal biopsies based on age and gender. Patients were excluded if they were <18 years old, inpatients, or had FMT. The primary outcome was history of AD use. The secondary outcome was use of NSAIDs or PPI's. OR was calculated for the primary outcome and binomial logistic regression modeling was used to control for other medication use. Statistical analysis and propensity score matching were performed in R using the MatchIt Package. RESULTS: 55/127 patients with MC and 45/127 patients with normal biopsies used AD's (OR 1.4; 95% CI (0.65–3.04). No differences were observed among the case and control groups with respect to age, gender, celiac disease, or PPI use. No statistical difference was seen in the lymphocytic (LC) vs. collagenous colitis (CC) subtypes among MC patients with AD use. More patients with AD use had LC than CC but this difference was not clinically or statistically significant. Logistic regression revealed that only NSAID use was a predictor of the development of MC (P < 0.001). Anti-depressant use was not a predictor of MC development. Neither combination of AD and NSAID (P = 0.7385) nor AD and PPI use (P = 0.6892) together was predictive of development of MC. CONCLUSION: In this study, a history of AD did not predict a pathologic diagnosis of MC in an at risk population. It remains unclear if PPI's or AD's are associated with the development of MC suggesting that MC development may be iatrogenic. Despite studies on the gut-brain axis and gut microbiota dysbiosis associated with AD's, our series showed no association between AD use and MC. Further studies may prove beneficial in relating the development of MC with long-term AD use and their influence on the microbiome, Based on our data, the diagnosis of MC does not warrant discontinuing AD's especially since depression itself may lead to worsened clinical stability of MC.

AGA Clinical Practice Update on Management of Inflammatory Bowel Disease in Elderly Patients: Expert Review

Background: Microscopic colitis (MC) is an increasingly recognized, frequent cause of chronic diarrhea. Its epidemiology was described in several Western countries, however epidemiologic data from Eastern Europe is lacking. We aimed to investigate MC cases in our single tertiary referral center cohort. Methods: All cases of microscopic colitis diagnosed at colonoscopy over a 17-year period (January 1997 – August 2014) were retrieved at the 1st Department of Pathology and retrospectively reviewed. The diagnostic criteria for lymphocytic colitis (LC) were ≥20 intraepithelial lymphocytes per 100 epithelial cells, and for collagenous colitis (CC) a collagenous layer of ≥10 µm. Several demographic and clinical parameters were analyzed. Results: 110 patients (91 patients with LC, and 19 patients with CC) were included in the study. 79 (71%) patients were female with a mean age of 52.0 years (SD ± 16.8) for LC and a mean age of 57.5 years (SD ± 17.0) for CC. Comparing the period 1997 – 2005 and 2006 – 2014, the incidence increased in both genders (30 females, 9 males vs. 49 females, 23 males). Chronic, watery diarrhea was the most common symptom (74%). The diagnosis of LC would have been missed in 11% of cases, if only left-sided biopsies had been taken, whereas all cases (100%) of CC were diagnosed with distal colonic biopsies alone. Osteodensitometry was performed in only 20% of cases, however it was pathological in 64% of the cases: osteoporosis was diagnosed in 46% and osteopenia in 18% of these cases. Among associated autoimmune diseases, celiac disease was the most common with 9%, followed by hypothyroidism (7.3%). 31.5% of patients were taking any of the previously associated drugs (proton pump inhibitors, ACE inhibitors, beta blockers, calcium antagonists, statins, acetylsalicylic acid or antidepressants). Conclusions: The incidence of MC is increasing in Hungary, but still below of that reported in Western countries. LC seems to be more common than CC, but this might be due to underdiagnosis. Our results should be further examined in multicenter studies. This study was supported by the Hungarian Scientific Research Fund (OTKA-K111743 grant).

Increasing Incidence of Microscopic Colitis in a Population-Based Cohort Study in Switzerland

Introduction: Microscopic colitis (MC) is an inflammatory bowel condition with two subtypes, lymphocytic colitis (LC) and collagenous colitis (CC). Unlike patients with ulcerative colitis (UC) and non-inflamed individuals, MC patients have reduced risk of developing colorectal cancer, possibly due to increased immune surveillance in MC patients.Aim: To examine differences in levels of immunomodulatory molecules, including those involved in immune checkpoint mechanisms, in sera from patients with MC and in colonic biopsies from patients with MC and UC compared with controls.Methods: Using Luminex, 23 analytes (4-1BB, 4-1BBL, APRIL, BAFF, BTLA, CD27, CD28, CD80, CTLA-4, E-cadherin, Galectin-3, GITR, HVEM, IDO, IL-2Rα, LAG-3, MICA, MICB, PD-1, PD-L1, PD-L2, sCD40L and TIM-3) were studied in serum from patients with active MC (n = 35) and controls (n = 23), and in colonic biopsies from patients with active LC (n = 9), active CC (n = 16) and MC in histological remission (LC n = 6, CC n = 6), active UC (n = 15) and UC in remission (n = 12) and controls (n = 58).Results: In serum, IDO, PD-1, TIM-3, 4-1BB, CD27, and CD80 were decreased whereas 4-1BBL and IL-2Rα were increased in MC patients compared with controls. In contrast, in biopsies, levels of PD-L2 and 4-1BB were increased in MC and UC patients with active disease. Furthermore, in biopsies from CC and UC but not LC patients with active disease, CTLA-4, PD-1, APRIL, BAFF, and IL-2Rα were increased compared with controls. PD-L1 was increased in CC but not UC or LC patients. CD27 and TIM-3 were decreased in biopsies from MC patients in comparison to controls whereas levels of MICB were decreased in patients with active UC compared with controls.Conclusions: Compared with non-inflamed controls, levels of soluble and membrane-bound immunomodulatory molecules were systemically and locally altered in MC and UC patients, with most analytes being decreased in serum but enhanced in colonic biopsies. These findings contribute to knowledge about checkpoint molecules and their role as biomarkers in MC and may also contribute to knowledge about possible mechanisms behind the seemingly protective effects of MC against colorectal cancer.

Collagenous and lymphocytic colitis: evaluation of clinical and histological features, response to treatment, and long-term follow-up

Ragged cuticles and erythematous hands and feet in a pediatric patient with chronic diarrhea

The incidence of collagenous and lymphocytic colitis is not well known. We sought to assess the incidence of collagenous and lymphocytic colitis in a well-defined population during a 5-yr study period. From January 1, 1993, to December 31, 1997, all new patients diagnosed with collagenous or lymphocytic colitis living in the catchment area of the Hospital Mutua de Terrassa (Barcelona, Spain) were identified. Since 1993 all patients with chronic diarrhea were referred for a diagnostic colonoscopy. Multiple biopsy sampling of the entire colon was performed when appearance of the colonic mucosa was grossly normal. Twenty-three cases of collagenous colitis and 37 of lymphocytic colitis were diagnosed. The female:male ratios were 4.75:1 and 2.7:1 for collagenous and lymphocytic colitis, respectively. The mean age at onset of symptoms was 53.4+/-3.2 (range, 29-82) yr for collagenous colitis, and 64.3+/-2.7 (range, 28-87) yr for lymphocytic colitis (p = 0.012). The mean annual incidence per 100,000 inhabitants based on the year of onset of symptoms was 1.1 (95% confidence interval [CI], 0.4-1.7) for collagenous colitis, and 3.1 (95% CI, 2.0-4.2) for lymphocytic colitis. A peak incidence was observed in older women in both diseases. A rate of microscopic colitis of 9.5 per 100 normal-looking colonoscopies performed in patients with chronic watery diarrhea was observed. Normal rectal biopsies were found in 43 % and 8% of patients with collagenous and lymphocytic colitis, respectively. The incidence of lymphocytic colitis is three times higher than that of collagenous colitis. Microscopic colitis should be considered as a major possibility in the work-up of chronic diarrhea in older women.