190 Anti-Depressant Use Does Not Predict Development of Microscopic Colitis: A Retrospective Case-Controlled Study

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.

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.

Introduction: Microscopic colitis (MC) refers to 2 medical conditions that cause chronic diarrhea: collagenous colitis (CC) and lymphocytic colitis (LC). Previous studies have reported an increased prevalence of microscopic colitis in the celiac disease population. These studies were limited by small numbers, and further characterization of the patients who harbor both conditions is needed. The aims of this study were: 1) to determine the strength of the association between MC and celiac disease; and 2) to compare the demographic and clinical characteristics of patients with MC and celiac sprue to those of patients with MC alone. Methods: Miraca Life Sciences is a nationwide pathology laboratory that receives specimens submitted by approximately 1,500 gastroenterologists distributed throughout the United States. From the electronic database of Miraca Life Sciences we extracted all patients who had an upper gastrointestinal endoscopy (EGD) and colonoscopy with biopsy sampling from the duodenum and colon between January 2008 and December 2013. We extracted demographic, clinical, and histopathologic information and stratified patients based on the presence of MC. We then performed a search of patients with celiac sprue, defined as duodenal villous atrophy (Marsh type 3a, b, or c histology), in a population of patients with MC, compared to a control population of patients without MC. Results: There were 156,399 patients who had both duodenal and colon biopsies during the study period. Of these, 4,417 had MC (2,266 with CC and 2,151 with LC). The mean age of the MC population was 61.9 years, with a female:male ratio of 3.83:1. Celiac sprue was diagnosed in 1,113 patients, of whom 116 also had microscopic colitis. Compared to controls without MC, there was a greater association of celiac sprue in patients with CC (OR 4.08; 95% CI 3.36, 4.96), LC (OR 4.71; 95% CI 3.66, 6.05), and all MC (OR 4.08; 95% CI 3.36, 4.96). In patients with MC and celiac sprue versus MC alone, average age was 54.0 years vs. 61.9 years (p<0.0001) with a similar female:male predominance (ratio 4.04:1). Of the 116 subjects with MC and celiac sprue, microscopic colitis was diagnosed before celiac sprue in 32 (28%) cases, simultaneously in 58 (50%), and after celiac sprue in 26 (22%). Conclusion: In a large nationwide pathology database, we found a significantly increased association of microscopic colitis and celiac disease. Such association could reflect on a shared set of risk factors or a common pathophysiology of the 2 disease entities. Disclosure - Dr. Genta is an employee of Miraca Life Sciences. Drs. Yen and Sonnenberg declare no relevant conflicts of interest.

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.

Objective To analyze the clinical characteristics and risk factors of lansoprazole-induced microscopic colitis(MC). Methods PubMed, Da-Yi medical search, CHKD and Wanfang databases were searched and articles related to MC induced by lansoprazole were collected. The patients'primary diseases, coexisting diseases, the dosage, the way of administration, combination drugs, latent period, clinical manifestations, colonoscopic findings, the treatment measures, and the outcomes were recorded and the clinical characteristics, the risk factors of MC induced by lansoprazole were analyzed. Results A total of 30 articles and 62 patients with MCinduced by lansoprazole were retrieved. All articles were case reports and no randomized controlled trials were found. Of all the 62 patients, 22 were male (35.5%) and 40 were female (64.5%) with age from 36 to 92 years and the average age was (69±12) years; 57 patients (91.9%) were ＞50 years; 43 patients were with collagenous colitis(CC)(69.4%), 18 patients (29%) were with lymphocytic colitis(LC), and one patient with LC changed into CC(1.6%). All patients were treated with oral lansoprazole. The latent period of MCinduced by lansoprazole were 5d-6 years and within 1-6 months in 31 patients(60.8%). The most common clinical manifestations were non-bloody watery diarrhea (3-10 times daily in 59 patients,＞10 times daily in 3 patients). Intestinal mucosal screening was performed for all the patients and mild abnormalities or edema were observed in 37 patients, mucosal defect and mucosal laceration in 11 patients, epithelial collagen layer thickening, inflammatory cells infiltration in lamina propria,increased lymphocytes in intraepithelial spaces in 18 patients. High-risk drugs for drug-induced MC were combined use in 20 patients and the combination drugs in 13 patients were non steroidal antiinflammatory drugs. Fifty-eight patients with mild or moderate drug-induced MC returned to normal after withdrawl of lansoprazole and treatment with omeprazole or rabeprazole sodium and 4 patients with severe drug-induced MC recovered after withdrawl of lansoprazole and treatment with glucocorticoids. Conclusions The clinical characteristics in patients with MC induced by lansoprazole are watery diarrhea, mild abnormality or edema of colon mucosa, and thickening in the epithelium of colonic mucosa in histopathology. Age, gender, and combined use of drugs may be related to occurrence of MC induced by lansoprazole. Key words: Lansoprazole; Proton pump inhibitor; Colitis

Microscopic colitis is a common cause of chronic diarrhea. Over the last years the incidence and the prevalence of microscopic colitis are rising and this rise is largely attributed to a rising awareness, and concomitantly an increasing number of diagnoses are made. Patients with microscopic colitis report watery, nonbloody diarrhea of chronic, intermittent, or chronic recurrent course. Following an unremarkable physical examination the diagnosis of microscopic colitis is made by colonoscopy, which shows essentially a normal colonic mucosa. Biopsies taken during the colonoscopy procedure will then finally establish the correct diagnosis. Histological workup can then confirm a diagnosis of microscopic colitis and can distinguish the two distinct histological forms, namely, collagenous colitis 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, though this may change in future. Depending on the patients age and gender 10–30% of patients investigated for chronic diarrhea will be diagnosed with microscopic colitis if biopsies are taken. Microscopic colitis is most common in older patients, especially in female patients and is frequently associated with autoimmune disorders and the consumption of several drugs. This review summarizes the present knowledge of the epidemiology, the pathophysiology, and the diagnosis of microscopic colitis and discusses the former and the present treatment options.

Background/AimsMicroscopic colitis is characterized by chronic watery diarrhea with specific pathological changes that can be diagnosed by microscopic examination. We performed immunohistochemical analysis of proinflammatory cytokines to investigate the pathogenic mechanism of microscopic colitis.MethodsThis study consisted of six patients with lymphocytic colitis, six patients with collagenous colitis, and six patients with functional diarrhea but normal pathology. We performed an immunohistochemical analysis of the colonic mucosal biopsies to assess the expression of cyclo-oxygenase-2, interleukin-17, nuclear factor-κB, interferon-γ, inducible nitric oxide synthase, and tumor necrosis factor-α. We compared the quantity score of immunohistochemical staining among the groups.ResultsThe microscopic colitis group showed significantly higher expression of cyclo-oxygenase-2, interleukin-17, nuclear factor-κB, and interferon-γ compared with the control group. Cytokine expression was similar between collagenous colitis and lymphocytic colitis. However, the expression of cyclo-oxygenase-2 was higher in collagenous colitis.ConclusionsProinflammatory cytokines, including interleukin-17 and interferon-γ, are highly expressed in microscopic colitis. The expression of cyclo-oxygenase-2 was higher in collagenous colitis than in lymphocytic colitis. This study is the first on interleukin-17 expression in microscopic colitis patients.

Use of antidepressants has been reported to cause considerable weight gain. The aim of this study was to assess the risk of diabetes mellitus associated with antidepressant treatment and to examine whether the risk is influenced by treatment duration or daily dose. This was a nested case-control study in a cohort of 165,958 patients with depression who received at least one new prescription for an antidepressant between January 1, 1990, and June 30, 2005. Data were from from the U.K. General Practice Research Database. Patients were at least 30 years of age and without diabetes at cohort entry. A total of 2,243 cases of incident diabetes mellitus and 8,963 matched comparison subjects were identified. Compared with no use of antidepressants during the past 2 years, recent long-term use (>24 months) of antidepressants in moderate to high daily doses was associated with an increased risk of diabetes (incidence rate ratio=1.84, 95% CI=1.35-2.52). The magnitude of the risk was similar for long-term use of moderate to high daily doses of tricyclic antidepressants (incidence rate ratio=1.77, 95% CI=1.21-2.59) and selective serotonin reuptake inhibitors (incidence rate ratio=2.06, 95% CI=1.20-3.52). Treatment for shorter periods or with lower daily doses was not associated with an increased risk. Long-term use of antidepressants in at least moderate daily doses was associated with an increased risk of diabetes. This association was observed for both tricyclic antidepressants and selective serotonin reuptake inhibitors.

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).

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

INTRODUCTION: Multiple studies have suggested that Celiac disease (CD) may be associated with microscopic colitis (MC); however, most of these studies were limited by their small sample size or the main scope of interest. Hence, we aimed to analyze the previously published literature on this association to determine the extent and significance of this relationship. METHODS: A systemic review was conducted in PUBMED, Embase, PubMed Central and ScienceDirect databases from inception through May 2020. Effect estimates from the individual studies were extracted and combined using the random effect, generic inverse variance method of DerSimonian and Laird and a pooled odds ratio (OR) and event rates were calculated. Forest plots were generated, and publication bias was assessed for using conventional techniques. RESULTS: Fifteen studies with a total of 4640 patients with MC were included in this Analysis. CD was significantly associated with MC (OR 6.221, 95% CI, 3.828–10.108, P < 0.005). The pooled event rate for MC in patients with CD was 6.7% (4.4%–10.0%, P < 0.005), while the pooled event rate for celiac disease in patients with MC was 7.7% (4.6%–12.6%, P < 0.005). CD was prevalent in both types of MC; 5.4% (1.3%–20%, P < 0.005) in collagenous colitis and 9.1% (4.5%–17.3%, P < 005) in lymphocytic colitis. We found no publication bias as assessed by the funnel plots and Egger’s regression asymmetry test. CONCLUSION: Our meta-analysis confirms a statistically significant association between CD and MC, with a high prevalence of CD in both types of MC. Gastroenterologists should be wary of this association when evaluating patients with either disease, particularly in patients with a sub-optimal response to first line therapy.Figure 1.: Forrest plot, pooled OR for the association between celiac disease and microscopic colitis.

INTRODUCTION: Collagenous colitis (CC), a subtype of Microscopic Colitis, is known to cause chronic diarrhea in the elderly. Steroid medication, particularly budesonide, has been rigorously studied and shown to be effective, leading to remission. Few studies have revealed the role diet has on decreasing these symptoms. CASE DESCRIPTION/METHODS: 69 y/o male with past medical history of chronic intermittent diarrhea for the past thirteen years. He initially presented with recurrence of non-bloody watery diarrhea, alternating with constipation and fecal incontinence for 2 weeks. Previous colonoscopy performed thirteen years ago revealed normal mucosa with diverticulosis. Further workup revealed a negative tTG- IgA, polypharmacy, or an infectious etiology. Labs were unremarkable. He underwent repeat colonoscopy, which demonstrated a fractured and nodular appearance of the cecum and ascending colon with small tears. Biopsies showed a focal increase in intraepithelial lymphocytes with a positive trichrome stain consistent with the diagnosis of CC. He was started on a GFD trial and had complete remission of his symptoms for three years. DISCUSSION: Chronic diarrhea affects approximately 5% of the population and at times can be challenging for gastroenterologists. When working up chronic diarrhea, microscopic colitis and celiac disease often play a large role. In this case, the patient was diagnosed with CC, however symptoms resolved on a GFD alone despite having multiple negative TTG levels. We believe that the multiple negative TTG levels were indicative of negative celiac disease. However, there is evidence showing that gluten can induce microscopic colitis. However, in women dietary gluten intake may not be a risk factor for the development of microscopic colitis in the absence of celiac disease. Nevertheless, the effects of gluten may be different in male veterans. CC is usually treated with a steroid based regimen, budesonide, to obtain remission. There are limited studies that have evaluated the impact that a GFD has upon the symptoms and histological findings in CC. Use of these medications can be associated with hyperglycemia, hypertension and metabolic bone disease which may be detrimental to the patient's health and prognosis. In conclusion, in patients diagnosed with CC consider starting a trial of GFD. Further studies are needed to evaluate the response of how a GFD affects the spectrum of severity in symptoms and histologic findings in patients diagnosed with CC, specifically in male veterans.

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.

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.