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BACKGROUND: Epidemiological studies from Europe and North America report an increasing incidence of microscopic colitis (MC) in the late twentieth century followed by a plateau. This population-based study assessed recent incidence trends and the overall prevalence of MC over the past decade. METHODS: Residents of Olmsted County, Minnesota diagnosed with collagenous colitis (CC) or lymphocytic colitis (LC) between January 1, 2011 and December 31, 2019 were identified using the Rochester Epidemiology Project. Clinical variables were abstracted by chart review. Incidence rates were age- and sex-adjusted to the 2010 US population. Associations between incidence and age, sex, and calendar periods were evaluated using Poisson regression analyses. RESULTS: A total of 268 incident cases of MC were identified with a median age at diagnosis of 64 years (range, 19–90); 207 (77%) were women. The age- and sex-adjusted incidence of MC was 25.8 (95% confidence interval [CI] 22.7–28.9) cases per 100,000 person-years. The incidence of LC was 15.8 (95% CI, 13.4–18.2) and CC 9.9 (95% CI, 8.1–11.9) per 100,000 person-years. A higher MC incidence was associated with increasing age and female sex (p

Microscopic colitis is an inflammatory bowel disease divided into two subtypes: collagenous colitis and lymphocytic colitis. With an increasing incidence of microscopic colitis exceeding those of ulcerative and Crohn’s disease among elderly people in some countries, microscopic colitis is a debilitating life experience. Therefore, physicians should be familiar with its clinical features and management strategies because the disease deserves the same attention as the classical inflammatory bowel diseases. Here, state-of-the-art knowledge of microscopic colitis is provided from a global perspective with reference to etiopathology and how to establish the diagnosis with the overall aim to create awareness and improve rational management in clinical practice. The immune system and a dysregulated immune response seem to play a key role combined with risk factors (e.g. cigarette smoking) in genetically predisposed individuals. The symptoms are characterized by recurrent or chronic nonbloody, watery diarrhea, urgency, weight loss, and a female preponderance. As biomarkers are absent, the diagnosis relies on colonoscopy with a histological assessment of biopsy specimens from all parts of the colon. Although the disease is not associated with a risk of colorectal cancer, a recent nationwide, population-based cohort study found an increased risk of lymphoma and lung cancer. Budesonide is the first-line therapy for management, whereas immunomodulatory drugs (including biologics) and drugs with antidiarrheal properties may be indicated in those failing, dependent, or intolerant to budesonide. In microscopic colitis induced by checkpoint inhibitors, a drug class used increasingly for a wide range of malignancies, a more aggressive therapeutic approach with biologics introduced early seems reasonable. However, particular attention needs to be drawn to the existence of incomplete forms of microscopic colitis with the risk of being overlooked in routine clinical settings.

In the preceding article (part 1), we proposed the third type of microscopic colitis: colitis nucleomigrans (CN). Microscopically, the nuclei of surface‐lining columnar cells were migrated in chain to the middle part of the cells, and apoptotic nuclear debris was scattered in the cytoplasm beneath the nuclei. For ultrastructural analysis, buffered formalin‐fixed biopsy tissue of CN (n = 2) was dug out of paraffin blocks. After deparaffinization, tissue blocks were prepared with conventional sequences. Ultrathin sections were stained with uranyl acetate and lead citrate. Fine morphological preservation was satisfactory even after paraffin embedding. Apoptotic nuclear debris was localized within the cytoplasm beneath the migrated nuclei of the surface‐lining columnar cells. Abnormality of cytoskeletal filaments (actin, cytokeratin and tubulin) was scarcely recognized in the epithelial cytoplasm. Macrophages located in the uppermost part of the lamina propria phagocytized electron‐dense globular materials. Intraepithelial lymphocytes with scattered dense bodies were observed among the columnar cells. We suppose that altered apoptotic processes in the colorectal surface‐lining epithelial cells may be involved in the pathogenesis of CN. Mechanisms of nuclear migration to the unusual position or impairment of nuclear anchoring to the basal situation in the surface‐lining epithelial cells remain unsettled, because cytoskeletal components showed little ultrastructural abnormality.

Microscopic colitis (MC), encompassing collagenous colitis and lymphocytic colitis, is featured by chronic diarrhea, normal-looking endoscopic findings and unique microscopic appearance. After reviewing biopsied nonspecific colitis, we propose the third type of MC: colitis nucleomigrans (CN). Histopathological criteria of CN included: (i) chained nuclear migration to the middle part of the surface-lining columnar epithelium; (ii) apoptotic nuclear debris scattered below the nuclei; and (iii) mild/moderate chronic inflammation in the lamina propria. Thirty-three patients (M:F = 20:13; median age 63 years, range 17-88) fulfilled our criteria. Seven cases demonstrated MC-like clinical/endoscopic features. Mucosal reddening with or without erosion/aphtha was endoscopically observed in the remaining 26 cases with inflammatory bowel disease (IBD)-like features: occult/gross hematochezia seen in 19, abdominal pain in two and mucin secretion in two. Cleaved caspase-3-immunoreactive apoptotic debris appeared more frequently in IBD-like CN than in MC-like CN, while CD8-positive intraepithelial lymphocytes comparably appeared in both. Proton pump inhibitors (PPIs) were administered in five (71%) cases with MC-like features, and in three diarrhea improved after drug cessation. In IBD-like CN cases, eight (31%) received PPIs. Four patients received chemotherapy against malignancies. Four patients associated immune-related disorders. Microscopic appearance of CN also appeared in a remission state of ulcerative colitis (12/20 lesions).

Lymphocytic colitis (LC) is characterized by chronic watery diarrhea and unremarkable endoscopic findings. Only one case of LC presenting as multiple colonic polyps has been reported. We report a case series of histologic LC pattern of injury (LCPI), presenting as endoscopic polyps, and compare them with typical LC cases. Eighteen archived (2009-2019) polypoid LCPI cases without an associated cause of polyp, such as adenoma, hyperplastic change, or lymphoid aggregate, were retrieved from 17 (12 female and 5 male) patients. The clinical history and endoscopic findings were noted. A total of 40 conventional LC cases were used as controls. Fisher's exact test was performed to evaluate associations between two variables. The mean age of the patients was 61.1 years. The indication for colonoscopy was chronic watery diarrhea (56%), screening/surveillance (33%), and rectal bleeding (11%). The mean number and size of the polyps was 1.6 and 2.9 mm, respectively. Seventy-six percent were located in the left colon, and 48% were sessile. When biopsied (14/18; 78%), the background colonic mucosa showed LCPI. There was no significant difference in age, gender, and the average number of lymphocytes in the two groups. Hypertension and history of malignancy was more common in the polypoid LCPI group than in the control LC group (P 0.05). LCPI may present as endoscopic polyps, frequently in patients with hypertension and history of malignancy. Polypoid LCPI may be a harbinger of LCPI in the background nonpolypoid colonic mucosa. A subset of polypoid LCPI (56%) cases represents true LC.

Background Microscopic colitides are chronic immune-inflammatory bowel diseases. The typical presentation is chronic, watery diarrhoea. Inflammation mostly cannot be visualized via macroscopic inspection. The diagnosis thus requires histologic sampling. The clinical picture can vary. New investigations can prove valuable in setting up recommendations. Patients A total of 103 patients with microscopic colitis (MC) [28 lymphocytic colitis (LC) 27.2%, 75 collagenous colitis (CC) 72.8%] in the Clinical Centre of the University of Debrecen (tertiary care centre) were included, diagnosed between 1993 and 2020. We aimed for a retrospective analysis characterizing Hungarian MC patients. We sought to compare two subgroups of patients (with either LC or CC). Our investigation focussed on dominant alteration of stool habits, autoimmune and allergic comorbidities. Autoimmune diseases were diagnosed in 39% (40) of the patients, allergic diseases in 26.2% (27) of patients and 22.2% of tested patients had alimentary hypersensitivity to certain foods (18 cases out of 81 tested). Results Age of diagnosis was younger in LC (44.5 years, SD: 5.3 vs. 51.9 years, SD: 12.8, difference= 7.4 years p = .0151). Autoimmune diseases were equally frequent in the two groups (LC: 10 patients 36%, CC: 30 patients, 40%, difference: 4%, p = .7124). Food-linked hypersensitivities were more common in CC (LC: 1 patient, CC: 17 patients). Difference in allergic diseases (asthma, rhinitis, urticaria) did not differ between groups (LC: 6 patients, 21%; CC: 21 patients, 28%, difference: 7% p = .4739). One-third of the patients did not complain about chronic diarrhoea. These patients had chronic constipation as the main symptom (34 patients, 33%). Conclusion Pre-existing autoimmune and allergic diseases were common in patients with MC. Chronic watery diarrhoea is not experienced in many cases. The absence of certain symptoms should not be used to rule out the condition.

Microscopic colitis (MC) is a well-recognised cause of chronic diarrhoea in Western countries. It is classically associated with normal endoscopic findings and a higher prevalence among patients with autoimmune disease. Local information regarding this disease remains scarce. We identified patients diagnosed with MC over a five-year period, and then proceeded to analyse the clinical characteristics of these cases.A retrospective study was conducted by identifying all histologically confirmed colitis cases diagnosed at Hospital Universiti Sains Malaysia from January 2015 until December 2019. Clinicodemographic data was retrieved from case notes of patients.Of the 299 cases with histological colitis, 23 (7.7%) were initially identified as MC. Two cases had incomplete data, while two others were excluded as the diagnoses were revised to inflammatory bowel disease. An incidence of 14 MC cases/1000 case-year was obtained using the 21 MC cases seen within the five-year period. MC subtypes for the 19 analysed cases i.e., lymphocytic colitis and collagenous colitis accounted for 13 (68.4%) and 6 (31.6%) cases, respectively. Eleven patients (57.9%) were females (M:F ratio 1:1.5) with a median age of 51 years. Only nine (47.3%) presented with diarrhoea; one subject (5.4%) had an autoimmune condition (Hashimoto thyroiditis). Normal endoscopic findings were found in 89.5% of patients.Approximately half of the subjects in our study who had histologically confirmed MC did not present with diarrhoea. Adequate biopsy samples despite normal colonoscopy findings are important in order to not miss the diagnosis of MC.

Teriflunomide is an oral monotherapy used to treat relapsing multiple sclerosis. Although teriflunomide may be associated with gastrointestinal symptoms, these events are mild and self-limiting. We present a 39-year-old female who developed severe diarrhea and lost 20 pounds within 3 weeks of starting teriflunomide. Despite discontinuing teriflunomide and undergoing cholestyramine washout, her symptoms persisted. Celiac disease on genetic testing was positive, but no anti-transglutaminase and anti-endomysial antibodies were detected. She underwent colonoscopy and biopsy was consistent with lymphocytic colitis. Remission was achieved within days of starting budenoside. Our case describes a rare, but serious, gastrointestinal adverse event of teriflunomide.

Background Epidemiological studies of microscopic colitis have shown varying but increasing incidence rates. Aim To assess the incidence of microscopic colitis in Sweden. Methods Nationwide cohort study performed in 1995-2015 based on biopsy reports. Age-specific and age-standardised incidence rates were calculated. Results We identified 13 844 patients with an incident diagnosis of microscopic colitis. Lymphocytic colitis (n = 9238) constituted 67% and collagenous colitis (n = 4606) 33% of microscopic colitis. The mean age at time of diagnosis of microscopic colitis was 60.2 years (58.6 for lymphocytic colitis, 63.3 for collagenous colitis). The lifetime risk of developing microscopic colitis was 0.87% in women (95% confidence interval, CI: 0.85-0.88) and 0.35% in men (95% CI: 0.34-0.36). From 2006, the overall incidence of microscopic colitis was approximately 10.5 cases per 100 000 person-years (95% CI: 9.8-11.3) with higher rates in women (72% of cases, incidence rate ratio = 2.4 (95% CI: 2.3-2.5) and the elderly with increasing rates up to 75-79 years. From 2006-2015, there was a significant increase of 1% per year (P = 0.02) in the overall microscopic colitis incidence rate in women; the estimated annual percent change was similar, although not statistically significant, in men (P = 0.15). Conclusions In Sweden, the incidence of microscopic colitis is still increasing in women, although the rate appears to be stabilising. The incidence is particularly high in women and the elderly up to age 75-79 years. Finally, across a lifetime, 1 in 115 females and 1 in 286 males are expected to be diagnosed with microscopic colitis and thus posing a considerable disease burden.

Lymphocytic colitis (LC) and LC incomplete (LCi) are common causes of chronic watery diarrhea. The diagnosis relies on clinical findings and histopathologic evaluation. The diagnostic criteria of LC are based on hematoxylin and eosin (HE) staining. However, supplementary immunohistochemical staining for highlighting the lymphocytes in borderline cases is now widely used. This change in diagnostics could lead to incorrectly diagnosing patients with LC and LCi if the present histologic criteria are used. The number of intraepithelial lymphocytes (IELs) was estimated and categorized in intervals based on HE- versus CD3-stained slides from patients with an HE diagnosis of normal colonic mucosa (n = 19), mucosa with nonspecific reactive changes (n = 24), LCi (n = 24), and LC (n = 40). The number of IELs was compared with clinical symptoms. Overall, the number of IELs was higher with CD3 stain compared with HE stain in 73% of cases, unchanged in 26% of cases, and lower in 1 case. The number of IELs detected was higher using the CD3 stain in 53%, 79%, 79%, and 75% of cases included as normal colonic mucosa, nonspecific reactive changes, LCi, and LC, respectively. Based on CD3 stain, 58% of the cases with nonspecific reactive changes fulfilled the HE criteria for LCi, and 79% of the cases with LCi fulfilled the HE criteria for LC. Automated image analysis of CD3-stained slides resulted in even higher numbers of IELs in all 4 diagnostic groups. Conclusively, our data support considering increased cutoff values for LCi and LC when assessed in CD3-stained specimens.

Background Evidence for second-line therapy in patients with microscopic colitis [MC] failing budesonide is scarce, although anti-tumour necrosis factors [anti-TNFs], methotrexate and azathioprine have been reported to be effective in small cohort studies. Vedolizumab, a monoclonal antibody targeting α4β7-integrin, prevents homing of T-cells to the gut. We evaluated clinical remission with vedolizumab in budesonide-refractory MC patients. Methods We solicited gastroenterologists in Europe and Canada for cases of MC treated with vedolizumab. Vedolizumab 300 mg IV was administered at weeks 0, 2 and 6, and then every 8 weeks. Clinical remission and histological remission were defined as less than three stools per day and normalization of histology, respectively, after induction treatment. Results Eleven cases were retrieved (nine females, lymphocytic colitis [LC] n = 5, collagenous colitis [CC] n = 6). Median [interquartile range] disease duration at vedolizumab initiation was 51 [29-70] months. Nine of 11 patients had failed one immunosuppressant and ten of 11 at least one anti-TNF agent. After three infusions of vedolizumab, clinical remission was observed in 5/11 patients [two LC and three CC] of whom three remained well with maintenance therapy [median duration of 13 months]. Biopsies were obtained from 9/11 patients. Histological remission was observed in 3/4 patients with clinical remission [2/3 CC, 1/1 LC] and 0/5 patients without clinical improvement. Conclusion In a series of highly refractory MC patients, vedolizumab induced clinical remission in 5/11 subjects, of whom 75% showed normalized histology. Larger randomized trials are needed to assess the efficacy of vedolizumab in patients with MC.

Aquaporin-5 (AQP5) is a member of a family of water channel proteins involved in the bidirectional transfer of water across cell membranes. Lymphocytic colitis (LC) and collagenous colitis (CC) are clinically similar diseases characterized by chronic watery diarrhea in patients with usually unremarkable colonic mucosa on colonoscopy. The aim of this study was to determine whether AQP5 expression in colonic epithelium is altered in LC and CC.Sections of formalin-fixed and paraffin-embedded colorectal biopsies from three control patients (CTL), 8 patients with chronic non-bloody diarrhea with biopsies negative for active inflammation or significant distortion (CTL-D), 8 patients with LC, and 5 with CC were stained for AQP5 using immunohistochemistry. The staining intensity was scored as 3 (strong), 2 (intermediate), 1 (weak), or 0 (no staining). Statistical analysis was performed using Prism 7 Statistical Soft-ware.AQP5 was strongly expressed (score 3) in the epithelial cells in all three CTL cases and all 8 CTL-D cases. In the 5 cases of CC, 3(60%) had score 3 and 2(40%) had score 2, but none had a score of 1 or 0. Of the 8 LC cases, 2(25%) had score 3, 3 had score 2(37.5%), and 3 had score 1(37.5%) (Colorectal AQP5 expression is reduced in most cases of LC. Markedly reduced AQP5 expression in LC may identify a subset of patients with suboptimal response to enteric steroid treatment. Additional larger studies are needed to confirm these findings.This abstract was presented in part at Digestive Diseases Week in San Diego, CA, May 2019.

BACKGROUND AND AIMS: Gastrointestinal infections have been linked to changes in the composition and function of gut microbiome and development of inflammatory bowel diseases. We therefore sought to examine the relationship between gastroenteritis and risk of microscopic colitis (MC). METHODS: We conducted a case-control study of all adult MC patients diagnosed between 1990–2016 in Sweden matched to up to 5 general population controls according to age, sex, calendar year, and county. Cases of MC were identified using SNOMED codes from the ESPRESSO study, a cohort of gastrointestinal pathology reports from all 28 pathology centers in Sweden. We used logistic regression modeling to estimate adjusted odds ratios (aORs) and 95% CIs. RESULTS: Through December of 2016, we matched 13,468 MC cases to 64,479 controls. The prevalence of previous diagnosed gastrointestinal infection was 7.5% among MC patients which was significantly higher than in controls (3.0%, P(comparison)

Summary Microscopic colitis (MC) is characterized by chronic watery diarrhea, endoscopically normal findings, and abnormal histology. While mostly encountered in adults, pediatric cases are rare and may show varying presentations. Our pathology data system was searched from 1984 to 2019 for patients ≤18 years of age with a lymphocytic colitis (LC) or collagenous colitis (CC) pattern of injury. Twenty-seven cases (23 LC and 4 CC) were retrieved. LC was more prevalent than CC (85% vs 15%, respectively) and affected slightly younger individuals (mean, 9.8 years versus 12.25 years). Immune dysregulation was documented in 11 (41%) patients. Most patients presented with watery diarrhea (n = 26, 96%) and either abdominal pain (n = 18, 67%), nausea/vomiting (n = 5, 19%), flatulence (n = 6, 22%), and/or weight loss (n = 1, 4%). A subset of patients (n = 10, 37%) demonstrated endoscopic abnormalities. Histologically, some patients with LC and CC displayed focal cryptitis or crypt abscess formation (n = 7, 26%) and focally increased crypt apoptosis (n = 9, 33%) in the absence of chronic injury. Clinical follow-up data were available for 23 (85%) patients with variable clinical responses recorded. Only 8 patients experienced complete symptom resolution. Twelve patients (11 LC and 1 CC) had subsequent biopsy material; of which, one developed histologic features of inflammatory bowel disease and another was found to have a CTLA-4 deficiency. Our study shows that pediatric patients with MC may have atypical clinical, histologic, and endoscopic findings and variable clinical responses. Underlying inflammatory and/or genetic conditions may be eventually unmasked, and genetic testing may be helpful in a small subset of patients.

There is an unmet need in investigating corticosteroid-sparing treatments for induction and maintenance of remission in microscopic colitis (MC). The authors' aim was to evaluate the outcomes of patients with MC treated with bile acid sequestrants (BAS).MC is a common chronic diarrheal illness. Budesonide is effective induction therapy, but relapses are high after cessation of treatment.Our cohort consisted of patients enrolled in our institutional MC registry, a biorepository of histology-confirmed diagnoses of MC. Patients receiving BAS for the treatment of MC were reviewed at each clinical visit for efficacy or ability to decrease budesonide maintenance dosing.The authors included 79 patients (29 collagenous colitis and 50 lymphocytic colitis) with a median follow-up period of 35 months (range, 1 to 120). Most patients were female individuals (78%) and the median age was 69 years (range, 29 to 87). BAS therapy was used in 21 patients who were budesonide-naive, with a response rate of 76% (16/21). In patients treated previously with budesonide, 46 patients were budesonide-dependent and given BAS as maintenance therapy. Of these patients, 23 (50%) were able to decrease their budesonide dosing and 9 (20%) were able to stop budesonide completely. Seven of 46 patients (15%) stopped BAS because of intolerance, perceived lack of benefit, or treatment of concomitant diarrhea illness.BAS may be an effective corticosteroid-sparing option in the treatment of MC and should be considered after budesonide induction. Larger controlled studies are needed to confirm the efficacy for long-term maintenance and tolerability of BAS in patients with MC.

BACKGROUND The long-term natural history of microscopic colitis remains uncertain. AIM To describe the mortality in a large unselected cohort of patients with microscopic colitis. METHODS All Danish patients above 18 years with an incident diagnosis of microscopic colitis from 2001 to 2018 were identified from nationwide registries and compared to age- and sex-matched controls (variable 1:10 ratio). Patients were categorised according to subtypes: lymphocytic colitis and collagenous colitis. The relative risk of death by any cause was analysed with Cox regression models estimating both crude and comorbidity-adjusted hazard ratios (HRs) with 95% confidence intervals (CIs). Cause-specific death was evaluated with cumulative incidence functions. An E-value was calculated to address the impact of unmeasured confounding. RESULTS The final cohort consisted of 14 024 patients with microscopic colitis. The mean follow-up was 5.8 (standard deviation SD, 2.9) years and the mean age at diagnosis was 61.1 (SD 13.9) years, 70% were women and 41% were diagnosed with lymphocytic colitis. The main results showed a 25% increased risk of all-cause death in patients with microscopic colitis; however, the relative risk was attenuated to 9% when adjusting for comorbidities (95% CI, 1.05-1.14). The E-value indicates that unmeasured confounding could explain the residual observed increased all-cause mortality. Mortality was significantly increased in patients with both lymphocytic colitis (HR 1.15; 95% CI, 1.08-1.23) and collagenous colitis (HR 1.06; 95% CI, 1.01-1.12) in fully adjusted analyses. The absolute difference in death between patients with microscopic colitis and matches was 0.9% at 1 year, 2.8% at 5 years, 5.0% at 10 years and 3.0% at 15 years. Cumulative incidence functions showed that patients with microscopic colitis were more likely to die due to smoking-related diseases including ischemic heart and lung diseases, but had a significant decreased risk of death due to colorectal cancers (P

Objective: Microscopic colitis (MC) is classically associated with normal or near-normal endoscopic appearances. However, non-specific macroscopic findings have been described, the importance of biopsy location for confirming a diagnosis of MC is unclear, and reported incidence data from the United Kingdom are limited. This study was designed to assess macroscopic features, incidence, demographics, and location and positivity of biopsy samples in MC. Materials and methods: Retrospective, cross-sectional study of individuals with newly diagnosed MC. Results: From 2010 to 2015, 540 cases of MC were reported. Macroscopic findings occurred in 16.5% (n = 89) cases, with trends towards increased frequency of ulceration or linear scarring in collagenous colitis (CC). The mean incidence of MC was 11.3 per 100,000 population/year, including 291 (53.9%) with CC (incidence 6.1 per 100,000/year), 203 (37.6%) with lymphocytic colitis (incidence 4.2 per 100,000/year) and 46 (8.5%) with MC, not otherwise specified. Most individuals were female (70.2%). Common features in patients with MC included symptom duration Conclusions: One in six patients with MC demonstrated distinct macroscopic findings at colonoscopy. Our data confirm a female preponderance in MC, a relatively short symptom duration and use of certain drugs as common features. Both right- and left-sided biopsies were frequently positive, suggesting flexible sigmoidoscopy and biopsy could confirm a diagnosis in certain individuals.

Programmed cell death protein 1 (PD-1) blocking agents are novel immunotherapeutics used for treatment of advanced-stage malignancies. They have shown promise in the treatment of several malignancies, with greater efficacy and better tolerability than cytotoxic T-lymphocyte antigen 4 (CTLA-4) blocking agents. However, as with anti-CTLA-4 agents, clinically significant colitis remains an important complication. Although there is growing awareness of the histopathologic features of anti-CTLA-4 therapy, there is little information on the pathologic features of anti-PD-1 colitis. We describe here the histopathologic findings in 8 patients who developed colitis while on anti-PD-1 monotherapy. The most common pattern of injury observed (5/8 cases) was an active colitis with neutrophilic crypt microabscesses and with prominent crypt epithelial cell apoptosis and crypt atrophy/dropout. These latter features are reminiscent of other colitides with prominent apoptosis such as acute graft-versus-host disease or certain drug-induced colitides. The remainder of cases (3/8) showed a lymphocytic colitis-like pattern, characterized by increased intraepithelial lymphocytes and surface epithelial injury. Apoptosis was also often increased in these cases but crypt atrophy/dropout was not present. In patients who experienced recurrence of anti-PD-1 colitis, histologic features were similar to the initial insult but, in addition, features of chronicity developed that mimicked inflammatory bowel disease (basal lymphoplasmacytosis and crypt architectural irregularity, and Paneth cell metaplasia in 1 case). Awareness of the clinical scenario, however, should allow pathologists to suggest anti-PD-1 colitis. Interestingly, recurrent colitis was observed in patients who had been off anti-PD-1 therapy for many months. As anti-PD-1 agents are increasingly used in oncology, we present this series to increase awareness of anti-PD-1 colitis among pathologists, to facilitate its timely diagnosis and treatment.

Microscopic colitis (MC) is still an underestimated cause of chronic, non-bloody watery diarrhea. It is typically manifested in elderly patients with a female predominance. The incidence of microscopic colitis has been increasing. The aetiology and pathophysiology remain unclear. Conditions associated with it include autoimmune diseases. There may be a genetic predisposition, as familial cases have been described. As implicated by the name microscopic colitis, the diagnosis is found by histological examination. There are mainly two subtypes, the lymphocytic colitis (LC) and the collagenous colitis (CC). Even if the condition's long-term course is benign, a chronic recurrent course of the symptoms is frequent. Due to the symptoms, there is an impairment of patient's health-related quality of life. A correct diagnosis and therapy is therefore mandatory. The aim of this paper is to create awareness for microscopic colitis.Zusammenfassung. Die mikroskopische Kolitis (MC) ist immer noch eine unterschätzte Ursache einer chronischen, nicht blutigen Diarrhö. Typischerweise manifestiert sich die Erkrankung bei älteren Patienten, mit einer Dominanz bei Frauen. Die Inzidenz ist zunehmend. Ursache und Pathophysiologie sind unklar, scheinen aber multifaktoriell zu sein. Die Erkrankung ist familiär gehäuft und tritt häufig in Zusammenhang mit anderen Autoimmunerkrankungen auf. Die Diagnose der mikroskopischen Kolitis wird, wie der Name impliziert, anhand der Histologie gestellt. Es lassen sich histologisch zwei Formen unterscheiden: Die lymphozytäre Kolitis (LC) und die kollagene Kolitis (CC). Der Krankheitsverlauf ist benigne, jedoch kommt es häufig zu einem chronisch rezidivierenden Verlauf. Durch die Symptome ist die Lebensqualität der Patienten beeinträchtigt. Aus diesem Grund sind die richtige Diagnose und damit die Zuführung zu einer adäquaten Therapie für den Patienten wichtig. Ziel ist, das Bewusstsein für die Erkrankung zu steigern.

Background: Lymphocytic (LC) and collagenous (CC) colitis are the two major forms of microscopic colitis (MC). The aim of this study was to identify similarities and differences in their mucosal immune characteristics. Methods: Colonic biopsies from 15 CC, 8 LC, and 10 healthy controls were collected. Mucosal lymphocytes were assessed by flow cytometry. Tissue gene expression and protein levels were determined by real-time PCR and ELISA, respectively. Results: LC patients had lower numbers of CD4+ and double-positive CD4+CD8+mucosal T lymphocytes, and higher numbers of CD8+ and CD4+TCRγδ+ mucosal T cells, compared with controls and CC patients. Regulatory Treg (CD4+CD25+FOXP3+) and double-negative (CD3+CD4-CD8-) T cell percentages were higher in both CC and LC compared with controls, coupled with higher levels of the anti-inflammatory IL-10, both at mRNA and protein levels. By contrast, Th1 and Th17 cells were lower in both CC and LC, although gene expression of Th1/Th17 cytokines was higher in both. Conclusion: CC and LC share some regulatory and effector mechanisms, but not others. Higher IL-10 levels and higher Treg and double-negative T cell percentages, found in both CC and LC, could be responsible for the lack of progression of structural damage and the blockade of proinflammatory cytokine production. However, CC and LC are revealed as separate, independent entities, as they show clearly different mucosal lymphocyte profiles, which could be caused by different luminal triggers of the two diseases. Hence, CC and LC are two closely related but independent intestinal disorders.

While the presence of intraepithelial lymphocytosis with surface epithelial damage is a unifying feature of lymphocytic colitis, there are non-classical features that create morphologic heterogeneity between cases. Limited data are available on the significance of these secondary histologic features. Cases of lymphocytic colitis diagnosed between 2002 and 2013 were identified using the Research Patient Data Registry of a tertiary referral center. Diagnostic biopsy slides were reviewed and evaluated for histologic features of lymphocytic colitis. Clinical data including type of therapy and response to treatment were collected. Chi-square (or Fischer's exact test) and logistic regression analysis were used where appropriate. Thirty-two cases of lymphocytic colitis with complete clinical data and slides available for review were identified. The mean age was 56.4 years, and the female-to-male ratio was 3:2. Eleven (11) patients improved with minimal intervention (Group 1), 14 patients responded to steroid therapy (Group 2), and 7 patients responded to mesalamine, bismuth subsalicylate and/or cholestyramine therapy (Group 3). Histologic differences in the characteristics of the subepithelial collagen table (p=0.018), the severity of lamina propria inflammation (p=0.042) and the presence of eosinophil clusters (p=0.016) were seen between groups 2 and 3. Patients in group 1 were more likely to have mild crypt architectural distortion in their biopsies than patients in groups 2 and 3. Lymphocytic colitis is a heterogeneous disease and the evaluation of histologic factors may help identify various subtypes and predict therapy response.

Background/Introduction Lymphocytic colitis (LC) and the incomplete form (LCi) are common causes of chronic watery diarrhea. Endoscopy is often inconspicuous, and the diagnosis relies on histopathological assessment of colonic biopsies. Digital Image Analysis (DIA) eliminates interobserver variation. The aim of this study was to establish digital cutoff values for LC and LCi on CD3 stained slides. Material and methods One hundred and six patients with a hematoxylin and eosin (HE) diagnosis of normal colonic mucosa (N = 19), non-specific reactive changes (N = 24), LCi (N = 23) and LC (N = 40) were eligible for analysis. The number of intraepithelial lymphocytes (IELs) reached by DIA in the total surface epithelium and in hot spots of the biopsies was compared with the diagnostic category assigned by the pathologists based on HE stained slides. The digitalized slides were analyzed for number of IELs using Visiopharm Quantitative Digital Pathology software. All digitalized slides were examined manually to identify differences in the approach to the evaluation of the biopsies by the pathologists and DIA. Results The median IEL counts and interquartile range in the total surface epithelium were 3.6 (3.2–4.3), 4.4 (3.4–5.3), 19.8 (16.6–30.0) and 41.3 (37.0–47.8) in normal colon mucosa, mucosa with non-specific reactive changes, LCi and LC, respectively. Discrimination between normal mucosa and non-specific reactive changes was not possible. Digital cutoff values with the best separation between non-LC, LCi and LC were > 13 IELs/100 epithelial cells for LCi and > 36 IELs/100 epithelial cells for LC. These cutoff values resulted in an agreement between the pathologist’s and DIA that was very good with a kappa value of 0.90. Conclusion Despite differences among the approach of DIA and the pathologist’s assessment of IELs in colonic mucosa DIA is able discriminate between the HE based diagnoses of the three subgroups non-LC, LCi and LC with high accuracy.

OBJECTIVES Onset of microscopic colitis (MC) in patients with ulcerative colitis (UC) or Crohn's disease (CD), or vice versa, has been reported occasionally but the subject is not well described. We therefore report a retrospective observational study of such patients and review the literature. METHODS Forty-six Swedish gastroenterology clinics were contacted about patients with diagnoses of both inflammatory bowel disease (IBD) and MC. Publications were searched on PubMed. RESULTS We identified 31 patients with onset of MC after a median (range) of 20 (2-52) years after diagnosis of IBD, or vice versa; 21 UC patients developed collagenous colitis (CC) (n = 16) or lymphocytic colitis (LC) (n = 5); nine CD patients developed CC (n = 5) or LC (n = 4); one CC patient developed CD. Of the 21 UC patients, 18 had extensive disease, whereas no consistent phenotype occurred in CD. Literature review revealed 27 comprehensive case reports of patients with diagnoses of both IBD and MC. Thirteen MC patients developed IBD, of which four required colectomy. Fourteen IBD patients later developed MC. There were incomplete clinical data in 115 additional reported patients. CONCLUSIONS Altogether 173 patients with occurrence of both IBD and MC were found. The most common finding in our patients was onset of CC in a patient with UC. Although these are likely random associations of two different disorders, MC should be considered in the patient with UC or CD if there is onset of chronic watery diarrhoea without endoscopic relapse of IBD.

Aim: This study assessed the prevalence, clinical presentation and outcome of lymphocytic colitis (LC) and eosinophilic gastrointestinal disease (EGID) in children with severe, recurrent abdominal pain (RAP), by describing the predominant symptoms, diagnostic approaches and treatment options. Methods: We performed a retrospective follow-up study at a Danish regional hospital by reviewing the histology reports of the children who had undergone gastrointestinal endoscopy for RAP. Data were retrieved from the medical records of those who met the diagnostic criteria for LC and, or, EGID from 2011 to 2016. The study population comprised 381 patients who underwent a diagnostic process to clarify RAP. Results: A total of 74 patients (39 females) aged 2–17 years, with severe RAP as the most predominant symptom underwent gastrointestinal endoscopy. This identified 16/74 (21.6%) with LC (n = 6) and, or, EGID (n = 11), which equated to 4.2% with RAP. No biochemical patterns of abnormalities were found. Medical treatment and, or, diet generally induced and maintained clinical remission. Conclusion: We found 16 children with LC and, or, EGID. The predominant symptom was severe RAP. All patients had a macroscopically normal mucosa at endoscopy, a specific histopathological feature and no characteristic biochemical findings. Endoscopy should be considered in these cases.

Lymphocytic colitis and microscopic enteritis are relatively common causes of chronic diarrhea and it is characterized by an intraepithelial lymphocytic infiltrate. There have been no previous reports of coexistence between these 2 pathologies.To describe histological and clinical characteristic in patients with coexistence of lymphocytic colitis and microscopic enteritis.All cases with simultaneous diagnosis of lymphocytic duodenosis and lymphocytic colitis were reevaluated during lapse time 2010-2016 in hospital Daniel Carrion. The slides were reviewed by 3 pathologists and clinical information was obtained from clinical records. Expression of CD3 and CD8 was detected in 6 cases by immunohistochemical assays.A total of 35 patients with coexistence of lymphocytic duodenitis and lymphocytic colitis were selected of the pathology archives, 80% were females, Anemia was identified in 28.5% of patients. Blastocysitis hominis infestation was identified in 31.8%. The mean intraepithelial lymphocyte CD8 and CD3 positive was 40% in microscopic enteritis, while the mean intraepithelial lymphocyte CD3 positive was 37.2% and CD8 positive was 29.2% Additionally, lymphocytic ileitis was diagnosed in 11 of our cases. Eosinophilic colitis was diagnosed in 9 cases of lymphocytic colitis Conclusion: We found that lymphocytic colitis, microscopic enteritis and even lymphocytic ileitis can coexist in a group of patients with chronic diarrhea. These findings bring the question if this concurrence of both pathologies constituted a more generalized gastrointestinal disorder, involving both the large and the small intestines.

Inflammatory bowel diseases, particularly ulcerative colitis (UC) and lymphocytic colitis (LC), affect many people. The role of melatonin in the pathogenesis of UC is precisely determined, whereas in LC it remains unknown. The aim of this study was to compare the expression of the melatonin-synthesizing enzymes tryptophan hydroxylase (TPH1), arylalkylamine-N-acetyltransferase (AANAT), and N-acetylserotonin methyltransferase (ASMT) in the colonic mucosa and urinary excretion of 6-sulfatoxymelatonin in patients with ulcerative and lymphocytic colitis. The study included 30 healthy subjects (group C), 30 patients with severe ulcerative colitis (group UC), and 30 patients with lymphocytic colitis (group LC). The diagnosis was based on endoscopic, histological, and laboratory examinations. Biopsy specimens were collected from right, transverse, and left parts of the colon. The levels of mRNA expression, TPH1, AANAT, and ASMT were estimated in the colonic mucosa with RT-PCR. The urine concentration of aMT6s was determined by the photometric method. The expression of TPH1, AANAT, and ASMT in colonic mucosa in UC and LC patients was significantly higher than in healthy subjects. Significant differences were found in the urinary aMT6s excretion: group C—13.4 ± 4.8 µg/24 h, group UC—7.8 ± 2.6 µg/24 h (p < 0.01), group LC—19.2 ± 6.1 µg/24 h (p < 0.01). Moreover, a negative correlation was found between fecal calprotectin and MT6s—in patients with UC − r = −0.888 and with LC − r = −0.658. These results indicate that patients with UC and those with LC may display high levels of melatonin-synthesizing enzymes in their colonic mucosa, which could possibly be related to increased melatonin synthesis as an adaptive antioxidant activity.

BACKGROUND: Microscopic colitis causes chronic watery diarrhoea and has previously been associated with the use of proton pump inhibitors.AIM: To explore the association between proton pump inhibitor use and microscopic colitis, including its dependency on timing, dose and choice of proton pump inhibitor.METHODS: Within a 10-year period, we identified 10 652 patients with a first-time diagnosis of microscopic colitis, including 6254 (59%) with collagenous colitis and 4398 (41%) with lymphocytic colitis. All microscopic colitis cases were histologically confirmed in the Danish Pathology Register. Information on proton pump inhibitor use was obtained from the Danish Prescription Register. In this case-control study, we estimated the adjusted odds ratios (aOR) for the association between proton pump inhibitor use and risk of microscopic colitis using conditional logistic regression while adjusting for potential confounders.RESULTS: We found strong associations between current proton pump inhibitor use and both collagenous colitis (aOR 6.98; 95% CI: 6.45-7.55) and lymphocytic colitis (aOR 3.95; 95% CI: 3.60-4.33). This association was observed with all PPIs. The strongest association was with the current use of lansoprazole for both collagenous colitis (aOR 15.74; 95% CI: 14.12-17.55) and lymphocytic colitis (aOR 6.87; 95% CI: 6.00-7.86). When considering timing, ORs were highest for current use of proton pump inhibitor and lower for recent or past exposure. No clear dose-response pattern was observed.CONCLUSIONS: We found a strong association between microscopic colitis and ongoing use of proton pump inhibitors, especially lansoprazole.

Background Long-term data on the influence of smoking on risk of microscopic colitis are limited. We therefore sought to examine and characterize the association between smoking and risk of incident microscopic colitis in two large prospective cohorts of women. Methods We conducted a prospective study of 231015 women enrolled in the Nurses' Health Study [NHS] and NHSII. Information regarding smoking, other lifestyle factors and medications were collected biennially from 1976 to 2012 in NHS and from 1989 to 2013 in NHSII. Incident cases of microscopic colitis were confirmed through physician medical record review. We used Cox proportional hazards modelling to examine the association between smoking and risk of microscopic colitis. Results We documented 166 incident cases of microscopic colitis over 6122779 person-years of follow up. Compared to non-smokers, the multivariable-adjusted hazard ratio [HR] for microscopic colitis was 2.52 (95% confidence interval [CI] 1.59-4.00) amongst current smokers and 1.54 [95% CI 1.09-2.17] amongst past smokers. The risk increased with higher pack-years of smoking [p trend = 0.001] and diminished following smoking cessation [p trend = 0.017]. Current smoking appeared to be more strongly associated with risk of collagenous colitis [HR 3.68; 95% CI 1.94-6.97] than lymphocytic colitis [HR 1.71; 95% CI 0.83-3.53]. Conclusion In two large prospective cohort studies, we observed an association between current smoking and risk of microscopic colitis. Risk of microscopic colitis appeared to increase with higher pack-years and diminish following smoking cessation. Future studies focused on characterizing the biological mechanisms underlying these associations are warranted.

AIM We report clinicopathological experience of microscopic colitis (MC) in a population-based case series in Northern Ireland over a 9-year period. METHOD The pathology laboratory information system within a large teaching centre serving two healthcare trusts was interrogated for cases coded between 2008 and 2016 as collagenous colitis (CC) or lymphocytic colitis (LC). Demographic, clinical and follow-up information was collected from healthcare records. RESULTS A total of 326 new diagnoses of MC were identified, an average annual incidence of 6.7 per 100 000 population. The average annual incidence of CC and LC was 5.0 and 1.7 per 100 000 population, respectively. For coding reasons it is likely that LC data are incomplete. Of 191 cases diagnosed by specialist gastrointestinal pathologists, 141 patients had CC and 50 patients had LC. Both CC and LC predominantly involved women aged 60-79. Some 15% demonstrated endoscopic abnormalities. Endoscopic sampling protocols varied widely: 30% of individuals with CC and 32% of those with LC had the right and left colon sampled separately, with histology concordant in 95% of cases. Of the 191 cases, only one case (of LC) was refractory to treatment; the rest exhibited a clinical response. Only 35 patients had follow-up endoscopy and biopsies, and three of each diagnosis showed persistent disease on histology. CONCLUSION Overall, CC and LC are benign conditions with similar demographics, clinical associations, management and outcomes. Separate sampling of the right and left colon is advised at colonoscopy if this diagnosis is being considered, but left colonic sampling, which can be performed at flexible sigmoidoscopy, will diagnose the vast majority of cases.

BACKGROUND/AIMS Although normal endoscopic findings are, as a rule, part of the diagnosis of microscopic colitis, sev-eral cases of macroscopic lesions (MLs) have been reported in collagenous colitis, but hardly in lymphocytic colitis (LC). The aim of this study was to investigate the endoscopic, clini-cal, and histopathologic features of LC with MLs. METHODS A total of 14 patients with LC who were diagnosed between 2005 and 2010 were enrolled in the study. Endoscopic, clini-cal, and histopathologic findings were compared retrospec-tively according to the presence or absence of MLs. RESULTS MLs were observed in seven of the 14 LC cases. Six of the MLs exhibited hypervascularity, three exhibited exudative bleeding and one exhibited edema. The patients with MLs had more severe diarrhea and were taking aspirin or pro-ton pump inhibitors. More intraepithelial lymphocytes were observed during histologic examination in the patients with MLs compared to the patients without MLs, although this difference was not significant. The numbers of mononuclear cells and neutrophils in the lamina propria were independent of the presence or absence of MLs. CONCLUSIONS LC does not always present with normal endoscopic findings. Hyper-vascularity and exudative bleeding are frequent endoscopic findings in patients with MLs. (Gut Liver, 2015;9197-201).

Characterized by colonic mucosa intraepithelial lymphocytosis, lymphocytic colitis is primarily an entity presented in the middle-aged to elderly patient population. Very few large series of lymphocytic colitis of childhood occurrence are available in the medical literature. Ten cases each of lymphocytic colitis and of colonic lymphocytosis of other diagnosis, all with duodenal disaccharidases analysis data, were collected from the files of our institution. The electronic medical records were reviewed and multiple variables were analyzed. The ten patients with lymphocytic colitis presented with diarrhea. Of these, three had abdominal pain. The age range was 2–18 years. Nearly all patients were Caucasian (90%) and 70% were female. Endoscopically, most had normal appearing colonic mucosa. Significant past medical history, family medical history and associated comorbidities included celiac disease, Down syndrome, juvenile arthritis and other autoimmune diseases. Interestingly, the most revealing observation was that the majority of cases (80%) were associated with lactase deficiency and, for the most part, gastrointestinal symptoms improved simply by treatment with Lactaid or avoidance of dairy products. This association is statistically significant. Our clinicopathological study indicates that the typical pediatric patient is a female Caucasian. A large of portion of the patients had associated lactase deficiency and improved on Lactaid supplement alone.

Background: Incidence rates of microscopic colitis are mainly based on regional data from a limited number of countries. To evaluate geographical differences and changes over time, more nationwide incidence rates are needed. Aims: The aim of this retrospective study was to assess the incidence rate of microscopic colitis in the Netherlands in a nationwide cohort. Methods: A search was performed in the Dutch pathology registry, covering records of all approximately 16.5 million inhabitants. Incident cases were defined as a first diagnosis of microscopic colitis (collagenous or lymphocytic colitis) between 2000 and 2012. Results: In total, 7228 incident cases were identified with a mean annual incidence rate of 3.4 per 100,000 person years. Collagenous colitis was present in 3741 cases and lymphocytic colitis in 2718 cases, with a mean annual incidence rate of 1.8 and 1.3 per 100,000 person years, respectively. Remaining 769 cases were described as undefined microscopic colitis. Collagenous and lymphocytic colitis incidence rates increased significantly over time (p < 0.001) with a male: female ratio of 1:3 and 1:2, respectively. Conclusion: The Dutch mean annual incidence rates of collagenous and lymphocytic colitis were considerably lower than previously reported by other countries. However, incidence rates increased gradually over time, with a clear female predominance. (C) 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

To describe the characteristics of a cohort of patients with microscopic colitis (MC; lymphocytic (LC) or collagenous (CC) colitis) and to compare them with patients with functional bowel disorder with diarrhea (FBD-D).Between September 2010 and June 2012, patients fulfilling the following inclusion criteria were prospectively included in 26 centers in France: (i) having at least three bowel movements daily with change in stool consistency; (ii) duration of abnormal bowel habit4 weeks; and (iii) normal or near-normal colonoscopy. Each patient underwent a colonoscopy and colonic biopsies. We compared the demographic, clinical, biological, and etiological characteristic of patients with MC (CC and LC) with those of control patients with FBD-D.A total of 433 patients were included: 129 with MC (87 LC and 42 CC), 23 with another organic disease, and 278 with FDB-D, including patients with diarrhea and abdominal pain who met the criteria of Rome III (irritable bowel syndrome with diarrhea) and patients with functional diarrhea without abdominal pain. Logistic regression analysis identified the following independent predictors of MC: age50 years (odds ratio (OR)=3.1, 95% confidence interval (CI)=1.6-5.9), presence of nocturnal stools (OR=2, 95% CI=1.1-3.9), weight loss (OR=2.5, 95% CI=1.3-4.7), duration of diarrhea12 months (OR=2.0, 95% CI=1.1-3.5), recent introduction of new drugs (OR=3.7, 95% CI=2.1-6.6; P0.0001), and the presence of a known autoimmune disorder (OR=5.5, 95% CI=2.5-12).Age50 years, the presence of nocturnal stools, weight loss, the introduction of a new drug, and the presence of a known autoimmune disease increase the probability of MC and thus the indication for colonoscopy with biopsies.

Background: Lymphocytic and collagenous colitis are emerging as common findings in subjects undergoing colonoscopy for chronic non-bloody diarrhea (CNBD). Data concerning microscopic colitis (MC) are still limited and affected by controversial epidemiological evidences. Recent converging lines of evidence suggest that MC correlates a lower risk of colorectal neoplasia. Accordingly, we prospectively assessed MC prevalence in a multicenter cohort of subjects submitted to colonoscopy for CNBD, thereby defining whether MC influences the risk of colorectal neoplasia. Methods: Consecutive patients with CNBD of unknown origin underwent pan-colonoscopy with multiple biopsies. The prevalence of neoplastic patients in MC was compared with that observed in negative CNBD subjects. Results: Among 8006 colonoscopy, 305 subjects were enrolled for CNBD. Patients with CNBD were more likely to be women than men (odds ratio ¼ 1.5; P ¼ 0.001). Histopathology detected high prevalence of MC (16%) with a clear predominance of collagenous colitis (70%). A striking agedependent rise in MC-associated risk was observed, depicting outstanding differences among varying age groups, as in the number needed to screen 1 new case. Gender distribution was balanced within MC patients (Female/Male ¼ 1.5/1), especially among lymphocytic colitis (Female/Male ¼ 1.2/1). MC patients were negatively associated with the risk of neoplastic polyps compared with negative CNBD subjects (odds ratio ¼ 0.22; P ¼ 0.035). Conclusions: MC is the first cause of CNBD in subjects submitted to colonoscopy. Multiple biopsies are strongly recommended, even in the case of uneventful endoscopic inspection, especially for age $40 years. MC has a reduced risk of colorectal neoplasia, suggesting that this model of chronic inflammation plays a protective effect against colorectal carcinogenesis. (Inflamm Bowel Dis 2014;20:882–891)

Watery diarrhea is the cardinal symptom of lymphocytic colitis (LC). We have previously shown that colonic Na malabsorption is one of the major pathologic alterations of LC and found evidence for an epithelial barrier defect. On these grounds, this study aimed to identify the inherent mechanisms of this epithelial barrier dysfunction and its regulatory features.Epithelial resistance (RREpithelial barrier dysfunction in LC occurs through downregulation of claudin-4, -5, and -8, and redistribution of claudin-5 and -8 off the tight junction, which contributes to diarrhea by a leak-flux mechanism. The key effector cytokines TNFα and IFNγ turned out to be the trigger for redistribution of claudin-5 and -8. Thus, alongside sodium malabsorption, leak-flux is yet another important diarrheal mechanism in LC.

Microscopic colitis (MC) is prevalent in adults investigated for chronic watery diarrhea, yet characterization of pediatric MC is limited.Our pathology database was searched from 1995 to 2011 for pediatric cases of lymphocytic colitis (LC) or collagenous colitis (CC). Those with diarrhea persisting for2 weeks and visually normal colonoscopy were accepted as cases. Demographics, laboratory results, medication use within 3 months of presentation, medical and family history of autoimmune disease, and response to treatment were abstracted.A total of 27 cases were histologically consistent with MC on biopsy; 5 with concomitant enteric infection or isolated abdominal pain were excluded. Twenty-two cases of MC (female patients, 59%; median age at diagnosis, 15.3 years) were included (19 LC and 3 CC). Two had type 1 diabetes mellitus, 2 were anti-nuclear antibody positive, and 2 had common variable immunodeficiency. Of 20 patients who underwent an esophagogastroduodenoscopy, 1 had collagenous sprue and 4 had celiac disease. One presented after the clearance of recurrent Clostridium difficile infection. Previous drug exposures included nonsteroidal anti-inflammatory drugs (n = 7), proton pump inhibitors (n = 6), and selective serotonin reuptake inhibitors (n = 3). Common symptoms in addition to diarrhea included abdominal pain (77.3%) and weight loss (27.3%). Of 17 patients with follow-up, all of the 8 treated with steroids had some response: 57.1% (4/7) responded to mesalamine and 42.9% (3/7) responded to bismuth subsalicylate.In this cohort of pediatric patients, LC was much more common than CC. As described in adults, we observed associations with celiac disease, type 1 diabetes mellitus, and medications; we additionally saw an association with immunodeficiency. Our patients showed greater response to steroids than mesalamine or bismuth.

The diagnosis of microscopic colitis (MC) is based on histologic findings and includes collagenous colitis (CC) and lymphocytic colitis (LC). Incomplete MC (MCi) denotes patients with chronic diarrhea and a normal endoscopy and morphological changes that do not completely meet the histologic criteria of LC or CC. The aim of this study was to investigate the intraobserver and interobserver agreement on the MC subtypes of CC, LC, and MCi and the ability to discriminate MCi from normal and inflammatory bowel disease/nonspecific reactive changes. A single hematoxylin and eosin-stained specimen from biopsies of the following 5 groups were randomly selected and blinded: CC, LC, MCi, inflammatory bowel disease, and normal. Three pathologists independently reviewed the specimens. The specimens were relabeled and reinterpreted 4 months later. Intraobserver and interobserver agreement was evaluated by κ statistics. κ values for intraobserver agreement were good for 5 diagnostic groups varying from 0.70 to 0.83 and very good when simplifying to only 3 diagnostic groups varying from 0.88 to 0.96, separating MC/MCi from non-MC. κ values for interobserver agreement varied from 0.60 to 0.75 for 5 diagnostic groups and 0.81 to 0.89 for 3 diagnostic groups. The study shows that the intraobserver and interobserver agreement is high for discriminating between MC/MCi and non-MC, whereas the ability to discriminate MCi from CC and LC is lower. A revision and consensus on the histologic criteria of the MC subtypes seem warranted.

Objective The aim of the present study was to study microscopic colitis (MC) in children with special reference to its role in chronic diarrhea and changes in mucosal biopsies. Methods A total of 100 consecutive children ages 3 to 12 years, with nonbloody diarrhea (passage of ≥3 loose stools per day) of >12 weeks' duration were screened and 26 were enrolled in the study in which no specific etiology could be found and colonoscopy did not reveal any mucosal abnormality. Colonic biopsies were evaluated for the presence of lymphocytic colitis or collagenous colitis and those with the characteristic changes were defined to have MC (group A). Colonic biopsies from patients with MC were compared with biopsies from patients with chronic diarrhea but no evidence of MC (group B). One hundred children ages 3 to 12 years with bleeding per rectum were screened and colonic biopsies from 45 patients (group C) who had colonic mucosal changes but no vascular or polyp lesion were compared with patients with MC. Results Of the 26 patients with chronic diarrhea, MC was found in 5 (3 lymphocytic colitis and 2 collagenous colitis). Significantly higher polymorphonuclear infiltration was seen in group A as compared with group B (13.8 [5.4-20.6] vs 7.2 [0-19.6]; P = 0.03) or group C (13.8 [5.4-20.6] vs 4 [0-13.4]; P = 0.007). Intraepithelial lymphocytes (12 [4-32] vs 4 [0-24]; P = 0.008) and basement membrane thickening (3.5 [2.9-10.6] vs 2.5 [1.6-5.86]; P = 0.008) were also significantly higher in group A as compared with group C. Conclusions MC was found to be present in children with nonbloody chronic diarrhea in children. Further multicentric studies may provide adequate data on its prevalence.

BACKGROUND Whether current smoking worsens the clinical course of microscopic colitis (MC) is unknown. The aim was to evaluate the impact of smoking on the clinical course of MC. METHODS One hundred and eighty-four patients (72% women; age, 62.4 ± 1.1 years) with MC (118 collagenous colitis (CC) and 66 lymphocytic colitis (LC) were evaluated (39 of them were current smokers). In all the patients, smoking habits and clinical data at presentation, response to therapy, and clinical relapses during follow-up were prospectively recorded. Risk factors for clinical relapse were studied in 160 patients after a mean follow-up of 28 ± 1 months. Cox regression analysis was used to adjust for confounding variables. RESULTS Age at diarrhea onset was 63.0 ± 1.4 years in nonsmokers and 50.4 ± 2.1 years in current smokers (P < 0.001). There was no significant influence of smoking habit on either clinical symptoms at diagnosis or clinical remission rate. Clinical relapse rate was 25.5% for CC and 29.6% for LC, with the mean relapse-free time 28.8 months (95% confidence interval, 26.3-31.4) for CC and 26.9 months (95% confidence interval, 26-30.3) for LC (P = 0.5). Multivariate analysis showed that age at diagnosis (

Serum gastrin levels exceeding 1000 pg/ml (normal

Background: Cigarette smoking is an important environmental factor affecting inflammatory bowel disease. The role of smoking has not been rigorously studied in microscopic colitis (MC). The aim of this study was to compare the association of cigarette smoking in individuals with MC compared to a control population without MC. Methods: We reviewed the records of patients with a clinical and histologic diagnosis of collagenous colitis (CC) or lymphocytic colitis (LC). Clinical history, including alcohol and smoking status at the time of diagnosis of MC, were reviewed. In this case–control study, age- and gender-matched patients without diarrhea presenting for outpatient colonoscopy served as the control population. Results: We analyzed a total of 340 patients with MC: 124 with CC and 216 with LC. Overall, any smoking status (former or current) was associated with MC (odds ratio [OR] 2.12, 95% confidence interval [CI]: 1.56–2.88). This risk was more prominent in current smokers (adjusted OR 5.36, 3.81, and 4.37 for CC, LC, and all MC, respectively, 95% CI all greater than 1). The association of smoking was not significantly affected by gender or average alcohol consumption. Conclusions: In our study population, cigarette smoking is a risk factor for the development of both forms of microscopic colitis. There were no significant differences between LC and CC, and current smoking and the development of microscopic colitis affected men and women similarly. We feel that these data are sufficient to discuss the potential risks of tobacco use in patients with microscopic colitis. (Inflamm Bowel Dis 2012)

The relationship between Microscopic Colitis and Inflammatory Bowel Disease is unclear. However, when both are diagnosed they seem to be part of a broader spectrum of the same disease, more than just a coincidence. We report a 55 years old woman with Ulcerative Colitis limited to the rectum with complete clinical and endoscopic response to standard treatment and adequate surveillance for 13 years, who abandoned treatment and control. After eight years, she consulted for mild-to-moderate non-bloody diarrhea lasting several months. Colonoscopy and basic laboratory did not show any alterations. Nevertheless, random biopsies had a characteristically pattern compatible with Lymphocytic Colitis. After the first week of treatment with budesonide the patient was asymptomatic and still in clinical remission, with negative fecal calprotectin at 6 months’ follow-up.

Microscopic colitides, including lymphocytic (LC) and collagenous colitis (CC), are well-described pathologic conditions. An altered immune response is implicated in the pathogenesis of both entities. CD8+ T lymphocytes (CTLs) secrete interleukin 2 which stimulates proliferation of regulatory T cells (Tregs), and Tregs, in turn, inhibit CTLs, inducing cytotoxic tissue damage. In Tregs, Foxp3 regulates T-cell–related immune responses. The distribution of Tregs and CTLs in microscopic colitides has remained underexplored. To characterize differences in the distribution pattern of Foxp3 in biopsy specimens from patients with LC and CC, 71 colonic biopsy specimens from 69 consecutive patients were categorized into 1 of 3 diagnoses: no significant histopathologic abnormality (NSHPA), LC, or CC. Further immunohistochemical evaluation of all biopsy specimens was conducted using a panel of markers including CD8 and Foxp3. Our study demonstrated that CTL distribution pattern differences exist among these 2 colitides and that differences in the immunologic recruitment of Foxp3+ Tregs in the colonic mucosa correlate with differences in the spectrum of morphologic changes seen in patients with either LC or CC. Upon completion of this activity you will be able to: The ASCP is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The ASCP designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit ™ per article. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity qualifies as an American Board of Pathology Maintenance of Certification Part II Self-Assessment Module. The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose. Questions appear on p 1009. Exam is located at [www.ascp.org/ajcpcme][1]. [1]: http://www.ascp.org/ajcpcme

BACKGROUND: Microscopic colitis (MC) is an umbrella term for collagenous colitis (CC) and lymphocytic colitis (LC). The incidence of these diseases is increasing for unclear reasons.OBJECTIVE: To identify factors that may impact diagnosis rates of MC in a North American population.METHODS: Population-based pathology and endoscopy databases were searched to identify all cases of MC and the number of lower endoscopy (LE) procedures performed over a five-year period (January 2004 to December 2008) in a catchment area of 1.2 million people. Endoscopist characteristics were compared with diagnostic rates.RESULTS: MC incidence increased from 1.68 per 10,000 in 2004, to 2.68 per 10,000 in 2008, with an average annual increase of 12% per year (95% CI 7% to 16%; PCONCLUSION: The incidence of MC is rising due to increased diagnosis of LC, while CC incidence remains stable. Patients with MC symptoms have stable endoscopy rates but are being biopsied more often. Physician training, practice type and endoscopy volume impact the diagnostic rates of MC.

Background Lymphocytic colitis (LC) causes watery diarrhea. We aimed to identify mechanisms of altered Na absorption and regulatory inputs in patients with LC by examining the epithelial Na channel (ENaC) function as the predominant Na transport system in human distal colon. Methods Epithelial Na channel function and regulation was analyzed in biopsies from sigmoid colon of patients with LC and in rat distal colon in Ussing chambers. ENaC-subunit expression was measured by real-time PCR and RNA sequencing. Correction factors for subepithelial resistance contributions were determined by impedance spectroscopy. Upstream regulators in LC were determined by RNA sequencing. Results Epithelial Na channel-mediated electrogenic Na transport was inhibited despite aldosterone stimulation in human sigmoid colon of patients with LC. The increase in γ-ENaC mRNA expression in response to aldosterone was MEK1/2-dependently reduced in LC, since it could be restored toward normal by MEK1/2 inhibition through U0126. Parallel experiments for identification of signaling in rat distal colon established MEK1/2 to be activated by a cytokine cocktail of TNFα, IFNγ, and IL-15, which were identified as the most important regulators in the upstream regulator analysis in LC. Conclusions In the sigmoid colon of patients with LC, the key effector cytokines TNFα, IFNγ, and IL-15 inhibited γ-ENaC upregulation in response to aldosterone through a MEK1/2-mediated pathway. This prevents ENaC to reach its maximum transport capacity and results in Na malabsorption which contributes to diarrhea.

A 41-year-old female patient with medical history of bipolar disorder, on topiramate and quetiapine for several years and on sertraline for the last4months, presented to theemergencydepartmentwithdiarrhea (6–8bowelmovementsperday,watery stools, no blood)andweight loss (20Kg) for thepast2–3months.Physical examinationrevealedmilddiscomfortonpalpationof the right lower quadrant without any peritoneal signs. Laboratory results showed mild and isolated leucocytosis (11 500/uL), CRP was within normal range. The patient was discharged with antispasmodic medication and was referred to our outpatient clinic one week later. Diarrhea laboratory investigation revealed positive anti-Saccharomyces antibodies (ASCA). Blood count, TSH, ferritin, B12 vitamin, folate, albumin and other liver function tests were within normal range and celiac disease screening and antineutrophil cytoplasmic antibodies (ANCA) were negative. A total colonoscopy and ileoscopy were performed and were normal (Figures A, terminal ileon; and B, cecum). Biopsies were taken from the right, transverse and descendent colon and from the rectum, revealing intraepithelial lymphocytosis (27 lymphocytes per 100 enterocytes) and mucosal oedema along the entire colon (Figure C, Hematoxylin and Eosin (HE and Figure D, CD45, 400 ). The most likely cause of her diarrhea is?