Increase In Intraepithelial Lymphocytes Research Articles

Pathology of celiac disease: a brief review.

Celiac disease is a gluten or prolamine-induced immunological disorder primarily affecting the intestines. Celiac disease is often missed since not only are clinical findings 'not typical' but also because many cases are asymptomatic. The diagnosis is based on a constellation of clinical, serological and histological findings in a duodenal biopsy, in addition to HLA genotype.and response to a gluten-free diet.Although some guidelines suggest that histology may not mandatory in every case, by and large changes in mucosal biopsies of the duodenum still remain an important diagnostic tool. The evaluation of a duodenal biopsy requires a properly oriented and satisfactory hematoxylin & eosin stained paraffin section. A poorly oriented and technically suboptimal biopsy is not uncommonly the reason for erroneous interpretation. An increase in intraepithelial lymphocytes [IELs] and an alteration of the crypt: villus ratio forms the basis of diagnosis. These are semiquantitavely classified. Despite varying opinions related to the cut-off values of IELs and findings that recommend appropriate site, number and size of the biopsy specimens, the sensitivity of biopsies vary from 90%-100%. Interpretation of histological findings require correlation with other evidences since the changes in duodenal biopsy may be similar to those seen in a host of other diseases including tropical sprue. It must also be mentioned that in the Indian subcontinent is that reference values for normal duodenal biopsies are lacking, making interpretation difficult especially when changes are mild. Histological changes in the duodenal mucosa often take months to normalize after clinical remission. This is a review of various aspects related to the histological changes in duodenal mucosal biopsies that aid in the diagnosis and follow-up of cases of celiac disease.

Histopathology of duodenal mucosal lesions in pediatric patients with inflammatory bowel disease: statistical analysis to identify distinctive features.

Histopathologic lesions of the upper gastrointestinal tract (UGT) are common in inflammatory bowel disease (IBD) patients. Pediatric patients have a higher incidence of IBD-associated gastritis and duodenitis than do adults. This study aimed to identify histopathologic features of duodenal lesions in the pediatric population that are characteristic of IBD, compared to duodenal pathology of different etiopathogenesis. We performed a retrospective analysis of UGT biopsies from pediatric patients with a histopathologic diagnosis of duodenitis (0-18 years of age) over a 7-year period. We identified 40 cases of duodenitis associated with Crohn's disease (CD) and 10 cases associated with ulcerative colitis (UC) and compared the histopathologic characteristics of the duodenitis with age-matched controls consisting of 40 cases duodenitis associated with celiac disease and 40 non-Helicobacter pylori-associated (NOS) etiology duodenitis cases. The histologic features that were evaluated included presence of granulomas, duodenal cryptitis, erosion, lamina propria eosinophils, villous blunting, increased intraepithelial lymphocytes (IELs), and crypt hyperplasia, among others. Additionally, we evaluated the presence of associated gastritis in all of these groups. Statistical analysis to identify significant differences was performed using Kruskal-Wallis testing. Cryptitis was the most distinctive feature of IBD-associated duodenitis. Granulomas were exceptionally rare. The severity of villous blunting and presence of IELs was significantly different in the IBD versus the celiac group. There is a significant overlap with duodenal lesions of different etiopathogenesis, including villous blunting and eosinophilia. With the exclusion of granulomas, cryptitis seems the most distinctive feature of the duodenal lesions associated with IBD.

The significance of fas/fasl expression in celiac disease, non-specific duedonitis and in duedonum biopsies showing increase in intraepithelial lymphocytes

Aim: Celiac disease (CD) is a chronic malabsorbtion disease of the small bowel. With a prevelance of about %1 it is a common disease in the community. FAS-FASL system which induces apopitosis is one of the most important pathways and responsible fort he development of mucosal atrophy in CD. The aim of this study is to investigate the patients who has the increase of intraepithelial lymphocytes (IEL) in duedonal mucosa and non specific duedonitis (NSD) and significance of FAS-FASL expression in these patients to distinct from CD.Materials and methods: 29 adults and 7 children celiac patients (with a preliminary diagnosis as iron deficiency anemia) and 17 adults and 6 children non-specific duedonitis patients included in the study. CD3, CD8, FAS and FASL expression were examined immunohistochemically from sections prepared from paraffin blocks in 28 adults and 7 children with normal duedonal mucosa and 24 adults and 6 children who has the increase of IEL in duedonum.Results: In all groups; the number of IEL seen much more with CD3 in HE (hematoxylin eosin) sections . Again in all groups it is determined that majority of IEL expresses CD3 and CD8. Both in adult and children group; in surface and crypt enterosits in IEL ; the highest FAS expression was seen in enterosits and lamina propria cells in CD .More expression was determined in patients with the group who has IEL in duedonum and with NSD when compared to control group. FASL expression is increased in CD in comparison with normal but it was low in the group who has IEL in duedonum and NSD group. We found that FAS-FASL expression is not only an effective mechanism in pathogenesis of CD. We suggest that the functional significance of FAS expression should be investigated by methods of evaluating apopitosis in patients with IELAG and NSD who has more FAS expression when compared to CD . Also in the detection of number of IEL in suspected cases routine use of CD3 immunohistochemical evaluation may be useful.

Olmesartan-Associated Sprue-Like Enteropathy

Introduction: We present a case of olmesartan-associated sprue-like enteropathy presenting with chronic diarrhea. Although this has been previously reported, it is critical to raise awareness of this rare side effect. A 67-year-old female with history of asthma, insulin-dependent diabetes, remote Clostridium difficile colitis, and hypertension presented with 1 month of severe, watery diarrhea accompanied by abdominal bloating and distention. Initial work-up was notable for mild hypokalemia with normal liver panel, lipase, and complete blood count. Infectious stool studies including fecal leukocytes, Clostridium difficile toxin PCR, rotavirus ELISA, bacterial cultures, as well as giardia and cryptosporidium antigen testing all returned negative. Fecal fat staining returned abnormal. Tissue transglutaminase IgA antibody testing was negative for celiac disease. Colonoscopy to the distal ileum was normal, finding 2 tubular adenomas, normal colonic mucosa, and biopsies negative for microscopic colitis. Her diarrhea persisted, and GI was reconsulted. A review of her medicines revealed she had been taking olmesartan for 2 years. Olmesartan-associated sprue was suspected, and EGD revealed duodenal mucosal changes consistent with sprue-like enteropathy with moderate villous blunting, mild active inflammation, and increased intraepithelial lymphocytes (IELs) by CD3 immunohistochemical staining. Improvement in diarrhea was seen after 1 week of discontinuation of olmesartan, and complete resolution was observed at 1 month. Olmesartan is 1 of several angiotensin II receptor antagonists available for the treatment of hypertension. In 2012, Rubio-Tapia et al identified 22 patients treated with olmesartan who developed clinical features of chronic diarrhea, weight loss, and sprue-like enteropathy, evidenced by villous atrophy and mucosal inflammation on intestinal biopsy. All cases demonstrated negative serologic testing for celiac disease by IgA tissue transglutaminase, and a majority had failed prior therapy with gluten-free diet. Notably, all 22 patients experienced resolution of symptoms with withdrawal of olmesartan and discontinuation of gluten-free diet. The mean duration of exposure to olmesartan was 3.1 years, suggesting a potential drug-induced cell-mediated damage rather than a type I hypersensitivy reaction. Our case report matches prior descriptions of olmesartan-associated sprue-like enteropathy. Though rare, clinicians should be aware of the association between olmesartan and sprue-like illness.

Covering the Cover

Covering the Cover

Predictive value of “Marsh 1” type histology in subjects with suspected cealic disease

Introduction. The diagnosis of celiac disease (CD) is based on histology in combination with anti-tissue transglutaminase (a-tTG) and anti-endomysial antibodies (EMAs). The increase of intraepithelial lymphocytes defines the Marsh 1 histology that appears not to be specific for CD. Aim: To explore the positive predictive value (PPV) and clinical relevance of Marsh 1 histology in suspected CD. Methods. We carried out an observational prospective study including all consecutive subjects with a Marsh 1 histology. All patients were tested for a-tTG and EMAs. Diagnosis of potential CD was defined in the presence of Marsh 1 with positive a-tTG and EMAs. Patients were investigated for symptoms, CD familial aggregation, other diseases, and current medication. Results. Sixty-three patients with Marsh 1 were included. Diagnosis of potential CD was made in 23 subjects (36%), so that Marsh 1 histology showed a PPV of 36%. With regard to familial aggregation, patients with potential CD showed a higher frequency of familiarity for CD (60.8% vs. 15.0%; p < 0.01). No significant difference was detected between CD and non-CD in terms of intestinal and extra-intestinal symptoms. We also documented the presence of conditions other than CD in the remaining population: 7 patients (17.5%) with immuno-mediated diseases while 5 patients (12.5%) showed Helicobacter pylori (HP) infection. About medication, 3 patients (7.5%) were on non-steroidal anti-inflammatory drugs, while another 4 (10%) patients were being treated with other drugs. Conclusion. The Marsh 1 type histology is not specific for CD and it can also be associated with immuno-mediated disorders, HP infection, and drugs.

An Italian prospective multicenter survey on patients suspected of having non-celiac gluten sensitivity.

BackgroundNon-celiac gluten sensitivity (NCGS) is still an undefined syndrome with several unsettled issues despite the increasing awareness of its existence. We carried out a prospective survey on NCGS in Italian centers for the diagnosis of gluten-related disorders, with the aim of defining the clinical picture of this new syndrome and to establish roughly its prevalence compared with celiac disease.MethodsFrom November 2012 to October 2013, 38 Italian centers (27 adult gastroenterology, 5 internal medicine, 4 pediatrics, and 2 allergy) participated in this prospective survey. A questionnaire was used in order to allow uniform and accurate collection of clinical, biochemical, and instrumental data.ResultsIn total, 486 patients with suspected NCGS were identified in this 1-year period. The female/male ratio was 5.4 to 1, and the mean age was 38 years (range 3–81). The clinical picture was characterized by combined gastrointestinal (abdominal pain, bloating, diarrhea and/or constipation, nausea, epigastric pain, gastroesophageal reflux, aphthous stomatitis) and systemic manifestations (tiredness, headache, fibromyalgia-like joint/muscle pain, leg or arm numbness, 'foggy mind,' dermatitis or skin rash, depression, anxiety, and anemia). In the large majority of patients, the time lapse between gluten ingestion and the appearance of symptoms varied from a few hours to 1 day. The most frequent associated disorders were irritable bowel syndrome (47%), food intolerance (35%) and IgE-mediated allergy (22%). An associated autoimmune disease was detected in 14% of cases. Regarding family history, 18% of our patients had a relative with celiac disease, but no correlation was found between NCGS and positivity for HLA-DQ2/-DQ8. IgG anti-gliadin antibodies were detected in 25% of the patients tested. Only a proportion of patients underwent duodenal biopsy; for those that did, the biopsies showed normal intestinal mucosa (69%) or mild increase in intraepithelial lymphocytes (31%). The ratio between suspected NCGS and new CD diagnoses, assessed in 28 of the participating centers, was 1.15 to 1.ConclusionsThis prospective survey shows that NCGS has a strong correlation with female gender and adult age. Based on our results, the prevalence of NCGS seems to be only slightly higher than that of celiac disease.Please see related article http://www.biomedcentral.com/1741-7015/12/86.

Commentary: duodenal intraepithelial lymphocytosis in children without coeliac disease - authors' reply.

gastrointestinal pathology in a cohort of children in Chile with respect to RAP, H. pylori and other concurrent infection, we showed that low-grade inflammation in the duodenum, manifest by increased intraepithelial lymphocytes (IELs), was associated with RAP (>20 in 74/105 patients) compared with controls (P = 0.04). A higher IEL count was also positively associated with parasite infection, seen in nine patients (P = 0.02). We also found that RAP was not associated with H. pylori as in this current study. While this study adds to the literature that RAP is not associated with H. pylori, the use of children with RAP as a control group may not be a true reflection of normal, and low-grade inflammation as reflected by LD, may represent pathology in RAP. An ideal control group is difficult in children due to ethical considerations, but perhaps those with endoscopy for nonmucosal disease (e.g. foreign body removal) may give a truer representation of normal histology in this age group. ACKNOWLEDGEMENT Declaration of personal interests: None. Declaration of funding interests: This study was funded under the Sixth Framework Programme of the European Union, Project CONTENT (INCO-DEV-3-032136), CONICYT/BM RUE #29 and FONDECYT #1100654.

Sa1026 Liver Transplantation Among the Baby Boomer Generation in the United States: an Analysis of the United Network for Organ Sharing Registry

127 patients had duodenal biopsies taken, amounting to a total of 152 biopsies performed. 87.5% (n: 133/152) of these were histologically normal. Sixteen patients showed abnormal histology and among those 7 patients (43.8%) were on MPA therapy at the time of biopsy. Symptoms in this cohort included diarrhoea (71.4%), weight loss (60%), nausea and vomiting (28.6%) and abdominal pain (14.3%) and occurred at a median of 2.8 years (range 49 3905 days) after initiation of MPA therapy. MPA-associated duodenal changes included shortened villi, an increase in intraepithelial lymphocytes (IELs), an increase in endocrine cell counts and an increase in apoptotic counts. In comparison, agematched patients with confirmed coeliac disease showed similar histological features however, with no increased apoptosis. Conclusion: Diarrhoea following OLT in patients on MPA therapy is a noteworthy entity as it causes significant morbidity and mortality. MPA therapy was associated with abnormal duodenal pathology in a small number of liver transplant cases. Pathologists should be aware of the histological features of MPA-associated duodenal injury, including coeliaclike changes together with an increase in apoptotic counts. CD3 and chromogranin immunohistochemistry can be used to help in this diagnosis. In those found to have abnormal histology, a discontinuation or a reduction in dosage of MPA therapy should be discussed where possible.

Tu1750 Microbial, Metabolomic, and Immunologic Dynamics During Disease Onset, Remission, and Relapse in a Mouse Model of Colitis Involving a Genetically Impaired Mucus Barrier

Introduction: Disturbances of the intestinal microbiota due to enhanced hygienic conditions or antibiotic use have been linked to the increasing prevalence of obesity, allergy, autoimmunity, and functional and inflammatory disorders of the gut, including celiac disease (CD). It is unknown whether perturbation of normal gut colonization plays a causal role in subsequent development of immune responses to gluten. Thus, our aim was to determine and characterize whether absence of gut commensals modifies the response to gluten using germ-free (GF), specific pathogen free (SPF) and altered Schaedler flora (ASF) colonized NOD/DQ8 mice. Methods: GF, SPF, and ASF 8-10 week old male and female NOD/DQ8 mice were mucosally sensitized with peptic tryptic (PT) gliadin (500μg) and cholera toxin (CT; 25μg) by oral gavage once a week for three weeks. Control mice were sensitized with CT alone. Following sensitization, mice were challenged three times a week for two weeks with 2mg of gluten by oral gavage. All materials for GF experiments were aseptically prepared and administered to mice housed in gnotobiotic isolators. Twenty-four hours following the final gluten challenge enteropathy was evaluated by intraepithelial lymphocyte (IEL) counts and villus/crypt (V/C) ratios. Anti-gliadin IgA antibodies (AGA) in intestinal washes were determined as markers of sensitization and specificity towards gliadin was tested by Western blot. Gliadin-specific T cell responses were tested using in vitro proliferation assays. Results: V/C ratios in GF NOD/DQ8 mice decreased by 52% following sensitization, which was significantly greater than SPF (40%) andASF (38%) gliadin-sensitizedmice (p<0.01). Gliadinsensitized GF mice also had the greatest increase in IELs compared to gliadin-sensitized SPF and ASF mice (p<0.01). No control GF, SPF or ASF mouse had a positive AGA result. In gliadin-sensitized mice, positive AGA was detected in 75% of GF mice, 33% of SPF mice and no ASF mice. The specificity of AGA towards gliadin was confirmed by Western blot. T cells isolated from mesenteric lymph nodes of GF gliadin-sensitized mice responded to PT-gliadin stimulation in vitro, but not to PT-zein stimulation. T cells from non-sensitized mice did not respond to PT-gliadin stimulation. Conclusions: Gluten-induced enteropathy and development of gliadin-specific AGA was enhanced under germ-free conditions in NOD/ DQ8 mice and T cell responses are gliadin-specific. These results suggest that the commensal intestinal microbiota may have a protective effect during gliadin-sensitization and challenge in NOD/DQ8mice. Themechanisms leading to this protective effect are under current investigation.

Tu1751 The Convergence of Stasis-Induced Dysbiosis, Colonic Metaplasia, and Genetic Susceptibility in Increasing Risk of Pouchitis and Ulcerative Colitis

Introduction: Disturbances of the intestinal microbiota due to enhanced hygienic conditions or antibiotic use have been linked to the increasing prevalence of obesity, allergy, autoimmunity, and functional and inflammatory disorders of the gut, including celiac disease (CD). It is unknown whether perturbation of normal gut colonization plays a causal role in subsequent development of immune responses to gluten. Thus, our aim was to determine and characterize whether absence of gut commensals modifies the response to gluten using germ-free (GF), specific pathogen free (SPF) and altered Schaedler flora (ASF) colonized NOD/DQ8 mice. Methods: GF, SPF, and ASF 8-10 week old male and female NOD/DQ8 mice were mucosally sensitized with peptic tryptic (PT) gliadin (500μg) and cholera toxin (CT; 25μg) by oral gavage once a week for three weeks. Control mice were sensitized with CT alone. Following sensitization, mice were challenged three times a week for two weeks with 2mg of gluten by oral gavage. All materials for GF experiments were aseptically prepared and administered to mice housed in gnotobiotic isolators. Twenty-four hours following the final gluten challenge enteropathy was evaluated by intraepithelial lymphocyte (IEL) counts and villus/crypt (V/C) ratios. Anti-gliadin IgA antibodies (AGA) in intestinal washes were determined as markers of sensitization and specificity towards gliadin was tested by Western blot. Gliadin-specific T cell responses were tested using in vitro proliferation assays. Results: V/C ratios in GF NOD/DQ8 mice decreased by 52% following sensitization, which was significantly greater than SPF (40%) andASF (38%) gliadin-sensitizedmice (p<0.01). Gliadinsensitized GF mice also had the greatest increase in IELs compared to gliadin-sensitized SPF and ASF mice (p<0.01). No control GF, SPF or ASF mouse had a positive AGA result. In gliadin-sensitized mice, positive AGA was detected in 75% of GF mice, 33% of SPF mice and no ASF mice. The specificity of AGA towards gliadin was confirmed by Western blot. T cells isolated from mesenteric lymph nodes of GF gliadin-sensitized mice responded to PT-gliadin stimulation in vitro, but not to PT-zein stimulation. T cells from non-sensitized mice did not respond to PT-gliadin stimulation. Conclusions: Gluten-induced enteropathy and development of gliadin-specific AGA was enhanced under germ-free conditions in NOD/ DQ8 mice and T cell responses are gliadin-specific. These results suggest that the commensal intestinal microbiota may have a protective effect during gliadin-sensitization and challenge in NOD/DQ8mice. Themechanisms leading to this protective effect are under current investigation.

Tu1749 Gluten-Induced Responses in NOD/DQ8 Mice Are Influenced by Bacterial Colonization

Introduction: Disturbances of the intestinal microbiota due to enhanced hygienic conditions or antibiotic use have been linked to the increasing prevalence of obesity, allergy, autoimmunity, and functional and inflammatory disorders of the gut, including celiac disease (CD). It is unknown whether perturbation of normal gut colonization plays a causal role in subsequent development of immune responses to gluten. Thus, our aim was to determine and characterize whether absence of gut commensals modifies the response to gluten using germ-free (GF), specific pathogen free (SPF) and altered Schaedler flora (ASF) colonized NOD/DQ8 mice. Methods: GF, SPF, and ASF 8-10 week old male and female NOD/DQ8 mice were mucosally sensitized with peptic tryptic (PT) gliadin (500μg) and cholera toxin (CT; 25μg) by oral gavage once a week for three weeks. Control mice were sensitized with CT alone. Following sensitization, mice were challenged three times a week for two weeks with 2mg of gluten by oral gavage. All materials for GF experiments were aseptically prepared and administered to mice housed in gnotobiotic isolators. Twenty-four hours following the final gluten challenge enteropathy was evaluated by intraepithelial lymphocyte (IEL) counts and villus/crypt (V/C) ratios. Anti-gliadin IgA antibodies (AGA) in intestinal washes were determined as markers of sensitization and specificity towards gliadin was tested by Western blot. Gliadin-specific T cell responses were tested using in vitro proliferation assays. Results: V/C ratios in GF NOD/DQ8 mice decreased by 52% following sensitization, which was significantly greater than SPF (40%) andASF (38%) gliadin-sensitizedmice (p<0.01). Gliadinsensitized GF mice also had the greatest increase in IELs compared to gliadin-sensitized SPF and ASF mice (p<0.01). No control GF, SPF or ASF mouse had a positive AGA result. In gliadin-sensitized mice, positive AGA was detected in 75% of GF mice, 33% of SPF mice and no ASF mice. The specificity of AGA towards gliadin was confirmed by Western blot. T cells isolated from mesenteric lymph nodes of GF gliadin-sensitized mice responded to PT-gliadin stimulation in vitro, but not to PT-zein stimulation. T cells from non-sensitized mice did not respond to PT-gliadin stimulation. Conclusions: Gluten-induced enteropathy and development of gliadin-specific AGA was enhanced under germ-free conditions in NOD/ DQ8 mice and T cell responses are gliadin-specific. These results suggest that the commensal intestinal microbiota may have a protective effect during gliadin-sensitization and challenge in NOD/DQ8mice. Themechanisms leading to this protective effect are under current investigation.

An Unusual Cause of Chronic Diarrhea

Case: 79-year-old Caucasian woman with diabetes and chronic bronchiectasis was admitted with nine months of refractory nausea, vomiting and diarrhea, and associated weight loss. Had large volume stools with nocturnal symptoms, without blood or mucus. There was no coincident travel or new medications. Nasojejunal feeds were initiated for intractable emesis. Labs showed anemia with elevated ESR and CRP. She also had low albumin, hypovitaminosis D, and coagulopathy. Stool studies were negative for infection or inflammation. Fecal elastase was undetectable, with stool osmolar gap suggestive of osmotic diarrhea. Qualitative fecal fat was normal. Upper and lower endoscopy revealed multiple discrete ulcers in the proximal colon, otherwise unremarkable. Duodenal biopsies revealed total villous atrophy and extensive subepithelial collagen deposits on trichrome stain, with denuded surface epithelium, consistent with collagenous sprue. There was no increase in intraepithelial lymphocytes. Histology of colonic ulcers noted focal areas of fibrosis that did not meet criteria for collagenous colitis. Celiac serology was negative for anti-TTG and anti-endomysial antibodies with low IgG and IgA levels; genotyping for HLA-DQ2 was positive. Testing for anti-enterocyte antibodies was negative. The patient was started on a gluten free diet (GFD), pancreatic enzymes and systemic steroids. She noted decreased stool frequency and tolerance of oral diet by day 3, and was discharged on prednisone taper. At one month, she was in clinical remission, and steroids were discontinued. Three months after diagnosis, she remains asymptomatic on GFD and pancreatic enzymes, with improvement of nutritional lab markers. Discussion: Collagenous sprue (CS) is a rare condition, originally described as a refractory form of celiac disease (CD). It is now considered more heterogeneous, with links to CVID or as a paraneoplastic syndrome. Our patient did not have positive CD serology. Low initial immunoglobulin levels normalized with clinical remission. CS presents with chronic diarrhea, malabsorption and weight loss. Diagnosis is established on intestinal biopsy with a subepithelial collagen layer greater than 10 mu and inflammatory cells in the lamina propria. Evaluation for coexisting microscopic colitis should be performed. Diarrhea is classically unremitting without aggressive immunosuppression. Steroids are the mainstay of therapy along with GFD, with remission rates of up to 80%. However, the clinical course is unpredictable and often poorly responsive to medical therapy. Early recognition of CS is essential to prevent significant morbidity and mortality. However, more data are needed to optimize therapeutic strategies.

Intestinal Spirochetosis: An Enigmatic Disease

Intestinal spirochetosis (IS) is a condition in which colonic and appendiceal epithelial cells are colonized by one of two anaerobic spirochetes, either the Brachyspira aalborgi or Brachyspira pilosicoli. There is much debate in the literature as to whether IS is a pathogen or a commensal inhabitant. A recent case of IS at our institution prompted a retrospective database search and review of the literature. A pathology database search for IS was performed at Carolinas Medical Center from 2003 through 2007. After patient identification, a retrospective review of the endoscopic record and the pathology report was performed. Pathology slides were reviewed for accuracy and special silver stains and/or immunostains were performed if needed. The following data were collected for each patient when available: age, gender, nationality, HIV status, and other co-morbid conditions when noted. We attempted to determine whether patients were treated for spirochetosis and if so, the treatment regimen used as well as the results. The database search detected 29 patients with biopsies showing IS. Three patients were subsequently removed due to incorrect identification. A total of 26 patients with an average age of 45years were reviewed. The most common symptoms were abdominal pain, diarrhea, and rectal bleeding. Most patients did not exhibit inflammatory changes despite the presence of spirochetosis. Pathologic examination revealed a relative increase in intra-epithelial lymphocytes in a subset of cases, a non-specific finding. Acute colitis or architectural distortion was not seen in any of the study cases. We were only able to obtain follow-up of two patients after treatment with metronidazole and both responded to therapy. To date, our study is the largest case series that includes both endoscopic and pathologic descriptions and confirms the "bland" nature of the condition. In <20% of our patients inflammation was present microscopically and it did not correlate well with endoscopic appearance. Symptoms reported by our patients were similar to those reported in previous studies, although our lack of endoscopic changes was different from one previous paper. There is no established standard of care for the treatment of IS and our study, reflects the enigmatic nature of IS as a disease process. In the absence of rigorous literature, physicians will need to use a logical and pragmatic approach to the evaluation and treatment of IS.

Gastrointestinal Pathology in Celiac Disease

The main histologic feature of celiac disease is increased intraepithelial lymphocytes (IELs) with or without villous atrophy of the duodenal mucosa. The aim of this study was to document a broad range of additional morphologic changes in intestinal mucosa biopsy specimens from patients with celiac disease. Our cohort comprised 150 patients with positive tissue transglutaminase serologic findings; 7 were at Corazza stage A1, 58 at stage B1, and 85 at stage B2. IEL counts per 100 epithelial cells ranged from 34 to 156 (mean, 88.6); a significant neutrophilic infiltrate was present in 85 cases (56.7%); eosinophil count ranged from 3 to 50 per high-power field (mean, 14.6). Additional findings included morphologic changes in enterocytes in 68.7%, subepithelial collagen thickening in 45.3%, and associated lymphocytic gastritis in 30.4% of patients. We demonstrated that these underrecognized features, which can be misleading, are not uncommon in celiac disease and were positively associated with more advanced stages of the disease (P < .0001).

Kinetics of the histological, serological and symptomatic responses to gluten challenge in adults with coeliac disease

ObjectiveCoeliac disease is defined by gluten responsiveness, yet there are few data on gluten challenge (GC) in adults on a gluten-free diet. Lack of data regarding the kinetics of responses...

Serum and Tissue CD23, IL‐15, and FasL in Cow's‐Milk Protein–sensitive Enteropathy and in Coeliac Disease

The aim of the study was to explore pathogenesis and find new serum markers for cow's-milk-sensitive enteropathy (CMSE) and coeliac disease (CD). We assessed the intestinal expression and serum concentration of CD23, IL-15, and FasL. We hypothesised that the serum levels of CD23, a protein expressed in the lymphoid follicles, would be associated with lymphonodular hyperplasia (LNH), a feature characteristic of CMSE. We also presumed that interleukin (IL)-15 and FasL, functionally connected with proliferation and apoptosis of the intraepithelial lymphocytes (IELs), would relate with the increased numbers of IELs present in both CMSE and CD. Twenty-three children with CMSE, 20 with untreated CD, and 14 controls were studied for CD3, α/β- and γ/δ-expressing IELs, and for duodenal and ileal expression of CD23, FasL, and IL-15 by immunohistochemistry, and for serum concentration of sCD23, sFasL, and sIL-15 by enzyme-linked immunosorbent assay. There was a trend for increase in sCD23 serum levels in untreated CMSE and in CD (P = 0.074; P = 0.077). CD23 was expressed in the mucosal germinal centres, but sCD23 was not related to presence of LNH. In CMSE, there was a trend for increase in serum sFasL (P = 0.07) and high levels associated with LNH (P = 0.025) and correlated with the IEL numbers (P < 0.05). Mucosal high endothelial venules adjacent to lymphoid follicles showed an intensive FasL expression. Serum sCD23 shows a trend of increment in CMSE and CD, and in the latter, sCD23 level may provide information about the severity of villous atrophy. In CMSE, high serum sFasL indicates both LNH and an increase of IELs, suggesting importance of FasL-mediated mechanisms in the pathogenesis of these features characteristic of CMSE. Further studies are necessary to evaluate whether intensive FasL expression in mucosal high endothelial venules presents a regulatory element in mucosal immunity.

High densities of serotonin and peptide YY cells in the colon of patients with lymphocytic colitis

To investigate colonic endocrine cells in lymphocytic colitis (LC) patients. Fifty-seven patients with LC were included. These patients were 41 females and 16 males, with an average age of 49 years (range 19-84 years). Twenty-seven subjects that underwent colonoscopy with biopsies were used as controls. These subjects underwent colonoscopy because of gastrointestinal bleeding or health worries, where the source of bleeding was identified as haemorrhoids or angiodysplasia. They were 19 females and 8 males with an average age of 49 years (range 18-67 years). Biopsies from the right and left colon were obtained from both patients and controls during colonoscopy. Biopsies were fixed in 4% buffered paraformaldehyde, embedded in paraffin and cut into 5 μm-thick sections. The sections immunostained by the avidin-biotin-complex method for serotonin, peptide YY (PYY), pancreatic polypeptide (PP) enteroglucagon and somatostatin cells. The cell densities were quantified by computerised image analysis using Olympus software. The colon of both the patient and the control subjects were macroscopically normal. Histopathological examination of colon biopsies from controls revealed normal histology. All patients fulfilled the diagnosis criteria required for of LC: an increase in intraepithelial lymphocytes (> 20 lymphocytes/100 epithelial cells) and surface epithelial damage with increased lamina propria plasma cells and absent or minimal crypt architectural distribution. In the colon of both patients and control subjects, serotonin-, PYY-, PP-, enteroglucagon- and somatostatin-immunoreactive cells were primarily located in the upper part of the crypts of Lieberkühn. These cells were basket- or flask-shaped. There was no statistically significant difference between the right and left colon in controls with regards to the densities of serotonin- and PYY-immunoreactive cells (P = 0.9 and 0.1, respectively). Serotonin cell density in the right colon in controls was 28.9 ± 1.8 and in LC patients 41.6 ± 2.6 (P = 0.008). In the left colon, the corresponding figures were 28.5 ± 1.9 and 42.4 ± 2.9, respectively (P = 0.009). PYY cell density in the right colon of the controls was 10.1 ± 1 and of LC patients 41 ± 4 (P = 0.00006). In the left colon, PYY cell density in controls was 6.6 ± 1.2 and in LC patients 53.3 ± 4.6 (P = 0.00007). The change in serotonin cells could be caused by an interaction between immune cells and serotonin cells, and that of PYY density might be secondary.

Ipilimumab Induced Enterocolitis - A Novel Cause of Diarrhea

Purpose: A 64 year-old man presented for evaluation of watery, non-bloody diarrhea. He was having up to ten bowel movements per day with multiple episodes of emesis. He was participating in a clinical trial comparing ipilimumab versus placebo for treatment of hormone refractory metastatic prostate cancer and had just completed his fourth infusion. On examination he was dehydrated, so he was admitted to the hospital for intravenous hydration. Enteric pathogen analysis including Clostridium difficile polymerase chain reaction was negative. The patient underwent a flexible sigmoidoscopy that demonstrated scattered focal erythema and erosions. Random colonic biopsies showed focal active colitis characterized by patchy infiltration of crypts by polymorphonuclear leukocytes. No increase in intraepithelial lymphocytes or granulomas was observed. Cytomegalovirus immunostaining was negative. His diarrhea improved with a five day course of methylprednisolone 125 mg daily and he was discharged home to complete a six week prednisone taper. Follow-up imaging one month later showed marked improvement in metastatic disease burden as well as prostate specific antigen levels. Ipilimumab is a cytotoxic T-lymphocyte-associated antigen 4 antibody that allows immune disinhibition of T cells leading to targeted tumor regression. It was recently approved for treatment of metastatic melanoma and is currently being evaluated for both prostate and lung cancer. Immune-mediated toxicities may represent a marker for treatment efficacy, as in the present case. Immune-mediated toxicity is most prevalent in the gastrointestinal tract with a reported incidence of enterocolitis in up to 21% of patients undergoing treatment. The cumulative dose administered does not appear to predict the risk for developing ipilimumab induced enterocolitis. The clinical hallmark of ipilimumab induced enterocolitis is profound watery diarrhea that may also present with abdominal pain, nausea, vomiting, and/or fever. Diagnosis is confirmed via endoscopic evaluation, which demonstrates colonic erythema, ulceration, and potentially gastritis and/or duodenitis. Histopathological findings include acute colonic neutrophilic and/or lymphocytic infiltrates. Oral corticosteroids can be used for treatment of mild cases (<6 bowel movements per day). Severe cases (>7 bowel movements per day) however, may require hospitalization with administration of high-dose intravenous steroids followed by an oral taper. Refractory cases have been successfully managed by administering one dose of infliximab (5 mg/kg). Timely diagnosis and treatment is critical to avoid unnecessary premature discontinuation of therapy or complications such as colonic perforation.

Mikroskopische Kolitis

Microscopic colitis is a clinicopathological entity which, in addition to typical symptoms such as watery diarrhea, is characterized by its specific histopathology. Since colonoscopy yields normal findings, microscopic colitis belongs in a histological domain. The term encompasses two forms: lymphocytic and collagenous colitis. Histologically, lymphocytic colitis shows an increase in intraepithelial lymphocytes of more than 20 lymphocytes per 100 surface colonocytes, while collagenous colitis is characterized by a thickened subepithelial collagen layer of more than 10µm. Specific stains help in the quantification of both. Since microscopic colitis does not always affect the entire colon and the number of intraepithelial lymphocytes varies physiologically, obtaining stepwise biopsies of the colon (with information on location where possible) is recommended. A thickened collagen layer is relatively specific for collagenous colitis, whereas intraepithelial lymphocytosis is also found in other diseases. Therefore, to make a correct diagnosis, it is important to correlate histological findings with clinical symptoms, including the main symptom of watery diarrhea.