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      Facing Terminal Ileitis: Going Beyond Crohn’s Disease

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          Abstract

          Terminal ileitis (TI) is an inflammatory condition of the terminal portion of the ileum that may occur acutely with right lower quadrant pain followed or not by diarrhea, or exhibit chronic obstructive symptoms and bleeding and normally it is associated to Crohn’s disease (CD) although it may be associated to other different conditions. This review intended to contribute to a better understanding of TI in order to help in the diagnosis, medical approach and patient care. This work was performed on a survey of articles collected in different databases and a retrospective search was carried out to identify relevant studies in the field. Pathological conditions such as ulcerative colitis, the intake of non-steroidal anti-inflammatory drugs, infectious diseases, eosinophilic enteritis, malignant diseases, spondyloarthropathies, vasculitides, ischemia, sarcoidosis, amyloidosis and others may be related to ileitis but it is commonly referred to CD. To a correct therapeutic approach, it is necessary to understand the causes of this inflammation process. The performance of a clinical, laboratory, endoscopic, and histopathological evaluation of the individuals is crucial to the correct diagnosis and treatment once the inflammation of the ileum may occur due to different pathological conditions besides CD, leading to difficulties in the diagnosis. Thus, an individual approach is necessary once the correct diagnosis is crucial for the immediate therapeutic approach and recovering of the patient.

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          Most cited references77

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          Caspase-8 regulates TNF-alpha induced epithelial necroptosis and terminal ileitis

          Dysfunction of the intestinal epithelium is believed to result in excessive translocation of commensal bacteria into the bowel wall that drives chronic mucosal inflammation in Crohn's disease; an incurable inflammatory bowel disease in humans characterized by inflammation of the terminal ileum 1 . Beside the physical barrier established by the tight contact of cells, specialized epithelial cells such as Paneth cells and goblet cells provide innate immune defence functions by secreting mucus and antimicrobial peptides which hamper access and survival of bacteria adjacent to the epithelium 2 . Epithelial cell death is a hallmark of intestinal inflammation and has been discussed as a pathogenic mechanism driving Crohn's disease (CD) in humans 3 . However, the regulation of epithelial cell death and its role in intestinal homeostasis remains poorly understood. Here we demonstrate a critical role for caspase-8 in regulating necroptosis of intestinal epithelial cells (IEC) and terminal ileitis. Mice with a conditional deletion of caspase-8 in the intestinal epithelium (Casp8 ΔIEC) spontaneously developed inflammatory lesions in the terminal ileum and were highly susceptible to colitis. Casp8 ΔIEC mice lacked Paneth cells and showed reduced numbers of goblet cells suggesting dysregulated anti-microbial immune cell functions of the intestinal epithelium. Casp8 ΔIEC mice showed increased cell death in the Paneth cell area of small intestinal crypts. Epithelial cell death was induced by tumor necrosis factor (TNF) -α, was associated with increased expression of receptor-interacting protein 3 (RIP3) and could be inhibited upon blockade of necroptosis. Finally, we identified high levels of RIP3 in human Paneth cells and increased necroptosis in the terminal ileum of patients with Crohn's disease, suggesting a potential role of necroptosis in the pathogenesis of this disease. Taken together, our data demonstrate a critical function of caspase-8 in regulating intestinal homeostasis and in protecting IEC from TNF-α induced necroptotic cell death.
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            The natural history of adult Crohn's disease in population-based cohorts.

            Natural history studies provide invaluable data on the disease course. First, they help define the end points for clinical trials that are designed to test drugs for the end point of disease modification in chronic disabling diseases. Natural history studies can also help to identify subsets of patients in whom the disease prognosis can be stratified according to clinical features. This comprehensive review summarizes our current knowledge of the natural history of Crohn's disease in adults as reported in population-based studies that include long-term follow-up results. We conducted a literature search of English and non-English language publications listed in the electronic databases of MEDLINE (source PUBMED, 1935 to December 2008). One-third of the patients had ileitis, colitis, or ileocolitis at the time of diagnosis. Disease location remained broadly stable over time. Up to one-third of the patients had evidence of a stricturing or penetrating intestinal complication at diagnosis, and half of all patients had experienced an intestinal complication within 20 years after diagnosis. Ten percent of the patients had prolonged clinical remission. Steroid dependency occurred in one-third of the patients, and surgery was required in one-third after initiation of steroid therapy. The annual incidence of hospitalizations was 20%. Half of the patients required surgery within 10 years after diagnosis. The risk of postoperative recurrence was 44-55% after 10 years. Crohn's disease is a disabling condition over time. The impact of changing treatment paradigms with increased use of immunosuppressants and biological agents on its natural history is poorly known.
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              SAMP1/YitFc mouse strain: a spontaneous model of Crohn's disease-like ileitis.

              The SAMP1/YitFc mouse strain represents a model of Crohn's disease (CD)-like ileitis that is ideal for investigating the pathogenesis of chronic intestinal inflammation. Different from the vast majority of animal models of colitis, the ileal-specific phenotype characteristic of SAMP1/YitFc mice occurs spontaneously, without genetic, chemical, or immunological manipulation. In addition, SAMP1/YitFc mice possess remarkable similarities to the human condition with regard to disease location, histologic features, incidence of extraintestinal manifestations, and response to conventional therapies. SAMP1/YitFc mice also display a well-defined time course of a predisease state and phases of acute and chronic ileitis. As such, the SAMP1/YitFc model is particularly suitable for elucidating pathways that precede the clinical phenotype that may lead to preventive, and therefore more efficacious, intervention with the natural course of disease, or alternatively, for the development of therapeutic strategies directed against chronic, established ileitis. In this review we summarize important contributions made by our group and others that uncover potential mechanisms in the pathogenesis of CD using this unique murine model of chronic intestinal inflammation. Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.
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                Author and article information

                Journal
                Gastroenterology Res
                Gastroenterology Res
                Elmer Press
                Gastroenterology Research
                Elmer Press
                1918-2805
                1918-2813
                February 2016
                08 March 2016
                : 9
                : 1
                : 1-9
                Affiliations
                [a ]Department of Gastroenterology, University Hospital - UNIMAR, Higino Muzzi Filho Avenue, 1001, Marilia, SP, Brazil
                [b ]Department of Biochemistry and Pharmacology, School of Medicine, University of Marilia and Food Technology School (FATEC), Higino Muzzi Filho Avenue, 1001, Marilia, SP, Brazil
                [c ]Diagnostic Center in Gastroenterology, Arthur Sampaio Street, 140, Ibaiti, PR, Brazil
                Author notes
                [d ]Corresponding Author: Sandra Maria Barbalho, School of Medicine, University of Marilia, Higino Muzzi Filho Avenue, 1001, Marilia, SP, Brazil. Email: smbarbalho@ 123456gmail.com
                Article
                10.14740/gr698w
                5051106
                27785317
                84948e13-5bd1-4f6f-83bf-d03d0ad659f7
                Copyright 2016, Goulart et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 24 February 2016
                Categories
                Review

                terminal ileitis,inflammatory processes,crohn’s disease,ulcerative colitis,behcet’s disease,infectious diseases

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