Novel Endoscopic Techniques in Celiac Disease

Celiac disease (CD) is a systemic, immune‐mediated illness that primarily affects the small bowel. A few decades ago, in the era of Watson and Crosby capsules, we used to sample the small bowel without even looking at it. Nowadays, with the continuous developing field of digestive endoscopy, we can even see the duodenal villi up closely, allowing for an optical, real‐time diagnosis of villous atrophy. Advanced endoscopic techniques such as magnification, chromoendoscopy (dye‐based and digital), water immersion, confocal endomicroscopy, endocytoscopy, and optical coherence tomography (OCT) have been evaluated in CD with good results: good agreement with histology, allowing for targeted biopsies and a reduction in the number of biopsies needed for diagnosis. Moreover, with the growing use of open‐access endoscopy in many parts of the world, endoscopy is now contributing to increasing the diagnostic rate of CD, by recognition of endoscopic markers in patients without clinical suspicion of this disease. This is however an observer‐dependent method; to overcome the endoscopists subjectiveness in assessing villous atrophy, in the last years, many papers have looked at means of computerized analysis of endoscopic images. Currently available data show that these automated, quantitative methods hold very promising for the future

The role of gluten challenge in the diagnosis of celiac disease : a review

Introduction: Duodenal biopsy is the gold standard in the diagnosis of celiac disease, with increasing utilization of serology. A gluten challenge may be required, for example, when dietary gluten reduction precedes appropriate diagnostic evaluations. Evidence on the best challenge protocol is currently sparse. Pharmaceutical trials in recent years may have provided new insights into the challenge and advanced the development of novel sensitive histological and immunological methods. Areas covered: This review outlines the current perspectives on the use of gluten challenge in the diagnosis of celiac disease and explores future directions in this area. Expert opinion: Comprehensive elimination of celiac disease before dietary gluten restriction is essential to avoid diagnostic uncertainties. Gluten challenge continues to have an important role in certain clinical scenarios, although it is important to understand its limitations in the diagnostic evaluation. The evidence so far permits no unequivocal recommendation considering the timing, duration, and amount of gluten used in the challenge. Thus, these decisions should be made on a case-by-case basis. Further studies with more standardized protocols and outcome measures are called for. In the future novel immunological methods may help to shorten or even avoid gluten challenge.Peer reviewe

Diagnosing Celiac Disease : Towards Wide-Scale Screening and Serology-Based Criteria?

Celiac disease is one of the most common food-related chronic disorders in children. Unfortunately, this multifaceted disease is challenging to recognize and remains markedly underdiagnosed. Screening of either known at-risk groups or even the whole population could increase the suboptimal diagnostic yield substantially. Many recent guidelines recommend screening of at least selected risk groups, but more wide-scale screening remains controversial. The increasing prevalence of celiac disease and the development of autoantibody assays have also led to a gradual shift in the diagnostics towards less invasive serology-based criteria in a subgroup of symptomatic children. The main open questions concern whether these criteria are applicable to all countries and clinical settings, as well as to adult patients. On the other hand, widening screening and the mistaken practice of initiating a gluten-free diet before the appropriate exclusion of celiac disease increase the number of borderline seropositive cases, which may also challenge the classical histopathological diagnostics. Sophisticated diagnostic methods and a deeper understanding of the natural history of early developing celiac disease may prove useful in these circumstances.Peer reviewe

Hematologic manifestations in celiac disease : a practical review

Celiac disease (CD) is a systemic autoimmune disease driven by gluten-ingestion in genetically predisposed individuals. Although it primarily affects the small bowel, CD can also involve other organs and manifest as an extraintestinal disease. Among the extraintestinal features of CD, hematologic ones are rather frequent and consist of anemia, thrombocytosis (thrombocytopenia also, but rare), thrombotic or hemorrhagic events, IgA deficiency, hyposplenism, and lymphoma. These hematologic alterations can be the sole manifestation of the disease and should prompt for CD testing in a suggestive clinical scenario. Recognition of these atypical, extraintestinal presentations, including hematologic ones, could represent a great opportunity to increase the diagnostic rate of CD, which is currently one of the most underdiagnosed chronic digestive disorders worldwide. In this review, we summarize recent evidence regarding the hematological manifestations of CD, with focus on practical recommendations for clinicians

Prevalence and diagnostic outcomes of children with duodenal lesions and negative celiac serology

Background: Celiac disease diagnostics begin by measuring autoantibodies, which may fail to identify seronegative patients. Duodenal lesion in the absence of antibodies is scarcely studied, especially in children. Aims: To investigate the prevalence and diagnostic outcomes of children with seronegative duodenal lesion in two countries with different disease profiles. Methods: Medical data, including the results of histology and transglutaminase (tTGab) and endomysium (EmA) antibody measurements were collected from 1172 Finnish and 264 Romanian children with systematic duodenal sampling. Database of 509 Finnish children with celiac disease was examined to identify earlier seronegative patients. Results: Celiac disease was diagnosed in 307 Finnish and 83 Romanian children in the endoscopy cohorts. No seronegative patients were found among 899 celiac disease patients, although some were only tTGab or EmA positive. Non-celiac duodenal lesion was detected in eight Finnish and 32 Romanian children, their most common diagnoses being inflammatory bowel disease and infections, respectively. Six children with morphological lesion received no diagnosis. None of them developed celiac disease during a follow-up of 3-11 years. Conclusion: Pediatric seronegative celiac disease is exceptional in the era of modern autoantibodies. Other reasons for duodenal lesion should therefore be sought, bearing in mind possible differences across countries. (C) 2019 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.Peer reviewe

X-ray microtomography is a novel method for accurate evaluation of small-bowel mucosal morphology and surface area

The often poorly orientated small-bowel mucosal biopsies taken for the diagnostics of celiac disease and other intestinal disorders are prone to misinterpretation. Furthermore, conventional histopathology has suboptimal sensitivity for early histopathological changes observed in short-term challenge studies. X-ray microtomography (micro-CT) is a promising new method for accurate imaging of human-derived biological samples. Here, we report that micro-CT could be utilized to create virtual reconstructions of endoscopically obtained intestinal biopsies. The formed digital 3D images enabled selection of always optimal cutting angles for accurate measurement of the mucosal damage and revealed diagnostic lesions in cases interpreted as normal with conventional histomorphometry. We also demonstrate that computer-assisted point cloud analysis can be used to calculate biologically meaningful surface areas of the biopsies in different stages of mucosal damage with excellent replicability and correlation with other disease parameters. We expect the improved diagnostic accuracy and capability to measure the surface areas to provide a powerful tool for the diagnostics of intestinal diseases and for future clinical and pharmaceutical trials.Peer reviewe

Polycomb Repressive Complex 2 Enacts Wnt Signaling in Intestinal Homeostasis and Contributes to the Instigation of Stemness in Diseases Entailing Epithelial Hyperplasia or Neoplasia

Abstract Canonical Wnt/β-catenin signaling regulates the homeostasis of intestinal epithelium by controlling the balance between intestinal stem cell self-renewal and differentiation but epigenetic mechanisms enacting the process are not known. We hypothesized that epigenetic regulator, Polycomb Repressive Complex-2 (PRC2), is involved in Wnt-mediated epithelial homeostasis on the crypt-villus axis and aberrancies therein are implicated both in celiac disease and in intestinal malignancies. We found that PRC2 establishes repressive crypt and villus specific trimethylation of histone H3 lysine 27 (H3K27me3) signature on genes responsible for, for example, nutrient transport and cell killing in crypts and, for example, proliferation and differentiation in mature villi, suggesting that PRC2 facilitates the Wnt-governed intestinal homeostasis. When celiac patients are on gluten-containing diet PRC2 is out-of-bounds active and consequently its target genes were found affected in intestinal epithelium. Significant set of effective intestinal PRC2 targets are also differentially expressed in colorectal adenoma and carcinomas. Our results suggest that PRC2 gives rise and maintains polar crypt and villus specific H3K27me3 signatures. As H3K27me3 is a mark enriched in developmentally important genes, identified intestinal PRC2 targets are possibly imperative drivers for enterocyte differentiation and intestinal stem cell maintenance downstream to Wnt-signaling. Our work also elucidates the mechanism sustaining the crypt hyperplasia in celiac disease and suggest that PRC2-dependent fostering of epithelial stemness is a common attribute in intestinal diseases in which epithelial hyperplasia or neoplasia prevails. Finally, this work demonstrates that in intestine PRC2 represses genes having both pro-stemness and pro-differentiation functions, fact need to be considered when designing epigenetic therapies including PRC2 as a drug target.</jats:p

Fingertip rapid point-of-care test in adult case-finding in coeliac disease

Background Coeliac disease (CD), due to its protean clinical manifestation, is still very under diagnosed in adults and delays in diagnosis may take years and even decades. Simple tools to find cases in primary care may help to identify patients for further diagnostic tests. We have evaluated the usefulness of an on site rapid fingertip whole blood point-of-care test (POCT) for such a purpose. Methods As CD is known to run within families, we tested 148 healthy relatives of 70 Romanian index cases with biopsy-proven CD (87% of all first-degree family members, median age 36 years) for the presence of circulating autoantibodies. In addition to performing the POCT (which measures blood erythrocyte self-TG2-autoantibody complexes) on site, blood was drawn for later evaluations of serum IgA-class endomysial antibodies (EMA). EMA-positive sera were further tested for transglutaminase 2 antibodies (TG2-IgA). All serological parameters were analyzed blindly in a centralized laboratory that had no knowledge of the on site POCT result. Endoscopic small intestinal biopsies was recommended for all POCT- or EMA-test positive subjects. Results In on site testing the POCT was positive in 12/148 first-degree relatives (8%) and all these subjects were also serum EMA-positive. A positive EMA test was found only in one other subject. All remaining 135 healthy first-degree relatives were negative for both POCT and EMA. Four subjects positive for both POCT and EMA were negative for TG2-IgA. Ten out of thirteen of the antibody-positive subjects agreed to undergo endoscopy. The POCT was found to be positive in 8/9 first-degree relatives having coeliac-type mucosal lesions of grade Marsh 2 (n = 3) or Marsh 3 (n = 6). The three POCT-positive subjects not agreeing to undergo endoscopy were also both EMA- and TG2-IgA-positive. Conclusion The fingertip whole blood rapid POCT might fulfill the unmet need for a simple and cheap case-finding biomarker for early detection and presumptive diagnosis of CD. Confirmatory studies are warranted in adult case-finding in specialized outpatient clinics and in primary care.BioMed Central open acces