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Background: Celiac disease (CD) is an autoimmune disorder triggered by gluten ingestion. Herein, we assessed clinical, serological and histopathological findings of a single-center, large cohort of CD patients diagnosed and followed-up over forty years. Methods: From January 1980 to December 2020, 1547 CD patients (1170 females; age range: 8–81 years; F:M ratio = 3.1:1) were diagnosed in an Italian tertiary referral center. Comorbidities and complications were recorded at diagnosis and during follow-up. Results: CD diagnoses quadrupled after 2000. The most frequent phenotype was the non-classical CD (63.3%), and the most prevalent histotype was Marsh 3C (44.7%). Gastrointestinal manifestations, detectable in 51% of patients, were diarrhea (24.3%), bloating (28%) and aphthous stomatitis (19.7%). The most common CD-associated disorder was osteopenia (59.9%), predominant in females (64.3%); extraintestinal manifestations included anemia (35.8% iron-deficiency; 87% folic acid malabsorption), cryptogenic hypertransaminasemia (27.9%), and recurrent miscarriages (11.5%). Thyroiditis (26.9%), type 1 diabetes mellitus (2.9%), and dermatitis herpetiformis (1.4%) were the most common CD-related autoimmune disorders. Six patients had inflammatory bowel disease. Complications and mortality rate occurred in 1.8% and 1.9%, respectively. Conclusions: This single-center, large cohort analysis confirmed that CD presentation changed over the years, with an increase of non-classical and subclinical clinical phenotypes. [ABSTRACT FROM AUTHOR]

Since the rise of awareness of gluten/wheat-related disorders in the academic and clinical field in the last few decades, misinformation regarding the gluten-free diet (GFD) and its impact on health has been spreading among the general population. Despite the established link between gluten and celiac disease (CD), where a GFD is mandatory to reach clinical and histological remission, things are more complicated when it comes to non-celiac gluten/wheat sensitivity (NCGWS) and other autoimmune/dysimmune disorders. In the last conditions, a beneficial effect of gluten withdrawal has not been properly assessed, but still is often suggested without strong supporting evidence. In this context, women have always been exposed, more than men, to higher social pressure related to nutritional behaviors and greater engagement in controlling body weight. With this narrative review, we aim to summarize current evidence on the adherence to a GFD, with particular attention to the impact on women's health. [ABSTRACT FROM AUTHOR]

Serology has significantly revolutionized the knowledge of celiac disease (CD), leading to the identification of unsuspected patients in at-risk CD groups, thereby increasing the number of CD diagnoses compared to the pre-screening era. Several markers for CD with a progressive diagnostic accuracy have been identified over the years, but only three of them, i.e. anti-tissue transglutaminase (antitTG), anti-endomysial (EmA) and anti-deamidated gliadin antibodies (DGP) are currently assessed in the daily clinical practice. A thorough review of the literature identified 44 original studies published between 1998 to 2022 for a total of 5098 pediatric and adult CD patients (without selective IgA deficiency) and 11930 disease controls. The results highlighted that anti-tTG IgA exhibited a higher sensitivity for CD (93.4%) than EmA IgA (92.8%), DGP IgG (81.8%) and DGP IgA (83.8%). The specificity of EmA IgA (99%) resulted to be higher than those of anti-tTG IgA (95.8%), DGP IgG (96.4%) and DGP IgA (92.1%). In patients with selective IgA deficiency, a condition closely related to CD, serological screening should include one of the three antibodies of IgG class, since anti-tTG, DGP and EmA have a very similar diagnostic accuracy in this clinical setting. According to age, there are two main diagnostic strategies for CD detection. In children, the revised ESPGHAN 2020 guidelines established that CD could be diagnosed in both symptomatic and asymptomatic children by high anti-tTG IgA titers (>10 times the cut-off) and EmA positivity with no need to obtain duodenal biopsy and HLA typing. In adult patients, although high tTG IgA titers (confirmed by EmA IgA positivity) correlate with villous atrophy, an intestinal biopsy is still considered mandatory for confirming CD diagnosis. Currently, a case finding approach in at-risk groups is preferred to mass screening for CD detection. [ABSTRACT FROM AUTHOR]

Celiac disease (CD) is an autoimmune disorder caused by gluten ingestion in genetically predisposed individuals. In addition to the typical gastrointestinal symptoms (e.g., diarrhea, bloating, and chronic abdominal pain), CD may also present with a broad spectrum of manifestations, including low bone mineral density (BMD) and osteoporosis. The etiopathology of bone lesions in CD is multifactorial and other conditions, rather than mineral and vitamin D malabsorption, may affect skeletal health, especially those related to the endocrine system. Here, we describe CD-induced osteoporosis in an attempt to enlighten new and less-known aspects, such as the influence of the intestinal microbiome and sex-related differences on bone health. This review describes the role of CD in the development of skeletal alterations to provide physicians with an updated overview on this debated topic and to improve the management of osteoporosis in CD. [ABSTRACT FROM AUTHOR]

Anti-ganglioside antibodies may therefore represent immunological markers for neurological dysfunction in CD patients and should be included in the work-up of CD patients. In all CD patients, intestinal villous atrophy was associated with a positivity for serological CD markers (anti-endomysial and/or anti-tissue transglutaminase antibodies) further supporting the diagnosis of CD. In their discussion of anti-ganglioside antibodies and analysis of the various human pathologies in which anti-ganglioside antibodies have been reported, the authors mention celiac disease (CD) as a condition associated with the presence of anti-GM1 antibodies. [Extracted from the article]

Minimal lesions of the small bowel are mucosal changes characterized by an increased number of intraepithelial lymphocytes (with or without crypt hyperplasia) and normal villous architecture. Such changes are associated with a wide spectrum of conditions, ranging from food intolerances to infections, and from drugs to immune diseases, with different clinical profiles and manifestations, which complicates the formulation of a differential diagnosis. Patient history, symptom evaluation, and histopathology are the diagnostic features needed to establish a correct diagnosis. Physicians should assist pathologists in formulating a precise morphological evaluation by taking well-oriented small intestinal biopsies and collecting informative clinical findings that inform histopathology. In this current clinical controversy, the authors provide the reader with an appraisal of the small intestine minimal lesions through a careful analysis of the major conditions (e.g., celiac disease and other non-celiac disorders) responsible for such changes and their differential diagnosis. Also, we acknowledge that some of the diseases detailed in this article may progress from an early minimal lesion to overt mucosal atrophy. Thus, the timing of the diagnosis is of paramount importance. [ABSTRACT FROM AUTHOR]

The coronavirus disease (Covid-19) has caused a pandemic with more than 600,000 deaths to date. It is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a member of the beta-coronavirus genus that also includes SARS and the Middle East Respiratory Syndrome Coronavirus (MERS). While the typical presentation is given by respiratory symptoms and fever, some patients also report gastrointestinal symptoms such as diarrhea, nausea, vomiting, and abdominal pain. Several studies have identified the SARS-CoV-2 RNA in stool specimens of infected patients, and its viral receptor angiotensin-converting enzyme 2 (ACE2) is highly expressed in enterocytes. In this short review, we report the frequency of gastrointestinal symptoms in infected patients and suggest possible implications for disease management, transmission, and infection control. [ABSTRACT FROM AUTHOR]

Background: Gastrointestinal (GI) and extra‐GI symptoms/manifestations represent key clinical features of patients with non‐celiac gluten/wheat sensitivity (NCG/WS). This study aimed to investigate neuro‐immune (focusing on mast cells, MCs) interactions in the duodenal submucosa of patients with NCG/WS. Methods: Submucosal whole mounts from duodenal biopsies of 34 patients with self‐reported NCG/WS, 28 with celiac disease (CD), 13 with functional dyspepsia (FD), and 24 healthy controls (HC) were analyzed by immunohistochemistry. Quantitative data on neuronal and MCs density and the percentage of MCs in close vicinity to nerves were obtained, and correlations among neurons, MC density and MC‐nerve distance (D), and symptoms were assessed in the three groups. Key Results: The number of submucosal neurons was not different among groups. In NCG/WS, MC density was not different from HC, while it was slightly increased vs. CD (P =.07) and significantly decreased vs. FD (P <.05). The percentage of MCs close to nerves (D < 15 µm) was similarly increased in all three pathological groups vs. HC (P <.001). In NCG/WS, MC infiltration correlated with bloating (P =.001) and abdominal pain severity (P =.03) and the percentage of MCs in proximity to neurons correlated with the number of GI symptoms (D < 5 µm; P =.05), bloating and abdominal pain severity (D < 15um; P =.01). Conclusions and Inferences: Submucosal MC infiltration and the close (within 15 µm) MC‐to‐nerve proximity in the duodenum of NCG/WS patients are features providing a histopathological basis to better understand GI symptoms in this condition. [ABSTRACT FROM AUTHOR]

Celiac disease (CD) is a risk factor for developing small-bowel carcinoma with a 14-fold higher risk compared with general population. As small-bowel carcinomas associated with CD (CD-SBCs) are extremely rare, very few molecular data are available about their pathogenesis, and information about their transcriptomic profiling is lacking. We generated RNA-seq data on 13 CD-SBCs, taken from the largest well-characterized series published so far, collected by the Small Bowel Cancer Italian Consortium, and compared the tumor transcriptional signatures with the four Consensus Molecular Subtypes (CMS) of colorectal carcinoma by applying the "CMS classifier." CpG Island Methylator Phenotype (CIMP) was evaluated using methylation-sensitive multiple ligation-dependent probe amplification. Up to 12 of 13 cancers fell within the two main subtypes exhibiting high immune and inflammatory signatures, i.e., subtypes 1 and 4. The first and predominant subset was commonly microsatellite unstable, and exhibited CIMP and high CD3+ and CD8+ T cell infiltration. Moreover, it showed increased expression of genes associated with T helper 1 and natural killer cell infiltration, as well as upregulation of apoptosis, cell cycle progression, and proteasome pathways. By contrast, cancers falling in subtype 4 showed prominent transforming growth factor-β activation and were characterized by complement-associated inflammation, matrix remodeling, cancer-associated stroma production, and angiogenesis. Parallel histologic and histochemical analysis confirmed such tumor subtyping. In conclusion, two molecular subtypes have been consistently identified in our series of CD-SBCs, a microsatellite instability-immune and a mesenchymal subtype, the former likely associated with an indolent and the latter with a worse tumor behavior. [ABSTRACT FROM AUTHOR]

Background: Bile acid malabsorption (BAM) and bile acid-related diarrhea represent an under-recognized cause of chronic diarrhea mainly because of limited guidance on appropriate diagnostic and laboratory tests. We aimed to perform a systematic review of the literature in order to identify and compare the diagnostic accuracy of different diagnostic methods for patients with BAM, despite a proven gold standard test is still lacking.Methods: A PubMed literature review and a manual search were carried out. Relevant full papers, evaluating the diagnostic accuracy of different methods for BAM, were assessed. Available data were analyzed to estimate the sensitivity and specificity of each published test.Results: Overall, more than one test was considered in published papers on BAM. The search strategy retrieved 574 articles; of these, only 16 were full papers (with a total of 2.332 patients) included in the final review. Specifically, n = 8 studies used 75Selenium-homotaurocholic-acid-test (75SeHCAT) with a < 10% retention threshold; n = 8 studies evaluated fasting serum 7-α-hydroxy-4-cholesten-3-one (C4); n = 3 studies involved total fecal bile acid (BA) excretion over 48 h; n = 4 studies assessed fibroblast growth factor 19 (FGF19). 75SeHCAT showed an average sensitivity and specificity of 87.32 and 93.2%, respectively, followed by serum C4 (85.2 and 71.1%) and total fecal BA (66.6 and 79.3%). Fasting serum FGF19 had the lowest sensitivity and specificity (63.8 and 72.3%). All the extracted data were associated with substantial heterogeneity.Conclusions: Our systematic review indicates that 75SeHCAT has the highest diagnostic accuracy for BAM, followed by serum C4 assay. The diagnostic yield of fecal BA and FGF19 assays is still under investigation. Our review reinforces the need for novel biomarkers aimed to an objective detection of BAM and therefore improving the management of this condition. [ABSTRACT FROM AUTHOR]

Background: Chronic intestinal pseudo‐obstruction (CIPO) is a rare condition due to severe impairment of gut motility responsible for recurrent subocclusive episodes. Although neuromuscular‐glial‐ICC abnormalities represent the main pathogenetic mechanism, the pathophysiology of CIPO remains poorly understood. Intestinal epithelial and vascular endothelial barrier (IEVB) abnormalities can contribute to neuroepithelial changes by allowing passage of harmful substances. Methods: To test retrospectively whether IEVB defects occur in patients with CIPO, we measured the jejunal protein expression of the major tight junction (TJ) components. CIPO patients were subdivided according to gut neuromuscular histopathology: apparently normal (AN); with inflammation (INF); or with degenerative alterations (DEG). The presence of occludin/claudin oligomers (index of TJ assembly), the amount of occludin, claudin‐4, and zonula occludens‐1 (ZO‐1), and the expression of vasoactive intestinal polypeptide (VIP) and glial fibrillary acidic protein (GFAP) immunoreactivities were evaluated on jejunal full‐thickness biopsies using Western blot. Key Results: Oligomers were absent in the 73% of CIPO. Total occludin decreased in CIPO with AN and INF changes. Claudin‐4 was upregulated in CIPO with INF and DEG features. ZO‐1 and VIP expression decreased selectively in DEG group. GFAP increased in CIPO regardless the histopathological phenotype. Conclusions & Inferences: The absence of oligomers demonstrated in our study suggests that IEBV is altered in CIPO. The mechanism leading to oligomerization is occludin‐dependent in AN and INF, whereas is ZO‐1‐dependent in DEG. Our study provides support to IEVB abnormalities contributing to CIPO clinical and histopathological features. [ABSTRACT FROM AUTHOR]

Non-celiac gluten sensitivity and celiac disease are known to be two distinct clinical entities, however, non-celiac gluten sensitivity has been detected in a proportion of first-degree relatives of celiac patients. Herein for the first time we describe the occurrence of asymptomatic celiac disease in two siblings, a girl and a boy, whose mother suffered from a proven non-celiac gluten sensitivity. Both the 12-year old girl and 9-year old boy were positive for anti-endomysial and anti-tissue transglutaminase antibodies of IgA class at a very high and low titer, respectively. Duodenal biopsy confirmed the diagnosis of active celiac disease (severe villous flattening) in the girl, whereas her brother had Marsh 1 lesion consistent with a potential celiac disease. This case report indicates that antibody screening for celiac disease can be recommended in any symptomatic or asymptomatic first-degree relatives of patients with nonceliac gluten sensitivity. [ABSTRACT FROM AUTHOR]

Aim: To assess the prevalence of celiac disease (CD) serological markers in a cohort of patients referred to an Italian rheumatological outpatient clinic. Background: Current guidelines do not suggest CD screening in patients with rheumatological diseases and these subjects are not considered to be at high risk for CD. Methods: A total of 230 sera of rheumatological patients referred to the Division of Internal Medicine at the Department of Medical and Surgical Sciences between January 2005 and December 2013 were screened for CD by testing IgA antitransglutaminase (TTG IgA), IgG deamidated gliadin peptides (DGP IgG) and IgA antiendomysium (EMA) antibodies. Of the 230 patients tested, 67 had a diagnosis of rheumatoid arthritis (RA), 52 Sjögren's syndrome (SjS), 42 systemic sclerosis (SCL), 35 systemic lupus erythematosus (SLE), 15 mixed connective tissue disease, 11 polymyositis and 10 dermatomyositis. Results: TTG IgA antibodies were identified in 7/230 cases (3%), 3 in SjS (3/42 -- 5.8%), 2 in SCL (2/42 -- 4.8%), 1 in RA (1/67 -- 1.5%) and 1 in SLE sera (1/35 -- 2.8%). All the seven sera were also positive for DGP IgG and EMA IgA. DGP IgG were the most frequent antibody detected, being found in 16 (7%) sera. Conclusion: This study identified a high prevalence of CD antibodies in adult patients referred to a rheumatology outpatient clinic. These results highlight the importance of CD screening in subjects presenting with rheumatological features. [ABSTRACT FROM AUTHOR]

Aim: Patients with Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA), and Fibromyalgia (FM) may have underlying non-diagnosed celiac disease (CD). Background: The aim of this study was to determine the prevalence of CD in patients with these underlying diseases in Iran. Methods: This cross-sectional study was performed among 300 consecutive patients with SLE, RA, and FM (each group 100 patients) since 2015 to 2017. The blood samples were collected and serum IgA anti-tissue trans-glutaminase (Anti-tTG) level was assessed for all patients. The seropositive patients underwent endoscopy and duodenal/jejunal biopsy according to the Marsh classification. Results: Out of 300 investigated patients with mean age of 41.2 years old, 92% of patients with SLE, RA and fibromyalgia were women. Among 100 patients with SLE, only 1 subject (1%), out of 100 patients with RA 3 subjects (3%), and none of the patients with fibromyalgia were seropositive for CD (with overall prevalence 1.4). All four patients were female and categorized as Marsh III. Conclusion: The results of the study indicated that patients with lupus have the same prevalence, but subjects with RA had three times higher prevalence rate than normal population for CD. Therefore, CD investigation in these individuals can improve their quality of life. [ABSTRACT FROM AUTHOR]

Gluten-related disorders have recently been reclassified with an emerging scientific literature supporting the concept of non-celiac gluten sensitivity (NCGS). New research has specifically addressed prevalence, immune mechanisms, the recognition of non-immunoglobulin E (non-IgE) wheat allergy and overlap of NCGS with irritable bowel syndrome (IBS)-type symptoms. This review article will provide clinicians with an update that directly impacts on the management of a subgroup of their IBS patients whose symptoms are triggered by wheat ingestion. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to estimate the economic burden of celiac disease (CD) in Iran. Background: The assessment of burden of CD has become an important primary or secondary outcome measure in clinical and epidemiologic studies. Methods: Information regarding medical costs and gluten free diet (GFD) costs were gathered using questionnaire and checklists offered to the selected patients with CD. The data included the direct medical cost (including Doctor Visit, hospitalization, clinical test examinations, endoscopies, etc.), GFD cost and loss productivity cost (as the indirect cost) for CD patient were estimated. The factors used for cost estimation included frequency of health resource utilization and gluten free diet basket. Purchasing Power Parity Dollar (PPP$) was used in order to make inter-country comparisons. Results: Total of 213 celiac patients entered to this study. The mean (standard deviation) of total cost per patient per year was 3377 (1853) PPP$. This total cost including direct medical cost, GFD costs and loss productivity cost per patients per year. Also the mean and standard deviation of medical cost and GFD cost were 195 (128) PPP$ and 932 (734) PPP$ respectively. The total costs of CD were significantly higher for male. Also GFD cost and total cost were higher for unmarried patients. Conclusion: In conclusion, our estimation of CD economic burden is indicating that CD patients face substantial expense that might not be affordable for a good number of these patients. The estimated economic burden may put these patients at high risk for dietary neglect resulting in increasing the risk of long term complications. [ABSTRACT FROM AUTHOR]

Introduction: Non-coeliac gluten/wheat sensitivity (NCG/WS) is a syndrome characterized by intestinal and extra-intestinal symptoms occurring a few hours or days after the ingestion of gluten and wheat proteins in patients testing negative for coeliac disease and wheat allergy. Areas covered: The present review deals with recent scientific acquisitions of this gluten-related syndrome, including pathogenetic mechanisms, clinical picture, symptom score, biomarkers and double-blind placebo-controlled trial for diagnosis, and treatment. The methodology used was a literature search on NCG/WS using Medline and Premedline from 1970 to August 2016. Expert commentary: We discussed the pathogenesis of symptom generation and altered gut physiology in NCG/WS. Possible mechanisms include innate and adaptive immune activation, impaired intestinal epithelial barrier and changes in gut microbiome. These interlinked factors may be exploited for their clinical relevance as possible biomarkers. A systemic immune response to microbial and wheat antigens, together with intestinal cell damage, occurs in patients with NCG/WS. Due to the lack of established biomarkers, it is mandatory to validate the diagnosis of the syndrome by means of a well-defined work-up involving dietary challenge. Finally, dietary and other therapeutic indications have been thoroughly reviewed. [ABSTRACT FROM PUBLISHER]

A tight link exists between dietary factors and irritable bowel syndrome (IBS), one of the most common functional syndromes, characterized by abdominal pain/discomfort, bloating and alternating bowel habits. Amongst the variety of foods potentially evoking "food sensitivity", gluten and other wheat proteins including amylase trypsin inhibitors represent the culprits that recently have drawn the attention of the scientific community. Therefore, a newly emerging condition termed non-celiac gluten sensitivity (NCGS) or nonceliac wheat sensitivity (NCWS) is now well established in the clinical practice. Notably, patients with NCGS/NCWS have symptoms that mimic those present in IBS. The mechanisms by which gluten or other wheat proteins trigger symptoms are poorly understood and the lack of specific biomarkers hampers diagnosis of this condition. The present review aimed at providing an update to physicians and scientists regarding the following main topics: the experimental and clinical evidence on the role of gluten/wheat in IBS; how to diagnose patients with functional symptoms attributable to gluten/wheat sensitivity; the importance of double-blind placebo controlled cross-over trials as confirmatory assays of gluten/wheat sensitivity; and finally, dietary measures for gluten/wheat sensitive patients. The analysis of current evidence proposes that gluten/wheat sensitivity can indeed represent a subset of the broad spectrum of patients with a clinical presentation of IBS. [ABSTRACT FROM AUTHOR]

Serotonin (5-hydroxytryptamine, 5-HT) and its transporters and receptors are involved in a wide array of digestive functions. In particular, 5-HT4 receptors are known to mediate intestinal peristalsis and recent data in experimental animals have shown their role in neuronal maintenance and neurogenesis. This study has been designed to test whether prucalopride, a well-known full 5-HT4 agonist, exerts protective effects on neurons, including enteric neurons, exposed to oxidative stress challenge. Sulforhodamine B assay was used to determine the survival of SH-SY5Y cells, human enteric neurospheres, and ex vivo submucosal neurons following H2O2 exposure in the presence or absence of prucalopride (1 nM). Specificity of 5-HT4- mediated neuroprotection was established by experiments performed in the presence of GR113808, a 5-HT4 antagonist. Prucalopride exhibited a significant neuroprotective effect. SH-SY5Y cells pretreated with prucalopride were protected from the injury elicited by H2O2 as shown by increased survival (73.5 0.1% of neuronal survival vs. 33.3 0.1%, respectively; P 0.0001) and a significant reduction of proapoptotic caspase-3 and caspase-9 activation in all neurons tested. The protective effect of prucalopride was reversed by the specific 5-HT4 antagonist GR113808. Prucalopride promotes a significant neuroprotection against oxidative-mediated proapoptotic mechanisms. Our data pave the way for novel therapeutic implications of full 5-HT4 agonists in gut dysmotility characterized by neuronal degeneration, which go beyond the well-known enterokinetic effect. [ABSTRACT FROM AUTHOR]

A 62-year-old woman complaining of severe malabsorption was diagnosed with celiac disease based on the findings of flat, small intestinal mucosa and HLA-DQ2 positivity, although celiac serology was negative. This diagnosis was questioned due to the lack of clinical and histological improvement after a long period of strict gluten-free diet. The detection of enterocyte autoantibodies guided to the correct diagnosis of autoimmune enteropathy, leading to a complete recovery of the patient following an appropriate immunosuppressive treatment. Autoimmune enteropathy should be considered in the differential diagnosis of malabsorption with severe villous atrophy, including those cases with negative celiac-related serology. [ABSTRACT FROM AUTHOR]

IBS is one of the most common types of functional bowel disorder. Increasing attention has been paid to the causative role of food in IBS. Food ingestion precipitates or exacerbates symptoms, such as abdominal pain and bloating in patients with IBS through different hypothesised mechanisms including immune and mast cell activation, mechanoreceptor stimulation and chemosensory activation. Wheat is regarded as one of the most relevant IBS triggers, although which component(s) of this cereal is/are involved remain(s) unknown. Gluten, other wheat proteins, for example, amylase-trypsin inhibitors, and fructans (the latter belonging to fermentable oligo-di-mono-saccharides and polyols (FODMAPs)), have been identified as possible factors for symptom generation/exacerbation. This uncertainty on the true culprit(s) opened a scenario of semantic definitions favoured by the discordant results of double-blind placebo-controlled trials, which have generated various terms ranging from non-coeliac gluten sensitivity to the broader one of non-coeliac wheat or wheat protein sensitivity or, even, FODMAP sensitivity. The role of FODMAPs in eliciting the clinical picture of IBS goes further since these short-chain carbohydrates are found in many other dietary components, including vegetables and fruits. In this review, we assessed current literature in order to unravel whether gluten/wheat/FODMAP sensitivity represent 'facts' and not 'fiction' in IBS symptoms. This knowledge is expected to promote standardisation in dietary strategies (gluten/wheat-free and low FODMAP) as effective measures for the management of IBS symptoms. [ABSTRACT FROM AUTHOR]

Aim: To assess anti-neuronal antibodies (NA) prevalence and their correlation with neurological disorders and bowel habits in celiac disease (CD) patients. Background: Neurological manifestations are estimated to occur in about 10% of celiac disease patients and NA to central nervous system (CNS) and enteric nervous system (ENS) are found in a significant proportion of them. Little is known about the clinical and immunological features in CD patients with neurological manifestations. Patients and methods: NA to CNS and ENS were investigated in 106 CD patients and in 60 controls with autoimmune disorders by indirect immunofluorescence on rat / primate cerebellar cortex and intestinal (small and large bowel) sections. Results: IgG NA to CNS (titer 1:50 - 1:400) were positive in 23 celiacs (21%), being more frequently detected in those with neurological disorders that in those without neurological dysfunction (49% vs. 8%, P< 0.0001). Of the 26 celiacs (24%) with IgG NA to ENS, 11 out of 12 with an antibody titer > 1:200 had severe constipation. Only one patient with cerebellar ataxia and intestinal sub-occlusion was positive for NA to CNS and ENS. NA to CNS and ENS were found in 7% and 5% of controls, respectively. Conclusion: In CD the positivity of NA to CNS can be regarded as a marker of neurological manifestations. High titer NA to ENS are associated with severe constipation. The demonstration of NA to CNS and ENS suggests an immune- mediated pathogenesis leading to central neural impairment as well as gut dysfunction (hence constipation), respectively. [ABSTRACT FROM AUTHOR]

Background: Celiac disease is a multiform, challenging condition characterized by extremely variable features. Our goal was to define clinical, serological and histopathological findings in a large cohort of celiacs diagnosed in a single referral center. Methods: From January 1998 to December 2012, 770 patients (599 females, median age 36 years, range 18-78 years) were diagnosed as celiacs at St.Orsola-Malpighi Hospital (Bologna, Italy). The clinical phenotypes were classified as: 1) classical (malabsorption syndrome); 2) non-classical (extraintestinal and/or gastrointestinal symptoms other than diarrhea); 3) subclinical. Serology, duodenal histology, comorbidities, response to gluten-free diet and complications were evaluated. Results: Disease onset was symptomatic in 610 patients (79%), while 160 celiacs showed a subclinical phenotype. In the symptomatic group the non-classical prevailed over the classical phenotype (66% vs 34%). Diarrhea was found in 27%, while other gastrointestinal manifestations were bloating (20%), aphthous stomatitis (18%), alternating bowel habit (15%), constipation (13%) and gastroesophageal reflux disease (12%). Extraintestinal manifestations included osteopenia/ osteoporosis (52%), anemia (34%), cryptogenic hypertransaminasemia (29%) and recurrent miscarriages (12%). Positivity for IgA tissue transglutaminase antibodies was detected in 97%. Villous atrophy was found in 87%, while 13% had minor lesions consistent with potential celiac disease. A large proportion of patients showed autoimmune disorders, i.e. autoimmune thyroiditis (26.3%), dermatitis herpetiformis (4%) and diabetes mellitus type 1 (3%). Complicated celiac disease was very rare. Conclusions: Our study demonstrates that the clinical profile of celiac disease changed over time with an increasing rate of non-classical and subclinical phenotypes. [ABSTRACT FROM AUTHOR]

Non-celiac gluten sensitivity is still an undefined syndrome with several unsettled issues despite the increasing awareness of its existence. Gluten is likely responsible for the clinical picture in a subset of patients, whereas in other cases it concurs to this syndrome together with fermentable mono-oligo-disaccharides and polyols and wheat proteins (e.g., amylase trypsin inhibitors). Innate immunity plays a pivotal role in the development of this syndrome, which is characterized by gut inflammation without villous atrophy and likely changes of intestinal barrier function. Data on its epidemiology are still undefined and largely variable. In the USA its prevalence varies from 0.6% to 6% in primary or tertiary care, respectively. Clinically, patients complain of gastrointestinal and extra-intestinal symptoms triggered by the ingestion of gluten without evidence of celiac disease and wheat allergy. Intestinal symptoms resemble those of irritable bowel syndrome, whereas neurological signs are quite common among extra-intestinal manifestations. So far, there are no biomarkers for non-celiac gluten sensitivity, but about half of patients shows anti-gliadin antibodies of immunoglobulin G class. Although not specific for non-celiac gluten sensitivity, the detection of such antibodies can support the diagnosis in patients with gluten-related symptoms. In the absence of diagnostic biomarkers a double-blind, placebo-controlled food challenge is currently the best way for confirming non-celiac gluten sensitivity. Studies aimed at clarifying the pathophysiological, clinical and laboratory features of non-celiac gluten sensitivity will help a better management of patients with this novel and intriguing clinical entity. [ABSTRACT FROM AUTHOR]

Background: Coeliac disease is a common enteropathy characterized by an increased mortality mainly due to its complications. The natural history of complicated coeliac disease is characterised by two different types of course: patients with a new diagnosis of coeliac disease that do not improve despite a strict gluten-free diet (type A cases) and previously diagnosed coeliac patients that initially improved on a gluten-free diet but then relapsed despite a strict diet (type B cases). Our aim was to study the prognosis and survival of A and B cases. Methods: Clinical and laboratory data from coeliac patients who later developed complications (A and B cases) and sex- and age-matched coeliac patients who normally responded to a gluten-free diet (controls) were collected among 11 Italian centres. Results: 87 cases and 136 controls were enrolled. Complications tended to occur rapidly after the diagnosis of coeliac disease and cumulative survival dropped in the first months after diagnosis of complicated coeliac disease. Thirty-seven cases died (30/59 in group A, 7/28 in group B). Type B cases presented an increased survival rate compared to A cases. Conclusions: Complicated coeliac disease is an extremely serious condition with a high mortality and a short survival. Survival depends on the type of natural history. [ABSTRACT FROM AUTHOR]

Background Non-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. Methods From 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. Results In 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 with 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. Conclusions This 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. [ABSTRACT FROM AUTHOR]

Objective. Celiac disease (CD) has strongly been established as associated with some site-specific gastrointestinal malignancies. On the contrary, according to the few reports available, the risk of colon carcinoma in CD patients has been described similar to that of general population. In this cohort study, we describe the risk of colon carcinoma in a group of Italian celiac patients. Materials and methods. The study population included all CD patients diagnosed at the Collaborating Centers of the Italian Registry of CD between 1st January 1982 and 31st December 2006. Upon diagnosis of CD and upon at every subsequent clinical control, the Collaborating Centers filled in a validated form for each CD patient reporting information about demographic data, possible occurrence of a neoplasm and adherence to a gluten-free diet. Results. Out of 1757 celiac patients enrolled, 6 developed a colon carcinoma during the follow-up period (mean: 18.1 years). The standardized incidence ratio (SIR) resulted 0.29 (95% CI = 0.07-0.45). Stratifying the risk for the dietary gluten intake, the SIR dropped to 0.07 (95% CI = 0.009-0.27) for CD patients with a strict adherence to a gluten-free diet. Conclusion. We confirm the previous finding that there is low risk to develop a colon cancer in celiac patients. [ABSTRACT FROM AUTHOR]

Background Overexpression of autologous proteins can lead to the formation of autoantibodies and autoimmune diseases. MHC class I polypeptide-related sequence A (MICA) is highly expressed in the enterocytes of patients with celiac disease, which arises in response to gluten. The aim of this study was to investigate anti-MICA antibody formation in patients with celiac disease and its association with other autoimmune processes. Methods We tested serum samples from 383 patients with celiac disease, obtained before they took up a gluten-free diet, 428 patients with diverse autoimmune diseases, and 200 controls for anti-MICA antibodies. All samples were also tested for anti-endomysium and anti-transglutaminase antibodies. Results Antibodies against MICA were detected in samples from 41.7% of patients with celiac disease but in only 3.5% of those from controls (P <0.0001) and 8.2% from patients with autoimmune disease (P <0.0001). These antibodies disappeared after the instauration of a gluten-free diet. Anti-MICA antibodies were significantly prevalent in younger patients (P <0.01). Fifty-eight patients with celiac disease (15.1%) presented a concomitant autoimmune disease. Anti-MICA-positive patients had a higher risk of autoimmune disease than MICA antibody-negative patients (P <0.0001; odds ratio = 6.11). The risk was even higher when we also controlled for age (odds ratio = 11.69). Finally, we found that the associated risk of developing additional autoimmune diseases was 16 and 10 times as high in pediatric patients and adults with anti-MICA, respectively, as in those without. Conclusions The development of anti-MICA antibodies could be related to a gluten-containing diet, and seems to be involved in the development of autoimmune diseases in patients with celiac disease, especially younger ones. [ABSTRACT FROM AUTHOR]

Background Non-celiac gluten sensitivity is a syndrome characterized by gastrointestinal and extraintestinal symptoms occurring in a few hours/days after gluten and/or other wheat protein ingestion and rapidly improving after exclusion of potential dietary triggers. There are no established laboratory markers for non-celiac gluten sensitivity, although a high prevalence of first generation anti-gliadin antibodies of IgG class has been reported in this condition. This study was designed to characterize the effect of the gluten-free diet on anti-gliadin antibodies of IgG class in patients with non-celiac gluten sensitivity. Methods Anti-gliadin antibodies of both IgG and IgA classes were assayed by ELISA in 44 non-celiac gluten sensitivity and 40 celiac disease patients after 6 months of gluten-free diet. Results The majority of non-celiac gluten sensitivity patients (93.2 %) showed the disappearance of anti-gliadin antibodies of IgG class after 6 months of gluten-free diet; in contrast, 16/40 (40 %) of celiac patients displayed the persistence of these antibodies after gluten withdrawal. In non-celiac gluten sensitivity patients anti-gliadin antibodies IgG persistence after gluten withdrawal was significantly correlated with the low compliance to gluten-free diet and a mild clinical response. Conclusions Anti-gliadin antibodies of the IgG class disappear in patients with non-celiac gluten sensitivity reflecting a strict compliance to the gluten-free diet and a good clinical response to gluten withdrawal. [ABSTRACT FROM AUTHOR]

Introduction: It has been shown that mortality rates of coeliac patients correlate with age at diagnosis of coeliac disease, diagnostic delay for coeliac disease, pattern of clinical presentation and HLA typing. Our aim was to create a tool that identifies coeliac patients at higher risk of developing complications. Methods: To identify predictors of complications in patients with coeliac disease, we organised an observational multicenter case-control study based on a retrospective collection of clinical data. Clinical data from 116 cases (patients with complicated coeliac disease) and 181 controls (coeliac patients without any complications) were collected from seven European centres. For each case, one or two controls, matched to cases according to the year of assessment, gender and age, were selected. Diagnostic delay, pattern of clinical presentation, HLA typing and age at diagnosis were used as predictors. Results: Differences between cases and controls were detected for diagnostic delay and classical presentation. Conditional logistic models based on these statistically different predictors allowed the development of a score system. Tertiles analysis showed a relationship between score and risk of developing complications. Discussion: A score that shows the risk of a newly diagnosed coeliac patient developing complications was devised for the first time. This will make it possible to set up the follow-up of coeliac patients with great benefits not only for their health but also for management of economic resources. Conclusions: We think that our results are very encouraging and represent the first attempt to build a prognostic score for coeliac patients. [ABSTRACT FROM AUTHOR]

Small bowel intraepithelial lymphocytosis (IL) may depend from different causes, including celiac disease (CD). Demonstration of increased number of duodenal T cell receptor gamma-delta (TCRγδ) positive intraepithelial lymphocytes (IELs) has been used to support CD diagnosis on frozen material. This work evaluates a new commercially available anti-TCRγ antibody on formalin-fixed paraffin embedded (FFPE) small bowel biopsies. Anti-CD3 and anti-TCR CγM1 (clone γ3.20) from Thermo Scientific were applied by immunohistochemistry on 59 FFPE biopsies from 18 cases of CD with mild/severe atrophy, 19 cases of IL in CD patients on gluten-free diet (IL-GFD), 14 cases of IL (6/14 with positive CD-related serology), and 8 controls (CTR) with mild duodenitis and negative CD serology and genotyping. IELs/100 epithelial cells were counted in at least six high power fields. CD3+ and TCRγ+ IELs were significantly higher in CD, IL-GFD, and IL compared with CTR, but in contrast to CD3+ IELs, TCRγ+ IELs were significantly increased in CD and IL-GFD compared with IL. Furthermore, TCRγ+ IELs discriminated between IL with negative and positive CD-related serology ( p = 0.02). TCRγ+ IELs can be identified on FFPE samples and their evaluation adds useful information for the work-up of small bowel biopsies in CD diagnosis. In fact, TCRγ staining coupled with CD3, may represent an additional tool to recognize cases of latent/potential CD when serology and clinical data are not conclusive or when the histological diagnosis remains equivocal. [ABSTRACT FROM AUTHOR]

Immunoglobulin G antibodies against deamidated gliadin peptides are now known to have diagnostic accuracy comparable to tissue transglutaminase and endomysium autoantibodies in patients with coeliac disease. However, little is known about their predictive value in infants with a suspected gluten enteropathy. We tested whether deamidated gliadin immunoglobulin G antibodies are more reliable than traditional tests for coeliac disease screening in infancy. Sixty-five children under 2 years of age (42 with malabsorption, 23 controls) were tested for deamidated gliadin immunoglobulin G, tissue transglutaminase and endomysium immunoglobulin A, and gliadin immunoglobulins A and G . Thirty-seven of the 42 children with malabsorption had deamidated gliadin antibodies, associated with tissue transglutaminase and endomysial antibodies in 33, and with gliadin immunoglobulins A and G in 21 and 29, respectively. Intestinal biopsy was performed in 34 of the 37 children positive for deamidated gliadin antibodies. Thirty-two/34 showed villous atrophy consistent with coeliac disease, while the remaining two had a Marsh 1 and a normal mucosa, respectively. Only gliadin immunoglobulins A (4.3 %) and G (39.1 %) were found in controls. The sensitivity of deamidated gliadin, tissue transglutaminase and endomysial antibodies for coeliac disease was significantly higher than that of gliadin immunoglobulins G and A. High titre deamidated gliadin antibodies correlated with severe intestinal damage. Deamidated gliadin antibodies showed a higher diagnostic accuracy for coeliac disease than gliadin antibodies in infancy. High titre deamidated gliadin antibodies predict a severe gluten-dependent duodenal damage. [ABSTRACT FROM AUTHOR]

The association between celiac disease and primary biliary cirrhosis is well established. The breakdown of gut-liver axis equilibrium plays a central role in the development of immune disorders involving the small bowel and liver. In celiac disease, immunologically active molecules generated from the cross-linking between tissue transglutaminase and food/bacterial antigens reach the liver through the portal circulation owing to the increased intestinal permeability. A molecular mimicry between bacterial antigens and the pyruvate dehydrogenase E2 component, recognized by antimitochondrial autoantibodies, may have a role in primary biliary cirrhosis pathogenesis. An aberrant intestinal T lymphocyte homing to the liver may contribute to trigger immune hepatic damage. Both celiac disease and primary biliary cirrhosis share several features, including a higher prevalence in females, autoimmune comorbidities and specific autoantibodies. Reciprocal screening for both diseases is recommended, as an early diagnosis with the appropriate treatment can improve the outcome of these patients. [ABSTRACT FROM AUTHOR]

The author highlights Coeliac Disease (CD), a chronic, multisystemic, autoimmune disorder, induced by gluten exposure in genetically sensitive individuals. He mentions the importance to underline that intestinal biopsy by itself is not always diagnostic and may present many pitfalls. He concludes the current knowledge and complex clinical problems it is evident that the final CD diagnosis is the decision made by the clinician.

The clinical spectrum of epilepsy related to celiac disease (CD) ranges from benign syndromes to intractable epilepsy with evolution to a severe encephalopathy, including progressive myoclonic epilepsy (PME). A more specific syndrome characterised by the association of CD, epilepsy, and occipital calcifications (CEC) has also been reported. This study describes the clinical, neuroradiological and neurophysiological features of eight consecutive epileptic patients with a diagnosis of CD confirmed by laboratory tests and duodenal biopsy, referring to our Epilepsy Centre. Despite its small size, this series reflects the broad spectrum of the association between the two diseases, since it includes four cases of CEC and a more heterogeneous group of patients without cerebral calcifications comprising one case of limbic encephalitis and a case of PME. Our cohort suggests that more complex pathogenic mechanisms may be involved in the association between epilepsy and CD, and that CD should be included in the screening for PME etiology. Our data also confirm the major involvement of the occipital lobe, and minimise both the importance of calcifications in epileptogenesis and folic acid deficit in the development of calcifications. [ABSTRACT FROM AUTHOR]

Celiac disease (CD) is one of the most frequent autoimmune disorders occurring in Type 1 diabetes mellitus (T1DM). The prevalence of CD in T1DM varies from 3 to 16%, with a mean prevalence of 8%. The clinical presentation of CD in T1DM is classified as symptomless in approximately half of cases, but a more accurate analysis often discloses a wide array of symptoms suggestive of CD. Both T1DM and CD show the same genetic background and an abnormal small intestinal immune response with inflammation and a variable grade of enteropathy. Serological screening for CD should be performed in all T1DM patients by means of antibodies to tissue transglutaminase at T1DM onset. T1DM patients found to be celiacs must be treated by a gluten-free diet. Potential CD cases (especially when asymptomatic) should be kept on a gluten-containing diet with a careful clinical and antibody follow-up, since many of them will not develop villous atrophy. [ABSTRACT FROM AUTHOR]

Summary: Introduction: Coeliac disease can be associated with hyposplenism and splenic atrophy, which may increase the patient''s risk for fatal infections caused by Streptococcus pneumoniae or Pneumococcus. It is general opinion that many more patients with coeliac disease have died from hyposplenism-related infections than those reported in literature. Case report: A 62-year-old woman with recently diagnosed coeliac disease was hospitalized with high fever, disorientation, and nuchal rigidity. Cerebral computed tomography was negative. Laboratory tests showed an elevated leukocyte count and very high levels of C reactive protein. The cerebrospinal fluid (CSF) contained an increased number of mononuclear cells associated with a low glucose level and high protein concentrations. The CSF culture was positive for Streptococcus pneumoniae. Neurological conditions rapidly deteriorated with the onset of coma, and magnetic resonance imaging of the brain revealed initial signs of encephalitis extending above and below the tentorium. Abdominal ultrasonography disclosed splenic hypotrophy that raised the suspicion of hyposplenism. The diagnosis of hyposplenism was confirmed by demonstration of Howell-Jolly bodies in a peripheral blood smear. Discussion: This is the first reported case of pneumococcal meningoencephalitis caused by splenic hypofunction in a patient with coeliac disease. When coeliac disease is diagnosed with a marked delay in an elderly patient, spleen function should always be assessed. If impaired, the patient should undergo vaccination with pneumococcal conjugate vaccine to prevent pneumococcal infections. [Copyright &y& Elsevier]