Celiac disease unveiled by palmoplantar pigmentation.

Management of Celiac Disease: Beyond the Gluten-Free Diet

Celiac disease: India on the global map

Celiac Disease-Even a Neurological Disorder

Gluten-free diet, chromosomal abnormalities, and cancer risk in coeliac disease.

Background Crohn disease and coeliac disease are two inflammatory conditions known to cause small intestine inflammation. Using high throughput transcriptomics, microbial, and bioinformatics approaches we aimed to capture differences and similarities linked to the pathogenesis and to future potential interventions for those chronic manifestations. Methods We performed high throughput transcriptomics and 16S microbial characterisation of 55 paediatric new-onset coeliac patients and controls using clinical pathology specimens, and compared those signatures to our previously reported 248 RISK Crohn’s disease newly diagnosed cohort. ToppGene/ToppCluster and ClueGO platforms were used for functional annotation enrichment analyses, and MaAsLin for microbial differential abundance. Results A substantial number (>90%) of genes passed the expression filtering criteria in both studies enabling the comparison. Of the 354 coeliac down-regulated genes, 59% (209/354) overlapped with the reduced Crohn signature. Shared reduced signatures and functions included a decrease in epithelial lipid metabolism, oxidoreductase activity, and brush border transport signatures. In contrast, a significantly smaller proportion [19% (97/427, Chi-squares p < 0.001] of the coeliac disease 524 up-regulated genes overlapped with the induced Crohn disease signature. We noted shared enriched signatures for adaptive immune-related pathways and interferon-γ in both coeliac and Crohn diseases. However, the Crohn disease signature exhibited more specific enrichments for signatures associated with innate immune pathways and with a strong signal for granulocytes, an extracellular matrix signature, and CXCR chemokines signalling, while the coeliac up-regulated signature showed unique enrichment for cell cycle and mitosis. As opposed to the robust dysbiosis previously characterised in Crohn disease, we were only able to identify significant enrichment for Bacteroidetes taxa in coeliac patients in comparison to controls. Conclusion We highlight important biologic differences between Crohn and coeliac diseases emphasising an intensified innate granulocytes activation signature in Crohn disease and a specific epithelial proliferative signal in coeliac disease. Unlike the robust dysbiosis linked to Crohn disease, the coeliac patient showed only modest enrichment for several Bacteroidetes taxa in comparison to controls. It is possible that microbial alteration in Crohn disease triggers granulocytes activation, and that this signal inhibits epithelial proliferation/renewal, eventually leading the epithelial damage seen in Crohn but not coeliac disease. Inhibiting innate immune activation or reverting Crohn dysbiosis may be a beneficial future therapy for Crohn disease.

Celiac Disease: Advances in Treatment via Gluten Modification

272 Integration of a child with celiac disease into a preschool institution

A negative fallout of COVID-19 lockdown in Italy: Life-threatening delay in the diagnosis of celiac disease

Intestinal biopsy, coeliac disease and resistance to change.

Celiac disease (CD) affects approximately 1% of the population. It is a disease that causes flattening of the epithelial lining of the small bowel and is characterized by (sub) total villous atrophy. The histological alterations in CD are graded according to the modified Marsh Classification from Marsch 0 (normal mucosa) to Marsch IIIc (total villous atrophy). Common symptoms include, but are not restricted to, malasborption, diarrhoea, malnutrition, failure to thrive in children and abdominal pain. Some patients with CD have no gastrointestinal symptoms or are asymptomatic (1). CD is caused by intolerance to gluten and a strict gluten free diet is the only available treatment. In the lamina propria of the small intestine of patients with CD there are T cells that respond to gluten fragments bound to the disease predisposing HLA-DQ2 and/or HLA-DQ8 molecules and secrete proinflammatory cytokines. The diagnosis of CD is based on the combination of HLA typing for DQ2 and DQ8, serum determination of specific CD antibodies (IgA anti-transglutaminase (tTG) and IgA antiendomisium (EMA) antibodies), on the results of small bowel biopsies and on the improvement of the symptoms after adherence to a gluten free diet (1–3). In this number of GHFBB, Rostami Nejad and co-authors report on the prevalence of CD in patients with dyspepsia and on the value of histology of the small bowel and of determination of specific CD antibodies in the diagnosis of CD in these patients (4). To study this, the authors performed small bowel biopsies and determined total IgA and IgA tTG (or IgG in case of IgA deficiency) in 407 randomly chosen adult patients who underwent diagnostic upper gastrointestinal endoscopy for dyspeptic symptoms. CD was identified by histological alterations characteristic of gluten sensitive enteropathy and by consistent CD serology. Biopsy results were classified as absence of CD (Marsh 0) or suggestive of CD (Marsh I to IIIc). There were 26 (6.4%) cases with enteropathy, among them 12 cases with Marsh I and 4 with Marsh II. Thirty three (8.1%) of the patients had tTGA level more than 15 u/ml, considered as tTGA positive, 10 of them (2.5%) had abnormal histology (Marsh I,-IIIc), including 5 patients with Marsh IIIa-c (1.3%). This last figure is in line with frequencies of CD previously reported among patients with dyspepsia (5–7). The authors discuss if the real frequency of CD in dyspepsia should be considered as high as 8%, as assessed by determination of specific CD antibodies, since they have been shown to perform better than histology in the diagnosis of CD (8). Some strong points of the study of Rostami Nejad and co-authors are, among others, its prospective design, the randomly inclusion of the 407 patients with dyspepsia who underwent upper gastrointestinal endoscopy during the study and the completeness of the total IgA and tTG results in their patients. However, the study has also shortcomings. The authors considered levels higher than 15 U/ml as tTGA positivity. This level possibly represents the cut-off of normality of the tTGA determination in serum in their laboratory. However, it is known that lower levels of tTGA are less indicative for CD than higher levels, and that in CD there is a correlation between the TGA levels and the degree of small bowel damage. So, it should have been useful if the authors had presented the data on the correlation between the tTGA levels and the Marsch classifications of their patients. This is especially important in the cases with Marsch I alterations, since in absence of specific CD antibodies, these lesions are almost never indicative of CD (7). In addition, it is also known that “false positive” levels of tTGA are almost always present at low levels and in absence of EMA. So, the addition of EMA determinations, especially in these patients with elevated tTGA, should have added strength to the study. The authors rightly state that there is no a single perfect test to diagnose CD in its own. One additional, but important, part of the diagnosis is the improvement of the symptoms after the start of a gluten free diet. In this contest, information over the improvement of the symptoms of dyspepsia in the studied patients after adherence to the diet should be important, especially if, as the authors suggest, CD screening should be done in all patients with these symptoms.

849 Gamma-Delta T-Lymphocytes As Diagnostic Criterium in Latent Celiac Disease

Celiac disease (CD) was initially a real enigma. There were many questions about what immunogenetics markers could influence the immune response (1). Immunogenetic studies provided important contributions to improve the understanding of critical pathogenetic factors at molecular levels (DQ2, DQ8) (2). An important discovery was the recognition of more precise serological markers for CD, specifically anti-endomysial and anti-tissue transglutaminase antibodies leading to an exploration of their increasingly important role in clinical diagnosis of CD (3). Our aim is to explore new and old challenges with unanswered questions in CD diagnosis. The last Prague consensus report challenges Re-evaluation of CD diagnostic with intestinal biopsy is required in this consesus (4). However, many patients with CD are still inaccurately diagnosed (or remain undiagnosed), even in referral populations whom were evaluated at tertiary care centers: the diagnosis of CD was confirmed in only 64 patients from 107 patients with previous diagnosis of CD (5). Recently, it was noted that even for some experts, the quality of duodenal bulb biopsies was unsatisfactory. This fact may create confusion and false-positive diagnoses which seem to be increasing in the pediatric population(6). However, histopathological classifications of CD have been debated for decades and some investigators have recently expressed concern regarding specific architectural changes, the degree of change and their relevance: Marsh, Marsh modified (Oberhuber), or Corazza classification. (7, 8). As immunologically-based assays evolve, the authors of this paper believe that serological markers are more useful for screening purposes in CD compared to small intestinal mucosal biopsy alone. At present, the gold standard for diagnosis is still small intestinal mucosal biopsy. Although data is still needed, it is conceivable that serological markers may eventually even become more useful for diagnostic purposes in CD compared to small intestinal mucosal biopsy alone (9). But an obvious serological algorithm is not specified. At present, the IgA anti-tissue transglutaminase antibody test appears to be the most sensitive and specific markers of CD screening (10) but a minority of CD patients are seronegative (11). The main task of gastroenterologists was to recognize untreated CD. In countries with weaker economies (i.e., the so-called developing nations), it is generally believed that the rate of diagnosis is low (12). Controversies remain in areas that include application of screening methods and evaluation of high risk groups for the CD, as well as diagnostic tests that lead to a final diagnosis of the CD (13). In addition, a number of immunologically-related challenges in gastroenterology remain for those involved in a CD care. IL-21 was lower in potential CD, than in active CD, so a key role for IL-21 in the progression of mucosal damage in CD needs to be further elucidated (14). Furthermore, HLA DQ8 in Southwest Asia, South America and the Middle East was positive in 49% (n=69) of CD patients and 13% (n=21) of control group, respectively. In conclusion, HLA DQ8 was found to be significantly higher in these geographical regions compared to European countries (15). However, HLA-DQ2 and/or -DQ8 expression: 38.1% in northern, 31.4% in northeastern, and 36.4% in southern India, did not appear to correlate with CD prevalence: 8.53/1,000 and 3.70/1,000 in northern, 4.66/1,000 and 3.92/1,000 in northeastern, and 0.11/1,000 and 1.22/1,000 in the southern India (16). A number of other associated immune-mediated or autoimmune disorders may co-exist with CD, possibly owing to a common genetic background (17). So, novel diagnostic antibodies for CD are neccesary (18).

Celiac disease (CD) in adults with type 1 diabetes has been associated with increased cardiovascular risk and the earlier occurrence of diabetes-associated complications. In the Search for Diabetes in Youth study, we aimed to assess the frequency of CD and the potential for undiagnosed CD among youth with childhood onset type 1 diabetes. In addition, we assessed the burden of cardiovascular risk factors and diabetes-associated complications in youth with type 1 diabetes by CD status and IgA tissue transglutaminase autoantibody (tTGA) levels. 2,444 youths with type 1 diabetes completed a CD questionnaire and underwent tTGA testing. Integrating the celiac disease questionnaire and tTGA results for this cross-sectional analysis, participants were categorized as follows: (1) reported CD; (2) seropositive for CD (no reported CD and seropositive tTGA); and (3) type 1 diabetes only (comparison group: no reported CD and seronegative tTGA). Subanalyses were performed on those with no reported CD and tTGA ≥10x ULN, designated potentially undiagnosed CD. Cardiovascular risk factors and diabetes-associated complications were evaluated by CD status and tTGA levels utilizing a Poisson model to estimate relative risk. Reported CD in youths with type 1 diabetes was 7%. Seropositivity for tTGA with no reported CD was present in 4%, and 1.2% had potentially undiagnosed CD. Youths with potentially undiagnosed CD had a 2.69x higher risk of diabetic retinopathy than comparison group. In addition, CD with tTGA <0.05 (controlled CD) was associated with lower HbA1c. Undiagnosed CD is likely present in youths with type 1 diabetes and potentially undiagnosed CD is associated with a higher risk of diabetic retinopathy. These findings indicate the importance of routine screening for CD in type 1 diabetes in youths.

Two recent articles have focused on the possible relationships between rotavirus infection and celiac disease (CD). The first study (1) is a prospective investigation into the natural history and the environmental triggers of diabetes and CD autoimmunity in genetically predisposed individuals. The authors found that frequent rotavirus infection predicted a higher risk of CD autoimmunity. However, infections were not diagnosed on the basis of clinical symptoms but were estimated by the number of increases in rotavirus antibody titers between clinic visits. Furthermore, only HLA-DR3–positive subjects were considered to be genetically predisposed to CD. The second study (2) aimed to clarify the role played by infectious agents in eliciting the autoimmune response in CD. It was based on a random peptide library approach, a strategy that was successfully implemented for the identification of other disease-related autoantigens. In this case a peptide sequence was found to be specifically recognized by sera from untreated patients with CD. This sequence shared a high degree of homology with the rotavirus serotype 1 major neutralizing protein VP7, but also with HSP60, desmoglein, Toll-like receptor 4 (TLR4), and in particular with tissue transglutaminase. In fact, antibodies to this peptide sequence (and to VP7) bind to endomysium; more important, these anti-tissue transglutaminase autoantibodies were shown to have functional consequences on TLR4 activation and epithelial cell permeability. These 2 studies brought up a number of relevant points pertaining to the pathogenesis of CD: the autoimmune features of the disease and the mechanisms of autoantibody induction; the biological activities of these autoantibodies and their contribution to the induction of mucosal damage; the environmental factors involved in the risk of developing the disease in genetically susceptible individuals, in particular the possible role of viruses and their ability to activate innate immunity mechanisms, setting the stage for the induction of adaptive gliadin-specific immune response; and perspectives opened in the area of prevention. CD can be considered to be an autoimmune disease because of the presence of autoantibodies in both the sera (3) and the intestinal mucosa of patients (4). Of note, CD is also associated with a high prevalence of concomitant autoimmune disease (5). The mechanisms leading to the development of autoimmunity in CD are largely unknown, and whether this is a direct consequence of gluten ingestion is unclear (6,7). Furthermore, the mechanisms leading to the formation of autoantibodies, in particular anti-tissue transglutaminase antibodies, in CD are still obscure. Several hypothesis have been proposed: upregulation of tissue transglutaminase in inflamed sites may generate additional antigenic epitopes by cross-linking or deamidating external or endogenous proteins; unmasking of cryptic epitopes has also been hypothesized in the context of an inflamed environment where antigen processing and presentation may be more efficient; help for the production of autoantibodies given by gliadin-specific T cells in the mucosa has been advocated to explain why these autoantibodies are dependent on the presence of gluten in the diet (8); and molecular mimicry has emerged as a possibility from the study by Zanoni et al (2). Interestingly, rotavirus infection has been associated with pancreatic islet autoimmunity via a mechanism of molecular mimicry (9). The possible role of these autoantibodies in the pathogenesis of celiac intestinal lesions has not been elucidated. Autoantibodies to TG2 partly inhibit enzyme activity (10). CD serum immunoglobulin A has been found to inhibit epithelial cell differentiation in a 3-dimensional fibroblast–epithelial cell coculture model (11). More recently, antibodies to surface TG2 have been shown to control some of the effects mediated by gliadin peptide p31-43 (12). Data from our laboratory suggest that these antibodies have a proliferative effect on the intestinal epithelial cells and uptake of gliadin peptides by epithelial cells (13). Zanoni and colleagues envisage a new biological action of anti-tissue transglutaminase antibodies on the activation of innate immunity. The 2 articles also shed light on the environmental factors involved in the disease risk for genetically susceptible individuals. The relevance of the environment in CD should be little given the strong role played by genetics; however, some evidence, such as that in these articles, suggests a role for it and is indicated by the high disease concordance in monozygotic twins (14). Among the environmental risk factors, gluten has been the only one to be considered. In children prone to CD exposure to wheat, barley, and rye in the first 3 months or in month 7 onward significantly increased their risk for developing CD-associated autoantibodies, compared with exposure at 4 to 6 months (15). Nonetheless, apart from gluten (in particular the modes of introduction into the diet during the first year of life) it is possible that infectious agents play a role. In the 1980s a 12-amino acid sequence homology was found between A-gliadin and the E16 protein from the human adenovirus type 12 (16). More recently epidemiological observations on the seasonal pattern of incidence of CD have sustained the hypothesis of a viral infection triggering the disease (17). Rotavirus, as seems obvious from the articles by Stene et al and Zanoni et al, is a good candidate. The scenario that can be envisioned is that the contact with gluten at a time when there is ongoing intestinal inflammation, altered intestinal permeability, and type I and type II interferon production, upregulation of HLA-DQ2 and HLA-DQ8 on dendritic cells, will increase the risk for developing CD, at least in a subset of individuals. At the same time, the phenomenon of molecular mimicry may trigger autoimmunity. The possibility that these antibodies, among their other biological activities, may modulate the innate immune response through activation of TLRs, is a new, intriguing observation. Attention has been directly increasingly at the possibility of preventing CD. The strategies envisaged are mainly focused on feeding patterns in the first year of life (breast-feeding, amount and timing of gluten introduction). These observations pointing to a possible role played by rotavirus in the pathogenesis of CD open perspectives on prevention strategies in this new era of rotavirus vaccination. Further studies are needed to exclude any risk for inducing autoantibodies by mechanisms of molecular mimicry. However, it is possible that protecting infants genetically predisposed to CD from repeated infection by the wild-type virus may interfere with the activation of innate immunity and with the consequent adaptive gliadin-specific immune response eventually leading to the disease. Large prospective studies in genetically prone subjects will provide the answer.

Association of celiac disease (CD) with systemic autoimmune diseases (ADs) remains controversial. Awareness of CD in these patients is important to prevent complications, including lymphoproliferative disorders. We evaluated previously diagnosed CD prevalence in systemic lupus erythematosus (SLE), primary Sjögren’s syndrome (pSS) and systemic sclerosis (SSc) patients in comparison to 14,298 matched controls. All patients were screened for subclinical CD. Data from 1458 unselected consecutive SLE (580), pSS (354) and SSc (524) patients were collected. Previously biopsy-proven CD diagnosis and both CD- and AD-specific features were registered. All patients without previous CD were tested for IgA transglutaminase (TG). Anti-endomysium were tested in positive/borderline IgA TG. Duodenal biopsy was performed in IgA TG/endomysium+ to confirm CD. CD prevalence in AD was compared to that observed in 14,298 unselected sex- and age-matched adults who acted as controls. CD was more prevalent in pSS vs controls (6.78% vs 0.64%, p < 0.0001). A trend towards higher prevalence was observed in SLE (1.38%, p = 0.058) and SSc (1.34%, p = 0.096). Higher CD prevalence was observed in diffuse cutaneous SSc (4.5%, p ≤ 0.002 vs controls). Subclinical CD was found in two SLE patients and one pSS patient. CD diagnosis usually preceded that of AD. Primary SS and SSc–CD patients were younger at AD diagnosis in comparison to non-celiac patients. Autoimmune thyroiditis was associated with pSS and CD. CD prevalence is clearly increased in pSS and diffuse SSc in comparison to the general population. The association of CD with diffuse but not limited SSc may suggest different immunopathogenic mechanisms characterizing the two subsets. CD screening may be considered in pSS and diffuse SSc in young patients, particularly at the time of diagnosis.