Untreated Coeliac Disease Research Articles

Coeliac Disease in Children—A Clinical Review Including Novel Treatment Agents

Coeliac disease (CD) affects almost of 1% of the population, yet remains undiagnosed in the majority. Though the demonstration of enteropathy in duodenal biopsy was traditionally the essential criterion for the diagnosis of coeliac disease, the guidelines published by the European Society of Paediatric Gastroenterology and Nutrition (ESPGHAN) in 2012, and revised in 2020, paved the way to a no-biopsy approach to diagnosis. In a select group of children meeting certain criteria, a definitive diagnosis of CD can now be made without the need for duodenal biopsies. This is being increasingly applied in clinical practice. It is well established that untreated coeliac disease is associated with several chronic adverse health conditions. At present, a strict gluten-free diet remains the only effective treatment for CD. The advances in our understanding of the pathogenesis of CD have led to a search for alternative treatment agents. Several investigational agents are in various phases of clinical trials at present. In this review, we outline the clinical aspects of coeliac disease and summarise various investigational treatment agents.

A new algorithm for coeliac disease based on the 'long forgotten' TCRγδ+ intra-epithelial lymphocytes detected with an antibody working on FFPE sections.

Diagnosis of coeliac disease (CD) with mild mucosal changes is difficult for all parties involved. We aimed to determine the power of Tcell receptor (TCR)γδ+ intra-epithelial lymphocytes (IELs) in discriminating CD from other causes of intra-epithelial lymphocytosis using a new monoclonal antibody. A total of 167 cases categorised as coeliac (117 untreated CD, classified according to Marsh, updated by Ensari, including 29 type 1, 29 type 2, 39 type 3 and 20 treated CD), and non-coeliac groups (24 controls and 26 non-coeliac IELosis) based on clinical, serological and histological data were studied for IEL counts enumerated per 100 enterocytes using haematoxylin and eosin, CD3, TCR δ-stains. TCRγδ+ IELs were significantly higher in CD (24.83 ± 16.13) compared to non-CD (6.72 ± 6.32) and were correlated with the degree of mucosal damage. Both γδ+ IEL count and ratio showed higher performance in differentiating untreated coeliacs from controls, with a sensitivity of 83.76; 85.57 and specificity of 95.83; 79.17, respectively. TCRγδ+ IEL counts distinguished type 1 CD (20.41 ± 13.57) from non-coeliac IELosis (9.42 ± 7.28) (p = 0.025). Discriminant analysis revealed that villus/crypt ratio, γδ+ and CD3+ IEL counts, γδ+/CD3+IEL ratio, IEL distribution pattern were potent discriminants and correctly classified 82.3% of cases while the algorithm accurately diagnosed 93.4% of cases. The new antibody detecting γδ+ IELs in FFPE sections revealed thresholds of 10.5 for γδ+ IELs and 14% for γδ+/CD3+IEL ratio which distinguished coeliacs from non-coeliacs with high sensitivity and specificity, particularly in cases with normal villus/crypt axis including type 1 CD, non-CD IELosis and controls. A 'coeliac algorithm' based on γδ+ IELs is proposed with the hope that it will be used in the histopathological diagnostic approach by the pathology community.

Gastrointestinal and Hepatobiliary Manifestations Associated with Untreated Celiac Disease in Adults and Children: A Narrative Overview.

Celiac disease (CeD) is a chronic inflammatory disease of the small intestine, produced by ingesting dietary gluten products in susceptible people. Gluten causes an impairment of the mucosal surface and, consequently, an abnormal absorption of nutrients. Although malabsorption of essential nutrients is a major risk factor for various CeD-associated morbidities, genetic, immunological, and environmental factors also play an important role. The clinical presentation of CeD widely varies and can range from asymptomatic to full-blown symptoms due to the multi-system nature of CeD. The typical gastrointestinal (GI) manifestations of CeD include abdominal pain, diarrhea, bloating, and weight loss, but several hepatobiliary manifestations and a poor nutritional status have also been described. Currently, a gluten-free diet (GFD) is the only current evidence-based treatment that leads to the complete recovery of mucosal damage and the reversibility of its progression. Conversely, undiagnosed CeD might have severe consequences in children as well as in adult patients. This narrative overview aims to characterize the GI and hepatobiliary manifestations, nutritional deficiencies, and delayed pediatric development associated with unrecognized CeD in order to identify it promptly. Moreover, the role of GFD and how it could prevent long-term complications of CeD are described.

Innovative Approaches to Clinical Diagnosis: Transfer Learning in Facial Image Classification for Celiac Disease Identification

Background: Celiac disease arises from gluten consumption and shares symptoms with other conditions, leading to delayed diagnoses. Untreated celiac disease heightens the risk of autoimmune disorders, neurological issues, and certain cancers like lymphoma while also impacting skin health due to intestinal disruptions. This study uses facial photos to distinguish individuals with celiac disease from those without. Surprisingly, there is a lack of research involving transfer learning for this purpose despite its benefits such as faster training, enhanced performance, and reduced overfitting. While numerous studies exist on endoscopic intestinal photo classification and a few have explored the link between facial morphology measurements and celiac disease, none have concentrated on diagnosing celiac disease through facial photo classification. Methods: This study sought to apply transfer learning techniques with VGG16 to address a gap in research by identifying distinct facial features that differentiate patients with celiac disease from healthy individuals. A dataset containing a total of 200 facial images of adult individuals with and without celiac condition was utilized. Half of the dataset had a ratio of 70% females to 30% males with celiac condition, and the rest had a ratio of 60% females to 40% males without celiac condition. Among those with celiac condition, 28 were newly diagnosed and 72 had been previously diagnosed, with 25 not adhering to a gluten-free diet and 47 partially adhering to such a diet. Results: Utilizing transfer learning, the model achieved a 73% accuracy in classifying the facial images of the patients during testing, with corresponding precision, recall, and F1 score values of 0.54, 0.56, and 0.52, respectively. The training process involved 50,178 parameters, showcasing the model’s efficacy in diagnostic image analysis. Conclusions: The model correctly classified approximately three-quarters of the test images. While this is a reasonable level of accuracy, it also suggests that there is room for improvement as the dataset contains images that are inherently difficult to classify even for humans. Increasing the proportion of newly diagnosed patients in the dataset and expanding the dataset size could notably improve the model’s efficacy. Despite being the first study in this field, further refinement holds promise for the development of a diagnostic tool for celiac disease using transfer learning in medical image analysis, addressing the lack of prior studies in this area.

Associations between Celiac Disease, Extra-Gastrointestinal Manifestations, and Gluten-Free Diet: A Narrative Overview.

Millions of children and adults worldwide suffer from undiagnosed and untreated celiac disease (CeD). The clinical picture of CeD is highly heterogeneous and comprises manifestations that can affect almost the whole body. This narrative overview is aimed at characterizing diseases and complaints that are associated with unrecognized CeD and that frequently involve sites other than the gastrointestinal (G.I.) tract, i.e., dental, otorhinolaryngological, and ocular complications; skin and hair abnormalities; afflictions of the bones, joints, and muscles; cardiovascular affectations; kidney diseases; neuro-psychiatric disorders; and gynecological-obstetrical manifestations. The association between CeD and extra-GI manifestations is frequently overlooked, which leads to a delay in diagnosis. Most CeD-mediated disorders can be treated with a strict gluten-free diet (GFD), but some of them are irreversible unless CeD is diagnosed in time. Some manifestations can be classified as risk factors for CeD, and CeD screening tests for affected patients should be selectively considered. Apart from gastroenterologists, specialists in other medical disciplines can play an important role in identifying people with unrecognized CeD and may help prevent its progress and long-term complications. Further comprehensive investigations are necessary to clarify the pathogenesis of extra-GI manifestations and the effect of a GFD.

Noninvasive Markers of Inflammation and Protein Loss Augment Diagnosis of Pediatric Celiac Disease.

Circulating tissue transglutaminase immunoglobulin A concentration is a sensitive and specific indicator of celiac disease, but discrepancies between serologic and histologic findings occur. We hypothesized that fecal markers of inflammation and protein loss would be greater in patients with untreated celiac disease than in healthy controls. Our study aims to evaluate multiple fecal and plasma markers in celiac disease and correlate these findings with serologic and histologic findings as noninvasive means of evaluating disease activity. Participants with positive celiac serologies and controls with negative celiac serologies were prospectively enrolled before upper endoscopy. Blood, stool, and duodenal biopsies were collected. Concentrations of fecal lipocalin-2, calprotectin, and alpha-1-antitrypsin and plasma lipocalin-2 were determined. Biopsies underwent modified Marsh scoring. Significance was tested between cases and controls, modified Marsh score and tissue transglutaminase immunoglobulin A concentration. Lipocalin-2 was significantly elevated in the stool ( P = 0.006) but not the plasma of participants with positive celiac serologies. There was no significant difference in fecal calprotectin or alpha-1 antitrypsin between participants with positive celiac serologies and controls. Fecal alpha-1 antitrypsin >100 mg/dL was specific, but not sensitive for biopsy-proven celiac disease. Lipocalin-2 is elevated in the stool but not the plasma of patients with celiac disease suggesting a role of local inflammatory response. Calprotectin was not a useful marker in the diagnosis of celiac disease. While random fecal alpha-1 antitrypsin was not significantly elevated in cases compared with controls, an elevation of greater than 100 mg/dL was 90% specific for biopsy-proven celiac disease.

Duodenal mucosa of untreated celiac disease patients has altered expression of the GAS6 and PROS1 and the negative regulator tyrosine kinase TAM receptors subfamily

Celiac disease (CD) is an immune-driven disease characterized by tissue damage in the small intestine of genetically-susceptible individuals. We evaluated here a crucial immune regulatory pathway involving TYRO3, AXL, and MERTK (TAM) receptors and their ligands PROS1 and GAS6 in duodenal biopsies of controls and CD patients. We found increased GAS6 expression associated with downregulation of PROS1 and variable TAM receptors levels in duodenum tissue of CD patients. Interestingly, CD3+ lymphocytes, CD68+, CD11c+ myeloid and epithelial cells, showed differential expressions of TAM components comparing CD vs controls. Principal component analysis revealed a clear segregation of two groups of CD patients based on TAM components and IFN signaling. In vitro validation demonstrated that monocytes, T lymphocytes and epithelial cells upregulated TAM components in response to IFN stimulation. Our findings highlight a dysregulated TAM axis in CD related to IFN signaling and contribute to a deeper understanding of the pathophysiology of CD.

CT and MR Enterography in the Evaluation of Celiac Disease.

Celiac disease is a common inflammatory disease of the small bowel that induces mucosal intestinal lesions. The disease is mediated by an immune response and triggered by the ingestion of gluten in genetically predisposed individuals. Gluten contains gliadin, a component found mostly in wheat, barley, and rye. This process leads to gastrointestinal malabsorption with symptoms such as diarrhea, constipation, abdominal pain, and distention. It has a prevalence of 1%-2% in the general adult population, who present with symptoms at any age, but is more frequently found in adult women in the 3rd or 4th decade of life. Recognition of the disease has increased, but it remains a challenge to diagnose. CT and MR enterography are noninvasive studies used for evaluation of small bowel neoplasms and inflammatory small bowel pathologic conditions such as celiac disease. The authors review the spectrum of intestinal and extraintestinal findings of celiac disease at CT and MR enterography, as well as its complications, and the importance of recognizing certain imaging features that help in the diagnosis of celiac disease. More common and specific findings of celiac disease such as inversion of the jejunoileal fold pattern and mesenteric lymphadenopathy are reviewed. More uncommon entities that are more frequently associated with refractory or untreated celiac disease, such as ulcerative jejunoileitis, cavitary mesenteric lymph node syndrome, and malignancies including small bowel adenocarcinoma and lymphoma, are described. ©RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material. The slide presentation from the RSNA Annual Meeting is available for this article.

Renal amyloidosis: a hidden complication of celiac disease (a case report)

We report a case of a 36-year-old female with untreated celiac disease, exhibiting both digestive discomfort and extra-digestive symptoms, including anemia. She subsequently developed a nephrotic syndrome. Biopsy of the accessory salivary gland confirmed amyloid deposits, as indicated by positive Congo red staining. Esophagogastroduodenal fibroscopy revealed characteristic signs of celiac disease and ruled out lymphoma. Further etiological screening identified celiac disease as the only possible cause of the amyloidosis. Complete remission was achieved after 3 months on a gluten-free diet, with later laboratory assessments indicating the absence of nephrotic syndrome and hematological abnormalities.

Classification of celiac disease using novel approach of three-level DWT decomposition and linear support vector machine

In the medical field, the requirement for automated medical diagnosis software has risen as the application uses machine learning to facilitate health analysis from different data points from a patient comparing it with massive amounts of medical data to diagnose and prevent disease. The automated system can run multiple tests simultaneously and thus resulting to faster turnaround time and enables timely patient care along with higher accuracy and reliability. The irregularities in the small intestine villi’s structure cause various autoimmune disorders. So, this work aims to find a novel technique for the feature extraction of upper endoscopy images of celiac disease. We employed CLAHE (Contrast Limited Adaptive Histogram Equalization) for the preprocessing step and the Sobel operator with gradient magnitude for the segmentation of the enhanced image. In this manuscript, we have proposed a novel approach by calculating texture features through gray level co-occurrence matrix and frequency analysis using 3-level discrete wavelet transform decomposition on endoscopy images that renders novelty to the work. Thereafter, linear SVM (support vector machine) with PCA (Principal Component Analysis) is used for classification. The ensemble approach attains accuracy, sensitivity, and specificity of 78.49 %, 90.32 %, and 77.27% respectively. The outcomes achieved with the suggested approach are compared with some state-of-the-art methods using the same dataset. The results are promising due to high sensitivity for the treatment of untreated celiac disease and can prove boom to the medical industry by assisting clinicians to diagnose the disease at an early stage.

Diagnostic Accuracy of Tissue Transglutaminase and Combined Assay of Tissue Transglutaminase and Deamidated Gliadin Peptide in Children with Coeliac Disease: A Cross-sectional Study

Introduction: Coeliac Disease (CD) is a systemic immune disorder caused by gluten in genetically susceptible individuals. A serological screening assay for CD has been designed to detect Immunoglobulin A (IgA) and IgG anti-tissue Transglutaminase (a-tTG) and IgA and IgG Deamidated Gliadin Peptide antibodies (a-DGP) simultaneously. The seronegative gap can be closed when these two antigens are combined on a single solid phase. This is primarily because untreated CD children who are negative for antibodies of one of the antigens may exhibit a positive result for the other. Aim: To determine the diagnostic parameters {sensitivity, specificity, Positive Predictive Value (PPV), Negative Predictive Value (NPV)} of tTG-IgA and htTG-DGP (Coeliac fusion- a combination of IgA and IgG to human tTG and synthetic DGP) for the diagnosis of CD in clinically symptomatic children. Materials and Methods: This cross-sectional study was conducted at the Paediatric Outpatient Department (OPD) of Santokhba Durlabhji Memorial Hospital, Jaipur, Rajasthan, India from April 2023 to November 2023. The study population comprised 45 children (age >6 months and <18 years) showing clinical features of CD. Considering biopsy as the gold standard, the diagnostic parameters (sensitivity, specificity, PPV, NPV) of tTG-IgA and htTG-DGP were calculated with a 95% confidence interval for both tests. To determine the agreement between the two tests, Cohen’s kappa was calculated. A p-value less than 0.05 was considered statistically significant. Results: Out of the study population, 23 (46%) CD patients were in the age group of 3-6 years, while 13 (26%) patients were in the age group of 6-9 years. A total of 24 (53.3%) CD patients were males, and 21 (46.7%) were females. Chronic diarrhoea was the most common clinical feature in 31 (62%) patients. Considering duodenal biopsy as the gold standard, the study results showed that the anti tTG-IgA antibody test had a sensitivity of 91.1%, specificity of 80%, PPV of 97.6, and NPV of 50%. In comparison, the htTG-DGP antibody test had a sensitivity of 95.6%, specificity of 100%, PPV of 100%, and NPV of 71.43%. Conclusion: Currently, tTG-IgA is considered the best CD screening test. However, the inclusion of DGP IgG could increase diagnostic sensitivity, and a Combined IgA/G-DGP/ tTG assay could be even better than tTG-IgA for the diagnosis of childhood CD.

Liver and celiac disease. Review

Celiac hepatitis is a gluten‑dependent liver disease that usually eliminates after 12 months of a strict gluten‑free diet. What is important is that liver histology also improves after a gluten‑free diet. Hypertransaminasemia (in 13—60% of cases) is common at the untreated celiac disease (CD). Conversely, CD presents in 9% of patients with unexplained hypertransaminasemia. Patients with CD have a higher risk of both subsequent liver disease and death caused by cirrhosis compared to the general population. Pathogenetic mechanisms underlying CD, have not been sufficiently studied. The permeability of the intestinal mucosa appears to be considerably higher in patients with CD and hypertransaminasemia than in patients with CD and normal liver tests. The normalization of intestinal permeability and transaminase levels after following a gluten‑free diet demonstrates that this phenomenon is gluten‑dependent. It has been suggested that increased intestinal permeability promotes the admission of toxins, microbial and other antigens, cytokines, and/or other mediators of liver damage into the portal circulation (and hence to the liver). However, liver damage is not usually observed in other intestinal pathologies associated with increased intestinal permeability. A liver biopsy is rarely performed in celiac hepatitis. Mild and/or non‑specific histological changes are observed. Severe liver fibrosis and cirrhosis occur rarely.
 Primary biliary cholangitis and autoimmune hepatitis may be associated with CD. The incidence of CD in patients with primary biliary cholangitis is 1—7%, while the incidence of primary biliary cholangitis in patients with CD is 0.1—3%. CD is revealed in 4—6% of patients with autoimmune hepatitis, both type 1 and type 2. Cases of primary sclerosing cholangitis combined with CD have been reported, too.
 No correlation has been found between CD and chronic hepatitis C. Treatment of hepatitis C with interferon‑a and/or ribavirin may activate occult or latent CD. The incidence of CD in patients with non‑alcoholic fatty liver disease ranges from 3% to 7%.
 The prevalence of CD in patients after liver transplantation for a variety of reasons ranges from 3% to 4.3%.
 Liver‑caused mortality is increased in patients with CD, although the absolute risk of mortality from liver failure is low.

Polysomnographic profile in children diagnosed with celiac disease before starting on a gluten free diet

Study aimsThe study assessed the presence of sleep abnormalities in children who had recently been diagnosed with celiac disease (CD) and not started a gluten free diet (GFD). The children's polysomnographic profiles were also characterized and further compared with healthy children of the same age. MethodsThis prospective cross-sectional study involved 46 pediatric subjects (aged 1–19 years) who had recently been diagnosed with CD and not started a GFD. The control group consisted of 32 healthy children (aged 2–17 years). All children underwent anthropometric measurement, laboratory testing and standard overnight observation with in-laboratory video-PSG. The study and control group were divided into subgroups according to the subjects’ median ages (8.1 years): celiac children aged less than 8.1 years (n = 23) and more than 8.1 years (n = 23), healthy children less aged than 8.1 years (n = 16) and more than 8.1 years (n = 16). ResultsNo significant differences in the basic demographic and anthropometric parameters between the celiac and control group were observed. Significantly prolonged sleep latency (SOL) was evident in the celiac subjects (21.89 ± 20.77 min. vs. 10.99 ± 7.94 min, p = 0.02), with a probability of prolonged SOL of 4.23-fold greater (OR = 4.23; 95 % CI 1.1–16.22) than the healthy controls, especially in the subgroup of older celiac patients. No significant differences in the sleep period time (SPT), total sleep time (TST), wake during sleep (WASO), sleep efficiency (SE) and sleep stage distribution and cyclization were found. The respiratory rates during sleep indicated a significantly greater incidence of the central apnea-hypopnea index (CAHI) (0.54 ± 0.78 vs. 0.18 ± 0.24, p = 0.03) with a 3.16-fold greater probability of pathological CAHI (OR = 3.16; 95 % CI 1.02–9.77) than the control group. An increased incidence of CSA in the subgroup of younger celiac patients compared to younger healthy controls was especially evident. ConclusionsThe findings of our study suggest a difference in sleep architecture and an increased incidence of CSA in children with untreated CD, but additional research is required to verify the results.

Incidentally Discovered Cryptogenic Cirrhosis in a Patient with Untreated Celiac Disease

Celiac disease is a common gastrointestinal disorder that primarily manifests its effects on the small bowel. However, the systemic nature of this condition, especially regarding the liver, has been gaining some recognition in the literature. Mild liver disease is common, but few cases progress to cirrhosis. We present a case of an asymptomatic 78-year-old male with a past medical history of longstanding celiac disease, atrial fibrillation, heart failure with preserved ejection fraction, type 2 diabetes mellitus (DM), and chronic kidney disease stage III who underwent a computed tomography (CT) scan for thoracic aortic aneurysm surveillance. Incidentally, on a CT scan, cirrhotic liver morphology was discovered. Right upper quadrant ultrasound confirmed heterogenous echotexture of the liver, consistent with a diagnosis of cirrhosis. Laboratory work-up demonstrated elevated alkaline phosphatase of 171, tissue transglutaminase (TTG) significantly elevated at > 100, and a negative panel of other chronic liver disease labs, including negative anti-smooth muscle antibody, antimitochondrial antibody, liver kidney microsomal antibody, HFE gene, ceruloplasmin, alpha-1-antitrypsin, and alpha-fetoprotein < 2 ng/mL. The patient was not taking any hepatotoxic medications. Although the patient did have type 2 DM, his hemoglobin A1c was well-controlled at 5.9%, and he had no hyperlipidemia and a normal body mass index, making a metabolic etiology of liver disease less likely. The patient had no significant alcohol use, either. The only patient’s major risk factor for liver disease was his untreated celiac disease, diagnosed in infancy. The patient was instructed to avoid any gluten, alcohol, and other hepatotoxic substances and was subsequently followed by a gastroenterologist. The following case report explores the pathogenesis of celiac-associated liver disease and the effect a gluten-free diet can have on the small bowel and the liver.

Gluten induces rapid reprogramming of natural memory αβ and γδ intraepithelial T cells to induce cytotoxicity in celiac disease.

Celiac disease (CD) is an autoimmune disease in which intestinal inflammation is induced by dietary gluten. The means through which gluten-specific CD4+ T cell activation culminates in intraepithelial T cell (T-IEL)-mediated intestinal damage remain unclear. Here, we performed multiplexed single-cell analysis of intestinal and gluten-induced peripheral blood T cells from patients in different CD states and healthy controls. Untreated, active, and potential CD were associated with an enrichment of activated intestinal T cell populations, including CD4+ follicular T helper (TFH) cells, regulatory T cells (Tregs), and natural CD8+ αβ and γδ T-IELs. Natural CD8+ αβ and γδ T-IELs expressing activating natural killer cell receptors (NKRs) exhibited a distinct TCR repertoire in CD and persisted in patients on a gluten-free diet without intestinal inflammation. Our data further show that NKR-expressing cytotoxic cells, which appear to mediate intestinal damage in CD, arise from a distinct NKR-expressing memory population of T-IELs. After gluten ingestion, both αβ and γδ T cell clones from this memory population of T-IELs circulated systemically along with gluten-specific CD4+ T cells and assumed a cytotoxic and activating NKR-expressing phenotype. Collectively, these findings suggest that cytotoxic T cells in CD are rapidly mobilized in parallel with gluten-specific CD4+ T cells after gluten ingestion.

Expression of transglutaminase 2 in human gut epithelial cells: Implications for coeliac disease.

Formation of complexes between transglutaminase 2 (TG2) and gluten can mechanistically explain why TG2 serves both as B-cell autoantigen and as an enzyme that creates deamidated gluten epitopes in coeliac disease (CeD). A model has been proposed where TG2 released from shed epithelial cells encounters high concentrations of dietary gluten peptides to form these TG2:gluten complexes. In this work we have characterised TG2 protein expression in gut epithelial cells in humans. Western blot analysis, immunofluorescence staining and mass spectrometry in combination with laser capture microdissection to gain spatial resolution were used to characterise TG2 expression in the epithelial cell layer of healthy and coeliac disease affected duodenum. TG2 is expressed in human duodenal epithelial cells, including cells in the apical region that are shed into the gut lumen. In untreated CeD the apical expression of TG2 is doubled. Enzymatically active TG2 is readily released from isolated human intestinal epithelial cells. Shed epithelial cells are a plausible source of pathogenic TG2 enzyme in CeD. Increased epithelial TG2 expression and increased epithelial shedding in active CeD may reinforce action of luminal TG2 in this condition.

Antibody detection by agglutination-PCR (ADAP) assays for the analysis of tissue transglutaminase autoantibodies in celiac disease

Background & aimsTissue transglutaminase autoantibodies (tTGA) are used as diagnostic markers of celiac disease. Different methods have been developed for the detection of tTGA of which enzyme-linked immunosorbent assays (ELISA), radiobinding assays (RBA) and electrochemiluminescence (ECL) assays are the most commonly used. Here we aimed to evaluate a novel antibody detection by agglutination-PCR (ADAP) assay for the detection of tTGA. MethodsIncluded were 126 children with untreated celiac disease (UCD), 64 disease controls (DC), 21 children with potential celiac disease (PCD), and 1501 children from the general population. Tissue TGA were determined using an automated ADAP assay platform and compared with two RBAs for the detection of IgA-tTG and IgG-tTG, respectively. ResultsADAP detected tTGA in 123/126 (97.6%) UCD children compared with 122/126 (96.8%) using RBA-IgA-tTG and RBA-IgG-tTG (p > 0.9999), respectively. Among DC, ADAP detected 5/64 (7.8%) children with tTGA compared with 4/64 (6.3%) with RBA-IgA-tTG (p > 0.9999) and 8/64 (12.5%) with RBA-IgG-tTG (p = 0.5600), respectively. Tissue TGAs were equally detected in children with PCD in both assays. In the general population, 4/1501 (0.3%) were tTGA positive using ADAP compared with 3/1501 (0.2%) for RBA-IgA-tTG and RBA-IgG-tTG (p > 0.9999), respectively. The area under the curves (AUCs) were 0.998 for ADAP, 0.994 for RBA-IgA-tTG, and 0.999 for RBA-IgG-tTG, respectively. ConclusionsNo difference in specificity and sensitivity of tTGA for the diagnosis of celiac disease was reported between ADAP and RBA. ADAP could be recommended as the first-line screening method of larger populations for celiac disease.

The Second Highest Prevalence of Celiac Disease Worldwide: Genetic and Metabolic Insights in Southern Brazilian Mennonites.

Celiac disease (CD), despite its high morbidity, is an often-underdiagnosed autoimmune enteropathy. Using a modified version of the Brazilian questionnaire of the 2013 National Health Survey, we interviewed 604 Mennonites of Frisian/Flemish origin that have been isolated for 25 generations. A subgroup of 576 participants were screened for IgA autoantibodies in serum, and 391 participants were screened for HLA-DQ2.5/DQ8 subtypes. CD seroprevalence was 1:29 (3.48%, 95% CI = 2.16-5.27%) and biopsy-confirmed CD was 1:75 (1.32%, 95% CI = 0.57-2.59%), which is superior to the highest reported global prevalence (1:100). Half (10/21) of the patients did not suspect the disease. HLA-DQ2.5/DQ8 increased CD susceptibility (OR = 12.13 [95% CI = 1.56-94.20], p = 0.003). The HLA-DQ2.5 carrier frequency was higher in Mennonites than in Brazilians (p = 7 × 10-6). HLA-DQ8 but not HLA-DQ2.5 carrier frequency differed among settlements (p = 0.007) and was higher than in Belgians, a Mennonite ancestral population (p = 1.8 × 10-6), and higher than in Euro-Brazilians (p = 6.5 × 10-6). The glutathione pathway, which prevents reactive oxygen species-causing bowel damage, was altered within the metabolic profiles of untreated CD patients. Those with lower serological positivity clustered with controls presenting close relatives with CD or rheumatoid arthritis. In conclusion, Mennonites have a high CD prevalence with a strong genetic component and altered glutathione metabolism that calls for urgent action to alleviate the burden of comorbidities due to late diagnosis.

Gluten-free diet affects fecal small non-coding RNA profiles and microbiome composition in celiac disease supporting a host-gut microbiota crosstalk

ABSTRACT Current treatment for celiac disease (CD) is adhering to a gluten-free diet (GFD), although its long-term molecular effects are still undescribed. New molecular features detectable in stool may improve and facilitate noninvasive clinical management of CD. For this purpose, fecal small non-coding RNAs (sncRNAs) and gut microbiome profiles were concomitantly explored in CD subjects in relation to strict (or not) GFD adherence over time. In this observational study, we performed small RNA and shotgun metagenomic sequencing in stool from 63 treated CD (tCD) and 3 untreated subjects as well as 66 sex- and age-matched healthy controls. tCD included 51 individuals on strict GFD and with negative transglutaminase (TG) serology (tCD-TG-) and 12 symptomatic with not strict/short-time of GFD adherence and positive TG serology (tCD-TG+). Samples from additional 40 healthy adult individuals and a cohort of 19 untreated pediatric CD subjects and 19 sex/age matched controls were analyzed to further test the outcomes. Several miRNA and microbial profiles were altered in tCD subjects (adj. p < .05). Findings were validated in the external group of adult controls. In tCD-TG-, GFD duration correlated with five miRNA levels (p < .05): for miR-4533-3p and miR-2681-3p, the longer the diet adherence, the less the expression differed from controls. tCD-TG+ and untreated pediatric CD patients showed a similar miRNA dysregulation. Immune-response, trans-membrane transport and cell death pathways were enriched in targets of identified miRNAs. Bifidobacterium longum, Ruminococcus bicirculans, and Haemophilus parainfluenzae abundances shifted (adj. p < .05) with a progressive reduction of denitrification pathways with GFD length. Integrative analysis highlighted 121 miRNA-bacterial relationships (adj. p < .05). Specific molecular patterns in stool characterize CD subjects, reflecting either the long-term GFD effects or the gut inflammatory status, in case of a not strict/short-time adherence. Our findings suggest novel host-microbial interplays and could help the discovery of biomarkers for GFD monitoring over time.

A Clinical Investigation on ADHD-Traits in Childhood Celiac Disease

Objective: There are no definitive results about either the presence of exact comorbidity between celiac disease (CD) and attention-deficit/hyperactivity disorders (ADHD) or etiology. We intend to screen ADHD-related cognitive and behavioral traits in children with biopsy-proven CD and investigate the possible association of these traits with certain vitamin levels, body-mass index, and gluten-free diet (GFD) compliance. Method: A total of 85 children with biopsy-proven CD (the ages of 8–18 years) were compared with age and sex-matched 72 healthy controls in terms of demographics, psychiatric symptoms, certain vitamin levels, and anthropometric measurements. Results: ADHD-like cognitive issues, such as inattention and learning difficulties, as well as psychosomatic symptoms and poor prosocial behavior, were all associated with GFD noncompliance in childhood CD. Conclusion: Untreated CD may predispose to ADHD-resembling symptoms. Physicians should be aware of the probability of ADHD misdiagnosing due to ADHD-resembling cognitive and behavioral traits in untreated CD.