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Background: Studies have indicated an association between cesarean section (CS), especially elective CS, and an increased risk of celiac disease (CD), but the conclusions of other studies are contradictory. The primary aim of this study (CD-deliver-IT) was to evaluate the rate of CS in a large population of CD patients throughout Italy.  METHODS: This national multicenter retrospective study was conducted between December 2020 and November 2021. The coordinating center was the Pediatric Gastroenterology and Liver Unit of Policlinico Umberto I, Sapienza, University of Rome, Lazio, Italy. Eleven other referral centers for CD have participated to the study. Each center has collected data on mode of delivery and perinatal period of all CD patients referring to the center in the last 40 years., Results: Out of 3,259 CD patients recruited in different Italian regions, data on the mode of delivery were obtained from 3,234. One thousand nine hundred forty-one (1,941) patients (60%) were born vaginally and 1,293 (40%) by CS (8.3% emergency CS, 30.1% planned CS, 1.5% undefined CS). A statistically significant difference was found comparing median age at time of CD diagnosis of patients who were born by emergency CS (4 years, CI 95% 3.40-4.59), planned CS (7 years, CI 95% 6.02-7.97) and vaginal delivery (6 years, CI 95% 5.62-6.37) (log rank p < 0.0001)., Conclusions: This is the first Italian multicenter study aiming at evaluating the rate of CS in a large population of CD patients through Italy. The CS rate found in our CD patients is higher than rates reported in the general population over the last 40 years and emergency CS seems to be associated with an earlier onset of CD compared to vaginal delivery or elective CS in our large nationwide retrospective cohort. This suggests a potential role of the mode of delivery on the risk of developing CD and on its age of onset, but it is more likely that it works in concert with other perinatal factors. Further prospective studies on other perinatal factors potentially influencing gut microbiota are awaited in order to address heavy conflicting evidence reaming in this research field., (© 2024. The Author(s).)

Importance: The extent and factors associated with risk of diagnostic delay in pediatric celiac disease (CD) are poorly understood., Objectives: To investigate the diagnostic delay of CD in childhood, and to assess factors associated with this delay., Design, Setting, and Participants: Multicenter, retrospective, cross-sectional study (2010-2019) of pediatric (aged 0-18 years) patients with CD from 13 pediatric tertiary referral centers in Italy. Data were analyzed from January to June 2023., Main Outcomes and Measures: The overall diagnostic delay (ie, the time lapse occurring from the first symptoms or clinical data indicative of CD and the definitive diagnosis), further split into preconsultation and postconsultation diagnostic delay, were described. Univariable and multivariable linear regression models for factors associated with diagnostic delay were fitted. Factors associated with extreme diagnostic delay (ie, 1.5 × 75th percentile) and misdiagnosis were assessed., Results: A total of 3171 patients with CD were included. The mean (SD) age was 6.2 (3.9) years; 2010 patients (63.4%) were female; and 10 patients (0.3%) were Asian, 41 (1.3%) were Northern African, and 3115 (98.3%) were White. The median (IQR) overall diagnostic delay was 5 (2-11) months, and preconsultation and postconsultation diagnostic delay were 2 (0-6) months and 1 (0-3) month, respectively. The median (IQR) extreme overall diagnostic delay (586 cases [18.5%]) was 11 (5-131) months, and the preconsultation and postconsultation delays were 6 (2-120) and 3 (1-131) months, respectively. Patients who had a first diagnosis when aged less than 3 years (650 patients [20.5%]) showed a shorter diagnostic delay, both overall (median [IQR], 4 [1-7] months for patients aged less than 3 years vs 5 [2-12] months for others) and postconsultation (median [IQR], 1 [0-2] month for patients aged less than 3 years vs 2 [0-4] months for others). A shorter delay was registered in male patients, both overall (median [IQR], 4 [1-10] months for male patients vs 5 [2-12] months for female patients) and preconsultation (median [IQR], 1 [0-6] month for male patients vs 2 [0-6] months for female patients). Family history of CD was associated with lower preconsultation delay (odds ratio [OR], 0.59; 95% CI, 0.47-0.74) and lower overall extreme diagnostic delay (OR, 0.75; 95% CI, 0.56-0.99). Neurological symptoms (78 patients [21.5%]; OR, 1.35; 95% CI, 1.03-1.78), gastroesophageal reflux (9 patients [28.1%]; OR, 1.87; 95% CI, 1.02-3.42), and failure to thrive (215 patients [22.6%]; OR, 1.62; 95% CI, 1.31-2.00) showed a more frequent extreme diagnostic delay. A previous misdiagnosis (124 patients [4.0%]) was more frequently associated with gastroesophageal reflux disease, diarrhea, bloating, abdominal pain, constipation, fatigue, osteopenia, and villous atrophy (Marsh 3 classification)., Conclusions and Relevance: In this cross-sectional study of pediatric CD, the diagnostic delay was rather short. Some factors associated with risk for longer diagnostic delay and misdiagnosis emerged, and these should be addressed in future studies.

Background and Aims: We have identified a decreased abundance of microbial species known to have a potential anti-inflammatory, protective effect in subjects that developed Celiac Disease (CeD) compared to those who did not. We aim to confirm the potential protective role of one of these species, namely Bacteroides vulgatus, and to mechanistically establish the effect of bacterial bioproducts on gluten-dependent changes on human gut epithelial functions., Methods: We identified, isolated, cultivated, and sequenced a unique novel strain (20220303-A2) of B. vulgatus found only in control subjects. Using a human gut organoid system developed from pre-celiac patients, we monitored epithelial phenotype and innate immune cytokines at baseline, after exposure to gliadin, or gliadin plus B. vulgatus cell free supernatant (CFS)., Results: Following gliadin exposure, we observed increases in epithelial cell death, epithelial monolayer permeability, and secretion of pro-inflammatory cytokines. These effects were mitigated upon exposure to B. vulgatus 20220303-A2 CFS, which had matched phenotype gene product mutations. These protective effects were mediated by epigenetic reprogramming of the organoids treated with B. vulgatus CFS., Conclusions: We identified a unique strain of B. vulgatus that may exert a beneficial role by protecting CeD epithelium against a gluten-induced break of epithelial tolerance through miRNA reprogramming., Impact: Gut dysbiosis precedes the onset of celiac disease in genetically at-risk infants. This dysbiosis is characterized by the loss of protective bacterial strains in those children who will go on to develop celiac disease. The paper reports the mechanism by which one of these protective strains, B. vulgatus, ameliorates the gluten-induced break of gut epithelial homeostasis by epigenetically re-programming the target intestinal epithelium involving pathways controlling permeability, immune response, and cell turnover., (© 2024. The Author(s).)

Objectives: Increased intestinal permeability seems to be a key factor in the pathogenesis of autoimmune diseases, including celiac disease (CeD). However, it is unknown whether increased permeability precedes CeD onset. This study's objective was to determine whether intestinal permeability is altered before celiac disease autoimmunity (CDA) in at-risk children. We also examined whether environmental factors impacted zonulin, a widely used marker of gut permeability., Methods: We evaluated 102 children in the CDGEMM study from 2014-2022. We included 51 CDA cases and matched controls, who were enrolled for 12 months or more and consumed gluten. We measured serum zonulin from age 12 months to time of CDA onset, and the corresponding time point in controls, and examined clinical factors of interest. We ran a mixed-effects longitudinal model with dependent variable zonulin., Results: Children who developed CDA had a significant increase in zonulin in the 18.3 months (range 6-78) preceding CDA compared to those without CDA (slope differential = β = 0.1277, 95% CI: 0.001, 0.255). Among metadata considered, zonulin trajectory was only influenced by increasing number of antibiotic courses, which increased the slope of trajectory of zonulin over time in CDA subjects (P = .04)., Conclusions: Zonulin levels significantly rise in the months that precede CDA diagnosis. Exposure to a greater number of antibiotic courses was associated with an increase in zonulin levels in CDA subjects. This suggests zonulin may be used as a biomarker for preclinical CeD screening in at-risk children, and multiple antibiotic courses may increase their risk of CDA by increasing zonulin levels., (Copyright © 2024 by the American Academy of Pediatrics.)

Aims: To evaluate the relationship between SARS-CoV-2 infection and autoimmunity in type 1 diabetes (T1D) and SARS-CoV-2 antibodies frequency at diagnosis of T1D during pandemic., Methods: The presence of T1D-specific autoimmunity was evaluated in a cohort of 99 children and adolescents without diabetes that contracted SARS-CoV-2 infection. Moreover, the frequency of IgM- and IgG-SARS-CoV-2 antibodies was evaluated in 41 newly diagnosed T1D patients not yet vaccinated against SARS-CoV-2 disease, collected during the pandemic, compared to healthy subjects (CTRL)., Results: None of the 99 patients that contracted SARS-CoV-2 infection during the pandemic period was found positive for T1D autoantibodies. The frequency of SARS-CoV-2 antibodies was not significantly different in patients newly diagnosed with T1D (12.2%), compared with CTRL (8.4%). Among SARS-CoV-2 antibody positive T1D patients, 80% were target of diabetes autoantibodies and 60% had another concomitant autoimmune disease. Among the CTRL subjects positive for SARS-CoV-2Abs (n = 10), none was found positive for T1D autoantibodies., Conclusions: The results of the present study do not confirm, at least in the short term, a role of COVID-19 as a potential trigger of T1D autoimmunity and do not provide evidence of an increased frequency of SARS-CoV-2 antibodies in newly diagnosed T1D patients in comparison with healthy population., (© 2023. The Author(s).)

Background: Most evidence on the coronavirus disease 2019 (COVID-19) pandemic, has been obtained from web- or telephone-based surveys. In particular, few laboratory data, often incomplete, have been reported on the frequency of COVID-19-related serology at celiac disease (CD) diagnosis or on the effects of COVID-19 on the development of CD-specific autoimmunity., Objectives: The objective of this retrospective cross-sectional case/control study was to: (1) evaluate the frequency of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in 78 children and adolescents at CD diagnosis (CD, 44 females, median age 7.4 years); (2) evaluate the frequency of IgA-anti-transglutaminase antibodies (IgA-tTGAbs) in 97 nonceliac patients (50 females, median age 9.0 years) who contracted SARS-CoV-2 infection during the pandemic (February-April 2021). As a control (CTRL) group, we analyzed 141 healthy subjects (79 females, median age 9.8 years) enrolled during the pandemic., Methods: SARS-CoV-2 IgM- and IgG-antibodies were detected by chemiluminescent microparticle immunoassays. IgA-tTGAbs were detected by a fluid-phase radioimmunoassay., Results: Six out of 78 (7.7%) CD patients tested positive for SARS-CoV-2Abs, with a frequency not significantly different from CTRL subjects (9.2%). None of the 97 nonceliac COVID-19 patients tested positive for IgA-tTG antibodies., Conclusion: These 2 distinct research approaches showed (1) similar frequencies of SARS-CoV-2 immunoreactivities in CD patients and CTRL subjects and, (2) no ability of SARS-CoV-2 to induce a CD-specific immune response, at least in the 3-4 months following SARS-CoV-2 infection., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background: Celiac disease is a common lifelong disorder. Recent studies indicate that the number of clinically detected cases has increased over the last decades, however little is known about changes in the prevalence and the detection rate of celiac disease., Aim: To evaluate the current prevalence and detection rate of celiac disease in Italy by a multicenter, mass screening study on a large sample of school-age children., Methods: children aged 5-11 years were screened at school by HLA-DQ2 and -DQ8 determination on a drop of blood in six Italian cities; total serum IgA and IgA anti-transglutaminase were determined in children showing HLA-DQ2 and/or -DQ8 positivity. Diagnosis of celiac disease was confirmed according to the European guidelines., Results: 5994 children were eligible, 4438 participated and 1873 showed predisposing haplotypes (42.2%, 95% CI=40.7-43.7). The overall prevalence of celiac disease was 1.65% (95% CI, 1.34%-2.01%). Only 40% of celiac children had been diagnosed prior to the school screening. Symptoms evoking celiac disease were as common in celiac children as in controls., Conclusion: In this multicenter study the prevalence of celiac disease in school-age Italian children was one of the highest in the world. Determination of HLA predisposing genotypes is an easy and fast first-level screening test for celiac disease. Without a mass screening strategy, 60% of celiac patients remain currently undiagnosed in Italy., Competing Interests: Conflict of interest Prof Carlo Catassi has served as scientific consultant for Dr. Schaer Food and NOOS s.r.l. The other co-authors have no conflict to declare., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Celiac disease (CD) is characterized by elevated serum titers of autoantibodies IgA anti-tissue transglutaminase 2 (TGA-IgA) and IgA anti-endomysial (EMA), with small bowel mucosa atrophy. We evaluated age differences between CD children exhibiting variable antibody titers at diagnosis., Methods: CD children diagnosed between January 2014 and June 2019, according to 2012 ESPGHAN guidelines were studied. All had EMA and TGA-IgA measurements, while a proportion of them underwent esophagogastroduodenoscopy (EGD). Patients were grouped based on serum TGA-IgA titers normalized to the upper limit of normal (ULN) and differences in median age (years) assessed by analysis of variance (ANOVA) and creation of orthogonal contrasts., Results: CD was diagnosed in 295 subjects (median age: 4.4 [IQR: 2.60-8.52]) with a biopsy sparing protocol (high titer: ≥ 10xULN) and in 204 by EGD biopsy. Of the latter, 142 (median age: 8.5 [IQR: 5.81-11.06]) and 62 (median age: 9.5 [IQR: 6.26-12.76]) had a low (< 5xULN) and a moderate (≥ 5 < 10xULN) TGA-IgA titer, respectively. Potential CD was diagnosed in 20 patients (median age: 3.6 [IQR: 2.47-6.91]). The median age was significantly lower in the no-biopsy group (ANOVA: F (3, 516)  = 25.98, p < .001) than in low- and moderate titer groups (p < 0.0001), while there was no statistical difference between biopsy-sparing and potential CD groups., Conclusion: CD patients with greatly elevated antibody titers (≥ 10xULN) were diagnosed at an earlier age than those with lower titers. This may indicate that an increase in TGA-IgA is independent of age and suggests a polarization of autoimmunity in younger individuals with higher serum antibody levels., (© 2023. The Author(s).)

Introduction: The purpose of this study was to identify possible serum biomarkers predicting celiac disease (CD) onset in children at risk., Methods: A subgroup from an ongoing, international prospective study of children at risk of CD was classified according to an early trajectory of deamidated gliadin peptides (DGPs) immunoglobulin (Ig) G and clinical outcomes (CD, potential CD, and CD autoimmunity)., Results: Thirty-eight of 325 children developed anti-tissue transglutaminase IgA antibody (anti-tTG IgA) seroconversion. Twenty-eight of 38 children (73.6%) showed an increase in anti-DGPs IgG before their first anti-tTG IgA seroconversion., Discussion: Anti-DGPs IgG can represent an early preclinical biomarker predicting CD onset in children at risk., (Copyright © 2023 by The American College of Gastroenterology.)

Background: Intestinal transglutaminase (TG2) IgA deposits represent early marker of coeliac disease (CeD) and can predict the evolution towards intestinal atrophy., Aims: To validate a double immunohistochemistry method for the determination of intestinal TG2 IgA deposits on formalin-fixed paraffin-embedded biopsies., Methods: Immunohistochemistry was tested on: 1) children with overt CeD [persistently positive serum IgA anti-tissue transglutaminase type 2 (TGA-IgA) with moderate or low titer, and histological findings of CeD]; 2) potential CeD (persistently positive serum TGA-IgA and normal intestinal mucosa) and 3) controls (negative serum TGA-IgA and normal intestinal mucosa)., Results: Samples from 61 children were analyzed (32 overt CeD, 14 potential CeD, and 15 controls). Deposits appeared as focal, multifocal, or confluent extracellular foci of red and brown staining colocalization in the sub-epithelium and around mucosal vessels. Deposits were present in all 32 children with overt CeD and in 9/14 potential CeD. Deposits were never observed in the 15 controls. Patients with higher serum level of TGA-IgA and with mucosal atrophy showed mostly a multifocal/diffuse pattern of deposits distribution. The bulb appeared most severely involved. In potential CeD deposits showed mainly a focal distribution., Conclusion: Our results indicate double immunohistochemistry as promising diagnostic tool to improve diagnosis of CeD., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2021 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Whether the diagnostic approach for celiac disease (CD) can really affect quality of life (QoL) and dietary compliance remains controversial. Aims: This study aimed to evaluate QoL and compliance to gluten-free diet (GFD) in adolescents/young adults diagnosed with CD through a screening strategy during childhood compared to age-matched CD patients diagnosed by case-finding and to assess whether follow-up at a referral center for CD influences compliance and QoL. Materials and Methods: Thirty-seven CD patients who were diagnosed by screening programs (SC-group) and 38 age-matched CD patients diagnosed due to symptoms (CF-group) were enrolled. Patients were asked to answer a questionnaire on QoL, dietary compliance, and follow-up care for CD. Results: Twenty-nine patients of the SC-group (median age 18.0 years, interquartile range [IQR] 16.0-19.0) and 31 patients of the CF-group (median age 17.0 years, IQR 15.5-18.0) completed the questionnaire. No significant difference relating adherence to the GFD and QoL was shown between the two groups. The majority (93.5%) of CF-group regularly had annual follow-up at a referral center compared to 37.9% of the SC-group ( p < 0.001). Conclusion: The diagnostic strategy does not seem to impact QoL and dietary compliance. However, implementation of follow-up might still be necessary for patients identified through screening., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Iorfida, Valitutti, Vestri, Di Rocco, Cucchiara, Lubrano and Montuori.)

Significant progress has been made in peptide self-assembly over the past two decades; however, the in situ cross-linking of self-assembling peptides yielding better performing nanomaterials is still in its infancy. Indeed, self-assembling peptides (SAPs), relying only on non-covalent interactions, are mechanically unstable and susceptible to solvent erosion, greatly hindering their practical application. Herein, drawing inspiration from the biological functions of tyrosine, we present a photo-cross-linking approach for the in situ cross-linking of a tyrosine-containing LDLK12 SAP. This method is based on the ruthenium-complex-catalyzed conversion of tyrosine to dityrosine upon light irradiation. We observed a stable formation of dityrosine cross-linking starting from 5 minutes, with a maximum peak after 1 hour of UV irradiation. Furthermore, the presence of a ruthenium complex among the assembled peptide bundles bestows unusual fluorescence intensity stability up to as high as 42 °C, compared to the bare ruthenium complex. Also, due to a direct deprotonation-protonation process between the ruthenium complex and SAP molecules, the fluorescence of the photo-cross-linked SAP is capable of exhibiting "off-on-off-on" luminescence switchable from acid to basic pH. Lastly, we showed that the photo-cross-linked hydrogel exhibited enhanced mechanical stability with a storage modulus of ∼26 kPa, due to the formation of a densely entangled fibrous network of SAP molecules through dityrosine linkages. As such, this ruthenium-mediated photo-cross-linked SAP hydrogel could be useful in the design of novel tyrosine containing SAP materials with intriguing potential for biomedical imaging, pH sensing, photonics, soft electronics, and bioprinting., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background: A growing body of evidence supports the intestinal trophism of SARS-CoV-2, with ciliated cells and intestinal enterocytes being target cells because of the high expression of ACE2 and TMPRSS2. Indeed, COVID-19 promotes a "cytokine storm" in the intestinal mucosa: the resulting epithelial damage leads to increased barrier permeability, allowing the passage of gliadin in the intestinal lamina., Methods: Based on current literature, we hypothesize the role of COVID-19 as a potential trigger factor for celiac disease in predisposed patients., Conclusions: Genetically predisposed patients could be more likely to develop celiac disease following SARS-CoV-2 infection, making COVID-19 a candidate culprit for a potential outbreak of celiac disease in the forthcoming future., (© 2021 John Wiley & Sons Ltd.)

Objectives: While the algorithm to diagnose celiac disease (CD) in children with elevated anti-transglutaminase IgA (TGA-IgA) titers (>10 times upper limit of normal, ULN) is well defined, the management of children with low TGA-IgA values represents a clinical challenge. We aimed to identify the diagnostic value of persistently low positive TGA-IgA titers in predicting CD in children., Methods: We retrospectively analyzed children with symptoms or signs of CD, not eligible for a no-biopsy approach. We included children with at least 2 TGA-IgA measurements, endomysial antibody (EMA) assessment and esophagogastroduodenoscopy with biopsies. TGA-IgA values were provided as multiples of ULN. Patients were classified in groups according to median TGA-IgA values: A (TGA-IgA>1 ≤ 5 × ULN; defined as "low-positive"), B (TGA-IgA > 5 < 10 × ULN; "moderate-positive"), and C (controls)., Results: Data of 281 children were analyzed. Of 162 children in group A, CD was diagnosed in 142 (87.7%), whereas normal duodenal mucosa was found in 20. In group B, all 62 children (100%) received a CD diagnosis. Group C included 57 controls. EMA were undetectable in 31 (15%) of mucosal atrophy cases. On the receiver-operating characteristic curve (area under the curve = 0.910), a mean value of 1.7 ULN showed a sensitivity of 81.4% and specificity of 81.8% to predict mucosal damage., Conclusions: Repeated low or moderate TGA-IgA values (<5 ULN or <10 ULN) are good predictors of a CD diagnosis. Symptomatic children with persistently low positive TGA-IgA titers should undergo esophagogastroduodenoscopy regardless of their EMA status., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Patients with celiac disease can have a low rate of protective hepatitis B (HBV) antibody titers after vaccination. We aimed to evaluate the HBV seroconversion in celiac disease (CD) children at the time of diagnosis as well as to identify the presence of possible predictive factors. Celiac disease children were prospectively enrolled and tested for antibodies against the S protein of HBV (HBsAg) at time of diagnosis between January 2009 and February 2020. Based on the serologic response to the vaccine, "responders" and "non-responders" were identified. Statistical analysis has been performed through R statistical software (3.5.1 version, R core Team) Of 96 CD children evaluated, 41.7% (n = 40) showed non-protective or absent antibody titers against HBV. Elevated IgA-antibodies against transglutaminase 2 (TGA-IgA) values and older age at diagnosis were associated with an absent seroconversion to HBV vaccine, while presenting symptoms were not significant. An elevated prevalence of absent seroconversion to HBV vaccine exists in this cohort of CD patients at the time of disease diagnosis. Elevated TGA-IgA titers and older age at diagnosis seem to negatively predict seroconversion. Further studies are needed to identify the real profile of "non-responders", aiming to organize surveillance and eventual revaccination strategy.

Objectives: Recent guidelines for celiac disease have allowed a biopsy-free approach in endomysial antibodies (EMAs) positive children with high antitransglutaminase (TGA-IgA) titer [>10 time upper limit of normal (ULN)]. Esophagogastroduodenoscopy is still necessary for diagnosis in children with lower title. Because elective pediatric endoscopy has been substantially shouted down during coronavirus disease (COVID-19) pandemic, many children remained undiagnosed - and therefore untreated - for a long time. We aimed to analyze the feasibility and accuracy of a biopsy-free approach in suspected celiac disease children with TGA-IgA values <10 ULN to facilitate the diagnostic process by avoiding endoscopy., Methods: In this study cohort, we retrospectively analyzed all biopsy-confirmed diagnosis of celiac disease in our center (between 2014 and 2019). The positive predictive value (PPV) of TGA-IgA titers between 5 and 10 ULN and positive EMA in diagnosing celiac disease were determined. Mucosal atrophy and resolution of symptoms after gluten-free diet (GFD) were considered to confirm initial diagnosis., Results: Of 430 celiac disease patients (F: 274; mean age 7.54 years) diagnosed by endoscopy, 84 (F: 46; mean age 8 years) with TGA-IgA between 5 and 10 ULN and positive EMA were identified. The PPV of TGA-IgA between 5 and 10 ULN and positive EMA was 0.93 (95% confidence interval 0.90-0.96). All these children had a symptom resolution and antibodies normalization after GFD., Conclusion: During the COVID-19 outbreak, a temporarily reduction of the TGA-IgA threshold for biopsy-sparing approach seems feasible in EMA positive children with TGA-IgA between 5 and 10 ULN.

Background: Celiac disease (CD) is an autoimmune digestive disorder that occurs in genetically susceptible individuals in response to ingesting gluten, a protein found in wheat, rye, and barley. Research shows that genetic predisposition and exposure to gluten are necessary but not sufficient to trigger the development of CD. This suggests that exposure to other environmental stimuli early in life, e.g., cesarean section delivery and exposure to antibiotics or formula feeding, may also play a key role in CD pathogenesis through yet unknown mechanisms. Here, we use multi-omics analysis to investigate how genetic and early environmental risk factors alter the development of the gut microbiota in infants at risk of CD., Results: Toward this end, we selected 31 infants from a large-scale prospective birth cohort study of infants with a first-degree relative with CD. We then performed rigorous multivariate association, cross-sectional, and longitudinal analyses using metagenomic and metabolomic data collected at birth, 3 months and 6 months of age to explore the impact of genetic predisposition and environmental risk factors on the gut microbiota composition, function, and metabolome prior to the introduction of trigger (gluten). These analyses revealed several microbial species, functional pathways, and metabolites that are associated with each genetic and environmental risk factor or that are differentially abundant between environmentally exposed and non-exposed infants or between time points. Among our significant findings, we found that cesarean section delivery is associated with a decreased abundance of Bacteroides vulgatus and Bacteroides dorei and of folate biosynthesis pathway and with an increased abundance of hydroxyphenylacetic acid, alterations that are implicated in immune system dysfunction and inflammatory conditions. Additionally, longitudinal analysis revealed that, in infants not exposed to any environmental risk factor, the abundances of Bacteroides uniformis and of metabolite 3-3-hydroxyphenylproprionic acid increase over time, while those for lipoic acid and methane metabolism pathways decrease, patterns that are linked to beneficial immunomodulatory and anti-inflammatory effects., Conclusions: Overall, our study provides unprecedented insights into major taxonomic and functional shifts in the developing gut microbiota of infants at risk of CD linking genetic and environmental risk factors to detrimental immunomodulatory and inflammatory effects. Video Abstract.

Objective: Almost 6% of celiac disease (CD) patients at diagnosis are positive for at least one of the main pancreatic islet autoantibodies that characterize type 1 diabetes (T1D). Few information, dated back to almost two decades ago, exist as to whether a gluten-free diet (GFD) could reduce the islet-specific autoimmunity detected in patients at CD diagnosis. Aim of the study was to evaluate the impact of GFD on 31 patients who presented islet-specific autoimmunity at CD diagnosis., Methods: CD patient sera collected at diagnosis and throughout the GFD were analyzed for the main humoral autoantibodies so far identified in T1D, directed against one or more among insulin, glutamic-acid decarboxylase, tyrosine-phosphatase 2, and zinc cation-efflux transporter autoantigens., Results: GFD (median duration 39 months) was associated to a decrease or disappearance of the islet-specific autoantibodies in 71% of CD patients. Almost 80% of the patients who became autoantibody-negative during the GFD were positive for only one of the islet-specific autoimmune markers at CD diagnosis, with none of them developing diabetes. Conversely, 80% of the CD patients positive at diagnosis for ≥2 islet-specific autoantibodies were still positive after more than two years of GFD, with 25% of them developing T1D., Conclusions: Various factors appear to influence, individually or in combination, the effects of the GFD on pancreatic islet-specific autoimmune response detected at CD diagnosis. These factors include the number of diabetes autoantibodies found at CD diagnosis, the adherence to the GFD, its duration and an asymptomatic clinical presentation of CD., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: No data are available on the frequency of organ-specific humoral autoimmunity at diagnosis of adult celiac disease (CD). Aim: To evaluate the humoral immunoreactivities specific of type 1 diabetes (T1D), thyroid (THD), atrophic-gastritis (AG) and Addison's (AD) diseases in 92 adult CD patients at diagnosis and 237 adult healthy subjects (CTRL). Methods: T1D, THD and AD specific autoantibodies were analyzed by radioimmunoprecipitation assays. AG autoantibodies were detected by enzyme-linked immunosorbent assay. Results: Of 92 CD patients, 31.5% were positive for at least one of the organ-specific autoantibodies investigated ( p  < .0001 vs CTRL). Thyroid, diabetes, gastric and adrenal-autoantibodies, that increase with age at diagnosis, were detected in 12.0%, 10.9%, 10.9%, 2.2% of CD patients, respectively. Gastric- and diabetes- rather than thyroid- and adrenal-autoimmunity seem to be specifically related to presence of CD. Conclusions: One third of adult CD patients at diagnosis is target of at least one organ-specific autoantibody. A systematic organ-specific autoantibody screening in these patients might be of value to promptly identify, prevent or treat the relative diseases.

Background and Aims: Neurotensin (NT) is a gut hormone secreted by specific endocrine cells scattered throughout the epithelial layer of the small intestine, which has been identified as an important mediator in several gastrointestinal functions and disease conditions. Its potential involvement in celiac disease (CD) has been investigated, but there are conflicting findings. The aim of this study was to evaluate serum NT levels in children with CD at diagnosis, compared to a control group, and to investigate whether NT correlated in CD patients with symptoms, antibody response, and intestinal mucosal damage. Materials and Methods . Children (1-16 years old) undergoing gastrointestinal endoscopy for CD or for other clinical reasons were included in this study. Patients with CD diagnosed according to the 2012 European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) guidelines without biopsy were also recruited. Fasting serum samples were analyzed for NT levels using ELISA. Logistic regression, Wilcoxon rank sum, and Spearman's rank tests were used for statistical analysis., Results: Thirty children (18 females, 2.2-15.9 years old) were enrolled. Of 25 patients who underwent endoscopy, 9 were CD patients, 13 were controls, and 3 were excluded due to nonspecific inflammation at duodenal biopsy. CD was diagnosed in 5 patients without biopsy. NT median was higher in CD patients compared to controls (13.25 (IQR 9.4-17.5) pg/ml vs. 7.8 (IQR 7.6-10) pg/ml; p = 0.02). No statistically significant association between NT and clinical, serological, or histological data of CD was observed in this CD cohort., Conclusions: To our knowledge, this is the first study that evaluates NT in CD children from Italy. Results show that NT is higher in the serum of CD children at diagnosis compared to controls. However, larger-scale studies are required to validate these findings. Whether serum NT levels can be an adjunctive marker for pediatric CD remains currently elusive., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this article., (Copyright © 2020 Donatella Iorfida et al.)

Potential celiac disease (PCD) is defined by the presence of positive serum antibodies, HLA-DQ2/DQ8 haplotypes, and a normal small intestinal mucosa (Marsh grade 0-1). This condition occurs in one-fifth of celiac disease (CD) patients and usually represents a clinical challenge. We reviewed genetic, histologic, and clinical features of this specific condition by performing a systematic search on MEDLINE, Embase, and Scholar database. Accordingly, we identified different genetic features in patients with PCD compared to the classical forms. Frequently, signs of inflammation (deposits of immunoglobulin A (IgA) and/or increased number of intraepithelial lymphocytes) can be clearly identify in the mucosa of PCD patients after an accurate histological assessment. Finally, the main challenge is represented by the treatment: the gluten-free diet should be considered only in the presence of gluten-dependent symptoms in both children and adults. What is known : (i) potential celiac disease (PCD) occurs in one-fifth of all celiac diseases (CD), and (ii) despite the absence of classical lesions, clear signs of inflammation are often detectable. What is new : (i) patients with PCD show different genetic features, and (ii) the presence of gluten-dependent symptoms is the main determinant to initiate the gluten-free diet, after a complete diagnostic work-up., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2019 Chiara Maria Trovato et al.)

Celiac disease (CD) is a systemic, chronic immune-mediated disorder elicited by gluten and related prolamines in genetically susceptible subjects. Main manifestations of CD involve the digestive tract; however, a growing body of evidence supports the theory that symptoms may occur in every part of the body. It is known that some patients with CD can be asymptomatic, and additionally, the incidence of "nonclassical" CD with extraintestinal presentation is apparently increasing. We aimed to perform a thorough review of existing evidence for neurological manifestations of CD, providing an up-to-date description of prevalence and examining the pathogenetic mechanisms possibly involved. Neurological presentations are rare in children but as many as 36% of adult patients present with neurological findings. With severe malnutrition after progression of CD, different vitamin deficiencies may develop. Such problems can in turn overlap with previous neurological abnormalities including ataxia, epilepsy, neuropathy, dementia, and cognitive disorders. Here, the most prevalent clinical manifestations in adults and children have been discussed in further detail. Further research is needed to achieve a complete understanding of the nervous system involvement in CD, but clinicians should always remember that neurological and psychiatric symptoms might be part of the CD spectrum of manifestations., (Copyright © 2019. Published by Elsevier Inc.)

In recent years, the role of atopic dermatitis epidermal skin barrier defects in inducing a transcutaneous allergic sensitization is highly debated, possibly explaining why some children with eczema are sensitized to foods they have never eaten. In our specific situation, the association between coeliac disease and wheat allergy might be particularly harmful owing to unavoidable strict food avoidance. We describe the case of a young boy affected by coeliac disease who, after an occasional unexpected ingestion of gluten, experienced a complete anaphylactic reaction characterized by urticarial, labial angioedema, wheezing, and hypotension. To better investigate the state of allergic sensitization to wheat in our patient, we then performed the component resolved diagnosis, which showed Tri a19 2 kU/l and Tri a14 0.3 kU/l. These results demonstrated the association of IgE-mediated allergy to wheat and coeliac disease. The natural course of specific IgE in allergic patients who are on a food-free diet needs further investigation, such as the possible influence that the increasing popularity of gluten-free diets may have on the epidemiology of wheat allergy in westernized societies. National and International registers of cases of anaphylaxis may improve the still limited knowledge in this field. The final message of our contribution is that the decision to eliminate a food should to take into account a patient's awareness of possible consequences.

Background: Celiac disease (CD) is a gluten-related immunological disorder resulting in inflammatory enteropathy., Aims: We assessed a stool marker of intestinal inflammation, the HMGB1 protein, in children with CD on a gluten free diet (GFD) at baseline and at follow up (FU)., Methods: Thirty-nine children were investigated at diagnosis and at FU. Traditional serum markers of CD (anti-transglutaminase and anti-endomysial antibodies) and faecal HMGB1 (by enzyme-linked immunosorbent assay and immunoblotting) were tested., Results: There was a marked increase at baseline in both serum anti-transglutaminase IgA (anti-tTGAs) and faecal HMGB1; the latter being undetectable in controls. A strong correlation occurred between the two markers. At 12-month FU in 24 patients on GFD, HMGB1 decreased in all subjects, yet still being detectable in six children: high anti-tTGAs where evident in three, while the three with normal anti-tTGAs were complaining of intestinal symptoms and reported a low GFD adherence., Conclusions: Faecal HMGB1 is a valuable marker of intestinal inflammation and may have a role in complementing serology in the management of CD children. Future studies including larger patient cohorts and small bowel mucosa histology will be designed to assess the relationship between faecal HMGB1 levels and duodeno-jejunal histopathology., (Copyright © 2018 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Objective: To assess the risk of mycotoxin exposure (aflatoxin M1, ochratoxin A, and zearalenone) in celiac disease (CD) breastfeeding mothers and healthy control mothers, as well as in their offspring, by quantifying these contaminants in breast milk., Study Design: Thirty-five breastfeeding women with CD on a gluten-free diet and 30 healthy breastfeeding controls were recruited. Milk sampling was performed three times per day for three consecutive days. Mycotoxin content was investigated by an analytical method using immunoaffinity column clean-up and high-performance liquid chromatography (HPLC) with fluorometric detection., Results: Aflatoxin M1 (AFM1) was detected in 37% of CD group samples (mean ± SD = 0.012 ± 0.011 ng/mL; range = 0.003-0.340 ng/mL). The control group showed lower mean AFM1 concentration levels in 24% of the analyzed samples (0.009 ± 0.007 ng/mL; range = 0.003-0.067 ng/mL, ANOVA on ranks, p -value < 0.01). Ochratoxin A and zearalenone did not differ in both groups., Conclusion: Breast milk AFM1 contamination for both groups is lower than the European safety threshold. However, the estimated exposures of infants from CD mothers and control mothers was much higher (≃15 times and ≃11 times, respectively) than the threshold set by the joint FAO/WHO Expert Committee on Food Additives (JECFA). Since incongruities exist between JECFA and the European Union standard, a novel regulatory review of the available data on this topic is desirable. Protecting babies from a neglected risk of high AFM1 exposure requires prompt regulatory and food-control policies., Competing Interests: C.C. receives a consultancy honorary from Schär and Menarini Diagnostics. The other authors have no conflicts of interest relevant to this article to disclose.

Background: To our knowledge no study has focused on the pattern of cereal-based products (CBP) consumption among people with celiac disease (CD). Our study aimed at evaluating the dietary intake of CBP among patients with CD and comparing it with a control population., Methods: Eighty-two volunteers with CD and 77 non-CD volunteers enrolled throughout Italy were asked to register their consumption of CBP on specific diaries for three days., Results: CD patients' median three-day intake of biscuits and crackers was higher compared to controls (65.8 g vs. 22.7 g and 44.7 g vs. 10.6 g, p < 0.05 respectively, Mann-Whitney test). A significant difference was observed also comparing the two groups for median three-day bread consumption, with the CD group consuming less bread than controls (109.5 g vs. 150.7 g, p < 0.05, Mann-Whitney test). When assessing regional and gender-related CBP consumption patterns, significantly higher rice consumption was found among CD women from Northern Italy compared to CD women from Central and Southern Italy ( p = 0.006 and p = 0.002 respectively, Fisher's exact test). No other significant differences were observed., Conclusions: Our results provide a snapshot of the overall consumption of CBP among Italian subjects with CD. Altogether, these data show that, despite minor differences, dietary consumption of CBP among CD patients is similar to the general population.

The follow-up of celiac disease (CD) is challenging due to the scarcity of published data and the lack of standardized evidence-based protocols. The worldwide frequency and methods of CD follow-up appear to be heavily influenced by expert opinions of the individual physicians who assess children with CD. The aim of this review was to summarize the available studies on CD follow-up in children. We conducted a literature search with the use of PubMed, Medline, and Embase (from 1900 to 15 December 2016) for terms relevant to this review, including CD, follow-up, dietary adherence or dietary compliance, nutrition, comorbidities, complications, and quality of life. The aims of follow-up are as follows: to ensure strict adherence to a gluten-free diet, to ensure nutritional adequacy, to improve quality of life, and to prevent disease complications. For the correct evaluation of children with CD at follow-up, a clinical and biochemical evaluation is necessary on a regular basis. It is advisable to assess compliance, nutrition, comorbidities, or possible complications once a year at the referral center. Laboratory tests might be useful for a thorough evaluation of any patient with CD to rule out a micronutrient deficiency (full blood count, ferritin, folic acid, vitamin B-6, and vitamin B-12) and possible cardiovascular risk factors (glucose, LDL cholesterol, triglycerides). Biochemical evaluation is essential when there are clinical problems and should be customized on the basis of the specific clinical suspicion. Associated autoimmune thyroiditis should also be screened for yearly by measuring thyroid-stimulating hormone and thyroid autoantibody concentrations, regardless of symptoms, because hypothyroidism is often subtle and methods for early treatment are available and desirable. Although evidence-based recommendations for follow-up of pediatric patients with CD have not yet been established, we advise a yearly follow-up visit as the safest approach., (© 2017 American Society for Nutrition.)

Background: Coeliac disease is a chronic small intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten, and possible relationships between coeliac disease and dental pathogenic conditions during childhood have been poorly investigated., Aim: The dental pulp plays a pivotal role in the immune defence against possible entry of pathogens from teeth, and the aim of this work was to investigate quantitative transcription levels of selected genes (IL-9, IL-11, IL-15, IL-18, IL-21, IL-27, MICA, IFN-γ) coding for pro-inflammatory immune innate activities in the pulp of primary teeth from healthy children and children with coeliac disease., Design: The pulp from primary teeth of 10 healthy children and 10 children with coeliac disease was used to extract RNA and prepare cDNA for quantitative PCR transcription analysis employing commercial nucleotide probes for selected genes., Results: In children with coeliac disease, the genes coding for pro-inflammatory cytokines IFN-γ, IL-11, IL-18, and IL-21 were significantly overexpressed, suggesting the possible importance of these cytokines in the relationships between coeliac disease and dental disorders., Conclusion: For the first time, we reported in dental pulp of children possible relationships between coeliac disease and modulation in transcription of cytokine-dependent inflammatory activities., (© 2015 BSPD, IAPD and John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: In 2012, European Society of Pediatric Gastroenterology, Hepatology, and Nutrition published novel guidelines on celiac disease (CD) diagnosis. Symptomatic children with serum anti-transglutaminase (anti-tTG) antibody levels ≥10 times upper limit of normal (ULN) could avoid duodenal biopsies after positive HLA test and serum anti-endomysial antibodies (EMAs). So far, both asymptomatic and symptomatic patients with anti-tTG titer <10 times ULN should undergo upper endoscopy with duodenal biopsies to confirm diagnosis. The aim of this study was to assess the accuracy of serological tests to diagnose CD in asymptomatic patients., Methods: We retrospectively reviewed data of 286 patients (age range: 10 months to 17 years) with CD diagnosis based on elevated titer of anti-tTG, EMA positivity, and histology. All patients were distinguished between symptomatic and asymptomatic; histological lesions were graded according to the Marsh-Oberhuber (MO) criteria. Fisher exact test was applied to analyze both groups in terms of diagnostic reliability of serological markers., Results: A total of 196 patients (68.53%) had anti-tTG titers ≥10 times ULN. Among them, a group of 156 patients (79.59%) also had symptoms suggestive of CD ("high-titer" symptomatic); of these, 142 patients (91.02%) showed severe lesion degree (3a, 3b, 3c MO). Conversely, 40 out of 196 patients (20.40%) were asymptomatic ("high-titer" asymptomatic) and 37 patients (92.5%) of them showed severe lesion degree (3a, 3b, 3c MO). No difference in histological damage was found between "high-titer" symptomatic and "high-titer" asymptomatic children (Fisher exact test, P=1.000)., Conclusions: If confirmed in large multicenter prospective studies, the "biopsy-sparing" protocol seems to be applicable to both symptomatic and asymptomatic patients with anti-tTG titer ≥10 times ULN, positive EMA, and HLA-DQ2/DQ8.

Coeliac disease (CD) is a chronic, gluten-dependent enteropathy with a prevalence of approximately 1% in Western countries. Up to now, CD has been described only in sporadic cases of obesity. Our study aimed to evaluate retrospectively CD prevalence in a large series of overweight/obese children and adolescents. Among the 1527 overweight/obese children and adolescents consecutively evaluated, 17 (7 boys, 1.11%) were positive for serology and showed villous atrophy. In all of the patients with CD a well-balanced gluten-free diet was started, and a loss of weight rapidly obtained. Our study demonstrates that CD prevalence in overweight/obese children is similar to the general paediatric population in Italy.

Objectives: Metabolic bone disease remains a significant and common complication of celiac disease (CD). Several studies have demonstrated low bone mineral density (BMD) at the time of CD diagnosis in both children and adults. Low BMD in children and adolescents is defined as an areal BMD <2 SD below the age-adjusted mean value (z score <-2 SD). The aim of the study was to evaluate the BMD in a pediatric population with CD at diagnosis and to correlate z score value, anti-tissue transglutaminase type 2 antibody (anti-tTG2) titer, symptoms, and Marsh-Oberhuber (MO) grading., Methods: We enrolled 99 patients with celiac disease (male 35, female 64) ages 4 to 15 years at the diagnosis. All of the patients had positive test results for anti-tTG2 antibodies and histological lesions graded according to MO classification, and underwent lumbar dual-energy x-ray absorptiometry. BMD was estimated by z score., Results: Low BMD (z score ≤-2 SD) was found in 13 (13.13%) patients; 22 (22.22%) patients with CD showed -2 < z score ≤ -1; -1 < z score < 0 was found in 41 (41.41%) patients. z score ≥ 0 was detected only in 23 (23.23%) patients with CD. Mean BMD value in patients with CD is z score -0.68. No correlations were found between z score value and anti-tTG2 titer (Spearman ρ 0.13), between z score value and MO degree (Spearman ρ -0.17), and between z score and symptoms (Spearman ρ-0.10)., Conclusions: BMD of patients with CD at diagnosis does not seem to correlate with MO degree, anti-tTG2 titer, and symptoms. At the moment, we do not have clinical predictors for low mineral density in children with CD.

Background: The "multiple-biopsy" approach both in duodenum and bulb is the best strategy to confirm the diagnosis of celiac disease; however, this increases the invasiveness of the procedure itself and is time-consuming., Aim: To evaluate the diagnostic yield of a single biopsy guided by narrow-band imaging combined with water immersion technique in paediatric patients., Methods: Prospective assessment of the diagnostic accuracy of narrow-band imaging/water immersion technique-driven biopsy approach versus standard protocol in suspected celiac disease., Results: The experimental approach correctly diagnosed 35/40 children with celiac disease, with an overall diagnostic sensitivity of 87.5% (95% CI: 77.3-97.7). An altered pattern of narrow-band imaging/water immersion technique endoscopic visualization was significantly associated with villous atrophy at guided biopsy (Spearman Rho 0.637, p<0.001). Concordance of narrow-band imaging/water immersion technique endoscopic assessments was high between two operators (K: 0.884). The experimental protocol was highly timesaving compared to the standard protocol., Conclusions: An altered narrow-band imaging/water immersion technique pattern coupled with high anti-transglutaminase antibodies could allow a single guided biopsy to diagnose celiac disease. When no altered mucosal pattern is visible even by narrow-band imaging/water immersion technique, multiple bulbar and duodenal biopsies should be obtained., (Copyright © 2014. Published by Elsevier Ltd.)

We describe a 5-year-old female affected by lamellar ichthyosis, diagnosed in the first month of life, who attended our pediatric clinic for Mycoplasma pneumoniae pneumonia. The evidence of severe osteoporosis with hyperparathyroidism secondary to malabsorption suggested the occurrence of celiac disease. Endoscopy with multiple duodenal biopsies revealed total villous atrophy. The child started a gluten-free diet, supported by oral calcium and vitamin D. After 1-year follow-up, the girl showed complete normalization of bone mineral density. The introduction of the gluten-free diet did not lead to lesion repair, but the child reported significant improvement of her quality of life.

Objective: The high prevalence of celiac disease (CD) prompted us to evaluate a new, noninvasive disease screening strategy. The aim was to identify CD in 6- to 8-year-old children for a timely diagnosis, start gluten-free diet (GFD) in compliant subjects, achieve the growth target, and prevent CD complications., Methods: Five thousand subjects were invited to participate in the study. Four thousand forty-eight saliva samples were tested for anti-tissue transglutaminase (tTG) immunoglobulin (Ig)A using a fluid-phase radioimmunoprecipitation method. Positive children were tested for serum radioimmunoassay tTG IgA, enzyme-linked immunosorbent assay tTG IgA, and anti-endomysium IgA. Children confirmed as positive by serum assays underwent endoscopy with duodenal biopsies and, at the diagnosis of CD, were suggested to start GFD., Results: Consent was obtained from 4242 parents (84.8%) for the screening to be performed, and adequate saliva samples were collected from 4048 children (95.4%). Thirty-two children were found to be salivary tTG IgA positive and 9 with borderline autoantibody levels. Thirty-one of the 32 and 3 of the 9 subjects were also serum positive. Twenty-eight children showed villous atrophy when undergoing intestinal biopsy, whereas 1 had Marsh 1 lesions; 3 children were suggested to start GFD without performing endoscopy. CD prevalence in the population investigated (including 19 CD known cases) was 1.16%. The ratio between screening-detected patients and those diagnosed before the screening was 3:2. The ratio between symptomatic and asymptomatic patients was 1:1.6., Conclusions: We demonstrated that it is possible to perform a powerful, simple, well-accepted, and sensitive CD screening using saliva. Until now, the compliance with GFD in children with CD has been optimal.

Background and Aims: Celiac disease (CD) is twice as frequent among female than male. Despite the large number of reports on the DQ2/DQ8 association, no systematic studies have investigated a possible different role of the HLA genes in the two genders. We performed case-control and family-based analyses of DR-DQ variants in a pediatric CD cohort with the aim of comparing female to male associations and to investigate the paternal/maternal inheritance of the disease-predisposing haplotypes., Methods: A total of 281 female and 156 male pediatric celiac patients, 292 nuclear families, and 551 controls were genotyped for HLA-DRB1, DQA1, and DQB1 loci. Odds ratio, parental origin of the disease-associated haplotypes, and transmission ratio distortion were evaluated in-between male and female cases., Results: DQ2/DQ8 were more frequent in female than in male patients (94% F, 85% M; P = 1.6 x 10(-3)) with a 99.1% and 90.5% calculated negative predictive value of the HLA test, respectively. Surprisingly, the majority of the 39 DQ2/DQ8 negative cases were male. The analysis of the DQ2 haplotype origin showed that 61% of female patients and 42% of male patients carried a paternal combination (P = 0.02). The transmission disequilibrium test (TDT) proved the major distortion in the DR3-DQ2 transmission from fathers to daughters., Conclusions: CD is confirmed to be more prevalent in female than in male (F:M = 1.8) but, in DQ2/DQ8 negative patients, we found an unexpected male excess (F:M = 0.7). Moreover, only the inheritance of a paternal DQ2 haplotype led to a daughters predominance. These data show a role of HLA genes on the disease sex bias and suggest a possible different effect of parent-specific epigenetic modifications in the two genders.