BACKGROUND:Intestinal transglutaminase 2 (TGM2)-IgA deposits represent an early marker of celiac disease (CeD). OBJECTIVE:This multicentre retrospective study aimed to assess the usefulness of a double immunohistochemistry technique for detecting TGM2-IgA deposits in formalin-fixed, paraffin-embedded duodenal biopsies from patients with CeD. METHODS:Duodenal biopsy sections were classified into: i) CeD, characterized by villous atrophy and serum TGM2 antibodies of IgA class (TGA-IgA) levels categorized as <5 × ULN (low), 5-10 × ULN (moderate), or >10 × ULN (high); ii) Potential CeD (pCeD), defined by normal mucosa with persistently positive TGA-IgA <10 × ULN; iii) Controls, with normal histology and no organic disease. A small cohort of CeD patients was analysed both at diagnosis and after a gluten-free diet. RESULTS:Double immunohistochemistry was performed on 166 CeD, 80 pCeD, and 80 control biopsies. TGM2-IgA deposits were identified in 100% of CeD cases, 72% of pCeD (Marsh 0/1) cases, and in none of the controls. Among 17 CeD patients re-evaluated after a gluten-free diet, all achieved mucosal healing (Marsh 0), 65% showed complete disappearance of deposits, and the remainder a marked reduction. CONCLUSIONS:TGM2-IgA double immunohistochemistry may help to refine diagnostic algorithms for CeD diagnosis.

Upper gastrointestinal endoscopy (UGIE) with duodenal biopsies remains the gold standard for diagnosing celiac disease (CD) in children and adolescents. Despite clear guidelines, clinical practices may vary across centers. This self-reported survey study assessed adherence to European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) guidelines for pediatric CD in endoscopic practice, focusing on pitfalls and the use of novel technologies. A web-based, multicenter survey was distributed to pediatric gastroenterology centers that are members of the Italian Society of Pediatric Gastroenterology, Hepatology, and Nutrition (SIGENP). Thirty-eight responses from 34 SIGENP centers were analyzed. Overall, 31/34 (91

Background: Celiac disease (CD) is an immune-mediated, gluten-induced enteropathy with intestinal and extraintestinal manifestations. Chronic urticaria (CU) is a heterogeneous inflammatory skin disorder often considered idiopathic, but emerging evidence suggests possible autoimmune causes. Methods: We describe a pediatric case in which CU and angioedema were the sole clinical expressions of CD. We also conducted a scoping review of the literature to assess the prevalence of CD in CU patients and the therapeutic impact of a gluten-free diet (GFD). Results: The child's CU resolved rapidly after initiating a GFD, with complete remission and normalization of anti-tissue transglutaminase at follow-up. Literature review shows that CD is significantly more common in CU patients than in the general population, and several case reports document remission of CU after GFD. However, leading guidelines for CD and CU do not currently recommend mutual screening, and pathophysiological mechanisms linking the two conditions remain incompletely understood. Conclusions: Chronic urticaria may be the sole clinical manifestation of CD. Screening for CD in patients with CU may be considered, particularly in those with autoimmune features or disease refractory to standard treatment. Initiating a GFD can lead to rapid symptom remission, reduce dependence on conventional therapies and improve quality of life.

Background and Clinical Significance: Celiac disease (CD) is a gluten-triggered immune enteropathy that may rarely present as Celiac crisis (CC), a life-threatening condition marked by severe diarrhea, dehydration, metabolic derangements, and acute malnutrition. Pediatric diagnostic criteria are lacking, and despite its reduced incidence in high-income countries, CC remains a critical complication, potentially associated with refeeding syndrome. Case Presentation: We report the case of a 23-month-old girl presenting with chronic diarrhea, weight loss, iron-deficiency anemia, hypoalbuminemia, and coagulation abnormalities. Serology confirmed CD, and a gluten-free diet (GFD) was initiated. However, the patient experienced clinical deterioration consistent with CC. Her course was further complicated by refeeding syndrome, ileo-ileal intussusception, and deep vein thrombosis, requiring corticosteroids, anticoagulation, and multidisciplinary nutritional support. Full clinical recovery was achieved within two months. Conclusions: This case highlights the life-threatening potential of CC and the necessity for early recognition. Timely GFD initiation, correction of metabolic abnormalities, and monitoring for refeeding syndrome are essential. We propose pediatric-adapted diagnostic criteria to facilitate earlier recognition and standardize the management of CC. The proposed framework includes major and minor criteria based on the rapid onset of gastrointestinal symptoms with serological evidence of CD autoimmunity, accompanied by clinical instability requiring hospitalization or intensive support and multiple indicators of systemic compromise.

OBJECTIVES:Gluten-free diet (GFD) is, to date, the only effective therapeutic intervention for coeliac disease (CeD). Evaluation of dietary adherence is of the utmost importance in the management of CeD. However, in the paediatric population, there is limited data concerning the adherence to the GFD in patients diagnosed via bioptic confirmation compared to those diagnosed through the biopsy-sparing method, according to the ESPGHAN 2012 guidelines. In this multicentric study, we investigated dietary adherence in a group of adolescents with CeD, comparing patients diagnosed with the two different diagnostic modalities, and we proposed the validation of an evaluation tool for the GFD compliance in this population. METHODS:A total of 206 patients aged 14-18 years, diagnosed between 2012 and 2019, all with CeD and on a GFD for at least 2 years, were included. Adherence was assessed using the Leffler questionnaire [Celiac Dietary Adherence Test (CDAT)] and the Biagi score. RESULTS:Among participants, 81.1% had been diagnosed through biopsy. No significant difference in Biagi scores was observed between the two groups ( P  = 0.057). Regarding the CDAT, poor or suboptimal adherence (score: ≥13) was identified in 66 patients diagnosed by biopsy and 12 patients diagnosed by the biopsy-sparing approach ( P  = 0.362). A multivariate analysis exploring the influence of diagnostic method, age at diagnosis, and education level on CDAT scores did not reach statistical significance ( P  = 0.1, R2  = 0.031). CONCLUSION:Adherence to a GFD does not differ between adolescents diagnosed by biopsy and those diagnosed through the biopsy-sparing approach, irrespective of age at diagnosis or educational level.

Background/Objectives: The distribution of body mass index (BMI) categories at celiac disease (CD) diagnosis in children is changing, and the impact of a gluten-free diet (GFD) on BMI status remains incompletely understood. We aimed to evaluate the distribution of BMI categories at CD diagnosis and their changes after 12-18 months on a GFD in Italian children. Methods: Children and adolescents aged 0-18 years who received a new diagnosis of CD at 23 Pediatric Gastroenterology referral centers in Italy were retrospectively enrolled. We analyzed their BMI status at diagnosis, classifying them as underweight, normal weight, overweight, or obese. BMI changes were assessed after 12-18 months on a GFD. Results: Among the 4967 children (mean age 7.1 ± 4.1 years, M:F = 1827:3140), 4.4% were underweight, 77.5% normal weight, 12.7% overweight, and 5.4% obese at diagnosis. Overweight/obese children were more likely to have a family history of CD, associated conditions, and an asymptomatic presentation. After 12-18 months of GFD, 55.7% of underweight children achieved normal weight, and 23% of overweight/obese reverted to normal weight. Conversely, 10.9% of normal-weight children and 3.2% of underweight children became overweight/obese. Conclusions: At diagnosis, most children were normal weight, but 18.1% presented with overweight/obesity. After 12-18 months on a GFD, BMI normalized in over half of underweight but in fewer than one-quarter of overweight/obese subjects.

OBJECTIVES:Autoimmune gastritis (AIG) has been poorly described in childhood. We sought to identify the patterns of manifestations of pediatric AIG at onset and to describe its laboratory, clinical, and histopathological features. METHODS:This was a retrospective, longitudinal, multicenter, cohort study enrolling histologically proven AIG patients with an onset in the pediatric age (<18 years old). We retrieved laboratory and clinical data at the time of onset and at last follow-up when available. Differences between Helicobacter pylori-exposed versus H. pylori-naïve, and anti-parietal cell antibody (PCA)-positive versus PCA-negative patients were investigated. RESULTS:Overall, 51 pediatric AIG patients (median age: 13 years, interquartile range: 11-16; F:M ratio 1.7:1) were included. Most patients were diagnosed with the overt type of AIG (47; 92.1%), while four (7.8%) were still in the potential phase. Atopic dermatitis (9.8%), rhinitis (7.8%), and asthma (5.9%) were common comorbidities, suggesting a link with T helper 2 (Th2) disorders. Two patients (3.9%) were found to have had previous or concurrent eosinophilic esophagitis, and five (9.8%) had eosinophilic gastritis. Notably, four patients (7.8%) presented with collagenous gastritis. On histological examination, the majority of patients were negative for H. pylori infection, except for 1 case out of 51 (2.0%) who had an active infection. CONCLUSIONS:AIG may affect pediatric patients and lead to complications in this population. At presentation, the disease may exhibit histologic patterns attributed to collagenous and/or eosinophilic gastritis. Moreover, a possible association between AIG and Th2 disorders has been observed, warranting further research.

Due to the need to reorganize the care network for the national screening mandated by law, a new healthcare model was required for the management of coeliac disease. The hub-and-spoke model is a new healthcare organizational system, here we describe its application (supported by telehealth), in the management of pediatric coeliac disease (CD) in Liguria. The results of the pilot phase are presented and the system's strengths and weaknesses discussed. A mixed-methods survey followed by an observational pilot study was performed. A multiphase approach was used including preparation setting, operative planning and application. The pilot phase involves a single primary center. The reduction of families’ expenditure and environmental impact was assessed using the Viamichelin calculator. A regional meeting followed by a survey (specifically developed for this study) and a needs analysis highlighted the priority to have an efficient, up to date and homogeneous model of care assistance throughout the network. A diagnostic and therapeutic care pathway (PDTC) was developed by the regional working group. The project involved 986 Ligurian families and allowed a 90

IntroductionAutoimmune thyroid diseases (ATD) are the most prevalent autoimmune disorders associated with celiac disease (CD). Both conditions can often be detected through serological screening in asymptomatic patients over several years. Various guidelines for screening thyroid disease (TD) are available in children with CD and vice versa.MethodsWe conducted a systematic review to identify the most recent and relevant guidelines, comparing their recommendations to analyze key differences and suggesting a practical clinical approach.ResultsOut of 1,294 articles reviewed, we identified 20 guidelines published between January 2013 and January 2024. These guidelines, primarily from gastroenterological organizations in Europe and North America, recommend different timings and methods for screening the co-occurrence of these diseases, both at diagnosis and during follow up. Some guidelines recommend only clinical follow-up without routine serological screening. There is limited consensus on screening for TD [using thyroid-stimulating hormone test (TSH)] in asymptomatic children newly diagnosed with CD, and even less agreement on screening for CD [using anti-transglutaminase antibodies (tTG) immunoglobulin A (IgA) test and total IgA] in children newly diagnosed with TD. No standardized procedures exist for managing patients with isolated low tTG and human leukocyte antigen (HLA) genotyping is rarely recommended as a first- line screening method.DiscussionOver the past decade, there has been a growing recognition of the importance of identifying children with co-occurrence of CD and TD who could benefit from early treatment, even in the absence of symptoms. However, international guidelines still show a lack of consensus regarding screening for these frequently associated autoimmune diseases, with notable differences in the use of HLA testing and follow-up protocols.

Background In pediatric patients, celiac disease (CD) may influence the health-related quality of life (HRQoL). Aims The study aimed to assess HRQoL and further characterise the clinical factors associated with reduced HRQoL, in a large multicenter pediatric cohort with CD. Methods The disease-specific questionnaire CD Dutch Questionnaire (CDDUX) and the generic questionnaire Paediatric Quality of Life Inventory (PedsQL) were used to assess the HRQoL. Clinical and sociodemographic characteristics were analyzed, univariate and multivariate analysis were conducted. Results Eleven different Italian pediatric centers and 871 families were involved. Mean age at interview was 12.9 ± 2.9 years. The mean total CDDUX score of CD patients was 47.1 ± 18.8, revealing a neutral HRQoL (47.1 ± 18.8), and a good to very good HRQoL according to the PedsQL (81.4 ± 12.6), parents indicated lower scores (p = 0.03) with both questionnaires (CDDUX 45.1 ± 18.6 and PedsQL 79.9 ± 14.5). Patients with lower HRQoL were mainly female, living in Northern Italy, with lower parent's education level and non-biopsy diagnosis of CD. In multivariate analysis, the main predictor of lower CDDUX score was non-biopsy diagnosis. Conclusions The HRQoL in a large cohort of Italian children is reported as neutral-good. This indicates a high level of adaptive behaviors in response to the daily challenges of CD. Parents tend to underestimate their children's HRQoL. Specific clinical factors, including non-biopsy diagnosis, may be associated to lower HRQoL.

Celiac disease (CeD) is a common immune-mediated condition that occurs in genetically predisposed individuals. In this study, we examined the trajectory of tissue transglutaminase IgA (tTG-IgA) antibodies in a prospective longitudinal cohort of over 500 children at risk of developing CeD due to having a first-degree relative with CeD. We identified 34 subjects from our cohort and examined tTG-IgA titers at seroconversion and 6 months before tTG-IgA seroconversion. We found that all subjects had normal tTG-IgA 6 months before seroconversion. Thus, we conclude that tTG-IgA elevation in subjects with CeD is a sudden event and its trajectory cannot be used as a marker to predict seroconversion in this population.

Background: Survivors of childhood brain cancer survivors (CBCS) have a higher risk of endothelial dysfunction and cardiovascular mortality. Recombinant human growth hormone (rhGH) replacement therapy may help reduce endothelial damage and the development of cardiovascular diseases (CVD). This study aimed to assess biochemical and biophysical endothelial function in CBCS with GH deficiency (GHD). Methods: CBCS who were at least two years post-treatment underwent clinical evaluation, including anthropometric measurements and metabolic assessments (adiponectin, blood clotting, and lipid profile). Endothelial function was evaluated using the estimation of the reactive hyperemia index (RHI) measured by the EndoPAT 2000. A value < 1.5 was considered pathologic. CBCS without GHD served as the control group. Results: The study included 60 participants: 12 controls (mean age 14 ± 4.7 years) and 48 CBCS with GHD (mean age 16.6 ± 4.9 years), 8 of whom were not receiving rhGH therapy. The cohort showed a high prevalence of abnormal RHI values. Although there were no significant differences in weight or body mass index between groups, those with GHD, especially those not on rhGH therapy, had a higher prevalence of an RHI < 1.5, lower pathological adiponectin levels and a disrupted lipid profile. Conclusions: CBCS exhibited altered RHI values consistent with early endothelial biophysical dysfunction. Among patients with GHD, this impairment was further associated with an adverse lipid profile and signs of adipose tissue dysfunction. Recombinant growth hormone replacement therapy may contribute to a partial improvement in biochemical indicators of endothelial function.

Abstract 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.

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.

Background and Clinical Significance: The use of point-of-care ultrasound (POCUS) in emergency departments is rapidly growing due to its ability to provide immediate and accurate diagnostic information at the bedside. Furthermore, it can provide precise and rapid information on the location of multidistrict effusions in patients with suspected lymphatic decompensation. Case Presentation: This unique clinical case report describes a patient who presented with massive, multidistrict chylous effusion secondary to acute lymphatic insufficiency, a rare and challenging condition. Due to a recent diagnosis of celiac disease, the patient had started a gluten-free diet ten days before the onset of symptoms, suggesting a possible causal link. Through comprehensive thoracoabdominal POCUS, the diagnosis was made promptly, avoiding delays in treatment and enabling timely decision-making. Conclusions: This case emphasizes the critical role of POCUS not only in expediting diagnosis but also in guiding invasive procedures, such as thoracentesis, by visualizing fluid accumulation and anatomical structures in real-time. Moreover, POCUS provides an invaluable tool for ongoing clinical ultrasound follow-up, facilitating continuous monitoring without exposing the patient to the risks of radiation, thus optimizing patient care and resource utilization.

ObjectivesThe aim of the study was to assess long-term health-related quality of life (HRQoL) in children and adolescents with coeliac disease (CD), and their parents.MethodsWe re-evaluated prospectively the HRQoL and clinical characteristics of 80 families, assessed 5 years earlier, using a disease-specific questionnaire, the CD Dutch Questionnaire (CDDUX), and a generic questionnaire, the Paediatric Quality of Life Inventory (PedsQL).ResultsAfter a 10-year follow-up, there was no significant change in the total CDDUX and PedsQL scores in children and their parents when compared to the evaluation conducted 5 years earlier. The total CDDUX score reflected a neutral QoL, while for the generic PedsQL was good-very good. The only significant decrease after 5 years was the PedsQL subdomain Emotional functioning. Patients who admitted voluntarily eating gluten reported lower score in CDDUX Diet. Lower scores in subdomain "Physical functioning" (PedsQL) were reported in patients with positivity of TTG or associated diseases.ConclusionsThe CDDUX score indicated a consistently stable and neutral QoL perception among coeliac patients and caregivers, even after 10-year postdiagnosis, suggesting minimal fluctuations in the impact of CD on disease-specific health domains over time. Furthermore, the consistently good PedsQL score could be a reflection of the resilience of coeliac families in coping with this chronic condition. Gluten-free diet compliance was confirmed to be determinant of HRQoL in the long term. The study confirms the importance of extending surveillance on these patients, possibly using different questionnaires, to assess QoL from different perspectives. The health-related quality of life in children with coeliac disease and their parents did not differ after 10 years from diagnosis. image Coeliac disease is a chronic disease associated with a negative impact on the health-related quality of life of children and their families. Health-related quality of life is a multidimensional concept that describes the patient's perception of their well-being. The use of generic (PedsQL) and disease-specific (CDDUX) questionnaires may detect discrepancies in the results which can be explained by the different sensitivity of the instruments to measure the real-life problems of children and adolescents with celiac disease.What is New The health-related quality of life in children, adolescents and their parents did not significantly differ after 10 years from diagnosis, compared with 5 years earlier, with scores corresponding to neutral (CDDUX) and good-very good (PedsQL) quality of life. In this study, the CDDUX is confirmed to be a simple, rapid, but complete tool to assess changes in quality of life over time in children and adolescents with coeliac disease, even on a long-term perspective. The children's CDDUX Diet health domain, that is, how the child feels about compliance to gluten-free diet restrictions, was negatively associated with a poor adherence to a gluten-free diet, even 10 years after diagnosis.

Background: Celiac disease (CD) is the most common multisystemic autoimmune disorder affecting the pediatric population. However, little data is available regarding SARS-CoV-2 vaccination coverage in pediatric patients with CD. This study aims to evaluate the adherence to national recommendations for SARS-CoV-2 vaccination in children and adolescents with CD and its variation over time. Methods: We retrospectively analyzed medical charts and electronic registry records of SARS-CoV-2 vaccination of patients aged 0-19 years diagnosed with CD in a tertiary center. The vaccination coverage was evaluated according to age groups (young children, children, and adolescents), considering the patients' eligibility for vaccination at different times. Results: Among the 172 patients enrolled, 44.8% received at least one dose of the SARS-CoV-2 vaccine, showing no significant differences compared to the Italian population of similar age. Vaccination coverage demonstrated a progressive reduction after an initial peak (up to 65.5% in December 2021) concomitant with a gradual extension of vaccinable eligibility and falling SARS-CoV-2 infections. Histological diagnosis and the presence of other associated autoimmune diseases were associated with higher levels of adherence to vaccination. Conclusions: Adherence to the SARS-CoV-2 vaccination in young Italian children with CD was very low, while it was better in adolescents and patients with other associated autoimmune diseases. Vaccine hesitancy remains a concern, particularly among those diagnosed using the biopsy-sparing approach. Hesitancy increased during the pandemic period, suggesting the need for ongoing efforts to improve adherence to SARS-CoV-2 vaccination recommendations.

Celiac disease (CD) is an immune-mediated systemic gluten-related disorder characterized by a wide spectrum of intestinal and extra-intestinal manifestations, including damage to cutaneous and connective tissue. We report a rare case of chronic severe dermatitis involving connective tissue and cutaneous vascular vessels as the main clinical presentation of undiagnosed seronegative gluten disorder. A gluten-free diet dramatically improved the intestinal and cutaneous clinical damage in the patient. Pitfalls and the steps of differential diagnosis are described. We also review the literature regarding studies of CD and connective tissue diseases to extend the knowledge of these rare associations. We propose a practical diagnostic approach in suspected CD in autoimmune cutaneous disorders.

[This corrects the article DOI: 10.3389/fendo.2022.975511.].