BACKGROUND AND OBJECTIVES:Recent changes in European diagnostic criteria allow for serologic diagnosis of celiac disease in children. Those guidelines have not been adopted in North America; hence, we aim to assess the positive predictive value (PPV) of tissue transglutaminase (tTG) immunoglobulin A (IgA) assays used in North America in identifying histologic findings of celiac disease. METHODS:Multicenter retrospective cohort study of children (<18 years) with an elevated tTG IgA within 6 months of an esophagogastroduodenoscopy between January 2016 and December 2021. Biopsy-confirmed celiac disease was determined by the presence of intraepithelial lymphocytosis and villous atrophy. The primary outcomes were the PPV of an elevated tTG IgA and tTG IgA greater than or equal to 10 times the upper limit of normal (10× ULN). RESULTS:Overall, 4019 children (63.3% female; 9% type 1 diabetes, 2% Down syndrome) were included. Histologic findings were consistent with celiac disease for 3321 children (PPV = 82.6% [95% CI, 81.4-83.8]). Among the 1739/4019 (43.2%) children with tTG IgA greater than or equal to 10× ULN, 1651 had biopsy-confirmed celiac disease (PPV10× = 94.9% [95% CI, 93.8-95.9]). Five percent (88/1739) of children did not have histologic findings of celiac disease, including 41/1739 (2%) with normal histology. Diagnostic accuracy of tTG IgA varied widely among assays used in North America (PPV range: 71.5%-88.8%; PPV10× range: 89.3%-97.3%). Assays performed worse in children with type 1 diabetes (PPV10× 89% [95% CI, 83.5-92.8]). CONCLUSIONS:Elevated tTG IgA in isolation is insufficient to confidently diagnose celiac disease. As tTG assay performance varied widely, diagnostic confirmation by a specialist prior to dietary changes is essential.

Food insecurity (FI) affects more than 18 million households in the United States. Children with celiac disease (CeD) depend exclusively on the gluten-free diet, yet gaps persist in screening for food-insecure households who could benefit from interventions. We developed a system to identify and address barriers to FI screening in a pediatric clinic for CeD. Using the Model for Improvement, we conducted quality initiatives for eligible households between January 1, 2024 and January 31, 2025. We surveyed the medical team to identify barriers to FI screening and designed a key driver diagram to inform plan-do-study-act cycles. We implemented a (1) validated screening form, (2) clinic flowsheet, (3) educational module, and (4) visual aid in the electronic health records. We measured the process of FI screening and documentation. We tracked outcomes on positive screens for general and gluten-free FI. Among 100 eligible children, the majority were female (63.0%), other race (55.0%), non-Hispanic (66.0%), and primary English-speakers (80.0%); and 66 received FI screening (66.0%). We identified top team-reported barriers to FI screening: language barriers, lack of FI resources, forgetting, and discomfort with asking questions. Applying the model for Improvement, we improved median FI screening from 0.0% to ≥75.0% within 12 months and sustained screening rates for ≥6 months. The average general and gluten-free FI among screened households was 19.7% and 14.8%, respectively. We implemented a systematic framework to address team-reported barriers, helping to increase FI screening for children with CeD. Developing interventions to address FI may improve poor outcomes among food-insecure households.

Objective To characterize how neighborhood socioeconomic deprivation affects tissue transglutaminase (tTG) IgA normalization, a marker of effective gluten elimination. Study design We conducted a single-center, retrospective cohort study of 207 children ≤18 years old with serology- or biopsy-based celiac disease diagnosed between 2013 and 2023. The primary exposure was the neighborhood deprivation index, a continuous measure (0-1) derived from the 2018 5-year American Community Survey. We categorized children from lowest to highest deprivation by quartiles (Q): Q1 (<0.15), Q2 (0.15-0.21), Q3 (0.21-0.29), or Q4 (>0.29). The primary outcome was tTG IgA normalization over the 60 months after seropositivity. We used Cox regression models to estimate hazard ratios (HRs) for tTG IgA normalization, adjusting for race, ethnicity, primary-spoken language, and insurance type in multivariable analyses. Results Of 207 children, the median deprivation index was 0.22 (IQR: 0.14, 0.29). Higher deprivation was associated with participants identifying as Black or Other race, Hispanic, non-English primary-speaking, and having public insurance. In univariate analysis, children in the highest quartile of neighborhood deprivation had a 50% lower normalization rate compared with those in the lowest quartile (HR 0.50; 95% confidence interval 0.27, 0.92; P = .03). In multivariable analysis, children in the highest quartile of neighborhood deprivation sustained a 67% lower normalization rate after adjusting for race, ethnicity, primary-spoken language, and insurance type (HR0.33; 95% confidence interval 0.15, 0.75; P = .008). Conclusions Children living in socioeconomically deprived neighborhoods may have inadequate dietary adherence. Addressing the barriers to gluten elimination in deprived neighborhoods may improve outcomes.

OBJECTIVE:To characterize how social adversities influence disease control in children with celiac disease (CeD). STUDY DESIGN:We conducted a cross-sectional analysis of data from 325 eligible children ≤18 years old with CeD enrolled between 2015 through 2023 into iCureCeliac, a patient-centered US registry for CeD. We evaluated the associations between financial insecurity, social stigmatization, decreased health knowledge, and mental health comorbidity with 2 validated patient-reported outcomes on disease activity and gluten-free diet adherence: celiac symptom index and CeD adherence test, respectively. We used multivariable logistic and linear regression analysis to adjust for race, primary spoken language, and socioeconomic status. RESULTS:Among 325 children with available financial insecurity data, the median age was 11 years (IQR 8, 15), 67% were female, and 88% were White. In multivariable logistic regression, the odds of elevated disease activity among children with financial insecurity, social stigmatization, decreased health knowledge, and mental health comorbidity were 2.6 (95% CI 0.9, 8.0; P = .09), 2.8 (95% CI 1.6, 5.1; P < .001), 4.8 (95% CI 2.4, 9.8; P < .001), and 1.9 (95% CI 1.1, 3.3; P = .03), respectively. For insufficient dietary adherence, the respective odds were 1.6 (95% CI 0.5, 4.7; P = .43), 3.3 (95% CI 1.7, 6.5; P < .001), 2.9 (95% CI 1.5, 5.7; P = .002), and 2.3 (95% CI 1.2, 4.2; P = .01). Statistically significant associations in logistic regression aligned with results of linear models. CONCLUSIONS:Social stigmatization, decreased health knowledge, and mental health comorbidity were associated with worse disease control in pediatric CeD. Targeted interventions aimed at addressing these social adversities may improve disease activity and dietary adherence.

Telehealth (TH) broadly encompasses remote activities of clinical care (telemedicine), provider and patient education, and general health services. The use of synchronous video for TH first occurred in 1964 and then catapulted to the forefront in 2020 during the coronavirus disease 2019 public health emergency. Due to the sudden need for increased TH utilization by nearly all health care providers at that time, TH became essential to clinical practice. However, its sustainable future is unclear in part given that best practices for TH in pediatric gastroenterology (GI), hepatology, and nutrition remain undefined and non-standardized. Key areas for review include historical perspective, general and subspeciality usage, health care disparities, quality of care and the provider-patient interaction, logistics and operations, licensure and liability, reimbursement and insurance coverage, research and quality improvement (QI) priorities, and future use of TH in pediatric GI with a call for advocacy. This position paper from the Telehealth Special Interest Group of North American Society of Gastroenterology, Hepatology and Nutrition provides recommendations for pediatric GI-focused TH best practices, reviews areas for research and QI growth, and presents advocacy opportunities.

Objectives: With the coronavirus disease 2019 public health emergency (PHE), telehealth (TH) became essential for continued delivery of care. Members of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) formed the Telehealth for Pediatric Gastrointestinal Care Now (TPGCN) working group and rapidly organized a telemedicine webinar to provide education and guidance. We aim to describe the webinar development and prospectively assess the effectiveness of this webinar-based educational intervention. Methods: NASPGHAN members who registered for the TPGCN webinar received pre- and post-webinar surveys. Outcome measures included a modified Telehealth Acceptance Model (TAM) survey and a Student Evaluation of Educational Quality (SEEQ) standardized instrument. Results: Seven hundred seventy-six NASPGHAN members participated in the webinar, 147 (33%) completed the pre-webinar survey; of these, 25 of 147 (17%) completed a post-webinar survey. Before the PHE, 50.3% of the pre-webinar survey participants had no TH knowledge. Webinar participants trended to have increased acceptance of TH for follow-up visits (pre-webinar, 68% versus post-webinar, 81%; P = 0.15) and chronic disease care (pre-webinar, 57% vs post-webinar, 81%; P = 0.01). The overall acceptance of TH as shown by TAM pre-webinar was 1.74 ± 0.8, which improved to 1.62 ± 0.8 post-webinar (lower scores indicate greater acceptance; P < 0.001). SEEQ results indicate that webinar material was understandable (post-webinar, 95%). Participants found breakout sessions informative and enjoyable (post-webinar, 91%). Conclusion: The TPGCN TH webinar was an effective educational intervention that fostered increased TH usage for follow-up and chronic care visits, improved TAM scores, and was well received by participants as seen by high SEEQ scores. Sustained and expanded pediatric gastrointestinal TH usage beyond the coronavirus disease 2019 PHE is expected.

With the coronavirus disease 2019 public health emergency (PHE), telehealth (TH) became essential for continued delivery of care. Members of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) formed the Telehealth for Pediatric Gastrointestinal Care Now (TPGCN) working group and rapidly organized a telemedicine webinar to provide education and guidance. We aim to describe the webinar development and prospectively assess the effectiveness of this webinar-based educational intervention.Methods:NASPGHAN members who registered for the TPGCN webinar received pre- and post-webinar surveys. Outcome measures included a modified Telehealth Acceptance Model (TAM) survey and a Student Evaluation of Educational Quality (SEEQ) standardized instrument.Results:Seven hundred seventy-six NASPGHAN members participated in the webinar, 147 (33%) completed the pre-webinar survey; of these, 25 of 147 (17%) completed a post-webinar survey. Before the PHE, 50.3% of the pre-webinar survey participants had no TH knowledge. Webinar participants trended to have increased acceptance of TH for follow-up visits (pre-webinar, 68% versus post-webinar, 81%; P = 0.15) and chronic disease care (pre-webinar, 57% vs post-webinar, 81%; P = 0.01). The overall acceptance of TH as shown by TAM pre-webinar was 1.74 ± 0.8, which improved to 1.62 ± 0.8 post-webinar (lower scores indicate greater acceptance; P < 0.001). SEEQ results indicate that webinar material was understandable (post-webinar, 95%). Participants found breakout sessions informative and enjoyable (post-webinar, 91%).Conclusion:The TPGCN TH webinar was an effective educational intervention that fostered increased TH usage for follow-up and chronic care visits, improved TAM scores, and was well received by participants as seen by high SEEQ scores. Sustained and expanded pediatric gastrointestinal TH usage beyond the coronavirus disease 2019 PHE is expected.

Patients with very early onset inflammatory bowel disease (VEO-IBD) have a higher incidence of monogenic disease compared to older age groups. Age, alone, is a strong predictor for monogenic disease. We discuss a case of VEO-IBD in which the patient presented with severe and refractory enteropathy, leading to diagnosis of CTLA-4 haploinsufficiency. Genetic workup showed de novo heterozygous deletions of the CTLA-4 and ICOS genes. This case was unique, as the patient did not have the other manifestations commonly present with the disease. We advocate for early and routine genetic workup of VEO-IBD, as patients with monogenic IBD have high morbidity and mortality, if inadequately treated. Our patient did not respond to conventional treatment modalities and required targeted treatment with Abatacept, a CTLA-4 agonist.

Objective The SI gene encodes the sucrase-isomaltase enzyme, a disaccharidase expressed in the intestinal brush border. Hypomorphic SI variants cause recessive congenital sucrase-isomaltase deficiency (CSID) and related gastrointestinal (GI) symptoms. Among children presenting with chronic, idiopathic loose stools, we assessed the prevalence of CSID-associated SI variants relative to the general population and the relative GI symptom burden associated with SI genotype within the study population. Methods A prospective study conducted at 18 centers enrolled 308 non-Hispanic white children ≤18 years old who were experiencing chronic, idiopathic, loose stools at least once per week for >4 weeks. Data on demographics, GI symptoms, and genotyping for 37 SI hypomorphic variants were collected. Race/ethnicity-matched SI data from the Exome Aggregation Consortium (ExAC) database was used as the general population reference. Results Compared with the general population, the cumulative prevalence of hypomorphic SI variants was significantly higher in the study population (4.5% vs. 1.3%, P < .01; OR = 3.5 [95% CI: 6.1, 2.0]). Within the study population, children with a hypomorphic SI variant had a more severe GI symptom burden than those without, including: more frequent episodes of loose stools (P < .01), higher overall stool frequency (P < .01), looser stool form (P = .01) and increased flatulence (P = .02). Conclusion Non-Hispanic white children with chronic idiopathic loose stools have a higher prevalence of CSID-associated hypomorphic SI variants than the general population. The GI symptom burden was greater among the study subjects with a hypomorphic SI variant than those without hypomorphic SI variants.

GoalThe aim of this study was to investigate gene expression levels of proteins involved in sphingosine-1-phosphate (S1P) metabolism and signaling in a pediatric inflammatory bowel disease (IBD) patient population.BackgroundIBD is a debilitating disease affecting 0.4% of the US population. The incidence of IBD in childhood is rising. Identifying effective targeted therapies that can be used safely in young patients and developing tools for selecting specific candidates for targeted therapies are important goals. Clinical IBD trials now underway target S1PR1, a receptor for the pro-inflammatory sphingolipid S1P. However, circulating and tissue sphingolipid levels and S1P-related gene expression have not been characterized in pediatric IBD.MethodsPediatric IBD patients and controls were recruited in a four-site study. Patients received a clinical score using PUCAI or PCDAI evaluation. Colon biopsies were collected during endoscopy. Gene expression was measured by qRT-PCR. Plasma and gut tissue sphingolipids were measured by LC-MS/MS.ResultsGenes of S1P synthesis (SPHK1, SPHK2), degradation (SGPL1), and signaling (S1PR1, S1PR2, and S1PR4) were significantly upregulated in colon biopsies of IBD patients with moderate/severe symptoms compared with controls or patients in remission. Tissue ceramide, dihydroceramide, and ceramide-1-phosphate (C1P) levels were significantly elevated in IBD patients compared with controls.ConclusionsA signature of elevated S1P-related gene expression in colon tissues of pediatric IBD patients correlates with active disease and normalizes in remission. Biopsied gut tissue from symptomatic IBD patients contains high levels of pro-apoptotic and pro-inflammatory sphingolipids. A combined analysis of gut tissue sphingolipid profiles with this S1P-related gene signature may be useful for monitoring response to conventional therapy.

BACKGROUND & AIMS The mechanisms of tissue destruction during progression of celiac disease are poorly defined. It is not clear how tissue stress and adaptive immunity contribute to the activation of intraepithelial cytotoxic T cells and the development of villous atrophy. We analyzed epithelial cells and intraepithelial cytotoxic T cells in family members of patients with celiac disease, who were without any signs of adaptive antigluten immunity, and in potential celiac disease patients, who have antibodies against tissue transglutaminase 2 in the absence of villous atrophy. METHODS We collected blood and intestinal biopsy specimens from 268 patients at tertiary medical centers in the United States and Italy from 2004 to 2012. All subjects had normal small intestinal histology. Study groups included healthy individuals with no family history of celiac disease or antibodies against tissue transglutaminase 2 (controls), healthy family members of patients with celiac disease, and potential celiac disease patients. Intraepithelial cytotoxic T cells were isolated and levels of inhibitory and activating natural killer (NK) cells were measured by flow cytometry. Levels of heat shock protein (HSP) and interleukin 15 were measured by immunohistochemistry, and ultrastructural alterations in intestinal epithelial cells (IECs) were assessed by electron microscopy. RESULTS IECs from subjects with a family history of celiac disease, but not from subjects who already had immunity to gluten, expressed higher levels of HS27, HSP70, and interleukin-15 than controls; their IECs also had ultrastructural alterations. Intraepithelial cytotoxic T cells from relatives of patients with celiac disease expressed higher levels of activating NK receptors than cells from controls, although at lower levels than patients with active celiac disease, and without loss of inhibitory receptors for NK cells. Intraepithelial cytotoxic T cells from potential celiac disease patients failed to up-regulate activating NK receptors. CONCLUSIONS A significant subset of healthy family members of patients with celiac disease with normal intestinal architecture had epithelial alterations, detectable by immunohistochemistry and electron microscopy. The adaptive immune response to gluten appears to act in synergy with epithelial stress to allow intraepithelial cytotoxic T cells to kill epithelial cells and induce villous atrophy in patients with active celiac disease.

Objective: Innate immune activation of epithelial cells, anti-gluten CD4T cell responses, and upregulation of natural killer activity in cytotoxic intraepithelial CD8T cells (IE-CTL) are central to CD pathogenesis. In this study we aim to dissect the distinct contributions of adaptive and innate immune pathways to small bowel mucosal atrophy and how they relate to each other.

Celiac disease is an autoimmune disorder occurring in genetically susceptible individuals, triggered by gluten and related prolamins. Well identified haplotypes in the human leukocyte antigen (HLA) class II region (either DQ2 [ DQA*0501-DQB*0201 ] or DQ8 [DQA*0301 -DQB1*0302 ]) confer a large part of the genetic susceptibility to celiac disease. Celiac disease originates as a result of a combined action involving both adaptive and innate immunity. The adaptive immune response to gluten has been well described, with the identification of specific peptide sequences demonstrating HLA-DQ2 or -DQ8 restrictive binding motifs across various gluten proteins. As for innate immunity, through specific natural killer receptors expressed on their surface, intra-epithelial lymphocytes recognize nonclassical major histocompatibility complex (MHC)-I molecules such as MICA, which are induced on the surface of enterocytes by stress and inflammation, and this interaction leads to their activation to become lymphokine-activated killing cells. Four possible presentations of celiac disease are recognized: (i) typical, characterized mostly by gastrointestinal signs and symptoms; (ii) atypical or extraintestinal, where gastrointestinal signs/symptoms are minimal or absent and a number of other manifestations are present; (iii) silent, where the small intestinal mucosa is damaged and celiac disease autoimmunity can be detected by serology, but there are no symptoms; and, finally, (iv) latent, where individuals possess genetic compatibility with celiac disease and may also show positive autoimmune serology, that have a normal mucosa morphology and may or may not be symptomatic. The diagnosis of celiac disease still rests on the demonstration of changes in the histology of the small intestinal mucosa. The classic celiac lesion occurs in the proximal small intestine with histologic changes of villous atrophy, crypt hyperplasia, and increased intraepithelial lymphocytosis. Currently, serological screening tests are utilized primarily to identify those individuals in need of a diagnostic endoscopic biopsy. The serum levels of immunoglobulin (Ig)A anti-tissue transglutaminase (or TG2) are the first choice in screening for celiac disease, displaying the highest levels of sensitivity (up to 98%) and specificity (around 96%). Anti-endomysium antibodies-IgA (EMA), on the other hand, have close to 100% specificity and a sensitivity of greater than 90%. The interplay between gliadin peptides and TG2 is responsible for the generation of novel antigenic epitopes, the TG2-generated deamidated gliadin peptides. Such peptides represent much more celiac disease-specific epitopes than native peptides, and deamidated gliadin antibodies (DGP) have shown promising results as serological markers for celiac disease. Serology has also been employed in monitoring the response to a gluten-free diet. Despite the gluten-free diet being so effective, there is a growing demand for alternative treatment options. In the future, new forms of treatment may include the use of gluten-degrading enzymes to be ingested with meals, the development of alternative, gluten-free grains by genetic modification, the use of substrates regulating intestinal permeability to prevent gluten entry across the epithelium, and, finally, the availability of different forms of immunotherapy.

Background and Objectives: Irritable bowel syndrome (IBS) is a common problem in pediatrics, for which no safe and effective treatment is available. Probiotics have shown some promising results in adult studies, but no positive study has been published on pediatric age. We aimed at investigating the efficacy of VSL#3 in a population of children and teenagers affected by IBS, in a randomized, double-blind, placebo-controlled, crossover study conducted in 7 pediatric gastroenterology divisions. Patients and Methods: Children 4 to 18 years of age, meeting eligibility criteria, were enrolled. The patients were assessed by a questionnaire for a 2-week baseline period. They were then randomized to receive either VSL#3 or a placebo for 6 weeks, with controls every 2 weeks. At the end, after a “wash-out” period of 2 weeks, each patient was switched to the other group and followed for a further 6 weeks. Results: A total of 59 children completed the study. Although placebo was effective in some of the parameters and in as many as half of the patients, VSL#3 was significantly superior to it (P < 0.05) in the primary endpoint, the subjective assessment of relief of symptoms; as well as in 3 of 4 secondary endpoints: abdominal pain/discomfort (P < 0.05), abdominal bloating/gassiness (P < 0.05), and family assessment of life disruption (P < 0.01). No significant difference was found (P = 0.06) in the stool pattern. No untoward adverse effect was recorded in any of the patients. Conclusions: VSL#3 is safe and more effective than placebo in ameliorating symptoms and improving the quality of life in children affected by IBS.

Our patient was a 4-year-old, previously healthy male who presented with a 4-day history of cough and upper respiratory tract symptoms. He progressed to develop lethargy, weakness, cough, and jaundice. One week prior to admission there was a history of nonbloody diarrhea that had resolved. On our initial examination, he appeared toxic and presented with a temperature of 37.3°C, heart rate of 134 beats per minute, respiratory rate of 57, blood pressure of 112/57 mm Hg, and oxygen saturation of 100% on room air. He was icteric and tachypneic, and on auscultation, the chest was clear. Periorally, there were visible petechiae. The abdomen was soft and not tender, with minimal hepatomegaly and no splenomegaly. Initial laboratory examination revealed hemoglobin of 3.7 g/dL, platelets of 53,000/μL, and WBC of 17,500/μL with a bandemia of 38%. Total bilirubin was 9.2 mg/dL, direct bilirubin 7.7 mg/dL, serum glutamic pyruvic transaminase (SGPT) 133 U/L and serum glutamic oxaloacetic transaminase (SGOT) 615 U/L. Prothrombin time and partial thromboplastin time were normal, and fibrinogen was 1156 mg/dL. Peripheral blood smear demonstrated schistocytes and decreased platelets. Blood chemistries were sodium 127 mEq/L, potassium 5 mEq/L, chloride Hemolytic uremic syndrome (HUS) is a multisystemic disorder defined by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. It is frequently associated with an enterotoxigenic Escherichia coli (E. coli) O157 H7 infection that produces a Shiga-like toxin that binds to endothelial cells, particularly in the kidney, resulting in the features of the syndrome. In approximately 5%-10% of cases, HUS has been related to Streptococcus pneumoniae infections (SP-HUS). First described by Klein in 1977, it was demonstrated that in patients with SP-HUS, the particular offending S. pneumoniae strains produced a neuramidase that cleaves n-acetyl neuraminic acid from the surface of red cells, platelets, and renal endothelial tissue to expose the ThomsenFriedenreich (TF) antigen. The exposure of TF antigen is believed to result in an immune reaction between naturally occurring anti-TF (IgM) antibodies that are present in the plasma of most individuals beyond infancy. This is believed to mediate red blood cell (RBC) and platelet destruction within glomerular arterioles and capillaries, with subsequent microthrombi formation. In our review of the literature, there have been few reported cases of symptomatic gall bladder disease secondary to cholelithiasis and stasis following HUS, and most are associated with E. coli O157 H7 disease. In several instances, surgical intervention was necessary owing to recurrence

IL-15 and NKG2D promote autoimmunity and celiac disease by arming cytotoxic T lymphocytes (CTLs) to cause tissue destruction. However, the downstream signaling events underlying these functional properties remain unclear. Here, we identify cytosolic phospholipase A2 (cPLA2) as a central molecule in NKG2D-mediated cytolysis in CTLs. Furthermore, we report that NKG2D induces, upon recognition of MIC+ target cells, the release of arachidonic acid (AA) by CTLs to promote tissue inflammation in association with target killing. Interestingly, IL-15, which licenses NKG2D-mediated lymphokine killer activity in CTLs, cooperates with NKG2D to induce cPLA2 activation and AA release. Finally, cPLA2 activation in intraepithelial CTLs of celiac patients provides an in vivo pathophysiological dimension to cPLA2 activation in CTLs. These results reveal an unrecognized link between NKG2D and tissue inflammation, which may underlie the emerging role of NKG2D in various immunopathological conditions and define new therapeutic targets.

Current Opinion in Gastroenterology 2008, 24:707–712 Purpose of review Research in celiac disease is unraveling new findings at a high rate, and major advances seem to occur in all areas such as genetics, environmental factor, pathophysiology, and even prospective therapeutic implications. Recent findings New insight is being gained into the interplay between genetic and environmental factors causing celiac disease. In addition to the known human leukocyte antigen haplotypes, genome-wide studies have now identified additional susceptibility loci and the majority of newly discovered risk regions harbor genes controlling immune pathways. The mechanism of translocation of gliadin peptides across the intestinal barrier has been the subject of much investigation, and there is now evidence that the toxic 33-mer peptide can also be translocated transcellularly. As for the paracellular route, this appears to be enhanced by gliadin’s stimulation of zonulin release. The growing role of the innate immunity is being recognized and the increased expression of some Toll-like receptors appears to delineate a new inherent defect in this branch of innate immunity. Finally, new perspectives are opening in the treatment of celiac disease based on new detoxified grains, enzymatic degradation of gluten, and prevention of its crossing the mucosal barrier. Summary The pace of new knowledge in this ‘ancient’ disease is very fast, and this review outlines the principal lines of such exciting developments.