BACKGROUND AND AIM:Celiac disease (CeD) is not adequately recognized in Asia. We aimed to assess the prevalence of CeD in patients with irritable bowel syndrome (IBS) in six Asian countries and identify high-risk groups meriting screening. METHODS:Patients with IBS (Rome III) were recruited from Japan, Thailand, Indonesia, Malaysia, Singapore, and India. A two-step noninvasive strategy was used [positive IgA anti-tissue transglutaminase antibody (IgA anti-tTG-Ab) followed by confirmation with IgA deamidated gliadin-peptide antibodies (anti-DGP-Ab)]. Consenting patients with positive serology also underwent duodenal biopsies. Positivity for both IgA-anti-tTG-Ab and IgA-anti-DGP-Ab was labeled as serologically defined CeD. Important predictors of CeD were identified using the Boruta algorithm, and a nomogram for predicting CeD was constructed. RESULTS:2546 patients with IBS were evaluated across 6 countries. Overall prevalence serologically defined CeD (positive for both IgA anti-tTG Ab and IgA anti-DGP antibodies) was 2.75% (n = 70; 95% CI, 2.11%-3.39%). Prevalence was highest in Malaysia (3.8%), India (3.75%), and Indonesia (3.61%) and lowest in Japan (0.1%). Duodenal biopsies were performed in 20 patients, and 14 of them showed villous abnormalities (modified Marsh grade 2 or more). Among IgA anti-tTG-Ab-positive patients (n = 204; 8.01% 95% CI, 6.96%-9.07%), 18 (0.71%), 21 (0.82%), and 165 (6.48%) exhibited anti-tTG-Ab titer more than 10-fold, 6-10-fold, and 1-5-fold above the upper limit of normal. We propose a nomogram to predict the risk of CeD in Asian patients with IBS based on country, hemoglobin, age, sex, and diarrhea. CONCLUSION:Overall prevalence of serologically defined CeD in Asian patients with IBS is 2.75% but differs across patient profiles. This study suggests the need for better awareness and further studies on the prevalence of CeD across Asia.

Coeliac disease is an autoimmune disease characterized by small intestinal villus atrophy and inflammation upon exposure to gluten. It has a global prevalence of approximately 1

INTRODUCTION:Hereditary alpha-tryptasemia (HαT) is caused by the increased copy number of TPSAB1 when encoding for alpha-tryptase, resulting in elevated basal serum tryptase (BST). Many affected individuals report irritable bowel syndrome-like and reflux symptoms. We aimed to assess the prevalence of HαT in celiac disease (CeD) and whether this genetic trait modifies disease course. METHODS:This study included a prospective cohort of subjects with CeD or nonceliac gluten sensitivity (NCGS) either at diagnosis (Dx), with persisting symptoms on a gluten-free diet, or in clinical remission. BST levels were determined by immunoassay, and tryptase genotyping was performed on genomic DNA using digital droplet polymerase chain reaction (PCR) [ddPCR]. Duodenal and gastric biopsies were stained for c-KIT, and mast cell (MC) counts were averaged over 5 high power field (hpf). RESULTS:There were 153 eligible subjects: 13 with NCGS and 140 with CeD (8 patients with new Dx, 66 with persisting symptoms, 66 in remission). HαT was found in 9 subjects, all symptomatic with CeD (6.4%). One was new Dx, and the others had persisting symptoms (12.3% of subgroup). Excluding HαT, BST levels were higher among patients with CeD vs NCGS (median 5.4 vs 3.9 mcg/L P < 0.05). Duodenal MC counts were higher in CeD vs controls ( P < 0.05) and 24% higher in those with HαT (median HαT CeD 27.3/hpf, non-HαT CeD 22.0/hpf, controls 18.4/hpf). MC counts did not differ based on villous atrophy or clinical presentation. DISCUSSION:The prevalence of HαT in CeD is similar to the general population; however, all participants with CeD and HαT had ongoing gastrointestinal (GI) symptoms. Evaluation for HαT should be considered in the management of patients with CeD and persisting symptoms.

INTRODUCTION:Ulcerative jejunitis (UJ) or ulcerative enteritis (UE) is a rare complication of celiac disease (CeD). Guidelines regarding diagnosis and management are missing, and these cases have seldom been reported in the United States. DESIGN:Case series of CeD in which UE developed at a large academic center in the United States. Clinical presentation, diagnosis, treatment, and evolution of disease were collected. RESULTS:Eight cases were identified (6 male/2 female, mean age 59.5 [38-77] years). Presentations included intestinal obstruction (n = 3), GI hemorrhage (n = 3), and malabsorption (n = 2). Ulcers were present in the duodenum in 4 patients and exclusively past the angle of Treitz in only 4 cases, which makes the term UE more appropriate than UJ. Six of 8 had T-cell receptor clonal gene rearrangements, and 2 had definite aberrant T cells. Corticosteroids were tried in all patients without improvement, and 5 underwent surgical resection. Three patients received cladribine. One patient received an autologous stem cell transplant, followed by ruxolitinib. Two were subsequently diagnosed with enteropathy-associated T-cell lymphoma, including 1 with cerebral enteropathy-associated T-cell lymphoma, and 1 died from hemophagocytic syndrome. Two are still alive, including only 1 on GFD and 2 were lost to follow-up after surviving at least 30-month posttreatment. DISCUSSION:UE seems a more appropriate term to describe an ulcerative complication of CeD at high risk of obstruction or bleeding. Steroids were not effective. Treatment outcomes were variable, but with a 50% death rate.

Enzymatic supplements designed to aid in gluten digestion can be found in the market, also in combination with enzymes targeting other macronutrients. Their impact on digestion of gluten sequences that are immunogenic and/or toxic for individuals with Celiac Disease (CeD), remains uncertain, especially within a complex food matrix. This study aims at applying a biochemical and immune-based approach for understanding the effect of such supplements on the degradation of gluten immunogenic peptides in pizza. Plane-pizza was digested using the INFOGEST model, with/without the addition of three over the counter gluten enzyme supplements (S1, S2 and S3). Proteins digestion was monitored in the gastric (G) and gastroduodenal (GD) phases using electrophoresis and primary amines detection. Residual immune-toxic epitopes were quantified by R5- and G12-based ELISA. Immunogenicity of resistant, deamidated peptides, was assayed on CeD-derived intestinal-T cell lines (iTCLs). The highest content of primary amines was determined in presence of S1 and S2 supplements, containing starch-degrading enzymes in addition to dipeptidyl-peptidase-IV (DPP-IV) and other proteases. The most rapid degradation of R5- and G12-immune-toxic epitopes was observed in presence of S3 supplements, containing prolyl-endopeptidase (An-PEP). Consistently, iTCLs showed significant IFN-γ decrease toward S3-treated peptides. Nevertheless, none of the supplements was able to abolish iTCLs response, particularly at the end of gastric phase, thus allowing to conclude that they work to different, but potentially limited extent. The developed approach, combining simulated gastric and gastroduodenal digestion, biochemical/immunochemical characterization and functional bioassays, has proven to be a robust tool to assess residual immunoreactivity of enzyme-treated foods.

Background Celiac disease (CeD) may be associated with elevated liver enzymes. However, little is known about the risk of chronic liver disease (CLD) of various etiologies or major adverse liver outcomes (MALO) in CeD. We aimed to investigate the long-term risk of CLD in patients with CeD. Methods Swedish nationwide cohort study. We identified 48,027 patients with biopsy-confirmed CeD between 1969 and 2017. Each patient was exactly matched with ≤5 general population reference individuals (n = 231,909) and followed through 2021. Flexible parametric survival models estimated adjusted hazard ratios (aHRs) of any and specific CLD (i.e., viral hepatitis, metabolic dysfunction-associated steatotic liver disease [MASLD], alcohol-related liver disease, and autoimmune liver disease) and MALO (compensated/decompensated cirrhosis, hepatocellular carcinoma, liver transplantation, and liver-related death). Findings During a median follow-up of 16.0 years, 649 patients with CeD and 1571 reference individuals developed any CLD (incidence rate: 79.4 vs. 39.5/100,000 person-years). CeD patients had a higher risk of developing any CLD than reference individuals (aHR = 2.01, 95%CI:1.82−2.22). This risk remained elevated ≥25 years after diagnosis, giving one extra CLD case per 110 CeD patients until then. Positive associations were present for autoimmune liver disease (aHR = 4.86), MASLD (aHR = 2.54), and alcohol-related liver disease (aHR = 1.51). Individuals with CeD were at significantly higher risk of incident MALO (aHR = 1.54). Sibling comparisons and sensitivity analyses confirmed the main findings. Interpretation CeD is associated with a persistently increased risk of any incident CLD, although the absolute risk is low. Physicians should be vigilant to early signs of liver dysfunction in patients with CeD. Funding European Crohn's and Colitis Organisation, the Swedish Society for Medical Research (project#: PG-23-0315-H-02), FORTE (project#: 2016-00424), Takeda, and the Swiss National Science Foundation (project#: P500PM_210866).

Follow-up of celiac disease (CeD) after diagnosis includes dietician education and assessment of gluten-free diet (GFD) adherence promoting resolution of symptoms, mucosal injury, and can reduce the risk of comorbidities including osteopenia, autoimmune diseases, and malignant complications. As a consequence, regular follow-up of CeD should include assessment of clinical response, GFD adherence, and CeD activity (ie, mucosal healing). This includes regular clinical evaluation and blood tests to check biological abnormalities resolution, in particular confirming correction of anemia and vitamin deficiencies. Villous recovery has a prognostic value, and follow-up duodenal biopsy is central to the investigation of unresponsive CeD.

LINKED CONTENT This article is linked to Knowles et al paper. To view this article, visit https://doi.org/10.1111/apt.17942

Coeliac disease (CeD) is an immunological disease triggered by the consumption of gluten contained in food in individuals with a genetic predisposition. Diagnosis is based on the presence of small bowel mucosal atrophy and circulating autoantibodies (anti-type 2 transglutaminase antibodies). After diagnosis, patients follow a strict, life-long gluten-free diet. Although the criteria for diagnosis of this disease are well defined, the monitoring phase has been studied less and there is a lack of specific guidelines for this phase. To develop a set of clinical guidelines for CeD monitoring, we followed the Grading of Recommendations Assessment, Development and Evaluation methodology. Statements and recommendations with the level of evidence were developed and approved by the working group, which comprised gastroenterologists, pathologists, dieticians and biostatisticians. The proposed guidelines, endorsed by the North American and European coeliac disease scientific societies, make recommendations for best practices in monitoring patients with CeD based on the available evidence. The evidence level is low for many topics, suggesting that further research in specific aspects of CeD would be valuable. In conclusion, the present guidelines support clinicians in improving CeD treatment and follow-up and highlight novel issues that should be considered in future studies. Coeliac disease is a chronic inflammatory disease triggered by gluten consumption in individuals with a genetic susceptibility. These Evidence-Based Guidelines provide recommendations for improving the health care of the patients and discuss future perspectives.

Several guidelines and reviews recommend screening for celiac disease (CeD) in women with unexplained infertility or suggest an association between CeD and infertility. However, research in this field is contradictory (1Hogen Esch C.E. Van Rijssen M.J.L. Roos A. Koning F. Dekker F.W. Mearin M.L. et al.Screening for unrecognized coeliac disease in subfertile couples.Scand J Gastroenterol. 2011; 46: 1423-1428Crossref PubMed Scopus (0) Google Scholar). We conducted this Mendelian randomization (MR) study to strengthen the causal assessment of CeD-infertility association. Figure 1 shows the study design. Single-nucleotide polymorphisms (SNPs) strongly associated with CeD were extracted from a genome-wide meta-analysis including 12,041 CeD cases and 12,228 controls (2Trynka G. Hunt K.A. Bockett N.A. Romanos J. Mistry V. Szperl A. et al.Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease.Nat Genet. 2011; 43: 1193-1201Crossref PubMed Scopus (627) Google Scholar). We pruned these genetic variants to reduce influence of linkage disequilibrium, leaving 58 SNPs as instrumental variables. We found no weak instruments (Fminimum >30 and Faverage = 233). Given the complexity of major histocompatibility complex (MHC) gene in health, we used secondary genetic instruments comprising 37 SNPs not within MHC. The 58 and 37 SNPs included explained approximately 45.3% and 6.5%, respectively, of the genetic variance of CeD (3Yuan S. Jiang F. Chen J. Lebwohl B. Green P.H.R. Leffler D. et al.Phenome-wide Mendelian randomization analysis reveals multiple health comorbidities of coeliac disease.EBioMedicine. 2024; 101: 105033Abstract Full Text Full Text PDF Scopus (3) Google Scholar).Detailed information on SNPs is shown in online supplements. Summary-level data on female infertility were obtained from FinnGen (14,759 cases and 111,583 controls) and the UK Biobank (3,038 cases and 194,024 controls). Female infertility was defined according to the International Classification of Diseases codes (ICD-10 N97, excluding N97.4; ICD9 628.0,2-4,8-9; ICD8 628). Single-nucleotide polymorphisms-infertility associations were computed using regenie method and adjusted for age, 10 principal components, and genotyping batch in both studies. The inverse variance weighted method under the multiplicative random effects was used as the primary analysis and supplemented by the weighted median, MR-Egger, and MR-PRESSO methods. We used Cochran's Q values to assess heterogeneity and MR-Egger intercept test to assess horizontal pleiotropy. The analyses were performed with TwoSampleMR package in R (version 4.1.1). The association with a 2-sided P<.05 was deemed significant. Genetic predisposition to CeD was not associated with risk of infertility among women in either FinnGen or UK Biobank (Fig. 2). The null association persisted in the sensitivity analyses and the analysis using SNPs not within MHC gene region (Fig. 2). We found low heterogeneity in either of the analyses (Cochran's Q < 51), no indication of horizontal pleiotropy (PMR-Egger intercept>.71), or no SNP outliers. The lack of association between genetic liability to CeD and infertility in our study is consistent with 2 large case series of women with unexplained infertility (1Hogen Esch C.E. Van Rijssen M.J.L. Roos A. Koning F. Dekker F.W. Mearin M.L. et al.Screening for unrecognized coeliac disease in subfertile couples.Scand J Gastroenterol. 2011; 46: 1423-1428Crossref PubMed Scopus (0) Google Scholar, 4Grode L.B. Agerholm I.E. Humaidan P. Parkner T. Bech B.H. Ramlau-Hansen C.H. et al.Unrecognised coeliac disease among men and women undergoing fertility treatment: a screening study.United European Gastroenterol J. 2018; 6: 1477-1484Crossref PubMed Scopus (0) Google Scholar). When Grode et al. (4Grode L.B. Agerholm I.E. Humaidan P. Parkner T. Bech B.H. Ramlau-Hansen C.H. et al.Unrecognised coeliac disease among men and women undergoing fertility treatment: a screening study.United European Gastroenterol J. 2018; 6: 1477-1484Crossref PubMed Scopus (0) Google Scholar) screened 453 women referred for infertility treatment, only 1 (0.22%) was positive for CeD. In a similar screening study of infertile couples in the Netherland (2Trynka G. Hunt K.A. Bockett N.A. Romanos J. Mistry V. Szperl A. et al.Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease.Nat Genet. 2011; 43: 1193-1201Crossref PubMed Scopus (627) Google Scholar), 6 of 1038 women (0.58%) were positive for CeD, a proportion consistent with the general population. Together, these studies argue against screening for CeD in women with infertility.

BACKGROUND & AIMS: Villus height to crypt depth ratio (Vh:Cd) and intraepithelial lymphocytes (IEL) are key measures of histology of the small intestine in celiac disease. Although the fi eld of celiac disease has advanced, there remains no broadly accepted measure of mucosal injury. We assessed whether a composite Vh:Cd and IEL scale (VCIEL) can improve accuracy and statistical precision for assessing histology, compared with individual measures. METHODS: The formulation of the VCIEL composite histologic scale was based on combining the Vh:Cd and IEL measurements for individual patients with equal weighting, by converting each scale to a fraction of their standard deviation and summing the results. The VCIEL formula was applied to several clinical trials and the results for Vh:Cd and IEL were compared with those for VCIEL with regards to clinical signi fi cance (effect size) and statistical signi fi cance. RESULTS: For the ALV003-1021 trial, we observed an effect size and P value (analysis of covariance) of 1.37 and 0.038 for AVh:Cd, 1.17 and 0.005 for AIEL, and 1.86 and 0.004 for AVCIEL. For the similar gluten-challenge IMGX003-NCCIH-1721 trial, the corresponding results were 0.76 and 0.057 for AVh:Cd, 0.98 and 0.018 for AIEL, and 1.14 and 0.007 for AVCIEL. Similar improvements with the use of VCIEL over individual Vh:Cd and IEL measures were observed for other studies, including a nontherapeutic gluten challenge study. CONCLUSIONS: The composite VCIEL scale combining Vh:Cd and IEL values seems to improve accuracy and statistical precision compared with either component alone.

BACKGROUND AND AIM:Celiac disease (CeD) is increasingly diagnosed but significant disparities exist in awareness, practices, resources, and legislation worldwide. We conducted a global online survey with CeD experts to assess this disparity internationally. METHODS:A 55 questions survey encompassing nine domains relevant to CeD care (awareness, gluten-free [GF] foods availability/cost/quality, GF labeling, CeD dietician availability, insurance for CeD patients, medical training, research funding, patient support groups, and unmet needs) was generated and sent to CeD experts worldwide electronically. Countries were stratified based on per capita income as high-income (HIC) and lower-income countries (LIC) (including upper-middle-, lower-middle-, and low-income countries). Survey responses were summarized as a single score using principal component analysis. RESULTS:Valid responses were obtained from 131(37.4%) [HIC: 71; LIC: 60] of contacted CeD experts from 63 countries. Compared with HIC, LIC experts perceived worse availability (HIC:80% vs LIC: 47%; P < 0.001), quality (52% vs 20%; P < 0.001), and legislation for labeling of GF foods (82% vs 37%; P < 0.001), with unfavorable reimbursement policies (27% vs 12%; P = 0.002), subsidies (32% vs 13%; P < 0.001), and insurance (76% vs 43%; P < 0.001) for CeD patients. LIC also lacked awareness about CeD among general physicians (69% vs 32%; P < 0.001), trained celiac dieticians (39% vs 12%; P = 0.002), and active CeD patient support groups (93% vs 50%; P < 0.001). All experts believed that GF foods were costly (94% vs 87%), frequently contaminated (27% vs 32%), and unfavorably taxed (97% and 93%). The experts agreed on key unmet needs and better research funding. Overall CeD preparedness score (median 58.3 vs 33.0; P < 0.001) was also associated with income. CONCLUSIONS:The present survey highlights the opinion of global experts on the challenges, opportunities, and preparedness related to CeD and differences worldwide by income.