The European Society of Paediatric Gastroenterology, Hepatology and Nutrition established guidelines in 2012 for a no-biopsy approach to diagnose coeliac disease in children. This guideline required symptoms suggestive of coeliac disease, positive human leukocyte antigen (HLA) DQ2/DQ8 haplotypes, tissue transglutaminase type-2 immunoglobulin A antibody titre at levels greater than 10 times the upper limit of normal, and positive endomysial immune-globulin A antibody test. An updated 2020 guideline excluded the need for symptoms and positive HLA.

To assess the pooled positive predictive value (PPV) of the no-biopsy approach with small bowel biopsy (SBB) data as the reference standard for comparison.

Database searches (October 2023) provided data that we combined using a random-effects meta-analysis to provide a pooled PPV, representing the probability that a positive test result means that an individual truly has the condition.

We included 23 studies. Study sample sizes totalled 23,769 but only 3007 children had comparative SBB. The proportion of coeliac disease confirmed by the no-biopsy approach and SBB ranged from 79.2% to 100%, with an overall pooled PPV of 97.4% (95% confidence interval 96.0, 98.6). Sensitivity analysis showed higher PPV for the criteria that included HLA (98.5% vs. 96.8%; p = 0.017).

Both no-biopsy criteria exhibit high PPV when compared to the reference standard. These results provide a consistent message of accuracy and feasibility to inform change and improve outcomes.

The accumulating data regarding a non-biopsy diagnosis of celiac disease has led to its adoption in certain scenarios, although debate on whether and when to use non-biopsy criteria in clinical practice is ongoing. Despite the growing popularity and evidence basis for a biopsy-free approach to diagnosis in the context of highly elevated serologies, there will continue to be a role for a biopsy in some groups. This review summarizes the current evidence supporting a non-biopsy approach and arguments supporting continued reliance on biopsy, and focuses on opportunities to improve both approaches.

To circumvent the need for an endoscopic biopsy to establish the diagnosis of coeliac disease (CD), the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) introduced a non-biopsy pathway for selected children in 2012. This pathway was recently updated to utilise anti-tissue transglutaminase IgA (anti-TTG IgA), 10× upper limit of normal (ULN) and positive endomysial antibodies (EMA). This study focused on the retrospective application of these guidelines in children from two regions of New Zealand.

Children aged <18 years who had anti-TTG IgA measured and underwent oesophagogastroduodenoscopy over a 30-month period were identified retrospectively. Medical records were reviewed to determine whether patients subsequently had biopsy-proven CD (Marsh ≥2).

One hundred and thirty-six children, with a mean age (±standard deviation) of 9.9 ± 4.2 years, fulfilled the study criteria and 101 (74%) of these children had positive anti-TTG IgA. Eighty-two of 136 (60%) children had biopsy-proven CD. Positive anti-TTG IgA and EMA were highly sensitive in diagnosing CD, 96.3 and 98.6%, respectively. Anti-TTG-IgA ≥10× ULN alone, and combined anti-TTG IgA ≥10× ULN with positive EMA, both provided positive predictive values of 100% in diagnosing CD. Nineteen of 103 (18%) children could have been diagnosed with CD based on the ESPGHAN non-biopsy criteria.

A proportion of New Zealand children with CD can potentially be diagnosed using the latest ESPGHAN non-biopsy criteria. However, prospective studies are required to validate this conclusion.

The evaluation of gastrointestinal pathology in children often requires a different approach from that in adults. In this concise review, the authors outline 3 diagnostic challenges that are often encountered in daily practice; these include eosinophilic diseases, duodenal intraepithelial lymphocytosis with preserved villous architecture, and terminal ileal inflammation in the setting of idiopathic inflammatory bowel disease.

The ESPGHAN 2012 coeliac disease (CD) diagnostic guidelines aimed to guide physicians in accurately diagnosing CD and permit omission of duodenal biopsies in selected cases. Here, an updated and expanded evidence-based guideline is presented.

Literature databases and other sources of information were searched for studies that could inform on 10 formulated questions on symptoms, serology, HLA genetics, and histopathology. Eligible articles were assessed using QUADAS2. GRADE provided a basis for statements and recommendations.

Various symptoms are suggested for case finding, with limited contribution to diagnostic accuracy. If CD is suspected, measurement of total serum IgA and IgA-antibodies against transglutaminase 2 (TGA-IgA) is superior to other combinations. We recommend against deamidated gliadin peptide antibodies (DGP-IgG/IgA) for initial testing. Only if total IgA is low/undetectable, an IgG-based test is indicated. Patients with positive results should be referred to a paediatric gastroenterologist/specialist. If TGA-IgA is ≥10 times the upper limit of normal (10× ULN) and the family agrees, the no-biopsy diagnosis may be applied, provided endomysial antibodies (EMA-IgA) will test positive in a second blood sample. HLA DQ2-/DQ8 determination and symptoms are not obligatory criteria. In children with positive TGA-IgA <10× ULN at least 4 biopsies from the distal duodenum and at least 1 from the bulb should be taken. Discordant results between TGA-IgA and histopathology may require re-evaluation of biopsies. Patients with no/mild histological changes (Marsh 0/I) but confirmed autoimmunity (TGA-IgA/EMA-IgA+) should be followed closely.

CD diagnosis can be accurately established with or without duodenal biopsies if given recommendations are followed.

Currently, the only effective treatment for celiac disease is complete removal of gluten from the diet. However, patients need to follow a strict gluten-free diet that results in symptomatic, serologic, and histologic remission in most patients. Histologic remission is usually complete in children, but recovery is slower and more frequently incomplete in adults. When remission has been achieved, yearly follow-up is recommended for adults, children, and adolescents. This article deals with conventional strategies used in order to follow-up patients on treatment and aiming to obtain the best clinical outcome.

Coeliac disease is increasingly recognized as a global problem in both children and adults. Traditionally, the findings of characteristic changes of villous atrophy and increased intraepithelial lymphocytosis identified in duodenal biopsy samples taken during upper gastrointestinal endoscopy have been required for diagnosis. Although biopsies remain advised as necessary for the diagnosis of coeliac disease in adults, European guidelines for children provide a biopsy-sparing diagnostic pathway. This approach has been enabled by the high specificity and sensitivity of serological testing. However, these guidelines are not universally accepted. In this Perspective, we discuss the pros and cons of a biopsy-avoiding pathway for the diagnosis of coeliac disease, especially in this current era of the call for more biopsies, even from the duodenal bulb, in the diagnosis of coeliac disease. In addition, a contrast between paediatric and adult guidelines is presented.

The guidelines of the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition allow for diagnosis of celiac disease without biopsies in children with symptoms and levels of immunoglobulin A against tissue-transglutaminase (TGA-IgA) 10-fold or more the upper limit of normal (ULN), confirmed by detection of endomysium antibodies (EMA) and positivity for HLA-DQ2/DQ8. We performed a large, international prospective study to validate this approach.

We collected data from consecutive pediatric patients (18 years or younger) on a gluten-containing diet who tested positive for TGA-IgA from November 2011 through May 2014, seen at 33 pediatric gastroenterology units in 21 countries. Local centers recorded symptoms; measurements of total IgA, TGA, and EMA; and histopathology findings from duodenal biopsies. Children were considered to have malabsorption if they had chronic diarrhea, weight loss (or insufficient gain), growth failure, or anemia. We directly compared central findings from 16 antibody tests (8 for TGA-IgA, 1 for TGA-IgG, 6 for IgG against deamidated gliadin peptides, and 1 for EMA, from 5 different manufacturers), 2 HLA-DQ2/DQ8 tests from 2 manufacturers, and histopathology findings from the reference pathologist. Final diagnoses were based on local and central results. If all local and central results were concordant for celiac disease, cases were classified as proven celiac disease. Patients with only a low level of TGA-IgA (threefold or less the ULN) but no other results indicating celiac disease were classified as no celiac disease. Central histo-morphometry analyses were performed on all other biopsies and cases were carefully reviewed in a blinded manner. Inconclusive cases were regarded as not having celiac disease for calculation of diagnostic accuracy. The primary aim was to determine whether the nonbiopsy approach identifies children with celiac disease with a positive predictive value (PPV) above 99% in clinical practice. Secondary aims included comparing performance of different serological tests and to determine whether the suggested criteria can be simplified.

Of 803 children recruited for the study, 96 were excluded due to incomplete data, low level of IgA, or poor-quality biopsies. In the remaining 707 children (65.1% girls; median age, 6.2 years), 645 were diagnosed with celiac disease, 46 were found not to have celiac disease, and 16 had inconclusive results. Findings from local laboratories of TGA-IgA 10-fold or more the ULN, a positive result from the test for EMA, and any symptom identified children with celiac disease (n = 399) with a PPV of 99.75 (95% confidence interval [CI], 98.61-99.99); the PPV was 100.00 (95% CI, 98.68-100.00) when only malabsorption symptoms were used instead of any symptom (n = 278). Inclusion of HLA analyses did not increase accuracy. Findings from central laboratories differed greatly for patients with lower levels of antibodies, but when levels of TGA-IgA were 10-fold or more the ULN, PPVs ranged from 99.63 (95% CI, 98.67-99.96) to 100.00 (95% CI, 99.23-100.00).

Children can be accurately diagnosed with celiac disease without biopsy analysis. Diagnosis based on level of TGA-IgA 10-fold or more the ULN, a positive result from the EMA tests in a second blood sample, and the presence of at least 1 symptom could avoid risks and costs of endoscopy for more than half the children with celiac disease worldwide. HLA analysis is not required for accurate diagnosis. Clinical Trial Registration no: DRKS00003555.

A diagnosis of celiac disease is made based on clinical, genetic, serologic, and duodenal morphology features. Recent pediatric guidelines, based largely on retrospective data, propose omitting biopsy analysis for patients with concentrations of IgA against tissue transglutaminase (IgA-TTG) >10-fold the upper limit of normal (ULN) and if further criteria are met. A retrospective study concluded that measurements of IgA-TTG and total IgA, or IgA-TTG and IgG against deamidated gliadin (IgG-DGL) could identify patients with and without celiac disease. Patients were assigned to categories of no celiac disease, celiac disease, or biopsy required, based entirely on antibody assays. We aimed to validate the positive and negative predictive values (PPV and NPV) of these diagnostic procedures.

We performed a prospective study of 898 children undergoing duodenal biopsy analysis to confirm or rule out celiac disease at 13 centers in Europe. We compared findings from serologic analysis with findings from biopsy analyses, follow-up data, and diagnoses made by the pediatric gastroenterologists (celiac disease, no celiac disease, or no final diagnosis). Assays to measure IgA-TTG, IgG-DGL, and endomysium antibodies were performed by blinded researchers, and tissue sections were analyzed by local and blinded reference pathologists. We validated 2 procedures for diagnosis: total-IgA and IgA-TTG (the TTG-IgA procedure), as well as IgG-DGL with IgA-TTG (TTG-DGL procedure). Patients were assigned to categories of no celiac disease if all assays found antibody concentrations <1-fold the ULN, or celiac disease if at least 1 assay measured antibody concentrations >10-fold the ULN. All other cases were considered to require biopsy analysis. ULN values were calculated using the cutoff levels suggested by the test kit manufacturers. HLA typing was performed for 449 participants. We used models that considered how specificity values change with prevalence to extrapolate the PPV and NPV to populations with lower prevalence of celiac disease.

Of the participants, 592 were found to have celiac disease, 345 were found not to have celiac disease, and 24 had no final diagnosis. The TTG-IgA procedure identified patients with celiac disease with a PPV of 0.988 and an NPV of 0.934; the TTG-DGL procedure identified patients with celiac disease with a PPV of 0.988 and an NPV of 0.958. Based on our extrapolation model, we estimated that the PPV and NPV would remain >0.95 even at a disease prevalence as low as 4%. Tests for endomysium antibodies and HLA type did not increase the PPV of samples with levels of IgA-TTG ≥10-fold the ULN. Notably, 4.2% of pathologists disagreed in their analyses of duodenal morphology-a rate comparable to the error rate for serologic assays.

In a prospective study, we validated the TTG-IgA procedure and the TTG-DGL procedure in identification of pediatric patients with or without celiac disease, without biopsy. German Clinical Trials Registry no.: DRKS00003854.

The aim of our study is to evaluate if in children with highly positive serology and HLA-DQ2/DQ8 (triple test, TT) and only extra-intestinal symptoms, it is possible to omit performing an intestinal biopsy for celiac disease (CD) diagnosis, as suggested by the new European Society for Pediatric Gastroenterology, Hepatology and Nutrition ESPGHAN guidelines.

In this retrospective study a total of 105 patients, suspected of having CD because of extra-intestinal symptoms and showing serum tissue transglutaminase antibody (anti-tTG) and anti-endomysial antibody (EMA) measurements and HLA genotyping, were considered for the final analysis (33 boys and 72 girls; age range 1.5-17.6 years).

Histological findings confirmed diagnosis of CD in 97 (92.4%) patients. Forty-one patients (39%) showed anti-tTG >10 times normal values, positive EMA and positive HLA-DQ2/DQ8 (positive TT). All of them had a diagnosis of CD, therefore there were no false positive cases. Sixty-four patients were negative for the TT. In eight cases, CD was ruled out and these were considered true negative cases. In the remaining 56 negative TT patients, intestinal biopsy confirmed CD diagnosis and they were considered false negatives. Based on these results, specificity for the TT was 100% and sensitivity was 42.3%.

On the basis of the present study, diagnosis of CD can be reliably performed without a duodenal biopsy in children with only extra-intestinal symptoms.

The incidence of celiac disease (CD) has increased over the last half-century, resulting in rising interest in identifying risk factors for CD. The necessity of duodenal biopsies in the diagnosis of CD has recently been challenged. Areas covered: This review covers the recent literature regarding the role of infant feeding practices, including breastfeeding and timing of gluten introduction, and the microbiota in the development of CD. Additionally, the application of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for a non-biopsy approach to the diagnosis of CD is reviewed. Expert commentary: Recent investigations have not revealed any significant effect of breastfeeding or timing of gluten introduction on the risk of CD in at-risk populations. There are alterations in the microbiota of CD patients. However, the role of the microbiome and whether its manipulation has a clinical effect are unknown. Preliminary data suggests a non-biopsy approach to diagnosis of pediatric CD can be applied to several populations, although additional studies are needed. Prospective investigations are underway to examine the interplay of infant feeding practices and the microbiome and to identify particular CD-specific biomarkers that may aid in the diagnosis and ultimately prevention of CD.

Since the first description of celiac disease (CeD) by Samuel Gee in 1888 and the later "miraculous discovery" that bread was responsible for this condition following World War II in Europe, there has been an exponential growth of knowledge regarding CeD. Just when we thought that we knew everything there was to know about it, the disease is, however, offering new challenges, with its presentation having significantly morphed over the years from cases of overt gastrointestinal symptoms, malnutrition, and atrophic villi on duodenal biopsies to that of largely extraintestinal, subtle, or mild symptoms. Along with these changes, unexpectedly a new parallel entity appeared a few years ago and is gaining ground: the so-called nonceliac gluten sensitivity, an improper name because it should actually be referred to as wheat intolerance syndrome given that the role of gluten in all such cases is far from demonstrated and the implication of an immune involvement suggested by the term "sensitivity" is still unfounded. Lastly, wheat can be an offender also through an immunoglobulin E-mediated allergy, whose presence must also be evaluated and ruled out in selected cases.The practicing physician is therefore now challenged with the task of discerning which patients need to be assessed for one or the other of these disorders, and how.This review aims at providing an updated, critical reassessment of these 2 entities.

Dietary exclusion of gluten-containing products has become increasingly popular in the general population, and currently ∼30% of people in the United States are limiting gluten ingestion. Although celiac disease (CD), wheat allergy (WA), and nonceliac gluten sensitivity (NCGS) constitute a spectrum of gluten-related disorders that require exclusion of gluten from the diet, together these account for a relatively small percentage of those following a gluten-free diet, and the vast majority has no medical necessity for doing so. Differentiating between CD, WA, and NCGS has important prognostic and therapeutic implications. Because of the protean manifestations of gluten-related disorders, it is not possible to differentiate between them on clinical grounds alone. This clinical report will compare and contrast the manifestations of gluten-related disorders, emphasize the importance of differentiating between these conditions, discuss initial and subsequent tests needed to confirm the diagnosis, and provide recommendations on treatment and follow-up for each condition.

The relationship between eosinophilic oesophagitis (EoE) and coeliac disease (CD) remains controversial, with studies yielding varied results.

To systematically review the evidence of a possible association between both diseases.

Electronic searches were performed with keywords relating to EoE and CD in the MEDLINE, EMBASE and SCOPUS databases. Summary estimates were calculated. A random-effects model was used depending on heterogeneity (I(2) ). Publication bias was assessed with the aid of funnel plot analysis, along with the Begg-Mazumdar, Harbord and Egger tests.

The search yielded 197 references; 30 were included in the quantitative summary, with most of these presenting methodological inconsistencies. Significant publication bias in favour of short studies reporting positive associations between both diseases was documented. The prevalence of EoE in CD ranged from 0% to 10.7% (I(2)  = 78.9%). Prevalence of CD in EoE varied between 0.16% and 57.1% (I(2)  = 89%). One high-quality, prospective, randomly selected, population-based study documented a 1.1% prevalence of CD, with no patients presenting EoE. Clinical and methodological heterogeneity hindered the performance of quantitative summaries for prevalence data. A gluten-free diet was effective in achieving histological remission of EoE in 32.1% of coeliac patients (95% confidence interval, 14.9-52.2%; I(2)  = 52.2%), which was similar to that expected for wheat elimination in EoE patients.

While a lack of valid studies prevents us from completely ruling out a true association between EoE and CD, currently available evidence does not support this hypothesis. Indeed, the only epidemiological study with sufficient validity points to the independence of both diseases.