Systematic Review With Meta-analysis

The Accuracy of Serological Tests to Support the Diagnosis of Coeliac Disease

Athena L. Sheppard; Martha M. C. Elwenspoek; Lauren J. Scott; Victoria Corfield; Hazel Everitt; Peter M. Gillett; Alastair D. Hay; Hayley E. Jones; Susan Mallett; Jessica Watson; Penny F. Whiting


Aliment Pharmacol Ther. 2022;55(5):514-527. 

In This Article

Abstract and Introduction


Background: There is growing support for a biopsy avoidant approach to diagnose coeliac disease in both children and adults, using a serological diagnosis instead.

Aims: To assess the diagnostic accuracy of serological tests for coeliac disease in adults and children.

Methods: Seven electronic databases were searched between January 1990 and August 2020. Eligible diagnostic studies evaluated the accuracy of serological tests for coeliac disease against duodenal biopsy. Risk of bias assessment was performed using QUADAS-2. Bivariate random-effects meta-analyses were used to estimate serology sensitivity and specificity at the most commonly reported thresholds.

Results:113 studies (n = 28,338) were included, all in secondary care populations. A subset of studies were included in meta-analyses due to variations in diagnostic thresholds. Summary sensitivity and specificity of immunoglobulin A (IgA) anti-tissue transglutaminase were 90.7% (95% confidence interval: 87.3%, 93.2%) and 87.4% (84.4%, 90.0%) in adults (5 studies) and 97.7% (91.0%, 99.4%) and 70.2% (39.3%, 89.6%) in children (6 studies); and of IgA endomysial antibodies were 88.0% (75.2%, 94.7%) and 99.6% (92.3%, 100%) in adults (5 studies) and 94.5% (88.9%, 97.3%) and 93.8% (85.2%, 97.5%) in children (5 studies).

Conclusions: Anti-tissue transglutaminase sensitivity appears to be sufficient to rule out coeliac disease in children. The high specificity of endomysial antibody in adults supports its use to rule in coeliac disease. This evidence underpins the current development of clinical guidelines for a serological diagnosis of coeliac disease. Studies in primary care are needed to evaluate serological testing strategies in this setting.


Coeliac disease is a chronic small intestinal immune-mediated enteropathy triggered by the ingestion of gluten, a protein found in wheat, rye and barley.[1] Exposure to gluten results in intestinal damage of varying severity in patients affected by coeliac disease. Symptomatic coeliac disease is characterised by gastrointestinal symptoms, including diarrhoea, nausea, vomiting and abdominal pain, and extraintestinal symptoms such as fatigue and weight loss.

Coeliac disease is estimated to affect around 1% of people in the UK,[2] however only 24% of those with coeliac disease are thought to be diagnosed.[3] These large numbers of undiagnosed patients—known as the "coeliac iceberg"—are thought to be a consequence of the non-specific nature of coeliac disease symptoms and variation in clinical presentation, from none (asymptomatic coeliac disease) to a broad spectrum of symptoms.[1] People with certain health conditions, such as type I diabetes, autoimmune thyroid disease or Down syndrome, as well as first-degree relatives of people with coeliac disease, are at higher risk of developing coeliac disease than the general population and are more likely to present without classical symptoms.[4]

Currently, the only treatment for coeliac disease is lifetime adherence to a gluten-free diet, which is expensive and can be difficult to comply with. Left undiagnosed and untreated, coeliac disease often leaves patients with troublesome symptoms that significantly affect their quality of life and lead to a higher risk of complications such as osteoporosis, infertility and small bowel cancer.[5] As such, a timely and accurate diagnosis of coeliac disease is important.

Coeliac disease is diagnosed using a combination of serological tests for coeliac-specific antibodies and endoscopic intestinal biopsy. Current guidelines by the National Institute for Health and Care Excellence recommend both adults and children with suspected coeliac disease first undergo serological testing for total immunoglobulin A (IgA) and IgA anti-tissue transglutaminase (tTG).[4] In IgA deficient patients, immunoglobulin G (IgG) endomysial antibodies (EMA), IgG deamidated gliadin peptide (DGP) or IgG tTG can be used. In adults, weakly positive for IgA tTG, IgA EMA should be measured. Seropositive adults should be referred for intestinal biopsy, while seropositive children should be referred for further investigation, which may include intestinal biopsy, IgA EMA, human leukocyte antigen (HLA) genetic testing, or a combination of the above.[4]

Intestinal biopsy is invasive and can be burdensome for patients, particularly children, who require general anaesthesia to undergo the procedure. Patients must consume a gluten-containing diet for at least six weeks prior to any serological test or biopsy, meaning those with coeliac disease may continue to experience painful and debilitating symptoms while they wait. Guidelines in the UK have begun to move towards biopsy-avoidance strategies for coeliac disease in children and, more recently, in adults. In their 2013 guidelines, the British Society of Paediatric Gastroenterology, Hepatology and Nutrition advised that children with IgA tTG greater than or equal to 10x the upper limit of normal for the assay, positive for IgA EMA and HLA positive do not need to undergo biopsy to confirm their coeliac disease diagnosis.[6] During the coronavirus pandemic, the British Society of Gastroenterology published interim guidance including a COVID-19 specific non-biopsy protocol for adults with suspected coeliac disease.[7]

Previous systematic reviews of the accuracy of serological testing for diagnosing coeliac disease suggest that the tests are highly sensitive and specific in both adults and children.[8–12] These systematic reviews, however, are all out-of-date and most have methodological limitations. Limitations included: limited search;[8–11] use of the Moses-Littenberg model[13] to pool estimates of sensitivity and specificity rather than the more robust bivariate or hierarchical summary receiver operating characteristic (HSROC) models[14,15] or no statistical synthesis of results;[10] and use of the original QUADAS-tool[16] to assess study quality (although at the time this was the most appropriate tool) the results of which were then not incorporated into the synthesis,[8,9,11] or no quality assessment.[10] The most recent, comprehensive review by Maglione et al, conducted for the AHRQ programme, was the only review to include more than 20 studies.[12] However, this review also included existing systematic reviews and only generated overall summary estimates for studies published since existing reviews; it did not produce overall estimates of the accuracy of the included serological tests. This review was restricted to studies that either included at least 300 participants or were conducted in an "at risk" population—reasons for the sample size restriction were not justified. None of the reviews considered the study threshold when calculating pooled estimates of sensitivity and specificity.

The purpose of this systematic review is to provide a robust and up-to-date evaluation of the accuracy of serological tests for coeliac disease in adults and children.