Rethinking Coeliac Disease Diagnosis: Is Biopsy Still Necessary?

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ACHAIKI IATRIKI | 2026; 45(1):11–13

Editorial

Lara Miruzzi, Pierre Ellul, Martina Sciberras

Department of Gastroenterology and Immunology, Mater Dei Hospital, Malta

Received: 30 Jun 2025; Accepted: 10 Jul 2025

Corresponding author: Dr Lara Miruzzi, Mater Dei Hospital Triq Dun Karm, L-Imsida, MSD 2090; Tel.: +35 625457579, E-mail: lara.miruzzi@gov.mt

 

Coeliac Disease (CeD) is a chronic autoimmune condition affecting the small bowel that is triggered by an abnormal immunological response to the gliadin component found in gluten. Globally, the prevalence of diagnosed CeD is estimated to be 1% of the population [1]. Currently, the diagnosis of CeD entails a complex process including referral to a gastroenterologist, assessment of patient symptomatology, serology and upper gastrointestinal (GI) endoscopy with biopsies from the second part of the duodenum and the duodenal bulb demonstrating villous atrophy and intraepithelial lymphocytosis (IEL) [2].

In fact, duodenal biopsies obtained through upper GI endoscopy have played a central role for years and are currently considered to be the gold standard for the diagnosis of CeD in adults. However, a gastroscopy is an invasive procedure with potential risks for patients [3]. Moreover, there may be variation in interpretation and grading by histopathologists and the patchy nature of CeD may miss certain cases. There is additional financial costs of the procedure and pathology specimens and a delay in diagnosis may occur due to waiting lists for endoscopy [4].

Paediatric guidelines by the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) have approved new criteria for a non-biopsy approach to CeD when IgA anti-tissue transglutaminase antibody (anti-TTG IgA) levels are more than 10 times the upper limit of normal (ULN) and anti-endomysial antibodies (EMA) are positive irrespective of value [5].

In adults, scientific literature supporting a non-biopsy approach for the diagnosis of CeD is growing and the implications of adopting such an approach are being debated. A recent systematic review and meta-analysis by Shiha MG et al, which included 18 international studies and more than 12,000 adult patients, concluded that selected adults with anti-TTG IgA ≥10 times the ULN and a moderate to high pre-test probability of CeD (guided by patient symptomatology and risk factors for CeD) can be diagnosed without undergoing invasive endoscopy and duodenal biopsies [6]. Further studies in adult patients found that, in different settings, anti-TTG IgA ≥10 the ULN predicts the presence of mucosal atrophy from 95.2% in low-risk populations to 100% in high-risk populations [7,8,9]. Patients were subclassified into risk categories based on clinical context: high risk included those with a strong clinical suspicion of CeD, moderate risk included first-degree family members of individuals with CeD, and low risk included individuals from the general population. The study by Penny et al, looked at a cohort of patients with high anti-TTG IgA titres, drawn from multiple international centres. Marsh 3 histology was used as the reference standard for determining CeD. The performance of anti-TTG IgA ≥10 the ULN was assessed against this benchmark, demonstrating a positive predictive value (PPV) of 95.2% in diagnosing CeD [8]. Supporting this, a Scottish study by Hoyle et al, reported that the majority of patients with TTG-IgA >10× ULN were confirmed to have CeD, with an even higher PPV of 99.58% [9]. A study by Baykan AR et al, postulates that a higher anti-TTG IgA correlates with more damage to the mucosa noted on histology with a higher score on the Marsh classification [10].

Anti-TTG IgA has been shown to have a strong PPV in the diagnosis of CeD. A prospective multicenter, international study provided further evidence for a non-biopsy approach as it confirmed that both a 5-fold and a 10-fold increase of TTG in a high-risk population were able to predict mucosal atrophy in 97.4% and 97.5%, respectively, when the biopsy was interpreted locally. The histology was then reviewed by the central expert pathologist and it was noted that the PPV of a 10-fold elevation in TTG was 99.4% [11]. This indicates that the discrepancy was mainly due to misinterpretation of the histology. The only case in this study with a 10-fold rise in TTG that did not show histological evidence of atrophy had an increased IEL and crypt hypertrophy. This patient was eventually diagnosed with CeD on the basis of a very high serological titer, symptomatology, and improvement reported by the patient after adopting a gluten-free diet (GFD) [12]. The results of a retrospective study by Cauchi S et al, also align with these findings. This latter study also showed that all patients with an anti-TTG IgA ≥10 the ULN had a positive EMA result and none of those with a negative result were diagnosed with CeD [13]. This supports the statement in the ESPGHAN guidelines that testing for EMA serology increases the accuracy of a non-biopsy approach [5].

During the COVID-19 pandemic the non-biopsy approach was implemented by the British Society of Gastroenterology guidance in those adult patients with an anti-TTG IgA ≥10 × ULN and no other alarm symptoms [10]. One prospective and two retrospective studies from the UK evaluating whether the non-biopsy approach in adults with an anti-TTG IgA ≥10×ULN was feasible, showed that no other concurrent pathology was found, and confirmed histological diagnosis of CeD was reported in >95% cases across all three studies [8,14,15].

A Finnish multicentre retrospective study by Ylönen V et al, compared the performance of four commercial anti-TTG IgA assays [16]. Serology samples from 836 Finnish adults with either a family history of CeD or suspected CeD were analysed. From the total cohort, 137 patients with suspected CeD and 85 patients with family history of CeD had histologically confirmed CeD. The PPV for a 10 × ULN threshold was 100% across all anti-TTG IgA assays [1]. Therefore, the serological diagnosis of CeD in adults using different commercial kits and applying the criterion of a value more than 10 × ULN was accurate. In addition, the study also suggested that a lower ULN threshold could be appropriate in the non-biopsy approach but that more research is needed [15].

Despite the above, applying the non-biopsy approach for the diagnosis of CeD is not as straightforward in adults as in pediatrics. There are several circumstances where a gastroscopy should still be performed, especially when patients present with ‘red flag’ symptoms. These include weight loss, iron deficiency anemia, dysphagia and persistent dyspepsia among others [8]. Some of these symptoms and signs are also common in CeD, underscoring the importance of referring patients to a gastroenterologist before establishing a diagnosis. Furthermore, biopsies should be considered where the serology results and clinical risk are not concordant or in cases with a borderline serology result. In addition, patients having persistent symptoms despite adherence to a GFD will require duodenal biopsies, as anti-TTG IgA is not a reliable marker of histological improvement [8].

Moreover, biopsies may be required when there is suspicion of CeD-related complications, including ulcerative jejunitis and small-bowel T cell lymphoma. Several risk factors have been identified for the development of such complications, including persistent diarrhoea, older age at diagnosis, having seronegative CeD as well as being homozygous for the HLA-DQ2.5 haplotype. These factors should be taken into consideration when considering a non-biopsy approach in the future [12,17].

The implementation of the non-biopsy approach requires a high level of anti-TTG IgA in order to avoid uncertain diagnoses or the misinterpretation of serological results especially by other medical professionals. A borderline increase in the serology may indicate a false positive result, the patient could have taken the test whilst already on a GFD or may have IgA deficiency thus creating a spurious result [12]. Another key issue is long-term adherence whereby patients who receive a biopsy-confirmed diagnosis may be more likely to adhere to a strict GFD compared to those diagnosed based solely on serology. This may be due to the perceived certainty of a histological diagnosis as compared solely to a serological diagnosis.

The non-biopsy approach to diagnosing CeD represents a step toward less invasive and more efficient diagnostic pathways. This strategy holds particular promise in lower-income countries or regions with limited access to timely gastroenterology services, where endoscopic resources may be scarce. While this method can reduce patient burden and healthcare costs, clinicians must carefully evaluate individual cases, balancing the benefits of avoiding unnecessary procedures with the need for diagnostic accuracy. Current evidence supports its use in selected adults with markedly elevated anti-TTG IgA antibody levels; however, further studies are necessary to refine the criteria, validate long-term outcomes, and ensure sustained adherence to a gluten-free diet.

Conflict of interest

None to declare.

Declaration of funding sources

None to declare.

Author contributions

LM, PE and MS: Literature review, Writing Original Draft & Final Approval of the manuscript.

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