Summary
Introduction
Over the past decade, the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) proposed the option of diagnosing coeliac disease (CD) in children without duodenal biopsy. The aim of our study was to assess the diagnostic approach in newly diagnosed children with CD in Slovenia.
Methods
In this prospective study, Slovenian paediatric gastroenterologists were invited to provide medical records of children under 19 years diagnosed with CD from March 2021 to October 2023. The analysis focused on tissue transglutaminase antibody (TGA) levels at diagnosis, diagnostic approach, adherence to ESPGHAN CD guidelines and diagnostic delays.
Results
Data from 160 newly diagnosed CD patients (61.9% female; median age 8 years; 16.9% asymptomatic) were available for the analysis. No-biopsy approach was used in 65% (N = 104) of children and the majority (N = 101) fulfilled all the criteria for the no-biopsy approach. Of 56 children diagnosed using duodenal biopsy, a further 10 (17.8%) would have also been eligible for the no-biopsy approach based on the very high levels of TGA. Median diagnostic delay from first symptoms to confirmation of diagnosis was 6 months (min 0 months, max 87 months). Use of the no-biopsy approach has risen significantly since 2016 (37.8% vs. 65.0%; p = 0.001) and diagnostic delays have shortened (6 vs. 7 months; p < 0.05).
Conclusion
This prospective study highlights the frequent use of a no-biopsy approach for diagnosing CD in children in Slovenia, showing large adherence to ESPGHAN guidelines. Also, diagnostic delays have shortened over recent years, likely due to various awareness-raising projects on CD conducted during this period.
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Introduction
Coeliac disease (CD) is a lifelong systemic autoimmune disorder elicited by gluten and related prolamins in genetically susceptible individuals [1]. It might present with a wide variety of gastrointestinal and extraintestinal symptoms that contribute to a significant delay in disease diagnosis, especially in adults [2]. Histological findings of villous atrophy and crypt hyperplasia with increased levels of intraepithelial T lymphocytes from duodenal biopsies, classified according to Marsh–Oberhuber, have been regarded as the gold standard for diagnosing CD for many years. In the past decade, the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) proposed the no-biopsy diagnostic approach under specific criteria (elevated tissue transglutaminase antibodies [TGA] > 10 × upper level of normal [ULN] and positive anti-endomysial antibodies [EMA] in a secondary blood sample) [1, 3]. Despite the potential advantages, concerns about missed pathologies and applicability in diverse populations have impeded the universal adoption of these guidelines [4]. Notably, the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) continues to recommend intestinal biopsy for confirming CD diagnosis in all cases, irrespective of TGA levels, since there is no standardisation of serological tests in the Unites States of America (USA) [5]. On the other hand, European studies clearly confirmed the reliability of serological tests in the no-biopsy approach [6, 7].
While ESPGHAN guidelines have reached acceptance in various regions over the years [8,9,10,11], guidelines for adults still emphasize the importance of biopsy confirmation for CD diagnosis [12, 13]. However, even for the adult population, ESPGHAN guidelines are gaining recognition and integration into diagnostic procedures, indicating a potential shift in the approach to diagnosing coeliac disease [13,14,15,16].
The aim of our study was to assess the diagnostic approach in children diagnosed with coeliac disease in Slovenia, and to calculate diagnostic delays in newly diagnosed symptomatic children.
Methods
The study was carried out between March 2021 and October 2023 as a part of the CD SKILLS project (DTP 571), co-financed by the European Union Danube Transnational Programme.
Participants and study design
For collection of patient data, a dedicated web-based form was designed within the scope of the Focus IN CD project (https://www.interreg-central.eu/Content.Node/surveys.html). This form underwent adaptation and translation into the Slovenian language. It encompassed inquiries regarding the coeliac disease diagnosis and management of newly diagnosed patients. Conducted as a prospective study, paediatric gastroenterologists across all hospitals in Slovenia responsible for managing children and adolescents with coeliac disease were invited to complete the questionnaire using medical documentation of children under 19 years who were diagnosed with CD between March 2021 and October 2023. The complete anonymization of reported data was ensured.
We analysed medical records of all included CD patients, focusing on levels of TGA at the time of diagnosis and determined whether the diagnosis was confirmed through a duodenal biopsy showing Marsh 2–3 lesions or through a no-biopsy approach. Additionally, we assessed the adherence to guidelines and calculated diagnostic delays, defined as the duration from the onset of first symptoms to confirmation of the diagnosis. We compared the results of Slovenian patients with the results of a similar study conducted in Central Europe within the Focus IN CD project in 2016.
Statistical analysis
Statistical analysis was performed using IBM SPSS Statistics 24.0 (IBM Corp., Armonk, NY, USA). Descriptive statistics, one-way analysis of variance (ANOVA), independent samples t‑test and chi-square test were used for the analysis.
The study was approved by the National Medical Ethics Committee of the Republic of Slovenia (0120-12/2021/9).
Results
Data from 160 children and adolescents (median age 8 years; min 7 months, max 18.5 years; 61.9% female) from five regional hospitals and two University Medical Centres in Slovenia were available for the analysis.
Twenty-seven children (16.9%) were asymptomatic at confirmation of the diagnosis (median age 9.5 years; min 2.5 years, max 18.5 years; 63% female) and were mostly diagnosed because of high-risk group screening (N = 25; 92.6%). The majority had a first-degree family member with CD (70.8%) and 20.8% had type‑1 diabetes mellitus. Other children were diagnosed with CD due to their signs and symptoms (median age 7 years; min 7 months, max 18 years; 61.7% female). Median diagnostic delay from first symptoms to confirmation of diagnosis was 6 months (min 0 months, max 7 years). There was no difference in diagnostic delays between symptomatic children diagnosed using biopsy and no-biopsy approaches (both 6 months).
The diagnostic procedure analysis revealed that 65% (N = 104) of included children (81.7% symptomatic) were diagnosed using a no-biopsy approach (median age 7 years). Among them, 97.1% (N = 101) of children had two separate serology samples, conforming to ESPGHAN 2020 guidelines. The remaining three children were diagnosed based on a single serological test and exhibited TGA > 10 × ULN and positive IgA EMA in the same blood sample.
Of the 56 children (86.7% symptomatic; median age 9 years; 91% Marsh–Oberhuber 2 or 3; 9% histological classification not used) who underwent duodenal biopsy, a further 10 children (17.8%) had TGA > 10 × ULN, making them eligible for the no-biopsy approach (Table 1). In these ten children, biopsies were predominantly conducted because parents insisted on the procedure (50.0%) or upper endoscopy was initially planned for other indications (40%). In a single case, biopsy was performed due to established institutional practice. Reasons for performing duodenal biopsies are presented in Table 2. None of the patients with TGA < 10 × ULN was diagnosed without duodenal biopsy.
Genetic tests were conducted in 39.4% of included children, with 92% testing positive for DQ2 and 17% for DQ8 (6.3%), despite guidelines not deeming it necessary. Among children diagnosed using duodenal biopsy, 50% underwent genetic testing, while only 30.8% of those diagnosed using a no-biopsy approach underwent genetic testing (p < 0.05).
Comparing with 2016 data from the Focus IN CD project, Slovenia has seen a significant increase in use of the no-biopsy approach in recent years (Table 3; p = 0.001). The percentage of children who would have been eligible for the no-biopsy approach and were diagnosed with duodenal biopsy has decreased significantly (39.3% in 2016 vs. 17.8%; p < 0.05). Also, median diagnostic delays have shortened compared to 2016 (6 months vs. 7 months; p < 0.05).
Discussion
In the past decade, ESPGHAN guidelines for CD diagnosis have allowed the use of a no-biopsy approach in children and adolescents, provided specific criteria are met [1]. Since its implementation, this approach has undergone multiple assessments and has proven to be safe, including a large prospective international study involving 707 paediatric patients, where the no-biopsy approach demonstrated a positive predictive value for enteropathy of over 99% [6]. Subsequent to its initial inclusion in the ESPGHAN guidelines in 2012 [3], several studies in the following years have explored the application of the no-biopsy approach in children with coeliac disease [6,7,8,9,10]. Our data indicate a widespread adoption of the no-biopsy approach in Slovenia, with 65% of included children being diagnosed using this method. Interestingly, only 10% of children diagnosed via duodenal biopsy would still be eligible for the no-biopsy approach. Importantly, duodenal biopsies were performed for other valuable reasons based on available data. Notably, the use of the no-biopsy approach has increased significantly compared to our previous study in selected countries of Central Europe in 2016, where only 20% of children were diagnosed using this approach, and an additional 51.9% of biopsied children would have been eligible for the approach without the biopsy. Remarkably, even then, Slovenia emerged as the country most frequently employing the no-biopsy approach [17]. As in the study in Central Europe, there were no differences in diagnostic delays with regard to the diagnostic approach. The ESPGHAN guidelines were also adopted in most European countries, including Austria, Switzerland and Germany, where national guidelines are based on existing ESPGHAN guidelines [18].
In recent years, there has been notable exploration of the no-biopsy approach for diagnosing coeliac disease in adult populations [14,15,16]. Initial concerns about omitting biopsy, particularly in adults, due to potential risks of missing significant concomitant conditions including malignancy, have been addressed by recent studies from Italy and England [16, 19,20,21,22]. Interestingly, recent guidelines from the American College for Gastroenterology have proposed the use of a no-biopsy approach for diagnosing coeliac disease in children under specific circumstances [13]. However, it is important to note that this approach is not yet incorporated into the NASPGHAN guidelines for paediatric CD diagnosis [5].
Harmonization of guidelines is crucial, especially when considering the transition of care from childhood to adolescence and adulthood. This period can raise doubts about the accuracy of the original coeliac disease diagnosis, both for the patient and the new healthcare provider. Nevertheless, if the initial diagnosis in childhood was based on the ESPGHAN guidelines, there should be no uncertainty regarding the diagnosis [4].
The diverse clinical presentation of coeliac disease contributes significantly to diagnostic delays, especially in adults [23]. Although children generally experience shorter delays, some regions still report unacceptably prolonged durations. In our study, the median diagnostic delay was 6 months, aligning with the findings of our earlier research on diagnostic delays in children in Central Europe in 2016 [24]. However, regarding Slovenian patients in both studies, diagnostic delays have shortened significantly, which might be the consequence of various awareness-raising campaigns in past years in Slovenia. Another paediatric study on diagnostic delays in coeliac disease was conducted in New Zealand in 2019 by Coppell et al. [25]. In their study, the median diagnostic delay was significantly longer compared to our findings, reaching 1.5 years. Kosovo stands out with a mean delay in diagnosing CD in children at 2.2 years, notably longer than in other recent paediatric studies [26]. This prolonged delay may be attributed to the non-recognition of children with nonclassical clinical presentations [26].
Recent research provides a diverse picture of diagnostic delays in adult CD patients. A study in Denmark by Kårhus et al. [27] reported long self-reported delays in adult CD patients, with a mean delay of 5.8 years. Lenti et al. [28] found a much shorter median delay of 8 months in Italy, while Mansueto et al. [29] reported a mean delay of 9 years. Notably, Mehta et al. [30] reported a median diagnostic delay of 27 months in their study, revealing a correlation between the severity of celiac disease and the duration of diagnostic delay. It is important to note that most of these studies were based on patient recall and not on health records and, contrary to ours, were retrospective.
In conclusion, diverse guidelines exist globally for diagnosing coeliac disease, reflecting regional variations in diagnostic pathways despite the uniform nature of the disease. However, recent years have seen a promising trend towards harmonization, particularly in children and adolescents, with ESPGHAN guidelines gaining acceptance in many regions. Nevertheless, NASPGHAN guidelines for paediatric coeliac disease currently do not endorse the no-biopsy diagnosis. In the realm of adult coeliac disease diagnosis, there is a growing acceptance of the no-biopsy approach, although its full implementation is pending. Notably, Finland has already incorporated the no-biopsy approach into its national guidelines for diagnosing coeliac disease in adults [31]. The gradual integration of ESPGHAN guidelines into diagnostic procedures is underway, potentially influencing both paediatric and adult coeliac disease diagnoses. Also, the recurring theme of delayed recognition of CD underscores the need for improved awareness and timely diagnosis.
References
Husby S, Koletzko S, Korponay-Szabó I, Kurppa K, Mearin ML, Ribes-Koninckx C, et al. European Society Paediatric Gastroenterology, Hepatology and Nutrition Guidelines for Diagnosing Coeliac Disease 2020. J Pediatr Gastroenterol Nutr. 2020;70(1):141–56. Jan.
Karunaratne D, Disease C. A Subtle yet Life Changing Diagnosis. J Patient Exp. 2021;8:2374373521998818.
Husby S, Koletzko S, Korponay-Szabó IR, Mearin ML, Phillips A, Shamir R, et al. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr. 2012;54(1):136–60. Jan.
Reilly NR, Husby S, Sanders DS, Green PHR. Coeliac disease: to biopsy or not? Nat Rev Gastroenterol Hepatol. 2018;15(1):60–6. Jan.
Hill ID, Fasano A, Guandalini S, Hoffenberg E, Levy J, Reilly N, et al. NASPGHAN Clinical Report on the Diagnosis and Treatment of Gluten-related Disorders. J Pediatr Gastroenterol Nutr. 2016;63(1):156–65. Jul.
Werkstetter KJ, Korponay-Szabó IR, Popp A, Villanacci V, Salemme M, Heilig G, et al. Accuracy in Diagnosis of Celiac Disease Without Biopsies in Clinical Practice. Gastroenterology. 2017;153(4):924–35. Oct.
Wolf J, Petroff D, Richter T, Auth MKH, Uhlig HH, Laass MW, et al. Validation of Antibody-Based Strategies for Diagnosis of Pediatric Celiac Disease Without Biopsy. Gastroenterology. 2017 Aug;153(2):410–419.e17.
Bishop J, Reed P, Austin P, Hurst M, Ameratunga R, Craigie A, et al. Prospective Evaluation of the ESPGHAN Guidelines for Diagnosis of Celiac Disease in New Zealand Children. J Pediatr Gastroenterol Nutr. 2018;67(6):749–54. Dec.
Benelli E, Carrato V, Martelossi S, Ronfani L, Not T, Ventura A. Coeliac disease in the ERA of the new ESPGHAN and BSPGHAN guidelines: a prospective cohort study. Arch Dis Child. 2016;101(2):172–6. Feb.
Gidrewicz D, Potter K, Trevenen CL, Lyon M, Butzner JD. Evaluation of the ESPGHAN Celiac Guidelines in a North American Pediatric Population. Am J Gastroenterol. 2015;110(5):760–7. May.
Murch S, Jenkins H, Auth M, Bremner R, Butt A, France S, et al. Joint BSPGHAN and Coeliac UK guidelines for the diagnosis and management of coeliac disease in children. Arch Dis Child. 2013;98(10):806–11. Oct.
Al-Toma A, Volta U, Auricchio R, Castillejo G, Sanders DS, Cellier C, et al. European Society for the Study of Coeliac Disease (ESsCD) guideline for coeliac disease and other gluten-related disorders. United Eur Gastroenterol J. 2019;7(5):583–613. Jun.
Rubio-Tapia A, Hill ID, Semrad C, Kelly CP, Greer KB, Limketkai BN, et al. American College of Gastroenterology Guidelines Update: Diagnosis and Management of Celiac Disease. Off J Am Coll Gastroenterol ACG. 2023 Jan;118(1):59.
Baykan AR, Cerrah S, Ciftel S, Vural MK, Kasap E. A No-Biopsy Approach for the Diagnosis of Celiac Disease in Adults: Can It Be Real? Cureus. 2022;14(7):e26521.
Shiha MG, Raju SA, Sidhu R, Penny HA. The debate in the diagnosis of coeliac disease—time to go ‘no-biopsy’? Curr Opin Gastroenterol. 2023;1;39(3):192–9. May.
Tashtoush LB, Bosanko NC, Broad SR, Chan YJ, Singhal N, Saji S, et al. Letter: the BSG COVID-19 interim coeliac disease guidance no-biopsy approach is safe in adults. Aliment Pharmacol Ther. 2021;54(8):1090–2. Oct.
Riznik P, Balogh M, Bódi P, De Leo L, Dolinsek J, Guthy I, et al. The Use of Biopsy and ‘No-Biopsy’ Approach for Diagnosing Paediatric Coeliac Disease in the Central European Region. Gastroenterol Res Pract. 2019;2019:9370397.
Felber J, Bläker H, Fischbach W, Koletzko S, Laaß M, Lachmann N, et al. Aktualisierte S2k-Leitlinie Zöliakie der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS). Z Gastroenterol. 2022;60(5):790–856. May.
Johnston RD, Chan YJ, Mubashar T, Bailey JR, Paul SP. No-biopsy pathway following the interim BSG guidance reliably diagnoses adult coeliac disease. Frontline Gastroenterol. 2022;13(1):73–6.
Paul SP, Lau WYS, Khan ZH, Letter HPA. no-biopsy pathway for diagnosing adult coeliac disease. Aliment Pharmacol Ther. 2021;53(2):357–8. Jan.
Penny HA, Raju SA, Lau MS, Marks LJ, Baggus EM, Bai JC, et al. Accuracy of a no-biopsy approach for the diagnosis of coeliac disease across different adult cohorts. Gut. 2021;70(5):876–83. May.
Mott T, Gray C, Storey JA. “no-biopsy” approach to diagnosing celiac disease. J Fam Pract. 2022;71(8):359–61. Oct.
Celiac Disease RL. A Common Unrecognized Health Problem with a Very Delayed Diagnosis. Med Kaunas Lith. 2019;26;56(1):E9. Dec.
Riznik P, De Leo L, Dolinsek J, Gyimesi J, Klemenak M, Koletzko B, et al. Diagnostic Delays in Children With Coeliac Disease in the Central European Region. J Pediatr Gastroenterol Nutr. 2019;69(4):443–8. Oct.
Coppell KJ, Stamm RA, Sharp KP. Diagnostic delays and treatment challenges in children with coeliac disease: The New Zealand Coeliac Health Survey. N Z Med J. 2019;8;132(1505):29–37. Nov.
Ramosaj-Morina A, Keka-Sylaj A, Zejnullahu AB, Spahiu L, Hasbahta V, Jaha V, et al. Celiac Disease in Kosovar Albanian Children: Evaluation of Clinical Features and Diagnosis. Curr Pediatr Rev. 2020;16(3):241–7.
Kårhus LL, Hansen S, Rumessen JJ, Linneberg A. Diagnostic Delay in Coeliac Disease: A Survey among Danish Patients. Can J Gastroenterol Hepatol. 2022;2022:5997624.
Lenti MV, Aronico N, Bianchi PI, D’Agate CC, Neri M, Volta U, et al. Diagnostic delay in adult coeliac disease: An Italian multicentre study. Dig Liver Dis Off J Ital Soc Gastroenterol Ital Assoc Study Liver. 2023 Jun;55(6):743–50.
Mansueto P, Spagnuolo G, Calderone S, D’Agate CC, Cosenza S, Leonardi G, et al. Improving the diagnostic approach to celiac disease: Experience from a regional network. Dig Liver Dis Off J Ital Soc Gastroenterol Ital Assoc Study Liver. 2022 Jun;54(6):771–5.
Mehta S, Agarwal A, Pachisia AV, Singh A, Dang S, Vignesh D, et al. Impact of delay in the diagnosis on the severity of celiac disease. J Gastroenterol Hepatol. 2023;14.
Keliakia [Internet]. [cited 2023 Dec 10]. Available from: https://www.kaypahoito.fi/hoi08001
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P. Rižnik, T. Kamhi Trop, M. Klemenak, T. Krenčnik, T. Milanič-Koron, E. Miler Mojškerc, T. Pavlin, T. Požek Šavs, J. Zupančič and J. Dolinšek declare that they have no competing interests.
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All procedures performed in studies involving human participants or on human tissue were in accordance with the ethical standards of the institutional and/or national research committee and with the 1975 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study. The study was approved by the National Medical Ethics Committee of the Republic of Slovenia (0120-12/2021/9).
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Rižnik, P., Kamhi Trop, T., Klemenak, M. et al. Insights into coeliac disease diagnosis: a 2021–2023 overview of diagnostic approach and delays in children in Slovenia. Wien Med Wochenschr (2024). https://doi.org/10.1007/s10354-024-01045-9
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DOI: https://doi.org/10.1007/s10354-024-01045-9