The options of celiac disease diagnostics in children with immunoglobulin A deficiency

Introduction. Serological methods remain the main tool for screening for celiac disease. The most sensitive and specific markers of the disease are anti-tissue transglutaminase and anti-endomysium IgA antibodies, but the possibility of their use is limited by the concentration of serum total IgA. Due to the frequent association of celiac disease with selective immunoglobulin A deficiency, the search for diagnostic markers in this group of patients is relevant.

Аim. Тo evaluate the diagnostic value of serological markers of celiac disease in children with decreased serum immunoglobulin A.

Materials and methods. The sensitivity, specificity, positive and negative predictive value of IgG antibodies to anti-tissue transglutaminase (anti-tTG IgG), deamidated gliadin peptides (anti- DPG IgG) and gliadin (AGA IgG) were analyzed in a group of 166 children aged 1 to 17 years, average age 6.04 years, with varying degrees of immunoglobulin A deficiency.

Results. The incidence of celiac disease in symptomatic patients with decreased serum immunoglobulin A concentrations was 13.2%, increasing up to 20% in the group of patients with selective IgA deficiency. Anti-tTG IgG demonstrated high values of sensitivity, specificity and positive predictive value as 85%, 97.3% and 85%, respectively. With comparable sensitivity and specificity, anti- DPG IgG were significantly worse with positive predictive value (26.7%). AGA IgG showed the lowest diagnostic value. When analyzing the dependence of the degree of histological changes on the concentration of tTG IgG, no statistically significant correlation was determined.

Conclusions. Frequent association of gluten enteropathy with hypogammaglobulinemia A determines the need for active screening for celiac disease among children with these type of humoral immunity. Anti-tTG IgG demonstrate high diagnostic value in children with IgA deficiency, however, verification of the diagnosis of celiac disease in patients with hypogammaglobulinemia A requires mandatory endoscopic and histological studies.

1. Боровик ТЭ, Захарова ИН, Потапов АС, Бельмер СВ, Хавкин АИ, Ревнова МО и др. Федеральные клинические рекомендации по оказанию медицинской помощи детям с целиакией. 2015. 22 с. Режим доступа: https://mosgorzdrav.ru/ru-RU/science/default/download/107.html.

2. Parfenov AI, Mayev IV, Baranov AA, Bakulin IG, Sabelnikova EA, Krums LM et al. The Russian consensus on diagnosis and treatment of coeliac disease in children and adults. Almanac of Clinical Medicine. 2016;44(6):661–688. (In Russ.) https://doi.org/10.18786/2072-0505-2016-44-6-661-688.

3. Husby S, Koletzko S, Korponay-Szabó, Kurppa K, Mearin ML, RibesKoninckx C et al. European Society Paediatric Gastroenterology, Hepatology and Nutrition Guidelines for Diagnosing Coeliac Disease 2020. J Pediatr Gastroenterol Nutr. 2020;70(1):141–156. https://doi.org/10.1097/MPG.0000000000002497.

4. Gostyukhina AD, Dmitrieva YuA, Osmanov IM, Maikova ID, Skorobogatova EV, Radchenko ER, Zakharova IN. Selective screening for celiac disease in patients with gastrointestinal symptoms: A retrospective study. Pediatrics. Consilium Medicum. 2024;(2):162–166. (In Russ.) https://doi.org/10.26442/26586630.2024.2.202950.

5. Dmitrieva YA, Zakharova IN, Osmanov IM, Gostyukhina AD, Teslenko SE, Radchenko ER et al. Diagnostic value of serological markers for celiac disease in children. Meditsinskiy Sovet. 2024;(11):180–187. (In Russ.) https://doi.org/10.21518/ms2024-315.

6. Yazdani R, Azizi G, Abolhassani H, Aghamohammadi A. Selective IgA deficiency: epidemiology, pathogenesis, clinical phenotype, diagnosis, prognosis and management. Scand J Immunol. 2017;85(1):3–12. https://doi.org/10.1111/sji.12499.

7. Bonilla FA, Khan DA, Ballas ZK, Chinen J, Frank MM, Hsu JT et al. Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol. 2015;136(5):1186–1205. https://doi.org/10.1016/j.jaci.2015.04.049.

8. Yel L. Selective IgA deficiency. J Clin Immunol. 2010;30(1):10–16. https://doi.org/10.1007/s10875-009-9357-x.

9. Jacob CM, Pastorino AC, Fahl K, Carneiro-Sampaio M, Monteiro RC. Autoimmunity in IgA deficiency: revisiting the role of IgA as a silent housekeeper. J Clin Immunol. 2008;28(1):56–61. https://doi.org/10.1007/s10875-007-9163-2.

10. Sheppard AL, Elwenspoek MMC, Scott LJ, Corfield V, Everitt H, Gillett PM et al. Systematic review with meta-analysis: the accuracy of serological tests to support the diagnosis of coeliac disease. Aliment Pharmacol Ther. 2022;55(5):514–527. https://doi.org/10.1111/apt.16729.

11. Коровина НА, Заплатников АЛ. Иммуноглобулины для внутривенного введения в педиатрической практике. М.; 2008. 60 с.

12. Дранник ГН. Клиническая иммунология и аллергология. М.: Медицинское информационное агентство; 2003. 604 с.

13. Janzi M, Kull I, Sjöberg R, Wan J, Melén E, Bayat N et al. Selective IgA deficiency in early life: association to infections and allergic diseases during childhood. Clin Immunol. 2009;133(1):78–85. https://doi.org/10.1016/j.clim.2009.05.014.

14. Corthésy B. Roundtrip ticket for secretory IgA: role in mucosal homeostasis? J Immunol. 2007;178(1):27–32. https://doi.org/10.4049/jimmunol.178.1.27.

15. Cunningham-Rundles C. Physiology of IgA and IgA deficiency. J Clin Immunol. 2001;21(5):303–309. https://doi.org/10.1023/a:1012241117984.

16. Aghamohammadi A, Cheraghi T, Gharagozlou M, Movahedi M, Rezaei N, Yeganeh M et al. IgA deficiency: correlation between clinical and immunological phenotypes. J Clin Immunol. 2009;29(1):130–136. https://doi.org/10.1007/s10875-008-9229-9.

17. Latiff AH, Kerr MA. The clinical significance of immunoglobulin A deficiency. Ann Clin Biochem. 2007;44(2):131–139. https://doi.org/10.1258/000456307780117993.

18. Dmitrieva YuA, Zakharova IN, Radchenko ER. Selective IgA deficiency in pediatrician practice. Pediatrics. Consilium Medicum. 2019;(3):122–126. (In Russ.) https://doi.org/10.26442/26586630.2019.3.190633.

19. Prince HE, Norman GL, Binder WL. Immunoglobulin A (IgA) deficiency and alternative celiac disease-associated antibodies in sera submitted to a reference laboratory for endomysial IgA testing. Clin Diagn Lab Immunol. 2000;7(2):192–196. https://doi.org/10.1128/CDLI.7.2.192-196.2000.

20. 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):136–160. https://doi.org/10.1097/MPG.0b013e31821a23d0.

21. Méndez Loayza DLÁ, Arriola Spátola MA, Gonzáles de Campos AL, Montenegro Pucci C, Olano Gossweiler C. Prevalence and characteristics of selective IgA deficiency in celiac patients. Rev Gastroenterol Peru. 2021;41(1):11–15. Available at: https://pubmed.ncbi.nlm.nih.gov/34347764.

22. Korponay-Szabó IR, Dahlbom I, Laurila K, Koskinen S, Woolley N, Partanen J et al. Elevation of IgG antibodies against tissue transglutaminase as a diagnostic tool for coeliac disease in selective IgA deficiency. Gut. 2003;52(11):1567–1571. https://doi.org/10.1136/gut.52.11.1567.

23. Villalta D, Alessio MG, Tampoia M, Tonutti E, Brusca I, Bagnasco M et al. Testing for IgG class antibodies in celiac disease patients with selective IgA deficiency. A comparison of the diagnostic accuracy of 9 IgG anti-tissue transglutaminase, 1 IgG anti-gliadin and 1 IgG anti-deaminated gliadin peptide antibody assays. Clin Chim Acta. 2007;382(1-2):95–99. https://doi.org/10.1016/j.cca.2007.03.028.

24. Schwertz E, Kahlenberg F, Sack U, Richter T, Stern M, Conrad K et al. Serologic assay based on gliadin-related nonapeptides as a highly sensitive and specific diagnostic aid in celiac disease. Clin Chem. 2004;50(12):2370–2375. https://doi.org/10.1373/clinchem.2004.036111.

25. Volta U, Villanacci V. Celiac disease: diagnostic criteria in progress. Cell Mol Immunol. 2011;8(2):96–102. https://doi.org/10.1038/cmi.2010.64.

26. Brusca I, Carroccio A, Tonutti E, Villalta D, Tozzoli R, Barrale M et al. The old and new tests for celiac disease: which is the best test combination to diagnose celiac disease in pediatric patients? Clin Chem Lab Med. 2011;50(1):111–117. https://doi.org/10.1515/CCLM.2011.714.

27. Gould MJ, Brill H, Marcon MA, Munn NJ, Walsh CM. In screening for celiac disease, deamidated gliadin rarely predicts disease when tissue transglutaminase is normal. J Pediatr Gastroenterol Nutr. 2019;68(1):20–25. https://doi.org/10.1097/MPG.0000000000002109.

28. Absah I, Rishi AR, Gebrail R, Snyder MR, Murray JA. Lack of Utility of AntitTG IgG to Diagnose Celiac Disease When Anti-tTG IgA Is Negative. J Pediatr Gastroenterol Nutr. 2017;64(5):726–729. https://doi.org/10.1097/MPG.0000000000001351.