Ultra-Short Celiac Disease: Clinical, Immunophenotypic, Morphological, and Genetic Features

Ultra-short celiac disease is one of the phenotypes of common celiac disease, it is characterized by hyper-regenerative atrophy and/or intraepithelial lymphocytosis in duodenal bulb along with no mucosal damage in distal duodenum, serological positivity, the presence of HLA-DQ2. However, seropositivity and classical HLA-DQ2 haplotypes frequency differs from usual celiac disease, thus, there are significant difficulties in differential diagnosis. Data on prevalence, clinical manifestations, histological lesions, genetic features, and outcome of ultra-short celiac disease is insufficient and should be accumulated. This review focuses on analyzing the studies results about ultra-short celiac disease and describes the clinical, immunological, and genetic features of this disease phenotype.

1. Catassi C, Verdu EF, Bai JC, Lionetti E. Coeliac disease. Lancet. 2022;399(10344):2413–2426. doi: https://doi.org/10.1016/s0140-6736(22)00794-2

2. Lindfors K, Ciacci C, Kurppa K, et al. Coeliac disease. Nat Rev Dis Primers. 2019;5(1):3. doi: https://doi.org/10.1038/s41572018-0054-z

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

4. Makharia GK, Singh P, Catassi C, et al. The global burden of coeliac disease: opportunities and challenges. Nat Rev Gastroenterol Hepatol. 2022;19(5):313–327. doi: https://doi.org/10.1038/s41575-021-00552-z

5. Tseliakiya u detei i vzroslykh: Monograph. Belmer SV, Revnova MO, eds. Moscow: GEOTAR-Media; 2024. 293 p. (In Russ).

6. Kondrat’eva EI, Yankina GN, Loshkova EV. Variants of wheat protein intolerance. Modern understanding. Voprosy Dietologii = Nutrition. 2016;3(3):57–66. (In Russ). doi: https://doi.org/10.20953/2224-5448-2016-3-57-65

7. Yankina GN, Kondrat’eva EI, Loshkova EV, Terentyeva AA. Specificities of diagnosis and management of various forms of wheat protein intolerance. Voprosy detskoi dietologii = Pediatric Nutrition. 2017;15(1):13–24. (In Russ). doi: https://doi.org/10.20953/1727-5784-2017-1-13-24

8. Yankina GN, Loshkova EV, Kondratyeva EI, et al. Comorbidity in celiac disease. Pediatria. Journal n.a. G.N. Speransky. 2017;96(6):140–149. (In Russ). doi: https://doi.org/10.24110/0031403X-2017-96-6-140-149

9. Khavkin АI, Bystrova VI, Schreiner ЕV, et al. Celiac disease: old problem, new solutions. Voprosy dietologii = Nutrition. 2023;13(4):64–71. (In Russ). doi: https://doi.org/10.20953/2224-5448-2023-4-64-71

10. Carroccio A, Rostami K, Fasano A, et al. Nonceliac Wheat Sensitivity: Bridging Research, Clinical Experience, Uncertainties, and Future Prospective. Gastrointest Endosc Clin N Am. 2025;35(4):893– 909. doi: https://doi.org/10.1016/j.giec.2025.02.010

11. Kowalski MK, Domżał-Magrowska D, Małecka-Wojciesko E. Celiac Disease-Narrative Review on Progress in Celiac Disease. Foods. 2025;14(6):959. doi: https://doi.org/10.3390/foods14060959

12. Khavkin AI, Loshkova EV, Kondratieva EI, et al. The Role of Macrophages in the Pathogenesis of Celiac Disease. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2024;34(4):86–93. (In Russ). doi: https://doi.org/10.22416/13824376-2024-34-4-86-93

13. Shapovalova NS, Novikova VP, Revnova MO, et al. Seronegative coeliac disease in the light of the guidelines by the European Society for the Study of Coeliac Disease (ESsCD) 2019. Voprosy detskoi dietologii = Pediatric Nutrition. 2019;17(6):14–22. (In Russ). doi: https://doi.org/10.20953/1727-5784-2019-6-14-22

14. Al-Toma A, Volta U, Auricchio R, et al. European Society for the Study of Coeliac Disease (ESsCD) guideline for coeliac disease and other gluten-related disorders. United European Gastroenterol J. 2019;7(5):583–613. doi: https://doi.org/10.1177/2050640619844125

15. Mooney PD, Kurien M, Evans KE, et al. Clinical and Immunologic Features of Ultra-Short Celiac Disease. Gastroenterology. 2016;150(5):1125–1134. doi: https://doi.org/10.1053/j.gastro.2016.01.029

16. Doyev R, Cohen S, Ben-Tov A, et al. Ultra-short Celiac Disease Is a Distinct and Milder Phenotype of the Disease in Children. Dig Dis Sci. 2019;64(1):167–172. doi: https://doi.org/10.1007/s10620018-5323-x

17. Volta U, Rostami K, Auricchio R, Lundin KEA. Diagnosis of Seronegative and Ultrashort Celiac Disease. Gastroenterology. 2024;167(1):104–115. doi: https://doi.org/10.1053/j.gastro.2024.01.029

18. Zifman E, Berliand J, Sofer B, et al. The Characteristics of Isolated Duodenal Bulb Coeliac Disease in Children: A Multicentre Retrospective Study. Acta Paediatr. 2025;114(10):2697–2701. doi: https://doi.org/10.1111/apa.70169

19. Ahmed M, Tolufase T, Gill P, Sayed MI. Effectiveness of duodenal bulb biopsies in histological diagnosis of coeliac disease. Eur J Pediatr. 2025;184(5):277. doi: https://doi.org/10.1007/s00431025-06113-9

20. Averkina NA, Baranov AA, Bel’mer SV, et al. “Celiac Disease-2025”: Project of Clinical Guidelines for the Diagnosis and Treatment of Celiac Disease in Children. Pediatricheskaya farmakologiya — Pediatric pharmacology. 2025;22(4):495–522. (In Russ). doi: https://doi.org/10.15690/pf.v22i4.2941

21. Mata-Romero P, Martín-Holgado D, Ferreira-Nossa HC, et al. Ultra-short celiac disease exhibits differential genetic and immunophenotypic features compared to conventional celiac disease. Gastroenterol Hepatol. 2022;45(9):652–659. doi: https://doi.org/10.1016/j.gastrohep.2022.03.011

22. Marsh MN. Gluten, major histocompatibility complex, and the small intestine: a molecular and immunobiologic approach to the spectrum of gluten sensitivity (‘celiac sprue’). Gastroenterology. 1992;102(1);330–354.

23. Rostami K, Aldulaimi D, Holmes G, et al. Microscopic enteritis: Bucharest consensus. World J Gastroenterol. 2015;21(9):2593– 2604. doi: https://doi.org/10.3748/wjg.v21.i9.2593

24. Owen DR, Owen DA. Celiac Disease and Other Causes of Duodenitis. Arch Pathol Lab Med. 2018;142(1):35–43. doi: https://doi.org/10.5858/arpa.2016-0608-RA

25. Kröger S, Repo M, Hiltunen P, et al. Differential diagnosis and long-term outcomes of non-atrophic duodenal changes in children. Front Pediatr. 2022;10:982623. doi: https://doi.org/10.3389/fped.2022.982623

26. Mäki M, Holm K, Collin P, Savilahti E. Increase in gamma/delta T cell receptor bearing lymphocytes in normal small bowel mucosa in latent coeliac disease. Gut. 1991;32(11):1412–1414. doi: https://doi.org/10.1136/gut.32.11.1412

27. Holm K, Mäki M, Savilahti E, et al. Intraepithelial gamma delta T-cell-receptor lymphocytes and genetic susceptibility to coeliac disease. Lancet. 1992;339(8808):1500–1503. doi: https://doi.org/10.1016/0140-6736(92)91262-7

28. Arranz E, Bode J, Kingstone K, Ferguson A. Intestinal antibody pattern of coeliac disease: association with gamma/delta T cell receptor expression by intraepithelial lymphocytes, and other indices of potential coeliac disease. Gut. 1994;35(4):476–482. doi: https://doi.org/10.1136/gut.35.4.476

29. Loft D, Marsh M, Crowe P. Rectal gluten challenge and diagnosis of coeliac disease. Lancet. 1990;335(8701):1293–1295. doi: https://doi.org/10.1016/0140-6736(90)91183-b

30. Ensari A, Marsh MN, Loft DE, et al. Morphometric analysis of intestinal mucosa. V. Quantitative histological and immunocytochemical studies of rectal mucosae in gluten sensitivity. Gut. 1993;34(9):1225–1229. doi: https://doi.org/10.1136/gut.34.9.1225

31. Abadie V, Discepolo V, Jabri B. Intraepithelial lymphocytes in celiac disease immunopathology. Semin Immunopathol. 2012;34(4):551–566. doi: https://doi.org/10.1007/s00281-012-0316-x

32. Alonso S, Edelblum K. Metabolic regulation of γδ intraepithelial lymphocytes. Discov Immunol. 2023;2(1):kyad011. doi: https://doi.org/10.1093/discim/kyad011

33. Nazmi A, McClanahan KG, Olivares-Villagomez D. Unconventional Intestinal Intraepithelial Lymphocytes in Health and Disease. Crit Rev Immunol. 2021;41(4):23–38. doi: https://doi.org/10.1615/CritRevImmunol.2021039957

34. Järvinen TT, Kaukinen K, Laurila K, et al. Intraepithelial Lymphocytes in Celiac Disease. Am J Gastroenterol. 2003;98(6): 1332–1337. doi: https://doi.org/10.1111/j.1572-0241.2003.07456.x

35. Kutlu T, Brousse N, Rambaud C, et al. Numbers of T cell receptor (TCR) alpha beta+ but not of TcR gamma delta+ intraepithelial lymphocytes correlate with the grade of villous atrophy in coeliac patients on a long term normal diet. Gut. 1993;34(2):208–214. doi: https://doi.org/10.1136/gut.34.2.208

36. Paparo F, Petrone E, Tosco A, et al. Clinical, HLA, and small bowel immunohistochemical features of children with positive serum antiendomysium antibodies and architecturally normal small intestinal mucosa. Am J Gastroenterol. 2005;100(10):2294–2298. doi: https://doi.org/10.1111/j.1572-0241.2005.41134.x

37. Villanacci V, Ciacci C, Salviato T, et al. Histopathology of celiac disease. Position statements of the Italian Group of Gastrointestinal Pathologists (GIPAD-SIAPEC). Transl Med UniSa. 2020;23:28–36. doi: https://doi.org/10.37825/2239-9747.1005

38. Salmi TT, Collin P, Korponay-Szabo IR, et al. Endomysial antibody-negative coeliac disease: clinical characteristics and intestinal autoantibody deposits. Gut. 2006;55(12):1746–1753. doi: https://doi.org/10.1136/gut.2005.071514

39. Popp A, Taavela J, Graziano P, et al. A New Intraepithelial γδ T-Lymphocyte Marker for Celiac Disease Classification in FormalinFixed Paraffin-Embedded (FFPE) Duodenal Biopsies. Dig Dis Sci. 2021;66(10):3352–3358. doi: https://doi.org/10.1007/s10620-020-06680-x

40. Christophersen A, Zühlke S, Lund EG, et al. Pathogenic T Cells in Celiac Disease Change Phenotype on Gluten Challenge: Implications for T-Cell-Directed Therapies. Adv Sci(Weinh). 2021;8(21):e2102778. doi: https://doi.org/10.1002/advs.202102778

41. Aitella E, Cozzolino D, Ginaldi L, Romano C. Celiac Disease: A Transitional Point of View. Nutrients. 2025;17(2):234. doi: https://doi.org/10.3390/nu17020234

42. Calleja S, Vivas S, Santiuste M, et al. Dynamics of nonconventional intraepithelial lymphocytes-NK, NKT, and γδ T-in celiac disease: relationship with age, diet, and histopathology. Dig Dis Sci. 2011;56(7):2042–2049. doi: https://doi.org/10.1007/s10620-010-1534-5

43. Nijeboer Q, van Gils T, Reijm M, et al. Gamma-delta T lymphocytes in the diagnostic approach of coeliac disease. J Clin Gastroenterol. 2019;53(5):e208–e213. doi: https://doi.org/10.1097/MCG.0000000000001060

44. Fernández-Bañares F, Crespo L, Nunez C, et al. Gamma delta*intraepithelial lymphocytes and coeliac lymphogram in a diagnostic approach to coeliac disease in patients with seronegative villous atrophy. Aliment Pharmacol Ther. 2020;51(7):699–705. doi: https://doi.org/10.1111/apt.15663

45. Kozan EN, Kırmızı BA, Kirsaclioglu CT, et al. A new algorithm for coeliac disease based on the ‘long forgotten’ TCRγδ+ intraepithelial lymphocytes detected with an antibody working on FFPE sections. Histopathology. 2025;86(3):397–409. doi: https://doi.org/10.1111/his.15330

46. Kornberg A, Botella T, Moon CS, et al. Gluten induces rapid reprogramming of natural memory αβ and γδ intraepithelial T cells to induce cytotoxicity in celiac disease. Sci Immunol. 2023;8(85):eadf4312. doi: https://doi.org/10.1126/sciimmunol.adf4312

47. Abadie V, Han AS, Jabri B, Sollid LM. New Insights on Genes, Gluten, and Immunopathogenesis of Celiac Disease. Gastroenterology. 2024; 167(1):4–22. doi: https://doi.org/10.1053/j.gastro.2024.03.042

48. Brown NK, Guandalini S, Semrad C, Kupfer SS. A clinician’s guide to celiac disease HLA genetics. Am J Gastroenterol. 2019;114(10):1587–1592. doi: https://doi.org/10.14309/ajg.0000000000000310

49. Liu E, Lee HS, Aronsson CA, et al. Risk of pediatric celiac disease according to HLA haplotype and country. N Engl J Med. 2014;371(1):42–49. doi: https://doi.org/10.1056/NEJMoa1313977

50. Raju SA, Greenaway EA, Schiepatti A, et al. New entity of adult ultra-short coeliac disease: the first international cohort and case-control study. Gut. 2024;73(7):1124–1130. doi: https://doi.org/10.1136/gutjnl-2023-330913