Skip to main content

Advertisement

Log in

Immunological Comorbity in Coeliac Disease: Associations, Risk Factors and Clinical Implications

  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

Purpose

Coeliac disease is frequently associated with other immunomediated diseases. Our aim was to identify immunological comorbidities and possible risk factors for their development in coeliac patients.

Methods

We recruited a cohort of 1,015 coeliac patients followed from 0 to 46 years in a single tertiary referral centre. Data were collected from the yearly scheduled clinical and serological evaluations. Possible risk factors such as demographic parameters, type of symptomatic presentation, gluten exposure, gluten-free diet compliance and family history were all evaluated. Subjects (848,606) from the regional health registry were investigated as controls.

Results

The prevalence of immunomediated diseases was higher in patients with coeliac disease compared to the registry population (23 % vs 0.4 %, p < 0.001). Diagnosis during paediatric age represented a risk factor for the presence of at least an immunomediated disease (hazard ratio = 1.62, 95 % confidence interval 1.15–2.29, p = 0.0061). Type of presentation and dietetic compliance did not represent risk factors. Long-standing gluten exposure reduced the risk of developing immunomediated diseases in coeliac subjects (hazard ratio for 1 year longer exposure 0.23, 95 % confidence interval 0.16–0.33, p < 0.0001). A familiar background characterized by the presence of immunological disorders was not a risk factor, although 419 (13 %) first degree relatives of coeliac patients out of 3,195 had an immunomediated disease.

Conclusions

Our study suggests the need to investigate coeliac patients for other associated immunomediated diseases, independently of sex, gluten exposure and compliance to therapy; also subjects diagnosed in paediatric age should be carefully screened during follow up.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Elli L, Bardella MT. Motility disorders in patients with celiac disease. Scand J Gastroenterol. 2005;40:743–9.

    Article  PubMed  Google Scholar 

  2. Elli L, Bergamini CM, Bardella MT, Schuppan D. Transglutaminases in inflammation and fibrosis of the gastrointestinal tract and the liver. Dig Liver Dis. 2009;41:541–50.

    Article  PubMed  CAS  Google Scholar 

  3. Dieterich W, Esslinger B, Schuppan D. Pathomechanisms in celiac disease. Int Arch Allergy Immunol. 2003;132:98–108.

    Article  PubMed  CAS  Google Scholar 

  4. Schuppan D, Junker Y, Barisani D. Celiac disease: from pathogenesis to novel therapies. Gastroenterology. 2009;137:1912–33.

    Article  PubMed  CAS  Google Scholar 

  5. Lindfors K, Kaukinen K, Maki M. A role for anti-transglutaminase 2 autoantibodies in the pathogenesis of coeliac disease? Amino Acids. 2009;36:685–91.

    Article  PubMed  CAS  Google Scholar 

  6. Dieterich W, Ehnis T, Bauer M, Donner P, Volta U, Riecken EO, et al. Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat Med. 1997;3:797–801.

    Article  PubMed  CAS  Google Scholar 

  7. Korponay-Szabo IR, Halttunen T, Szalai Z, Laurila K, Kiraly R, Kovacs JB, et al. In vivo targeting of intestinal and extraintestinal transglutaminase 2 by coeliac autoantibodies. Gut. 2004;53:641–8.

    Article  PubMed  CAS  Google Scholar 

  8. Cooper BT, Holmes GK, Cooke WT. Coeliac disease and immunological disorders. Br Med J. 1978;1:537–9.

    Article  PubMed  CAS  Google Scholar 

  9. Counsell CE, Taha A, Ruddell WS. Coeliac disease and autoimmune thyroid disease. Gut. 1994;35:844–6.

    Article  PubMed  CAS  Google Scholar 

  10. Berti I, Trevisiol C, Tommasini A, Citta A, Neri E, Geatti O, et al. Usefulness of screening program for celiac disease in autoimmune thyroiditis. Dig Dis Sci. 2000;45:403–6.

    Article  PubMed  CAS  Google Scholar 

  11. Larizza D, Calcaterra V, De Giacomo C, De Silvestri A, Asti M, Badulli C, et al. Celiac disease in children with autoimmune thyroid disease. J Pediatr. 2001;139:738–40.

    Article  PubMed  CAS  Google Scholar 

  12. Hadithi M, de Boer H, Meijer JW, Willekens F, Kerckhaert JA, Heijmans R, et al. Coeliac disease in Dutch patients with Hashimoto’s thyroiditis and vice versa. World J Gastroenterol. 2007;13:1715–22.

    PubMed  Google Scholar 

  13. Collin P, Salmi J, Hallstrom O, Reunala T, Pasternack A. Autoimmune thyroid disorders and coeliac disease. Eur J Endocrinol. 1994;130:137–40.

    Article  PubMed  CAS  Google Scholar 

  14. Sategna-Guidetti C, Volta U, Ciacci C, Usai P, Carlino A, De Franceschi L, et al. Prevalence of thyroid disorders in untreated adult celiac disease patients and effect of gluten withdrawal: an Italian multicenter study. Am J Gastroenterol. 2001;96:751–7.

    Article  PubMed  CAS  Google Scholar 

  15. Bardella MT, Elli L, De Matteis S, Floriani I, Torri V, Piodi L. Autoimmune disorders in patients affected by celiac sprue and inflammatory bowel disease. Ann Med. 2009;41:139–43.

    Article  PubMed  Google Scholar 

  16. Elfstrom P, Montgomery SM, Kampe O, Ekbom A, Ludvigsson JF. Risk of thyroid disease in individuals with celiac disease. J Clin Endocrinol Metab. 2008;93:3915–21.

    Article  PubMed  Google Scholar 

  17. Sorensen HT, Thulstrup AM, Blomqvist P, Norgaard B, Fonager K, Ekbom A. Risk of primary biliary liver cirrhosis in patients with coeliac disease: Danish and Swedish cohort data. Gut. 1999;44:736–8.

    Article  PubMed  CAS  Google Scholar 

  18. Kingham JG, Parker DR. The association between primary biliary cirrhosis and coeliac disease: a study of relative prevalences. Gut. 1998;42:120–2.

    Article  PubMed  CAS  Google Scholar 

  19. Bardella MT, Quatrini M, Zuin M, Podda M, Cesarini L, Velio P, et al. Screening patients with celiac disease for primary biliary cirrhosis and vice versa. Am J Gastroenterol. 1997;92:1524–6.

    PubMed  CAS  Google Scholar 

  20. Freeman HJ. Hepatobiliary and pancreatic disorders in celiac disease. World J Gastroenterol. 2006;12:1503–8.

    PubMed  CAS  Google Scholar 

  21. Bardella MT, Valenti L, Pagliari C, Peracchi M, Fare M, Fracanzani AL, et al. Searching for coeliac disease in patients with non-alcoholic fatty liver disease. Dig Liver Dis. 2004;36:333–6.

    Article  PubMed  CAS  Google Scholar 

  22. Caprai S, Vajro P, Ventura A, Sciveres M, Maggiore G. Autoimmune liver disease associated with celiac disease in childhood: a multicenter study. Clin Gastroenterol Hepatol. 2008;6:803–6.

    Article  PubMed  Google Scholar 

  23. Di Biase AR, Colecchia A, Scaioli E, Berri R, Viola L, Vestito A, et al. Autoimmune liver diseases in a paediatric population with coeliac disease—a 10-year single-centre experience. Aliment Pharmacol Ther. 2010;31:253–60.

    PubMed  Google Scholar 

  24. Lawson A, West J, Aithal GP, Logan RF. Autoimmune cholestatic liver disease in people with coeliac disease: a population-based study of their association. Aliment Pharmacol Ther. 2005;21:401–5.

    Article  PubMed  CAS  Google Scholar 

  25. Barker JM, Yu J, Yu L, Wang J, Miao D, Bao F, et al. Autoantibody “subspecificity” in type 1 diabetes: risk for organ-specific autoimmunity clusters in distinct groups. Diabetes Care. 2005;28:850–5.

    Article  PubMed  CAS  Google Scholar 

  26. Ludvigsson JF, Ludvigsson J, Ekbom A, Montgomery SM. Celiac disease and risk of subsequent type 1 diabetes: a general population cohort study of children and adolescents. Diabetes Care. 2006;29:2483–8.

    Article  PubMed  Google Scholar 

  27. Sategna-Guidetti C, Grosso S, Pulitano R, Benaduce E, Dani F, Carta Q. Celiac disease and insulin-dependent diabetes mellitus. Screening in an adult population. Dig Dis Sci. 1994;39:1633–7.

    Article  PubMed  CAS  Google Scholar 

  28. Maki M, Hallstrom O, Huupponen T, Vesikari T, Visakorpi JK. Increased prevalence of coeliac disease in diabetes. Arch Dis Child. 1984;59:739–42.

    Article  PubMed  CAS  Google Scholar 

  29. Cronin CC, Shanahan F. Insulin-dependent diabetes mellitus and coeliac disease. Lancet. 1997;349:1096–7.

    Article  PubMed  CAS  Google Scholar 

  30. Reunala T, Collin P. Diseases associated with dermatitis herpetiformis. Br J Dermatol. 1997;136:315–8.

    Article  PubMed  CAS  Google Scholar 

  31. Tack GJ, Verbeek WH, Schreurs MW, Mulder CJ. The spectrum of celiac disease: epidemiology, clinical aspects and treatment. Nat Rev Gastroenterol Hepatol. 2010;7:204–13.

    Article  PubMed  CAS  Google Scholar 

  32. Ludvigsson JF, Wahlstrom J, Grunewald J, Ekbom A, Montgomery SM. Coeliac disease and risk of sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2007;24:121–6.

    PubMed  Google Scholar 

  33. Wei L, Spiers E, Reynolds N, Walsh S, Fahey T, MacDonald TM. The association between coeliac disease and cardiovascular disease. Aliment Pharmacol Ther. 2008;27:514–9.

    Article  PubMed  CAS  Google Scholar 

  34. Ventura A, Magazzu G, Greco L. Duration of exposure to gluten and risk for autoimmune disorders in patients with celiac disease. SIGEP Study Group for Autoimmune Disorders in Celiac Disease. Gastroenterology. 1999;117:297–303.

    Article  PubMed  CAS  Google Scholar 

  35. Sategna Guidetti C, Solerio E, Scaglione N, Aimo G, Mengozzi G. Duration of gluten exposure in adult coeliac disease does not correlate with the risk for autoimmune disorders. Gut. 2001;49:502–5.

    Article  PubMed  CAS  Google Scholar 

  36. Cosnes J, Cellier C, Viola S, Colombel JF, Michaud L, Sarles J, et al. Incidence of autoimmune diseases in celiac disease: protective effect of the gluten-free diet. Clin Gastroenterol Hepatol. 2008;6:753–8.

    Article  PubMed  Google Scholar 

  37. Kagnoff MF. AGA institute medical position statement on the diagnosis and management of celiac disease. Gastroenterology. 2006;131:1977–80.

    Article  Google Scholar 

  38. Viljamaa M, Kaukinen K, Huhtala H, Kyronpalo S, Rasmussen M, Collin P. Coeliac disease, autoimmune diseases and gluten exposure. Scand J Gastroenterol. 2005;40:437–43.

    Article  PubMed  CAS  Google Scholar 

  39. Barker JM, Liu E. Celiac disease: pathophysiology, clinical manifestations, and associated autoimmune conditions. Adv Pediatr. 2008;55:349–65.

    Article  PubMed  Google Scholar 

  40. Barker JM. Clinical review: type 1 diabetes-associated autoimmunity: natural history, genetic associations, and screening. J Clin Endocrinol Metab. 2006;91:1210–7.

    Article  PubMed  CAS  Google Scholar 

  41. Fesus L, Piacentini M. Transglutaminase 2: an enigmatic enzyme with diverse functions. Trends Biochem Sci. 2002;27:534–9.

    Article  PubMed  CAS  Google Scholar 

  42. Roncoroni L, Elli L, Doneda L, Piodi L, Ciulla MM, Paliotti R, et al. Isolation and culture of fibroblasts from endoscopic duodenal biopsies of celiac patients. J Transl Med. 2009;7:40.

    Article  PubMed  Google Scholar 

  43. Griffin M, Verderio E. Tissue transglutaminase in cell death. Symp Soc Exp Biol. 2000;52:223–40.

    PubMed  CAS  Google Scholar 

  44. Kim SY. Transglutaminase 2 in inflammation. Front Biosci. 2006;11:3026–35.

    Article  PubMed  CAS  Google Scholar 

  45. Fesus L, Szondy Z. Transglutaminase 2 in the balance of cell death and survival. FEBS Lett. 2005;579:3297–302.

    Article  PubMed  Google Scholar 

  46. Shoenfeld Y, Tincani A, Gershwin ME. Sex gender and autoimmunity. J Autoimmun. 2012;38:J71–3.

    Article  PubMed  CAS  Google Scholar 

  47. Akbari MR, Mohammadkhani A, Fakheri H, Javad Zahedi M, Shahbazkhani B, Nouraie M, et al. Screening of the adult population in Iran for coeliac disease: comparison of the tissue-transglutaminase antibody and anti-endomysial antibody tests. Eur J Gastroenterol Hepatol. 2006;18:1181–6.

    Article  PubMed  Google Scholar 

  48. Whitacre CC. Sex differences in autoimmune disease. Nat Immunol. 2001;2:777–80.

    Article  PubMed  CAS  Google Scholar 

  49. Bardella MT, Elli L, Velio P, Fredella C, Prampolini L, Cesana B. Silent celiac disease is frequent in the siblings of newly diagnosed celiac patients. Digestion. 2007;75:182–7.

    Article  PubMed  Google Scholar 

  50. Hall NJ, Rubin G, Charnock A. Systematic review: adherence to a gluten-free diet in adult patients with coeliac disease. Aliment Pharmacol Ther. 2009;30:315–30.

    Article  PubMed  CAS  Google Scholar 

  51. Leffler DA, Edwards George JB, Dennis M, Cook EF, Schuppan D, Kelly CP. A prospective comparative study of five measures of gluten-free diet adherence in adults with coeliac disease. Aliment Pharmacol Ther. 2007;26:1227–35.

    Article  PubMed  CAS  Google Scholar 

  52. Scheinecker C, McHugh R, Shevach EM, Germain RN. Constitutive presentation of a natural tissue autoantigen exclusively by dendritic cells in the draining lymph node. J Exp Med. 2002;196:1079–90.

    Article  PubMed  CAS  Google Scholar 

  53. He P. Leucocyte/endothelium interactions and microvessel permeability: coupled or uncoupled? Cardiovasc Res. 2010;87:281–90.

    Article  PubMed  CAS  Google Scholar 

  54. Lohi S, Maki M, Rissanen H, Knekt P, Reunanen A, Kaukinen K. Prognosis of unrecognized coeliac disease as regards mortality: a population-based cohort study. Ann Med. 2009:1–8.

  55. Godfrey JD, Brantner TL, Brinjikji W, Christensen KN, Brogan DL, Van Dyke CT, et al. Morbidity and mortality among older individuals with undiagnosed celiac disease. Gastroenterology. 2005;139:763–9.

    Article  Google Scholar 

Download references

Conflict of Interest

The authors have no conflict of interest

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Luca Elli.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Elli, L., Bonura, A., Garavaglia, D. et al. Immunological Comorbity in Coeliac Disease: Associations, Risk Factors and Clinical Implications. J Clin Immunol 32, 984–990 (2012). https://doi.org/10.1007/s10875-012-9693-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-012-9693-0

Keywords

Navigation