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.
Similar content being viewed by others
References
Elli L, Bardella MT. Motility disorders in patients with celiac disease. Scand J Gastroenterol. 2005;40:743–9.
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.
Dieterich W, Esslinger B, Schuppan D. Pathomechanisms in celiac disease. Int Arch Allergy Immunol. 2003;132:98–108.
Schuppan D, Junker Y, Barisani D. Celiac disease: from pathogenesis to novel therapies. Gastroenterology. 2009;137:1912–33.
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.
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.
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.
Cooper BT, Holmes GK, Cooke WT. Coeliac disease and immunological disorders. Br Med J. 1978;1:537–9.
Counsell CE, Taha A, Ruddell WS. Coeliac disease and autoimmune thyroid disease. Gut. 1994;35:844–6.
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.
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.
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.
Collin P, Salmi J, Hallstrom O, Reunala T, Pasternack A. Autoimmune thyroid disorders and coeliac disease. Eur J Endocrinol. 1994;130:137–40.
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.
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.
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.
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.
Kingham JG, Parker DR. The association between primary biliary cirrhosis and coeliac disease: a study of relative prevalences. Gut. 1998;42:120–2.
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.
Freeman HJ. Hepatobiliary and pancreatic disorders in celiac disease. World J Gastroenterol. 2006;12:1503–8.
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.
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.
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.
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.
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.
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.
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.
Maki M, Hallstrom O, Huupponen T, Vesikari T, Visakorpi JK. Increased prevalence of coeliac disease in diabetes. Arch Dis Child. 1984;59:739–42.
Cronin CC, Shanahan F. Insulin-dependent diabetes mellitus and coeliac disease. Lancet. 1997;349:1096–7.
Reunala T, Collin P. Diseases associated with dermatitis herpetiformis. Br J Dermatol. 1997;136:315–8.
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.
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.
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.
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.
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.
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.
Kagnoff MF. AGA institute medical position statement on the diagnosis and management of celiac disease. Gastroenterology. 2006;131:1977–80.
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.
Barker JM, Liu E. Celiac disease: pathophysiology, clinical manifestations, and associated autoimmune conditions. Adv Pediatr. 2008;55:349–65.
Barker JM. Clinical review: type 1 diabetes-associated autoimmunity: natural history, genetic associations, and screening. J Clin Endocrinol Metab. 2006;91:1210–7.
Fesus L, Piacentini M. Transglutaminase 2: an enigmatic enzyme with diverse functions. Trends Biochem Sci. 2002;27:534–9.
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.
Griffin M, Verderio E. Tissue transglutaminase in cell death. Symp Soc Exp Biol. 2000;52:223–40.
Kim SY. Transglutaminase 2 in inflammation. Front Biosci. 2006;11:3026–35.
Fesus L, Szondy Z. Transglutaminase 2 in the balance of cell death and survival. FEBS Lett. 2005;579:3297–302.
Shoenfeld Y, Tincani A, Gershwin ME. Sex gender and autoimmunity. J Autoimmun. 2012;38:J71–3.
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.
Whitacre CC. Sex differences in autoimmune disease. Nat Immunol. 2001;2:777–80.
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.
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.
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.
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.
He P. Leucocyte/endothelium interactions and microvessel permeability: coupled or uncoupled? Cardiovasc Res. 2010;87:281–90.
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.
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.
Conflict of Interest
The authors have no conflict of interest
Author information
Authors and Affiliations
Corresponding author
Rights 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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10875-012-9693-0