Background: Celiac disease (CD) is a small-intestinal inflammatory disease that is triggered by the ingestion of the storage proteins (gluten) of wheat, barley and rye. Key Messages: Endocrine autoimmunity is prevalent in patients with CD and their relatives. The genes that predispose to endocrine autoimmune diseases, e.g. type 1 diabetes, autoimmune thyroid diseases, and Addison's disease, i.e. DR3-DQ2 and DR4-DQ8, are also the major genetic determinants of CD, which is the best understood HLA-linked disease. Thus, up to 30% of first-degree relatives both of patients with CD and/or endocrine autoimmunity are affected by the other disease. In CD, certain gluten proteins bind with high affinity to HLA-DQ2 or -DQ8 in the small-intestinal mucosa, to activate gluten-specific T cells which are instrumental in the destruction of the resorptive villi. Here, the autoantigen tissue transglutaminase increases the T cell response by generating deamidated gluten peptides that bind more strongly to DQ2 or DQ8. Classical symptoms such as diarrhea and consequences of malabsorption like anemia and osteoporosis are often absent in patients with (screening-detected) CD, but this absence does not significantly affect these patients' incidence of endocrine autoimmunity. Moreover, once autoimmunity is established, a gluten-free diet is not able to induce remission. However, ongoing studies attempt to address how far a gluten-free diet may prevent or retard the development of CD and endocrine autoimmunity in children at risk. Conclusions: The close relationship between CD and endocrine autoimmunity warrants a broader immune genetic and endocrine screening of CD patients and their relatives.

Keywords:
Celiac disease, Autoimmune thyroid disease, Endocrine autoimmunity, Polyglandular autoimmune syndrome, Type 1 diabetes
1.
Dieterich W, Ehnis T, Bauer M, et al: Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat Med 1997;3:797-801.
2.
Green PH, Cellier C: Celiac disease. N Engl J Med 2007;357:1731-1743.
3.
Schuppan D, Junker Y, Barisani D: Celiac disease: from pathogenesis to novel therapies. Gastroenterology 2009;137:1912-1933.
4.
Fasano A, Catassi C: Clinical practice. Celiac disease. N Engl J Med 2012;367:2419-2426.
5.
Leffler DA, Schuppan D: Update on serologic testing in celiac disease. Am J Gastroenterol 2010;105:2520-2524.
6.
Sollid LM, Jabri B: Triggers and drivers of autoimmunity: lessons from coeliac disease. Nat Rev Immunol 2013;13:294-302.
7.
Koning F: Pathophysiology of celiac disease. J Pediatr Gastroenterol Nutr 2014;59(suppl 1):S1-S4.
8.
Badenhoop K, Dieterich W, Segni M, Hofmann S, Hufner M, Usadel KH, Schuppan D: HLA DQ2 and/or DQ8 is associated with celiac disease-specific autoantibodies to tissue transglutaminase in families with thyroid autoimmunity. Am J Gastroenterol 2001;96:1648-1649.
9.
Frohlich-Reiterer EE, Hofer S, Kaspers S, Herbst A, Kordonouri O, Schwarz HP, et al: Screening frequency for celiac disease and autoimmune thyroiditis in children and adolescents with type 1 diabetes mellitus - data from a German/Austrian multicentre survey. Pediatr Diabetes 2008;9:546-553.
10.
Boelaert K, Newby PR, Simmonds MJ, Holder RL, Carr-Smith JD, Heward JM, et al: Prevalence and relative risk of other autoimmune diseases in subjects with autoimmune thyroid disease. Am J Med 2010;123:183.e1-e9.
11.
Dittmar M, Libich C, Brenzel T, Kahaly GJ: Increased familial clustering of autoimmune thyroid diseases. Horm Metab Res 2011;43:200-204.
12.
Dittmar M, Kahaly GJ: Immunoregulatory and susceptibility genes in thyroid and polyglandular autoimmunity. Thyroid 2005;15:239-250.
13.
Villano MJ, Huber AK, Greenberg DA, Golden BK, Concepcion E, Tomer Y: Autoimmune thyroiditis and diabetes: dissecting the joint genetic susceptibility in a large cohort of multiplex families. J Clin Endocrinol Metab 2009;94:1458-1466.
14.
Dultz G, Matheis N, Dittmar M, Bender K, Kahaly GJ: CTLA-4 CT60 polymorphism in thyroid and polyglandular autoimmunity. Horm Metab Res 2009;41:426-429.
15.
Dultz G, Matheis N, Dittmar M, Rohrig B, Bender K, Kahaly GJ: The protein tyrosine phosphatase non-receptor type 22 C1858T polymorphism is a joint susceptibility locus for immunthyroiditis and autoimmune diabetes. Thyroid 2009;19:143-148.
16.
Ban Y, Davies TF, Greenberg DA, Concepcion ES, Tomer Y: The influence of human leucocyte antigen (HLA) genes on autoimmune thyroid disease (AITD): results of studies in HLA-DR3 positive AITD families. Clin Endocrinol 2002;57:81-88.
17.
Ide M, Dittmar M, Wurm M, Kanitz M, Kahaly GJ: Polymorphisms of MICA microsatellites in thyroidal autoimmunity. Med Klin 2007;102:11-15.
18.
Tomer Y, Menconi F: Type 1 diabetes and autoimmune thyroiditis: the genetic connection. Thyroid 2009;19:99-102.
19.
Kordonouri O, Klinghammer A, Lang EB, Gruters-Kieslich A, Grabert M, Holl RW: Thyroid autoimmunity in children and adolescents with type 1 diabetes: a multicenter survey. Diabetes Care 2002;25:1346-1350.
20.
Denzer C, Karges B, Nake A, Rosenbauer J, Schober E, Schwab KO, et al: Subclinical hypothyroidism and dyslipidemia in children and adolescents with type 1 diabetes mellitus. Eur J Endocrinol 2013;168:601-608.
21.
Kordonouri O, Dieterich W, Schuppan D, Webert G, Müller C, Sarioglu N, Becker M, Danne T: Autoantibodies to tissue transglutaminase are sensitive serological parameters for detecting silent coeliac disease in patients with type 1 diabetes mellitus. Diabet Med 2000;17:441-444.
22.
Pociot F, McDermott MF: Genetics of type 1 diabetes mellitus. Genes Immun 2002;3:235-249.
23.
Todd JA: Etiology of type 1 diabetes. Immunity 2010;32:457-467.
24.
Bluestone JA, Herold K, Eisenbarth G: Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature 2010;464:1293-1300.
25.
Tuomilehto J: The emerging global epidemic of type 1 diabetes. Curr Diab Rep 2013;13:795-804.
26.
Morahan G: Insights into type 1 diabetes provided by genetic analyses. Curr Opin Endocrinol Diabetes Obes 2012;19:263-270.
27.
Steck AK, Rewers MJ: Genetics of type 1 diabetes. Clin Chem 2011;57:176-185.
28.
Atkinson MA, Eisenbarth GS, Michels AW: Type 1 diabetes. Lancet 2014;383:69-82.
29.
Barker JM: Clinical review: type 1 diabetes-associated autoimmunity: natural history, genetic associations, and screening. J Clin Endocrinol Metab 2006;91:1210-1217.
30.
Perros P, McCrimmon RJ, Shaw G, Frier BM: Frequency of thyroid dysfunction in diabetic patients: value of annual screening. Diabet Med 1995;12:622-627.
31.
Triolo TM, Armstrong TK, McFann K, Yu L, Rewers MJ, Klingensmith GJ, et al: Additional autoimmune disease found in 33% of patients at type 1 diabetes onset. Diabetes Care 2011;34:1211-1213.
32.
Arlt W, Allolio B: Adrenal insufficiency. Lancet 2003;361:1881-1893.
33.
Mitchell AL, Pearce SH: Autoimmune Addison disease: pathophysiology and genetic complexity. Nat Rev Endocrinol 2012;8:306-316.
34.
Erichsen MM, Løvås K, Skinningsrud B, et al: Clinical, immunological, and genetic features of autoimmune primary adrenal insufficiency: observations from a Norwegian registry. J Clin Endocrinol Metab 2009;94:4882-4890.
35.
Kahaly GJ: Polyglandular autoimmune syndromes. Eur J Endocrinol 2009;161:11-20.
36.
Dittmar M, Kahaly GJ: Polyglandular autoimmune syndromes: immunogenetics and long-term follow-up. J Clin Endocrinol Metab 2003;88:2983-2992.
37.
Weinstock C, Matheis N, Barkia S, Haager MC, Janson A, Markovic A, et al: Autoimmune polyglandular syndrome type 2 shows the same HLA class II pattern as type 1 diabetes. Tissue Antigens 2011;77:317-324.
38.
Selmi C: Autoimmunity in 2011. Clin Rev Allergy Immunol 2012;43:194-206.
39.
Anaya JM: The diagnosis and clinical significance of polyautoimmunity. Autoimmun Rev 2014;13:423-426.
40.
Cutolo M: Autoimmune polyendocrine syndromes. Autoimmun Rev 2014;13:85-89.
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2015
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