Thyroid Imbalances due to Autoimmunity
Hashimoto’s thyroiditis (HT) is the leading cause of hypothyroidism in the United States.1 It is one of the most common organ-specific autoimmune disorders of the thyroid, among Graves’ disease, trophic thyroiditis, primary myxedema, and postpartum thyroiditis. HT has characteristic features of lymphocytic infiltration along with the presence of serum anti-thyroperoxidase antibody (TPOAb) and/or anti-thyroglobulin antibody (TgAb).2
The symptoms of a clinical hypothyroidism picture in HT are variable for a few reasons. First, there exists individual variance in thyroid gland destruction and disease manifestations. One study found that approximately 90% of the thyroid must be destroyed in order for the disease to display symptoms of hypothyroidism.3
In addition to gland destruction, the difference in circulating antibodies present is also a factor in HT symptomatology. There is a correlation between an increase in serum antibodies and development from a euthyroid to hypothyroid state. However, the rate at which those who progress to overt hypothyroidism is not dependent on specific levels or ranges of antibodies present.3,4
Some studies have suggested that TPOAb, an immunoglobulin G (IgG), which is found in about 95% of cases of HT, is the result of an injury.3,5 All 4 subclasses of IgG have been found in HT, with each subclass responsible for different biological functions. Therefore, studies on the IgG subclass distribution of TPOAb might provide clues to the mechanism of symptomatology expression in HT. For example, when a 2008 study compared the different subtypes of IgG in HT, the results indicated that IgG2 and IgG4 subclasses were highest in those with subclinical and clinical hypothyroidism as compared to the euthryoid patients.3
This lack of correlation between individuals, antibody levels, and disease manifestation is not limited to HT. Other autoimmune disorders have been studied in relation to the amount of antibodies present and disease manifestations.6 According to the 2003 New England Journal of Medicine’s finding on systemic lupus erythematosus (SLE), autoantibodies were typically present many years before diagnosis.7 These findings may warrant serum autoantibody screening tests in those who carry various risk factors for HT in order to prevent complete destruction of the thyroid gland.
A final reason why the clinical hypothyroidism picture in HT varies is that those diagnosed with HT have a higher incidence of comorbid autoimmune diseases. These include celiac disease, rheumatoid arthritis, vitiligo, diabetes mellitus, Addison’s disease, and pernicious anemia.1,4,8,9
In fact, it has been stated that celiac disease1,8-11 is 5 times more common in those with HT vs. the overall population and 57% of those diagnosed with pernicious anemia have thyroid antibodies. A further study in 2007 assessed 104 patients with HT and 184 patients with celiac and concluded that the association was bi-directional.9
A study in 2001 in the American Journal of Gastroenterologystated that it was probable that 21 out of 31 hypothyroid patients were not experiencing autoimmune regulation disorders, but rather a decreased thyroid hormone synthesis related to malnutrition or iodide organification defect.12 (Iodine use has been shown in one study to suppress hyperthyroidism at the expense of hypothyroidism).13 Other studies have demonstrated how factors such as the presence of bacterial antigens and intestinal permeability issues link to HT.1,8,10,11,14 These studies provide evidence that hypothyroidism could potentially be misdiagnosed as an etiological factor of an existing immune dysfunction or vice versa.
Although the exact mechanism of the cause of HT is still unclear,3 the implications for discovering the etiology could provide useful information for prognosis. Several theories have been suggested in the pathogenesis of HT. One study showed that HT demonstrated an increase of CD8+ cells initiated by CD4+ cell activation and resulting B cells.5 Furthermore, a recent 2009 study linked the pathogenesis of HT to the presence of TgAb and its resultant monocolonal B cell proliferation. The authors of the later study concluded that this proliferation in B cells created an increased risk to the development of thyroid mucosa-associated lymphoid tissue (MALT) lymphoma.15
Genetics may also play in a role in determining the pathogenesis and mechanism of HT. Various genetic markers have been linked to HT. These markers include human leukocyte antigen class II, cytotoxic T-lymphocyte antigen 4 (CTLA-4), and protein tyrosine phosphatase non-receptor type 22 h (PTPN-22). The mechanisms behind these genetic variations vary and are as follows: CTLA-4 suppresses T-cell function by either competing with CD28 activity during T-cell activation or suppressing the T-cell receptor. PTPN-22 acts as a powerful T cell receptor signaling inhibitor.
Still, all of the above theories ultimately trace the mechanism of HT to T and B cell expression with resulting antibody production. Furthermore, one study found that human leukocyte antigen class II, CTLA-4, and PTPN-22 was common in those with both HT and type 1 diabetes. This genetic link could provide additional evidence for a contributing mechanism to comorbid autoimmune disorders and provide clues to diagnosis and prognosis of certain autoimmune conditions.16
Other risk factors associated with HT include female gender and family associations. Epidemiological studies have revealed increased incidence with family associations to other thyroid and organ-specific autoimmune conditions.13,16,17
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1. Baskin HJ, Cobin RH, Duick DS, et al, for the American Association of Clinical Endocrinologists. AACE Medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. Endocr Pract. 2002;8(6):457-469.
2. Desailloud R, Hober D. Viruses and thyroiditis: an update. Viro J. 2009;6:5.
3. Xie LD, Gao Y, Li MR, Lu GZ, Guo XH. Distribution of immunoglobulin G subclasses of anti-thyroid peroxidase antibody in sera from patients with Hashimoto’s thyroiditis with different thyroid functional status. Clin Exp Immunol. 2008;154(2):172-176.
4. Orgentec Diagnostika GmbH. Immunometric Enzyme Immunoassay for the quantitative determination of antibodies against thyroglobulin (TG). http://www.orgentec.com/user_images/73/307576124_... Updated August 2005. Accessed February 11, 2010.
5. Aksoy DY, Kerimoglu U, Okur H, et al. Effects of prophylactic thyroid hormone replacement in euthyroid Hashimoto’s thyroiditis. Endocr J. 2005;52(3):337-343.
6. Betterle C, Zanchetta R. Update of autoimmune polyendocrine syndrome (APS). Acta Biomed. 2003;74(1):9-33.
7. Arbuckle MR, McClain MT, Rubertone MV, et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med. 2003;349(16):1526-1533.
8. Calgar E, Ugurlu S, Ozenoglu A, Can G, Kadioglu P, Dobrucali A. Autoantibody frequency in celiac disease. Clinics (Sao Paolo). 2009;64(12):1195-1200.
9. Hadithi M, de Boer H, Meijer JW, et al. Coeliac disease in Dutch patients with Hashimoto’s thyroiditis and vice versa. World J Gastroenterol. 2007;13(11):1715-1722.
10. Duntas LH. Does celiac disease trigger autoimmune thyroiditis? Nat Rev Endocrinol. 2009;5(4):190-191.
11. Kon YC, DeGroot LJ. Painful Hashimoto’s thyroiditis as an indication for thyroidectomy: clinical characteristics and outcome in seven patients. J Clin Endocrinol Metab. 2003;88(6):2667-2672.
12. Sategna-Guidetti C, Volta U, Ciacci C, 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(3):751-757.
13. Strieder TG, Tijssen JG, Endert E, Wiersinga WM. Prediction of progression to overt hypothyroidism or hyperthyroidism in female relatives of patients with autoimmune thyroid disease using the Thyroid Events Amsterdam (THEA) score. Arch Intern Med.2008;168(15):1657-1663.
14. Harkiolaki M, Holmes SL, Svendsen P, et al. T cell-mediated autoimmune disease due to low-affinity crossreactivity to common microbial peptides. Immunity. 2009;30(3):348-357.
15. Munemasa M, Yoshino T, Kobayashi K, et al. Expression of thyroglobulin on follicular dendritic cells of thyroid mucosa-associated lymphoid tissue (MALT) lymphoma. Acta Med Okayama. 2009;63(2):71-78.
16. Huber A, Menconi F, Corathers S, Jacobson EM, Tomer Y. Joint genetic susceptibility to type 1 diabetes and autoimmune thyroiditis: from epidemiology to mechanisms. Endocr Rev. 2008;29(6):697-725.
17. Wen WB, Lui FY. Autoantibodies highly increased in patients with thyroid dysfunction. Cell Mol Immunol. 2007;4(3):233-236.
Article from NDNR 2010
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