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Varieties and Subtypes of Graves' Disease

© elaine moore

It’s long been known that there are many varieties or subtypes of Graves’ disease. In some subtypes, patients have mild symptoms and variable periods of remission while in other subtypes, symptoms are severe and generally worsen without medical intervention. Some subtypes are associated with the development of Graves’ ophthalmopathy whereas in other subtypes, even with risk factors such as cigarette smoking and radioiodine ablation, ophthalmopathy is rare or extremely mild.

While these subtypes lack formal names, they’re generally classified according to the associated thyroid autoantibodies or HLA antigens. For instance, in our laboratory, we test for a combination of thyroglobulin and thyroid peroxidase antibodies. In the test interpretation we include with the results, we explain that, while these antibodies are more often associated with Hashimoto’s thyroiditis, they are also known to exist “in some varieties of Graves’ disease.” However, we don’t distinguish what these varieties are.

Is their any significance associated with GD subtypes? Yes, there are diagnostic applications, especially when only thyroid eye disease is present and a connection to autoimmune thyroid disease is in question. The antibodies present in patients with GD can also suggest the final outcome of one’s disease course. For instance, patients who initially have blocking TSH receptor antibodies are more likely to progress to spontaneous hypothyroidism. These antibodies contribute to eventual hypothyroidism in one-third of cases of GD.

Several forms of thyroid stimulating immunoglobulins (TSI, stimulating TSH receptor antibodies) are known to exist, one of which offers a protective effect. While TSI are known to stimulate the TSH receptor, there are several different types of binding sites on the TSH receptor that TSIs can bind to. Consider the TSH receptor as a pinwheel linked to the surface of thyroid cells. Different binding sites or pinpoints along the wheel are the sites of different activities. And the different types of TSI react at different types of binding sites.

Some binding sites on the TSH receptor offer protection since they’re not stimulated by TSI. TSI that bind at these locations do not cause excess thyroid hormone production. And on some binding sites, either TSI or TSH itself may react. Still other binding sites are influenced by TSI alone. Before the immunology nature of TSI was discovered, these antibody proteins were referred to as long acting thyroid stimulator or LATS and long acting thyroid protector (LATS-P). Patients with a predominance of protective TSI have milder disease symptoms.

Furthermore, GD patients with high titers of thyroid growth immunoglobulins (TGI) as well as TSI are more likely to experience goiters. And according to some researchers, individuals with both TSI and TGI experience more severe disease symptoms than patients without TGI. Furthermore, several studies show that patients with blocking TSH receptor antibodies are more likely to develop Graves’ ophthalmopathy than patients without these antibodies.