Abstract

Graves' disease (GD) is the most common cause of hyperthyroidism in the United States. GD occurs more often in women than in men with a female: male ratio of 5:1 and a population prevalence of 1-2%. A genetic determinant to the susceptibility to GD is suspected because of familial clustering of the disease, a high sibling recurrence risk, the familial occurrence of thyroid autoantibodies, and the 30% concordance in disease status between identical twins. About 30-50% of subjects with GD develop Graves' orbitopathy (GO), which is usually of mild to moderate severity. This eye disorder usually lasts 1 to 2 years and often improves on its own. GO can occur before, at the same time as, or after other symptoms of hyperthyroidism develop. GO is severe in 5% of people who have the disorder, and smoking makes GO worse. Common symptoms of hyperthyroidism include nervousness or irritability, heat intolerance, rapid and irregular heartbeat, frequent bowel movements or diarrhea, weight loss and goiter. Symptoms of GO include dry, irritated eyes, light sensitivity, pressure of pain in the eyes, puffy eyelids, bulging eyes, trouble moving the eyes, double vision, and in rare cases vision loss.

GD is an autoimmune thyroid disorder characterized by the infiltration of immune effector cells and thyroid-antigen-specific T cells into the thyroid and thyroid stimulating hormone receptor (TSHR) expressing tissues, with the production of autoantibodies to well-defined thyroidal antigens such as thyroid peroxidase, thyroglobulin, and the TSHR. The TSHR expressed on the plasma membrane of thyroid epithelial cells, is central to the regulation of thyroid growth and function. However, it is also expressed on a variety of other tissues, including adipocytes and bone cells. The TSHR is the major autoantigen in the autoimmune hyperthyroidism of GD where T cells and autoantibodies are directed at the TSHR antigen. Stimulatory autoantibodies in GD activate TSHR on thyroid follicular cells, leading to thyroid hyperplasia and unregulated thyroid hormone production and secretion. The close clinical relationship between Graves' hyperthyroidism and GO has suggested that immunoreactivity against the TSHR present in both the thyroid and orbit underlies both conditions. Numerous studies did demonstrate that TSHR mRNA and protein are present and expressed as an autoantigen in affected orbital tissues of patients with GO.

Below-normal levels of baseline serum TSH, normal to elevated levels of T4, elevated levels of T3, elevated levels of TSHR autoantibodies, and a diffusely enlarged, heterogeneous, hypervascular (increased Doppler flow) thyroid gland confirm diagnosis of GD. During entire pregnancy of patients with GD circulating anti-TSHR-antibodies can pass to the baby and cause either neonatal autoimmune thyrotoxicosis (functionally stimulating immunoglobulins) or hypothyroidsm (blocking autoantibodies). Currently, two different methods of assessing autoantibodies directed against the TSHR are being used. The TSH binding inhibitory immunoglobulin (TBII) quantifies the titer of patient's immunoglobulins that inhibit the binding of TSH to purified or recombinant TSHR. It thus measures both thyroid-stimulating autoantibodies (TSI) and thyroid-blocking autoantibodies targeting the receptor. The second method is a bioassay that can distinguish between TSHR-stimulating, -neutral and -blocking autoantibodies through their effect on cyclic adenosine monophosphate (cAMP) production in a cell line stably transfected with the receptor.