An infiltrative ophthalmopathy with resultant exophthalmos, noted in as many as 40% of patients
A localized, infiltrative dermopathy (sometimes designated pretibial myxedema), seen in a minority of cases
Graves disease has a peak incidence between 20 and 40 years of age, with women being affected up to seven times more commonly than men. This is a common disorder, estimated to affect 1.5% to 2% of women in the United States. Genetic factors are important in Graves disease; the incidence is increased in relatives of affected patients, and the concordance rate in monozygotic twins is as high as 60%. As with other autoimmune disorders, a genetic susceptibility to Graves disease is associated with the presence of certain human leukocyte antigen (HLA) haplotypes, specifically HLA-DR3, and polymorphisms in genes whose products regulate T-cell responses, including the inhibitory T-cell receptor CTLA-4 and the tyrosine phosphatase PTPN22.
Many manifestations of Graves disease are caused by autoantibodies against the TSH receptor that bind to, and stimulate, thyroid follicular cells independent of endogenous trophic hormones. Multiple autoantibodies are produced in Graves disease, including the following: • Thyroid-stimulating immunoglobulin (TSI). This IgG antibody binds to the TSH receptor and mimics the action of TSH, stimulating adenyl cyclase, with resultant increased release of thyroid hormones. Almost all individuals with Graves disease have detectable amounts of this autoantibody, which is relatively specific for Graves disease.
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Thyroid growth-stimulating immunoglobulins. Also directed against the TSH receptor, these antibodies have been implicated in the proliferation of thyroid follicular epithelium.
TSH-binding inhibitor immunoglobulins. These anti-TSH receptor antibodies prevent TSH from binding to its receptor on thyroid epithelial cells and in so doing may inhibit thyroid cell function. The coexistence of stimulating and inhibiting immunoglobulins in the serum of the same patient is not unusual, and may explain why some patients develop episodes of hypothyroidism.
A T-cell–mediated autoimmune phenomenon also is involved in the development of the infiltrative ophthalmopathy characteristic of Graves disease. In Graves ophthalmopathy, the volume of the retroorbital connective tissues and extraocular muscles is increased due to (1) marked infiltration of the retroorbital space by mononuclear cells, predominantly T cells; (2) inflammatory edema and swelling of extraocular muscles; (3) accumulation of extracellular matrix components, specifically hydrophilic glycosaminoglycans such as hyaluronic acid and chondroitin sulfate; and (4) increased numbers of adipocytes (fatty infiltration). These changes displace the eyeball forward, potentially interfering with the function of the extraocular muscles.
Autoimmune thyroid diseases thus span a continuum in which Graves disease, characterized by hyperfunction of the thyroid, lies at one extreme and Hashimoto disease, manifesting as hypothyroidism, occupies the other end. Sometimes hyperthyroidism may supervene on preexisting Hashimoto thyroiditis, while at other times individuals with Graves disease may spontaneously develop thyroid hypofunction; occasionally, Hashimoto thyroiditis and Graves disease may coexist within an affected kindred. Not surprisingly, there is also an element of histologic overlap between the autoimmune thyroid disorders (most characteristically, prominent intrathyroidal lymphoid cell infiltrates with germinal center formation). In both disorders, the frequency of other autoimmune diseases, such as systemic lupus erythematosus, pernicious anemia, type 1 diabetes, and Addison disease, is increased.