Graves’ disease (or Basedow-Graves’ disease) is an autoimmune disease that primarily affects the thyroid gland. It is the most common cause of hyperthyroidism which involves enlargement of the thyroid gland (goiter) and overproduction of thyroid hormone. Symptoms of hyperthyroidism include rapid heartbeat, muscle weakness, disturbed sleep, and irritability. Some patients with GD also have involvement of the eyes (Graves’ Orbitopathy or Ophthalmopathy; GO) with inflammatory infiltration of the orbit that can cause bulging eyes (exophthalmos) and other inflammatory changes that lead to visual disturbances and other visual symptoms. Graves’ disease (GD) is caused by the production of autoantibodies to the thyroid-stimulating hormone receptor (TSHR). Stimulatory autoantibodies in GD activate the TSHR on thyroid follicular cells, leading to thyroid hyperplasia and unregulated thyroid hormone production and secretion. In some patients antibodies can antagonize TSHR by either blocking TSH binding or interacting with TSHR epitopes that inhibit cAMP production. There is a genetic predisposition to the development of GD and there is about an 8:1 female to male ratio in patients diagnosed with GD. Smoking is associated with the more serious eye manifestations.
The classic presentation of GD includes the presence of a goiter in association with symptoms of an overactive thyroid gland. These symptoms range from mild symptoms of palpitations, racing heart, weight loss, muscle weakness, and tremors to frank thyrotoxicosis or thyroid storm which is associated with severe and life-threatening consequences of hyperthyroidism. Patients may also present with signs and symptoms of eye disease such as ‘bug eyes’ (exophthalmos). Some patients present with classic Graves’ eye disease, but are euthyroid at the time of presentation. A significant number of patients present with atypical or non-classic symptoms such as isolated tremors, atrial fibrillation, or anxiety. In these cases the diagnosis of GD is not considered for many months and definitive diagnosis is unfortunately delayed.
The diagnosis of GD starts with a health care worker recognizing the signs and symptom and considering the possibility of hyperthyroidism. This is followed by measurement of TSH which if below normal (suppressed), confirms the hyperthyroid state. Elevation of thyroid hormone levels then would confirm the presence of clinical hyperthyroidism. The differential diagnosis of hyperthyroidism includes GD as well as non-autoimmune causes such as multinodular goiter and thyroiditis. Traditionally, the next step would be radioactive iodine uptake and scanning to define and characterize the overactivity of the gland often in anticipation of radioactive iodine ablation of the gland as definitive therapy. More commonly the diagnostic evaluation involves anatomical characterization of the thyroid gland with ultrasonography which defines the size of the gland and determines the degree of vascularity (blood flow). A diffuse increase in both size and vascularity are consistent with the diagnosis of GD. This evaluation, when combined with the clinical signs and symptoms and the hormone levels may be sufficient to make the diagnosis and initiate therapy. Many cases of GD are not easily diagnosed and measurement of thyroid receptor-stimulating autoantibodies (anti-TSHR or TRAb) is often very helpful to confirm the diagnosis.
Measurement of anti-TSHR autoantibodies
Two types of tests are available for clinical laboratories to measure anti-TSHR autoantibodies. One type is a competitive binding test. This test is usually called a TRAb test and measures the ability of the antibodies to bind to the TSHR regardless of the biological activity of the antibodies. Another type of test, referred to as bioassays, measure the ability of the anti-TSHR to stimulate thyroid cells. These test measure what are called thyroid-stimulating immunoglobulin (TSI) or thyroid-stimulating antibody (TSAb). TSI are specific for GD because it is the stimulating antibodies that lead to hyperthyroidism. Recent data show that TSI levels correlate with the severity of GO.
There are three possible forms of treatment for the hyperthyroidism of GD. Radioiodine ablation involves administering an appropriate dose of 131I which concentrates in the thyroid and destroys thyroid cells. Following this form of therapy the patient loses thyroid function and becomes hypothyroid and thus dependent on thyroid hormone replacement for life. There are two anti-thyroid drugs (ATD) available for treatment of GD, propylthiouracil (PTU) and methimazole (MMI). Response to these drugs is general 50% or less. Total thyroidectomy can be performed if radiodine is contraindicated and ATD are not effective or not tolerated.
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Lytton, S. D., and G. J. Kahaly. 2010. Bioassays for TSH-receptor autoantibodies: an update. Autoimmun Rev 10:116-22.
Lytton, S. D., K. A. Ponto, M. Kanitz, N. Matheis, L. D. Kohn, and G. J. Kahaly. 2010. A novel thyroid stimulating immunoglobulin bioassay is a functional indicator of activity and severity of Graves' orbitopathy. J Clin Endocrinol Metab 95:2123-31.