Graves' disease

ALSO KNOWN AS: Basedow’s disease; diffuse toxic goiter; exophthalmic goiter; Graves’ ophthalmopathy

DEFINITION: Graves’ disease, an autoimmune disorder and the most common type of hyperthyroidism, occurs in about 1–3 percent of the US population. In Graves’ disease, the body produces antibodies against the thyroid gland, causing diffuse enlargement of the gland (goiter) and overproduction of thyroid hormone, a critical regulator of body metabolism and other functions. Antibodies are also directed against eye tissues, which causes clinical symptoms (ophthalmopathy) in about 40 percent of cases.

Risk Factors

Risk factors include having a family member with the disease and being female. Graves’ disease is five to ten times more common in women and is more common in white and Asian populations than in black populations. Smoking increases the risk of eye symptoms, and stressful life events may also contribute to the development of symptoms.

Etiology and Genetics

The causative mechanisms in Graves’ disease are complex, considering that it affects tissues as seemingly diverse as the thyroid gland, the eye, and the skin. The normal thyroid gland, the butterfly-shaped gland in front of the windpipe (trachea) at the base of the neck, secretes a hormone, thyroxine, that regulates the rate of body metabolism and plays an important role in all bodily functions, including growth and development, reproduction, and muscle functioning. The amount of hormone secreted is largely regulated by blood levels of thyroid-stimulating hormone (thyrotropin), which is produced by the pituitary gland at the base of the brain. If the blood level of thyroxine is too low, then the pituitary gland produces more thyrotropin, causing the thyroid gland to produce more thyroxine. This feedback mechanism also causes the thyroid gland to decrease production when the blood level of thyroxine is too high.

In Graves’ disease, the body produces thyroid antibodies, which are protein molecules that respond to certain substances in the blood and target thyroid cells. Patients with Graves’ disease have antibodies to several thyroid antigens (proteins that stimulate production of antibodies), including thyroglobulin, thyroid peroxidase, and the thyrotropin receptor. Unlike antibodies in some other autoimmune diseases, such as Lupus erythematosus, the antibodies in Graves’ disease do not destroy the target cells. They instead attach to the receptors and stimulate excess thyroxine production, in spite of the feedback mechanism from the pituitary gland that is signaling for the cells to produce less. These antibodies also block the real thyrotropin molecules from attaching to the thyroid receptors, thus interrupting the feedback mechanism. The result is runaway thyroxine production, or hyperthyroidism. The number of thyroid cells also increases, resulting in an enlarged thyroid gland that causes a palpable and often visible bulge in the throat, known as a goiter. The tissues of the eye also have receptors for thyroid hormone (believed to be essential to the development of fat cells), and the autoimmune reaction causes the muscles, connective tissues, and fatty tissues of the eye to become inflamed and accumulate fluid-rich molecules, which causes them to thicken. A similar process can take place when thyroid antibodies infiltrate the skin and cause inflammation and plaque buildup. This results in redness, swelling, and bumpy thickening of the skin, most commonly over the shins.

There is a genetic predisposition for Graves’ disease, as evidenced by numerous studies in twins that indicate an increased disease rate of up to 50 percent in the other twin when one identical (monozygotic) twin has the disease. The comparative risk in fraternal (dizygotic) twins is only about 5 percent. Research has suggested that mechanisms leading to the production of antibodies against the thyrotropin receptor are inherited. The genetic predisposition, however, does not indicate a simple on-off mechanism for inheritance of Graves’ disease. Although patients with Graves’ disease have in common some genetic disease susceptibility loci, which are variations or mutations at particular genes—such as the HLA-DRB1, CTLA4, CD40, CYP27B1, SCGB3A2, and PTPN22 genes, at the chromosomal loci 6p21.3, 2q33, 20q12-q13.2, 12q14.1, 5q32, and 1p13.2, respectively—no specific gene for Graves’ disease has been found. However, there are commonalities in certain immune-system cell types in people with Graves’ disease, and these gene types may put people at a higher risk of developing the disease. For example, fibroblasts, cells that are targets of one of the autoimmune responses in Graves’ disease, seem to need a particular phenotype (manifestation of gene combinations) for the disease to develop. Some studies in patients with Graves’ disease have shown a deficiency of the type of T cells that suppress autoimmune reactions, and this deficiency may contribute to the development of Graves’ disease. In patients with Graves’ disease, tissues from behind the eye express some of the same antigens and the same genotypes (gene combinations) as do thyroid cells.

Symptoms

Symptoms of Graves’ disease include diffuse enlargement of the thyroid gland and eye disturbances such as protruding eyeballs (exophthalmos), shortening of eyelids, fatty or fibrous overgrowth behind the eye, and visual disturbances. Accompanying symptoms of hyperthyroidism include weight loss, irritability, sweating and heat intolerance, an unusually fast heart rate (tachycardia), and tremors. Patchy skin changes (pretibial myxedema) may also be present.

Screening and Diagnosis

The thyrotropin level is the standard thyroid function screening test. Blood levels of thyrotropin, thyroxine, and triiodothyronine, another thyroid hormone, are all important tests in Graves’ disease. Because certain results of these tests merely indicate hyperthyroidism, however, the diagnosis of Graves’ disease also relies on the history and a physical examination, which usually reveals a goiter and one of the other signs of Graves’ disease, such as exophthalmos, vision disturbances, or shortening of the eyelids. Any family history of thyroid disease is also taken into account. Blood tests for antibodies to thyroperoxidase and thyrotropin receptor may confirm the diagnosis.

Treatment and Therapy

Treatment options for Graves’ disease include therapy with antithyroid drugs or corticosteroids, thyroid-gland irradiation, and surgery to remove excess thyroid tissue or the entire gland. There is no cure, but most people are relieved of symptoms with treatment. Most patients diagnosed with Graves' disease are prescribed beta-blockers that regulate heartbeat and safeguard the heart before treatment with antithyroid drugs begins. Antithyroid drugs block the production of thyroid hormone. Thyroid-gland irradiation, or radioiodine therapy, involves taking a single dose of radioactive iodine that slowly destroys thyroid gland cells over the course of two to three months. Drug treatment does not shrink the enlarged eye tissues, but bulging eyeballs and shortening of the eyelids can be successfully treated with new eye-surgery techniques or radiation to the eye. Eye surgery is also an option when overgrowth of eye tissues results in pressure on the optic nerve, a condition that, if left untreated, could cause blindness. People who undergo removal of the thyroid gland must continue therapy with oral thyroxine for life. After successful treatment, all patients are at risk of developing subnormal levels of thyroxine (hypothyroidism) and must be monitored closely.

Prevention and Outcomes

No method of prevention is known for Graves’ disease. Most patients resume normal functioning after treatment, although surgical treatment carries a risk of permanent damage to the parathyroid glands, located on either side of the thyroid gland. For this reason, surgery is usually performed only if other treatments fail. Graves’ disease is rarely life-threatening, although very high levels of thyroxine may cause thyroid storm, which requires urgent treatment and can be fatal.

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