What is Graves’ Disease?

Overview

Graves' disease (GD) is an autoimmune thyroid disorder that primarily affects the thyroid gland, causing hyperthyroidism. It may also affect the eyes, causing Graves' ophthalmopathy (thyroid eye disease or TED); the skeletal muscles causing myopathy or muscle weakness; and the skin, causing pretibial myxedema and acropachy. There are many GD variants or subtypes, and each individual case of GD is unique.

Graves' disease is caused by stimulating TSH receptor antibodies or thyroid stimulating immunoglobulins (TSI). TSI activate the TSH receptor on thyroid cells, mimicking the action of TSH, the latter a pituitary hormone which regulates thyroid hormone levels in the blood. 

The concentration of TSH present in the blood is generally a good indicator of thyroid status, and levels of TSH are often used to diagnose thyroid disorders. Normally, TSH stimulates the thyroid gland to produce and release thyroid hormone. But bypassing all normal regulatory controls, TSI causes the thyroid gland to release excess thyroid hormone, causing hyperthyroidism. TSI also stimulates orbital cells, causing Graves' ophthalmopathy and they stimulate dermal cells, causing pretibial myxedema.

When thyroid hormone levels in the blood are low, the hypothalamus orders the pituitary to secrete more TSH and TSH levels are high. When thyroid hormone levels are elevated, the hypothalamus halts TSH release. 

Thyroid hormones include thyroxine (T4)and triiodothyronine (T3). Normally, the thyroid primarily produces T4 along with a small amount of T3. T3, which is 10 times more active than T4, is mainly produced in the body by conversion (or losing one iodine molecule) from T4. Thyroid hormone is 65% iodine. Thus, in hyperthyroidism, levels of TSH are low, frequently lower than the detection level (usually <0.01 IU/L). 

T4 has 4 iodine atoms, whereas T3 has 3 iodine atoms. However, in GD the thyroid gland produces more T3 relative to T4 than usual. This results in a condition known as T3 toxicosis. Despite it's ominous sound, T3 toxicosis is a good indicator of a favorable response to anti-thyroid drug therapy.

The true prevalence of GD is unknown, but it has been estimated to be slightly less than 1% of the U.S. population. In additon, as many as 3% to 4% of the population is thought to have subclincial Graves' disease, a condition in which the patient has no symptoms although lab tests paint a picture of hyperthyroidism. Graves' disease affects many times more women than men. The peak age for GD is 20-40 years, although young children and the elderly are also affected, i.e. GD can affect individuals of any age.  Symptoms of GD in males are often more severe and men are more likely to develop muscle disorders.

Genetic Factors

In 2002, Dr Shamael Waheed and colleagues at Bart's and the Royal London Hospital used molecular genetic technology to examine the genes of people with Grave's disease. These researchers found that the genes that control programmed cell death or apoptosis in thyroid cells are switched on in people with Graves’ disease. This results in these cells lasting longer and being more vulnerable to attack by the immune system. 

Another gene, one that controls vitamin D absorption and transport by binding proteins, has also been found to be defective in patients in Graves’ disease. This leads to the characteristically low vitamin D levels seen in Graves’ disease. Low vitamin D levels in Graves’ disease lead to poor absorption of calcium and symptoms of muscle wasting, bone loss, and nervous system disorders. 

A polymorphism to the CYP27B1 transporter gene has been demonstrated in a Polish population of Graves’ disease patients. Polymorphisms in the CTLA-4 gene and in several genes for cytokines have also been demonstrated in Graves’ disease. The high incidence of genetic changes seen in Graves’ disease may account for the considerable variation seen in symptoms, signs and the disease course of patients with Graves’ disease.

Autoimmune Factors

Graves’ disease is considered an antibody-mediated autoimmune disorder. Here, stimulating TSH receptor antibodies (also known as thyroid stimulating immunoglobulins or TSI) react with the TSH receptor protein on thyroid cells, ordering these cells to produce excess thyroid hormone. 

The immune system in patients with Graves’ disease leans towards a Th2 rather than a Th1 response. The Th2 response promotes autoimmunity and is characteristically seen in many autoimmune diseases including Graves’ disease and type 1 diabetes.

While the immediate goals in treating Graves’ disease are to reduce thyroid hormone levels and lessen the effects of hyperthyroidism, the long-term goals are to heal the immune system and reduce the production of TSI. There is some variation in TSI. This explains why Graves’ patients with very high TSI levels can have mild symptoms and Graves’ patients with moderate TSI levels can have severe symptoms. It’s suspected that there are several subtypes of TSI. Presumably, these subtypes determine the type of epitopes or binding sites on the TSH receptor that TSI can bind to. TSI may bind to epitopes that result in stimulation of thyroid cells or they may bind to epitopes that are less potent. Many patients with Graves’ disease also have blocking TSH receptor antibodies. These antibodies block both TSH and TSI from reacting with the TSH receptor, thereby preventing thyroid cells from producing excess thyroid hormone.

Environmental Triggers

Various environmental agents have been found to trigger the development of Graves’ disease. These include cigarette smoke, stress, allergens, infectious agents, estrogens, aspartame, low selenium levels, excess dietary iodine, iodine contrast dyes, interferon-beta, and interleukins. Other suspected triggers include: goserelin acetate, which is a gonadotropin-releasing hormone (GnRH) –agonist and various monoclonal antibodies. ♦