Graves' disease


Graves' disease, also known as toxic diffuse goiter or Basedow's disease, is an autoimmune disease that affects the thyroid. It frequently results in and is the most common cause of hyperthyroidism. It also often results in an enlarged thyroid. Signs and symptoms of hyperthyroidism may include irritability, muscle weakness, sleeping problems, a fast heartbeat, poor tolerance of heat, diarrhea and unintentional weight loss. Other symptoms may include thickening of the skin on the shins, known as pretibial myxedema, and eye bulging, a condition caused by Graves' ophthalmopathy. About 25 to 30% of people with the condition develop eye problems.
The exact cause of the disease is unclear, but symptoms are a result of antibodies binding to receptors on the thyroid, causing over-expression of thyroid hormone. Persons are more likely to be affected if they have a family member with the disease. If one monozygotic twin is affected, a 30% chance exists that the other twin will also have the disease. The onset of disease may be triggered by physical or emotional stress, infection, or giving birth. Those with other autoimmune diseases, such as type 1 diabetes and rheumatoid arthritis, are more likely to be affected. Smoking increases the risk of disease and may worsen eye problems. The disorder results from an antibody, called thyroid-stimulating immunoglobulin, that has a similar effect to thyroid stimulating hormone. These TSI antibodies cause the thyroid gland to produce excess thyroid hormones. The diagnosis may be suspected based on symptoms and confirmed with blood tests and radioiodine uptake. Typically, blood tests show a raised T3 and T4, low TSH, increased radioiodine uptake in all areas of the thyroid, and TSI antibodies.
The three treatment options are radioiodine therapy, medications, and thyroid surgery. Radioiodine therapy involves taking iodine-131 by mouth, which is then concentrated in the thyroid and destroys it over weeks to months. The resulting hypothyroidism is treated with synthetic thyroid hormones. Medications such as beta blockers may control some of the symptoms, and antithyroid medications such as methimazole may temporarily help people, while other treatments are having an effect. Surgery to remove the thyroid is another option. Eye problems may require additional treatments.
Graves' disease develops in about 0.5% of males and 3.0% of females. It occurs about 7.5 times more often in women than in men. Often, it starts between the ages of 40 and 60, but can begin at any age. It is the most common cause of hyperthyroidism in the United States. The condition is named after Irish surgeon Robert Graves, who described it in 1835. Many prior descriptions also exist.

Signs and symptoms

The signs and symptoms of Graves' disease virtually all result from the direct and indirect effects of hyperthyroidism, with the main exceptions being Graves ophthalmopathy, goiter, and pretibial myxedema. Symptoms of the resultant hyperthyroidism are mainly insomnia, hand tremor, hyperactivity, hair loss, excessive sweating, oligomenorrhea, itching, heat intolerance, weight loss despite increased appetite, diarrhea, frequent defecation, palpitations, periodic partial muscle weakness or paralysis in those especially of Asian descent, and skin warmth and moistness. Further signs that may be seen on physical examination are most commonly a diffusely enlarged, nontender thyroid, lid lag, excessive lacrimation due to Graves' ophthalmopathy, arrhythmias of the heart, such as sinus tachycardia, atrial fibrillation, and premature ventricular contractions, and hypertension.

Cause

The exact cause is unclear, but it is believed to involve a combination of genetic and environmental factors. While a theoretical mechanism occurs by which exposure to severe stressors and high levels of subsequent distress such as post-traumatic stress disorder could increase the risk of immune disease and cause an aggravation of the autoimmune response that leads to Graves disease, more robust clinical data are needed for a firm conclusion.

Genetics

A genetic predisposition for Graves' disease is seen, with some people more prone to develop TSH receptor-activating antibodies due to a genetic cause. Human leukocyte antigen DR appears to play a role. To date, no clear genetic defect has been found to point to a single-gene cause.
Genes believed to be involved include those for thyroglobulin, thyrotropin receptor, protein tyrosine phosphatase nonreceptor type 22, and cytotoxic T-lymphocyte–associated antigen 4, among others.

Infectious trigger

Since Graves disease is an autoimmune disease that appears suddenly, often later in life, a viral or bacterial infection may trigger antibodies, which cross-react with the human TSH receptor, a phenomenon known as antigenic mimicry.
The bacterium Yersinia enterocolitica bears structural similarity with the human thyrotropin receptor and was hypothesized to contribute to the development of thyroid autoimmunity arising from other reasons in genetically susceptible individuals.
In the 1990s, Y. enterocolitica was suggested to be possibly associated with Graves' disease.
More recently, the role of Y. enterocolitica has been disputed.
Epstein–Barr virus is another potential trigger.

Mechanism

Thyroid-stimulating immunoglobulins recognize and bind to the TSH receptor, which stimulates the secretion of thyroxine and triiodothyronine. Thyroxine receptors in the pituitary gland are activated by the surplus hormone, suppressing additional release of TSH in a negative feedback loop. The result is very high levels of circulating thyroid hormones and a low TSH level.

Pathophysiology

Graves' disease is an autoimmune disorder, in which the body produces antibodies that are specific to a self-protein - the receptor for thyroid-stimulating hormone.
These antibodies cause hyperthyroidism because they bind to the TSHr and chronically stimulate it. The TSHr is expressed on the thyroid follicular cells of the thyroid gland, and the result of chronic stimulation is an abnormally high production of T3 and T4. This, in turn, causes the clinical symptoms of hyperthyroidism, and the enlargement of the thyroid gland is visible as a goiter.
The infiltrative exophthalmos frequently encountered has been explained by postulating that the thyroid gland and the extraocular muscles share a common antigen, which is recognized by the antibodies. Antibodies binding to the extraocular muscles would cause swelling behind the eyeball.
The "orange peel" skin has been explained by the infiltration of antibodies under the skin, causing an inflammatory reaction and subsequent fibrous plaques.
The three types of autoantibodies to the TSH receptor are:
  1. Thyroid stimulating immunoglobulins: these antibodies act as long-acting thyroid stimulants, activating the cells through a slower and more drawn-out process compared to TSH, leading to an elevated production of thyroid hormone.
  2. Thyroid growth immunoglobulins: these antibodies bind directly to the TSH receptor and have been implicated in the growth of thyroid follicles.
  3. Thyrotrophin binding-inhibiting immunoglobulins: these antibodies inhibit the normal union of TSH with its receptor.
  4. * Some actually act as if TSH itself is binding to its receptor, thus inducing thyroid function.
  5. * Other types may not stimulate the thyroid gland, but prevent TSI and TSH from binding to and stimulating the receptor.
Another effect of hyperthyroidism is bone loss from osteoporosis, caused by an increased excretion of calcium and phosphorus in the urine and stool. The effects can be minimized if the hyperthyroidism is treated early. Thyrotoxicosis can also augment calcium levels in the blood by as much as 25%. This can cause stomach upset, excessive urination, and impaired kidney function.

Diagnosis

Graves' disease may present clinically with one or more of these characteristic signs:
  • Rapid heartbeat
  • Diffuse palpable goiter with audible bruit
  • Tremor
  • Exophthalmos, periorbital edema
  • Fatigue, weight loss with increased appetite in young people and poor appetite in the elderly, and other symptoms of hyperthyroidism/thyrotoxicosis
  • Heat intolerance
  • Tremulousness
  • Palpitations
Two signs are truly diagnostic of Graves' disease : exophthalmos and non-pitting edema. Goiter is an enlarged thyroid gland and is of the diffuse type. Diffuse goiter may be seen with other causes of hyperthyroidism, although Graves' disease is the most common cause of diffuse goiter. A large goiter will be visible to the naked eye, but a small one may be detectable only by physical examination. Occasionally, goiter is not clinically detectable, but may be seen only with computed tomography or ultrasound examination of the thyroid. Another sign of Graves' disease is hyperthyroidism, that is, overproduction of the thyroid hormones T3 and T4. Normal thyroid levels are also seen, and occasionally hypothyroidism, which may assist in causing goiter. Hyperthyroidism in Graves' disease is confirmed, as with any other cause of hyperthyroidism, by measuring elevated blood levels of free T4.
Other useful laboratory measurements in Graves' disease include thyroid-stimulating hormone, and protein-bound iodine. Serologically detected thyroid-stimulating antibodies, radioactive iodine uptake, or thyroid ultrasound with Doppler, all can independently confirm a diagnosis of Graves' disease.
Biopsy to obtain histological testing is not normally required, but may be obtained if thyroidectomy is performed.
The goiter in Graves' disease is often not nodular, but thyroid nodules are also common. Differentiating common forms of hyperthyroidism, such as Graves' disease, single thyroid adenoma, and toxic multinodular goiter is important to determine proper treatment. The differentiation among these entities has advanced, as imaging and biochemical tests have improved. Measuring TSH-receptor antibodies with the h-TBII assay has been proven efficient and was the most practical approach found in one study.