It affects up to 2% of the female population, sometimes appears after childbirth, and occurs seven to eight times more often in women than in men.^[1] Genetic factors are a major factor accounting for possibly around 80% of the risk.^[2] Smoking and exposure to second-hand smoke are associated with the eye manifestations, but not the thyroid manifestations.^{[citation needed]}

Diagnosis is usually made on the basis of symptoms, although thyroid hormone tests may be useful, particularly to monitor treatment.^[3] It is classified as a type II noncytotoxic hypersensitivity.

The signs and symptoms of Graves' disease virtually all result from the direct and indirect effects of hyperthyroidism, with main exceptions being Graves' ophthalmopathy, goitre, andpretibial myxedema (which are caused by the autoimmune processes of the disease). Symptoms of the resultant hyperthyroidism are mainly insomnia, hand tremor, hyperactivity, hair loss, excessive sweating, shaking hands, itching, heat intolerance, weight loss despite increased appetite, diarrhea, frequent defecation, palpitations, muscle weakness, and skin warmth and moistness.^[4] Further signs that may be seen on physical examination are most commonly a diffusely enlarged (usually symmetric), 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.^[4] People with hyperthyroidism may experience behavioral and personality changes including: psychosis, mania, anxiety, agitation, and depression.^[5]

Cause[edit]

Thyroid stimulating immunoglobulins recognize and bind to the thyrotropin receptor (TSH receptor). It mimics the TSH to that receptor and activates the secretion of thyroxine (T4) and triiodothyronine (T3), and the actual TSH level will decrease in the blood plasma. The TSH levels fall because the hypothalamus-pituitary-thyroid negative feedback loop is working. The result is very high levels of circulating thyroid hormones and the negative feedback regulation will not work for the thyroid gland.^{[citation needed]}

The trigger for autoantibody production is not known. There appears to be a genetic predisposition for Graves' disease, suggesting some people are more prone than others to develop TSH receptor activating antibodies due to a genetic cause. HLA DR (especially DR3) appears to play a significant role.^[6]

Since Graves' disease is an autoimmune disease which appears suddenly, often quite late in life, a viral or bacterial infection may trigger antibodies which cross-react with the human TSH receptor (a phenomenon known as antigenic mimicry, also seen in some cases of type I diabetes).^{[citation needed]}

One possible culprit is the bacterium Yersinia enterocolitica (a cousin of Yersinia pestis, the agent of bubonic plague). Although indirect evidence exists for the structural similarity between the bacteria and the human thyrotropin receptor, direct causative evidence is limited.^[6] Yersinia seems not to be a major cause of this disease, although it may contribute to the development of thyroid autoimmunity arising for other reasons in genetically susceptible individuals.^[7] It has also been suggested that Yersinia enterocolitica infection is not the cause of auto-immune thyroid disease, but rather is only an associated condition; with both having a shared inherited susceptibility.^[8] More recently the role for Yersinia enterocolitica has been disputed.^[9]

Emotional stress has been posited as a possible cause of Graves' disease, as well, based largely on anecdotal evidence. While theoretical mechanisms occur by which stress could cause an aggravation of the autoimmune response that leads to Graves' disease, more robust clinical data are needed for a firm conclusion.^[10]

Diagnosis[edit]

Graves' disease may present clinically with one of these characteristic signs:

• exophthalmos (protuberance of one or both eyes)
• fatigue, weight loss with increased appetite, and other symptoms of hyperthyroidism/thyrotoxicosis
• rapid heart beat
• muscular weakness

Two signs are truly 'diagnostic' of Graves' disease (i.e., not seen in other hyperthyroid conditions): exophthalmos and nonpitting edema (pretibial myxedema). Goitre is an enlarged thyroid gland and is of the diffuse type (i.e.,spread throughout the gland). Diffuse goitre may be seen with other causes of hyperthyroidism, although Graves' disease is the most common cause of diffuse goitre. A large goitre will be visible to the naked eye, but a small goitre (mild enlargement of the gland) may be detectable only by physical examination. Occasionally, goitre is not clinically detectable, but may be seen only with CT or ultrasound examination of the thyroid.

Another sign of Graves' disease is hyperthyroidism, i.e., overproduction of the thyroid hormones T3 and T4. Normothyroidism is also seen, and occasionally also hypothyroidism, which may assist in causing goitre (though it is not the cause of the Graves' disease). Hyperthyroidism in Graves' disease is confirmed, as with any other cause of hyperthyroidism, by measuring elevated blood levels of free (unbound) T3 and T4.

Other useful laboratory measurements in Graves' disease include thyroid-stimulating hormone (TSH, usually low in Graves' disease due to negative feedback from the elevated T3 and T4), and protein-bound iodine (elevated). Thyroid-stimulating antibodies may also be detected serologically.

Biopsy to obtain histiological testing is not normally required but may be obtained if thyroidectomy is performed.

Differentiating two common forms of hyperthyroidism such as Graves' disease and toxic multinodular goiter is important to determine proper treatment. Measuring TSH-receptor antibodies with the h-TBII assay has been proven efficient and was the most practical approach found in one study.^[11]