graves' disease graves' disease graves' disease (german: morbus basedow), also known as toxic diffuse goiter, 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. graves' diseaseother namestoxic diffuse goiter, flajani–basedow–graves diseasethe classic finding of exophthalmos and lid retraction in graves' diseasespecialtyendocrinologysymptomsenlarged thyroid, irritability, muscle weakness, sleeping problems, fast heartbeat, weight loss, poor tolerance of heat, anxiety, tremor of hands or fingers, warm and moist skin, increased perspiration, goiter, changes in menstrual cycle, easy bruising, erectile dysfunction, reduced libido, frequent bowel movements, bulging eyes (graves' ophthalmopathy), thick red skin on shins or the top of foot (pretibial myxedema)complicationsgraves' ophthalmopathycausesunknownrisk factorsfamily history, other autoimmune diseasesdiagnostic methodblood tests, radioiodine uptaketreatmentradioiodine therapy, medications, thyroid surgeryfrequency0.5% (males), 3% (females) the exact cause of the disease is unclear; however, it is believed to involve a combination of genetic and environmental factors. a person is more likely to be affected if they have a family member with the disease. if one 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 (tsi), that has a similar effect to thyroid stimulating hormone (tsh). 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 effect. surgery to remove the thyroid is another option. eye problems may require additional treatments. graves' disease will develop in about 0.5% of males and 3% 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 (about 50 to 80% of cases). the condition is named after irish surgeon robert graves, who described it in 1835. a number of prior descriptions also exist. signs and symptoms main article: signs and symptoms of graves' disease graves' disease symptoms the signs and symptoms of graves' disease virtually all result from the direct and indirect effects of hyperthyroidism, with main exceptions being graves' ophthalmopathy, goiter, and pretibial 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, 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 (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. cause the exact cause is unclear; however, 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 ptsd (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 (especially dr3) 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 (ptpn22), and cytotoxic t-lymphocyte–associated antigen 4, among others. infectious trigger since graves' disease is an autoimmune disease which 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 for other reasons in genetically susceptible individuals. in the 1990s, it was suggested that y. enterocolitica may be associated with graves' disease. more recently, the role for y. enterocolitica has been disputed. epstein–barr virus (ebv) is another potential trigger. mechanism thyroid-stimulating immunoglobulins recognize and bind to the thyrotropin receptor (tsh receptor) which stimulates the secretion of thyroxine (t4) and triiodothyronine (t3). 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 histopathological image of diffuse hyperplasia of the thyroid gland (clinically presenting as hyperthyroidism) 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. (antibodies to thyroglobulin and to the thyroid hormones t3 and t4 may also be produced.) 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 (the cells that produce thyroid hormone), 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 visible as 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 currently recognized are: thyroid stimulating immunoglobulins: these antibodies (mainly igg) act as long-acting thyroid stimulants (lats), activating the cells through a slower and more drawn out process compared to tsh, leading to an elevated production of thyroid hormone. thyroid growth immunoglobulins: these antibodies bind directly to the tsh receptor and have been implicated in the growth of thyroid follicles. thyrotrophin binding-inhibiting immunoglobulins: these antibodies inhibit the normal union of tsh with its receptor. some actually act as if tsh itself is binding to its receptor, thus inducing thyroid function. 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 (80%) diffuse palpable goiter with audible bruit (70%) tremor (40%) exophthalmos (protuberance of one or both eyes), periorbital edema (25%) fatigue (70%), weight loss (60%) with increased appetite in young people and poor appetite in the elderly, and other symptoms of hyperthyroidism/thyrotoxicosis heat intolerance (55%) tremulousness (55%) palpitations (50%) two signs are truly 'diagnostic' of graves' disease (i.e., not seen in other hyperthyroid conditions): exophthalmos and nonpitting edema (pretibial myxedema). goiter is an enlarged thyroid gland and is of the diffuse type (i.e., spread throughout the gland). 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 (mild enlargement of the gland) 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 also hypothyroidism, which may assist in causing goiter (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 undetectable in graves' disease due to negative feedback from the elevated t3 and t4), and protein-bound iodine (elevated). serologically detected thyroid-stimulating antibodies, radioactive iodine (rai) uptake, or thyroid ultrasound with doppler all can independently confirm a diagnosis of graves' disease. biopsy to obtain histiological 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. eye disease further information: graves' ophthalmopathy thyroid-associated ophthalmopathy (tao), or thyroid eye disease (ted), is the most common extrathyroidal manifestation of graves' disease. it is a form of idiopathic lymphocytic orbital inflammation, and although its pathogenesis is not completely understood, autoimmune activation of orbital fibroblasts, which in tao express the tsh receptor, is thought to play a central role. hypertrophy of the extraocular muscles, adipogenesis, and deposition of nonsulfated glycosaminoglycans and hyaluronate, causes expansion of the orbital fat and muscle compartments, which within the confines of the bony orbit may lead to dysthyroid optic neuropathy, increased intraocular pressures, proptosis, venous congestion leading to chemosis and periorbital edema, and progressive remodeling of the orbital walls. other distinctive features of tao include lid retraction, restrictive myopathy, superior limbic keratoconjunctivitis, and exposure keratopathy. severity of eye disease may be classified by the mnemonic: "no specs": class 0: no signs or symptoms class 1: only signs (limited to upper lid retraction and stare, with or without lid lag) class 2: soft tissue involvement (oedema of conjunctivae and lids, conjunctival injection, etc.) class 3: proptosis class 4: extraocular muscle involvement (usually with diplopia) class 5: corneal involvement (primarily due to lagophthalmos) class 6: sight loss (due to optic nerve involvement) typically the natural history of tao follows rundle's curve, which describes a rapid worsening during an initial phase, up to a peak of maximum severity, and then improvement to a static plateau without, however, resolving back to a normal condition. management treatment of graves' disease includes antithyroid drugs that reduce the production of thyroid hormone, radioiodine (radioactive iodine i-131) and thyroidectomy (surgical excision of the gland). as operating on a hyperthyroid patient is dangerous, prior to thyroidectomy, preoperative treatment with antithyroid drugs is given to render the patient euthyroid. each of these treatments has advantages and disadvantages, and no single treatment approach is considered the best for everyone. treatment with antithyroid medications must be administered for six months to two years to be effective. even then, upon cessation of the