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Graves' disease

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Graves' disease, also known as toxic diffuse goiter or Basedow’s disease, is an autoimmune disease that affects the thyroid.<ref name=NIH2012/> It frequently results in and is the most common cause of hyperthyroidism.<ref name=Hen2015/> It also often results in an enlarged thyroid.<ref name=NIH2012/> Signs and symptoms of hyperthyroidism may include irritability, muscle weakness, sleeping problems, a fast heartbeat, poor tolerance of heat, diarrhea and unintentional weight loss.<ref name=NIH2012/> Other symptoms may include thickening of the skin on the shins, known as pretibial myxedema, and eye bulging, a condition caused by Graves' ophthalmopathy.<ref name=NIH2012/> About 25 to 30% of people with the condition develop eye problems.<ref name=NIH2012>Template:Cite web</ref><ref name=NEJM2008/>

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.<ref name=Men2014>Template:Cite journal</ref> Persons are more likely to be affected if they have a family member with the disease.<ref name=NIH2012/> If one monozygotic twin is affected, a 30% chance exists that the other twin will also have the disease.<ref name=Nik2012/> The onset of disease may be triggered by physical or emotional stress, infection, or giving birth.<ref name=NEJM2008/> Those with other autoimmune diseases, such as type 1 diabetes and rheumatoid arthritis, are more likely to be affected.<ref name=NIH2012/> Smoking increases the risk of disease and may worsen eye problems.<ref name=NIH2012/> The disorder results from an antibody, called thyroid-stimulating immunoglobulin (TSI), that has a similar effect to thyroid stimulating hormone (TSH).<ref name=NIH2012/> These TSI antibodies cause the thyroid gland to produce excess thyroid hormones.<ref name=NIH2012/> The diagnosis may be suspected based on symptoms and confirmed with blood tests and radioiodine uptake.<ref name=NIH2012/><ref name=NEJM2008>Template:Cite journal</ref> Typically, blood tests show a raised T3 and T4, low TSH, increased radioiodine uptake in all areas of the thyroid, and TSI antibodies.<ref name=NEJM2008/>

The three treatment options are radioiodine therapy, medications, and thyroid surgery.<ref name=NIH2012/> Radioiodine therapy involves taking iodine-131 by mouth, which is then concentrated in the thyroid and destroys it over weeks to months.<ref name=NIH2012/> The resulting hypothyroidism is treated with synthetic thyroid hormones.<ref name=NIH2012/> 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.<ref name=NIH2012/> Surgery to remove the thyroid is another option.<ref name=NIH2012/> Eye problems may require additional treatments.<ref name=NIH2012/>

Graves disease develops in about 0.5% of males and 3.0% of females.<ref name=Hen2015>Template:Cite journal</ref> It occurs about 7.5 times more often in women than in men.<ref name=NIH2012/> Often, it starts between the ages of 40 and 60, but can begin at any age.<ref name=Nik2012/> It is the most common cause of hyperthyroidism in the United States (about 50 to 80% of cases).<ref name=NIH2012/><ref name=NEJM2008/> The condition is named after Irish surgeon Robert Graves, who described it in 1835.<ref name=Nik2012/> A number of prior descriptions also exist.<ref name=Nik2012>Template:Cite book</ref>

Signs and symptoms

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Template:Main

File:HyperaldosteronismSymptoms.jpeg
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,<ref>Template:Cite book</ref> and skin warmth and moistness.<ref name=agabegi2nd157>page 157 in:Template:Cite book</ref> 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.<ref name=agabegi2nd157/><ref>Template:Cite journal</ref>

Cause

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The exact cause is unclear, but it is believed to involve a combination of genetic and environmental factors.<ref name=Men2014/> 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.<ref>Template:Cite journal</ref>

Genetics

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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.<ref name="EndocrReview1993">Template:Cite journal</ref> To date, no clear genetic defect has been found to point to a single-gene cause.Template:Citation needed

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.<ref name=NEJM2016>Template:Cite journal</ref>

Infectious trigger

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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.<ref>Template:Cite journal</ref>

The bacterium Yersinia enterocolitica bears structural similarity with the human thyrotropin receptor<ref name="EndocrReview1993"/> and was hypothesized to contribute to the development of thyroid autoimmunity arising for other reasons in genetically susceptible individuals.<ref>Template:Cite journal</ref> In the 1990s, Y. enterocolitica was suggested to be possibly associated with Graves' disease.<ref>Template:Cite journal</ref> More recently, the role for Y. enterocolitica has been disputed.<ref>Template:Cite journal</ref>

Epstein–Barr virus is another potential trigger.<ref>Template:Cite book</ref>

Mechanism

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Thyroid-stimulating immunoglobulins recognize and bind to the 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.Template:Citation needed

Pathophysiology

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File:Histopathology of Graves' disease - medium mag.jpg
Histopathology of a case of Graves' disease. It shows marked hyperplasia of thyroid follicular cells, generally more so than toxic multinodular goitre, forming papillae into the thyroid follicles, and with scalloping of the peripheral colloid.

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 are:

  1. 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.
  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.
    • 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.<ref>Template:Cite web</ref>

Diagnosis

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Graves disease may present clinically with one or more of these characteristic signs:Template:Citation needed

  • 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 non-pitting 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.Template:Citation needed 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) 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 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.<ref name="pmid_9709909">Template:Cite journal</ref> Differentiating common forms of hyperthyroidism such as Graves' disease, single thyroid adenoma, and toxic multinodular goiter is important to determine proper treatment.<ref name="pmid_9709909"/> 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.<ref name="pmid_15127319">Template:Cite journal</ref>

Eye disease

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Template:Further 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.<ref>Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Other distinctive features of TAO include lid retraction, restrictive myopathy, superior limbic keratoconjunctivitis, and exposure keratopathy.Template:Citation needed

Severity of eye disease may be classified by the mnemonic: "NO SPECS":<ref name="pmid15310608">Template:Cite journal</ref>

  • 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.<ref>Template:Cite journal</ref>

Management

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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.Template:Citation needed

Treatment with antithyroid medications must be administered for six months to two years to be effective. Even then, upon cessation of the drugs, the hyperthyroid state may recur. The risk of recurrence is about 40–50%, and lifelong treatment with antithyroid drugs carries some side effects such as agranulocytosis and liver disease.<ref name=":0">Template:Cite journal</ref> Side effects of the antithyroid medications include a potentially fatal reduction in the level of white blood cells. Therapy with radioiodine is the most common treatment in the United States, while antithyroid drugs and/or thyroidectomy are used more often in Europe, Japan, and most of the rest of the world.

β-Blockers (such as propranolol) may be used to inhibit the sympathetic nervous system symptoms of tachycardia and nausea until antithyroid treatments start to take effect. Pure β-blockers do not inhibit lid retraction in the eyes, which is mediated by alpha adrenergic receptors.

Antithyroid drugs

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The main antithyroid drugs are carbimazole (in the UK), methimazole (in the US), and propylthiouracil/PTU. These drugs block the binding of iodine and coupling of iodotyrosines. The most dangerous side effect is agranulocytosis (1/250, more in PTU). Others include granulocytopenia (dose-dependent, which improves on cessation of the drug) and aplastic anemia. Patients on these medications should see a doctor if they develop sore throat or fever. The most common side effects are rash and peripheral neuritis. These drugs also cross the placenta and are secreted in breast milk. Lugol's iodine may be used to block hormone synthesis before surgery.Template:Citation needed

A randomized control trial testing single-dose treatment for Graves found methimazole achieved euthyroid state more effectively after 12 weeks than did propylthyouracil (77.1% on methimazole 15 mg vs 19.4% in the propylthiouracil 150 mg groups).<ref name="pmid11298092">Template:Cite journal</ref>

No difference in outcome was shown for adding thyroxine to antithyroid medication and continuing thyroxine versus placebo after antithyroid medication withdrawal. However, two markers were found that can help predict the risk of recurrence. These two markers are a positive TSHr antibody (TSHR-Ab) and smoking. A positive TSHR-Ab at the end of antithyroid drug treatment increases the risk of recurrence to 90% (sensitivity 39%, specificity 98%), and a negative TSHR-Ab at the end of antithyroid drug treatment is associated with a 78% chance of remaining in remission. Smoking was shown to have an impact independent to a positive TSHR-Ab.<ref name="pmid11331213">Template:Cite journal</ref>

Radioiodine

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File:Basedow-vor-nach-RIT.jpg
Scan of affected thyroid before (top) and after (bottom) radioiodine therapy

Radioiodine (radioactive iodine-131) was developed in the early 1940s at the Mallinckrodt General Clinical Research Center. This modality is suitable for most patients, although some prefer to use it mainly for older patients. Indications for radioiodine are failed medical therapy or surgery and where medical or surgical therapy are contraindicated. Hypothyroidism may be a complication of this therapy, but may be treated with thyroid hormones if it appears. The rationale for radioactive iodine is that it accumulates in the thyroid and irradiates the gland with its beta and gamma radiations, about 90% of the total radiation being emitted by the beta (electron) particles. The most common method of iodine-131 treatment is to administer a specified amount in microcuries per gram of thyroid gland based on palpation or radiodiagnostic imaging of the gland over 24 hours.<ref>Template:Cite book</ref> Patients who receive the therapy must be monitored regularly with thyroid blood tests to ensure they are treated with thyroid hormone before they become symptomatically hypothyroid.<ref>Template:Cite journal</ref>

Contraindications to RAI are pregnancy (absolute), ophthalmopathy (relative; it can aggravate thyroid eye disease), or solitary nodules.<ref name="btf-thyroid.org">Template:Cite web</ref>

Disadvantages of this treatment are a high incidence of hypothyroidism (up to 80%) requiring eventual thyroid hormone supplementation in the form of a daily pill(s). The radioiodine treatment acts slowly (over months to years) to destroy the thyroid gland, and Graves' disease–associated hyperthyroidism is not cured in all persons by radioiodine, but has a relapse rate that depends on the dose of radioiodine which is administered.<ref name="btf-thyroid.org"/> In rare cases, radiation induced thyroiditis has been linked to this treatment.<ref>Template:Cite journal</ref>

Surgery

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Template:Further This modality is suitable for young people and pregnant females. Indications for thyroidectomy can be separated into absolute indications or relative indications. These indications aid in deciding which people would benefit most from surgery.<ref name=":0" /> The absolute indications are a large goiter (especially when compressing the trachea), suspicious nodules or suspected cancer (to pathologically examine the thyroid), and people with ophthalmopathy and additionally if it is the person's preferred method of treatment or if refusing to undergo radioactive iodine treatment. Pregnancy is advised to be delayed for six months after radioactive iodine treatment.<ref name=":0" />

Both bilateral subtotal thyroidectomy and the Hartley-Dunhill procedure (hemithyroidectomy on one side and partial lobectomy on other side) are possible.

Advantages are immediate cure and potential removal of carcinoma. Its risks are injury of the recurrent laryngeal nerve, hypoparathyroidism (due to removal of the parathyroid glands), hematoma (which can be life-threatening if it compresses the trachea), relapse following medical treatment, infections (less common), and scarring.<ref name=":0" /> The increase in the risk of nerve injury can be due to the increased vascularity of the thyroid parenchyma and the development of links between the thyroid capsule and the surrounding tissues. Reportedly, a 1% incidence exists of permanent recurrent laryngeal nerve paralysis after complete thyroidectomy.<ref name=":0" /> Risks related to anesthesia are many, thus coordination with the anesthesiologist and patient optimization for surgery preoperatively are essential. Removal of the gland enables complete biopsy to be performed to have definite evidence of cancer anywhere in the thyroid. (Needle biopsies are not so accurate at predicting a benign state of the thyroid). No further treatment of the thyroid is required, unless cancer is detected. Radioiodine uptake study may be done after surgery, to ensure all remaining (potentially cancerous) thyroid cells (i.e., near the nerves to the vocal cords) are destroyed. Besides this, the only remaining treatment will be levothyroxine, or thyroid replacement pills to be taken for the rest of the patient's life.

A 2013 review article concludes that surgery appears to be the most successful in the management of Graves' disease, with total thyroidectomy being the preferred surgical option.<ref>Template:Cite journal</ref>

Eyes

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Mild cases are treated with lubricant eye drops or nonsteroidal anti-inflammatory drops. Severe cases threatening vision (corneal exposure or optic nerve compression) are treated with steroids or orbital decompression. In all cases, cessation of smoking is essential. Double vision can be corrected with prism glasses and surgery (the latter only when the process has been stable for a while).

Difficulty closing eyes can be treated with lubricant gel at night, or with tape on the eyes to enable full, deep sleep.

Orbital decompression can be performed to enable bulging eyes to retreat back into the head. Bone is removed from the skull behind the eyes, and space is made for the muscles and fatty tissue to fall back into the skull. <ref>Template:Cite journal</ref>

For management of clinically active Graves disease, orbitopathy (clinical activity score >2) with at least mild to moderate severity, intravenous glucocorticoids are the treatment of choice, usually administered in the form of pulse intravenous methylprednisolone. Studies have consistently shown that pulse intravenous methylprednisolone is superior to oral glucocorticoids both in terms of efficacy and decreased side effects for managing Graves' orbitopathy.<ref>Template:Cite journal</ref>

Prognosis

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If left untreated, more serious complications could result, including birth defects in pregnancy, increased risk of a miscarriage, bone mineral loss<ref name=Ken2001/> and, in extreme cases, death (e.g. indirectly through complications, or through a thyroid storm event). Graves' disease is often accompanied by an increase in heart rate, which may lead to further heart complications, including loss of the normal heart rhythm (atrial fibrillation), which may lead to stroke. If the eyes are proptotic (bulging) enough that the lids do not close completely at night, dryness will occur – with the risk of a secondary corneal infection, which could lead to blindness. Pressure on the optic nerve behind the globe can lead to visual field defects and vision loss, as well. Prolonged untreated hyperthyroidism can lead to bone loss, which may resolve when treated.<ref name="Ken2001">Template:Cite book</ref>

Epidemiology

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File:Causes of hyperthyroidism.png
Most common causes of hyperthyroidism by age<ref>Template:Cite journal</ref>

Graves' disease occurs in about 0.5% of people.<ref name=NEJM2008/> Graves' disease data has shown that the lifetime risk for women is around 3% and 0.5% for men.<ref>Template:Citation</ref> It occurs about 7.5 times more often in women than in men<ref name=NIH2012/> and often starts between the ages of 40 and 60.<ref name=Nik2012/> It is the most common cause of hyperthyroidism in the United States (about 50 to 80% of cases).<ref name=NIH2012/><ref name=NEJM2008/>

History

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Graves disease owes its name to the Anglo-Irish doctor Robert James Graves,<ref>Template:WhoNamedIt</ref> who described a case of goiter with exophthalmos in 1835.<ref>Graves, RJ. Newly observed affection of the thyroid gland in females Template:Webarchive. (Clinical lectures.) London Medical and Surgical Journal (Renshaw), 1835; 7 (part 2): 516–517. Reprinted in Medical Classics, 1940;5:33–36.</ref> (Medical eponyms are often styled nonpossessively; thus Graves' disease and Graves disease are variant stylings of the same term.)

The German Karl Adolph von Basedow independently reported the same constellation of symptoms in 1840.<ref>Von Basedow, KA. Exophthalmus durch Hypertrophie des Zellgewebes in der Augenhöhle. [Casper's] Wochenschrift für die gesammte Heilkunde, Berlin, 1840, 6: 197–204; 220–228. Partial English translation in: Ralph Hermon Major (1884–1970): Classic Descriptions of Disease. Springfield, C. C. Thomas, 1932. 2nd edition, 1939; 3rd edition, 1945.</ref><ref>Von Basedow, KA. "Die Glotzaugen". [Casper's] Wochenschrift für die gesammte Heilkunde, Berlin, 1848: 769–777.</ref> As a result, on the European continent, the terms "Basedow syndrome",<ref name="WNI" /> "Basedow disease", or "Morbus Basedow"<ref name="TMHP">Template:Cite-TMHP, pages 82, 294, and 295.</ref> are more common than "Graves' disease".<ref name="WNI">Template:WhoNamedIt – the history and naming of the disease</ref><ref>Template:EMedicine</ref>

Graves disease<ref name=WNI/><ref name=TMHP/> has also been called exophthalmic goiter.<ref name=TMHP/>

Less commonly, it has been known as Parry disease,<ref name=WNI/><ref name=TMHP/> Begbie disease, Flajan disease, Flajani–Basedow syndrome, and Marsh disease.<ref name=WNI/> These names for the disease were derived from Caleb Hillier Parry, James Begbie, Giuseppe Flajani, and Henry Marsh.<ref name=WNI/> Early reports, not widely circulated, of cases of goiter with exophthalmos were published by the Italians Giuseppe Flajani<ref>Flajani, G. Sopra un tumor freddo nell'anterior parte del collo broncocele. (Osservazione LXVII). In Collezione d'osservazioni e reflessioni di chirurgia. Rome, Michele A Ripa Presso Lino Contedini, 1802;3:270–273.</ref> and Antonio Giuseppe Testa,<ref>Testa, AG. Delle malattie del cuore, loro cagioni, specie, segni e cura. Bologna, 1810. 2nd edition in 3 volumes, Florence, 1823; Milano 1831; German translation, Halle, 1813.</ref> in 1802 and 1810, respectively.<ref>Template:WhoNamedIt</ref> Prior to these, Caleb Hillier Parry,<ref>Template:Cite book</ref> a notable provincial physician in England of the late 18th century (and a friend of Edward Miller-Gallus),<ref>Template:Cite journal</ref> described a case in 1786. This case was not published until 1825 - ten years ahead of Graves.<ref>Template:WhoNamedIt</ref>

However, fair credit for the first description of Graves disease goes to the 12th-century Persian physician Sayyid Ismail al-Jurjani,<ref>Sayyid Ismail Al-Jurjani. Thesaurus of the Shah of Khwarazm.</ref> who noted the association of goiter and exophthalmos in his Thesaurus of the Shah of Khwarazm, the major medical dictionary of its time.<ref name=WNI/><ref>Template:Cite journal</ref>

Society and culture

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Notable cases

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File:Marty Feldman.png
Marty Feldman used his bulging eyes, caused by Graves' disease, for comedic effect.

Literature

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Research

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Agents that act as antagonists at thyroid stimulating hormone receptors are under investigation as a possible treatment for Graves' disease.<ref>Template:Cite web</ref>

References

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Template:Medical condition classification and resources Template:Thyroid disease Template:Autoimmune diseases Template:Authority control

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