Graves disease

Graves disease is a thyroid disorder characterized by goiter, exophthalmos, infiltrative dermopathy, and hyperthyroidism. It is caused by an antibody-mediated auto-immune reaction, but the trigger for this reaction is still unknown. It is the most common cause of hyperthyroidism.

In some parts of Europe the term Basedow’s disease or Graves-Basedow disease is preferred to Graves' disease.

History
Ljunggren (1983) suggests that the Persian physician Sayyid Ismail Al-Jurjani should be credited with recognising the disease, having noted the association of goiter and exophthalmos, in "Thesaurus of the Shah of Khwarazm", the most famous of his five books, and the major medical dictionary of its time.

In modern times, the first detailed description of exophthalmic goiter seems to be that of Caleb Hillier Parry in 1786, but this was not published until 1825, three years after his death. The same condition was also described by the Italians Giuseppe Flajani and Antonio Giuseppe Testa, in 1802 and 1810 respectively. However, the disease owes its name in the English-speaking world to the Irishman Robert James Graves who described it in 1835. The German Karl Adolph von Basedow independently reported the same constellation of symptoms in 1840. (As a result, on the European Continent the term Basedow's disease is the more common, while it is known as Graves' disease in the English-speaking world.)

Diagnosis
Graves' disease may present clinically with one of the following characteristic signs:
 * goiter (a swelling in the neck just below the adam's apple)
 * exophthalmos (protuberance of one or both eyes)
 * a non-pitting edema described as "peau d'orange", i.e. resembling the skin of an orange, usually found on the lower extremities
 * fatigue, weight loss, and other symptoms of hyperthyroidism

The two signs characteristic of Graves' disease (i.e. not seen in other hyperthyroid conditions) are exophthalmos and nonpitting edema. Goiter, which is caused by an enlarged thyroid gland, can be present with other forms of hyperthyroidism, although Graves' disease is the most common cause. A large goiter is visible to the naked eye, but a smaller goiter may not be clinically detectable, though X-rays or ultrasound can assist in detecting it.

Another diagnostic hallmark of Graves' disease is hyperthyroidism, i.e. over-production of thyroid hormone (T4 or T3). The clinical symptoms of this condition are due to changes in cellular metabolism. Hyperthyroidism can be confirmed by measuring elevated blood levels levels of the thyroid hormones T3 and T4. Other useful laboratory measurements include thyroid-stimulating hormone (TSH, low in Graves' disease due to negative feedback from the elevated T4 and T3), and protein-bound iodine (elevated). Thyroid-stimulating antibodies may also be detected serologically. However, definitive diagnosis requires a biopsy.

Incidence and epidemiology
The disease occurs most frequently in women (8:1 compared to men). It occurs most often in middle age (most commonly in the third to fifth decades of life), but is not uncommon in adolescents, during pregnancy, at the time of menopause and in people over age 50. There is a marked family preponderance, which has led to speculation that there may be a genetic component. To date, no clear genetic defect has been found that would point at a monogenic cause.

Pathophysiology
Graves' disease is an example of a type II hypersensitivity autoimmune disorder. Most features are due to the production of autoantibodies that bind to the receptor for Thyroid-stimulating hormone (TSH). Other autoantibodies may also be found which bind to thyroglobulin and to the thyroid hormones (T3 and T4).

The TSH receptor is expressed on the follicular cells of the thyroid gland (the cells that produce thyroid hormone). When antibodies chronically bind to the TSH receptor, the result is an abnormally high production of the thyroid hormones T3 and T4. This in turn causes the symptoms of hyperthyroidism, and the enlargement of the thyroid gland visible as goiter.

The infiltrative exophthalmos that is frequently encountered has been explained by the expression of the TSH receptor on retroorbital tissue, causing swelling of the extraocular muscles.

The "peau d'orange" dermopathy has been explained by the infiltration of autoantibodies under the skin, causing an inflammatory reaction and subsequent fibrous plaques.

There are 3 types of autoantibodies to the TSH receptor currently recognized:


 * TSI, Thyroid stimulating inmunoglobulins: these antibodies (mainly IgG) act as LATS (Long Acting Thyroid Stimulants), activating the cells in a longer and slower way than TSH, leading to an elevated production of thyroid hormone.


 * TGI, Thyroid growth immunoglobulins: these antibodies bind directly to the TSH receptor and have been implicated in the growth of thyroid follicles.


 * TBII, Thyroid Bind Inhibiting Inmunoglobulins: these antibodies inhibit the normal union of TSH with its receptor. By doing this, several other antibodies that normally would inhibit TSH function will actually act as if TSH itself was binding to its receptor, thus inducing thyroid function.

Etiology
The trigger for auto-antibody production is not known. There appears to be a genetic predisposition for Graves' disease, suggesting that 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.

Since Graves' disease is an autoimmune disease which appears suddenly, often quite late in life, it is thought that 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).

One possible culprit is the bacterium Yersinia enterocolitica (a cousin of Yersinia pestis, the agent of bubonic plague). However, although there is indirect evidence for the structural similarity between the bacteria and the human thyrotropin receptor, direct causative evidence is limited. 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. It has also been suggested that Y. 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. More recently the role for Y. enterocolitica has been disputed.

The ocular manifestations of Graves disease are more common in smokers and tend to worsen (or develop for the first time) following radioiodine treatment of the thyroid condition. Thus, they are not caused by hyperthyroidism per se; this common misperception may result from the fact that hyperthyroidism from other causes may cause eyelid retraction or eyelid lag (so-called hyperthyroid stare) which can be confused with the general appearance of proptosis/exophthalmos, despite the fact that the globes do not actually protrude in other causes of hyperthyroidism. Also, both conditions (globe protrusion and hyperthyroid lid retraction) may exist at the same time in the hyperthyroid patient with Graves disease.

Treatment
Medical treatment of Graves' disease includes antithyroid drugs, radioactive iodine and thyroidectomy (surgical excision of the gland).

Treatment of the hyperthyroidism of Graves-Basedow disease may be with medications such as methimazole or propylthiouracil (PTU), which reduce the production of thyroid hormone, or with radioactive iodine. Surgical removal of the thyroid is another option, but still requires preoperative treatment with methimazole or PTU. This is done to render the patient "euthyroid" (i.e. normothyroid) before the surgery since operating on a frankly hyperthyroid patient is dangerous. Therapy with radioactive iodine (I-131) is the most common treatment in the United States and in many other parts of the world. Thyroid blocking drugs and/or surgical thyroid removal is used more often than radioactive iodine as definitive treatment in Japan, perhaps because of general fear of radioactivity among many Japanese.

The development of radioactive iodine (I-131) in the early 1940s at the Mallinckrodt General Clinical Research Center and its widespread adoption as treatment for Graves' Disease has led to a progressive reduction in the use of surgical thyroidectomy for this problem. In general, RAI therapy is effective, less expensive, and avoids the small but definite risks of surgery. Treatment with antithyroid medications must be given for six months to two years, in order to be effective. Even then, upon cessation of the drugs, the hyperthyroid state may recur. Side effects of the antithyroid medications include a potentially fatal reduction in the level of white blood cells.

Antithyroid drugs
The main antithyroid drugs are methimazole (US), carbimazole (UK) 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); this is an idiosyncratic reaction which does not stop on cessation of drug). 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.

Radioiodine
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.

Contraindications to RAI are pregnancy (absolute), ophthalmopathy (relative- it can aggravate thyroid eye disease), solitary nodules. Disadvantages of this treatment are a high incidence of hypothyroidism (up to 80%) requiring hormone supplementation. It acts slowly and has a relapse rate that depends on the dose administered.

Surgery
This modality is suitable for young patients and pregnant patients. Indications are: a large goitre (especially when compressing the trachea), suspicious nodules or suspected cancer (to pathologically examine the thyroid) and patients with ophthalmopathy.

Both bilateral subtotal thyroidectomy and the Hartley-Dunhill procedure (hemithyroidectomy on 1 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) and scarring.

Eye disease

 * For mild disease - artificial tears, steroid eyedrops, oral steroids (to reduce chemosis)
 * For moderate disease - lateral tarsorrhaphy
 * For severe disease - orbital decompression or retro-orbital radiation

No treatment
If left untreated, more serious complications could result, including birth defects in pregnancy, increased risk of a miscarriage, and in extreme cases, death. Graves-Basedow disease is often accompanied by an increase in heart rate, which may lead to further heart complications. If the eyes are proptotic (bulging) severely enough that the lids do not close completely at night, severe dryness will occur with a very high 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.

Noted sufferers

 * United States President George H. W. Bush developed new atrial fibrillation and was diagnosed in 1991 with hyperthyroidism due to the disease and was treated at Walter Reed Army Medical Center with radioactive iodine. By coincidence (or so it is presumed, since the ultimate cause of this disease remains unknown), the president's wife Barbara Bush also developed the disease about the same time, which in her case produced severe infiltrative exophthalmos and a cosmetic change in the appearance of her eyes.
 * Canadian Minister of Citizenship and Immigration Diane Finley announced in the House of Commons that she was suffering from the disease. She now wears sunglasses to protect her eyes from the bright lighting in the chamber.
 * Nadezhda Krupskaya (1869-1939), wife of Vladimir Lenin was believed to have suffered from the disease, which caused her eyes to bulge and her neck to tighten. This was the reason that her Bolshevik codename was 'Fish'. Since Graves' Disease disrupts the menstrual cycle, it is believed that this is why the couple never had children.
 * Bobby Engram, NFL wide receiver with the Seattle Seahawks, formerly of the Chicago Bears, Penn State Nittany Lions, and Camden High School Bulldogs (diagnosed October 2006)
 * German folk singer and musician Heino, who has since become famous for his wearing of dark sunglasses to protect his eyes from bright sunlight.
 * NASCAR champion Bobby Labonte, who was diagnosed with the disorder in the mid-1990s.
 * English composer Herbert Howells was diagnosed with the disease in 1915 and given six months to live, but made a recovery after undergoing experimental radium treatment and went on to live to the age of ninety.
 * British actress Maggie Smith came down with the disease but recovered swiftly due to close help from her son.