Graves' disease

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Graves-Basedow disease or known simply as Graves disease is a medical disorder that may manifest several different conditions including hyperthyroidism (over-activity of thyroid hormone production), infiltrative exophthalmos (protruberance of one or both eyes and associated problems) and infiltrative dermopathy (a skin condition usually of the lower extremities). This disorder is the most common cause of hyperthyroidism. It is known to be related to an antibody mediated type of auto-immunity, but the trigger for the reaction is unknown.

Also known in the English-speaking world simply as Graves' disease, the disease occurs most frequently in women (8:1 compared to men). It occurs most often in middle age but is not uncommon in adolescents, during pregnancy, at the time of menopause and in people over age 50. Symptoms may include fatigue, weight loss (despite a good appetite), rapid heart beat, heat intolerance, muscle weakness, palpitation, increased bowel activity, emotional lability, and restlessness. In premenopausal women, there may be a reduction in the amount of menses (oligomenorrhea). Because similar antibodies to those stimulating the thyroid may also react with the eye muscles, patients may develop an enlargement of the ocular muscles with resultant forward movement of the eyeball (proptosis, also called exopthalmos) and inflammation of the tissues around the eye. Enlargement of the eye muscles may result in difficulty with proper movement and coordination of the eyes, and cause double vision and an obvious disparity in the relative position of both eyes.

The ocular manifestations of Graves-Basedow 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/exopthalmos, despite the fact that the globes do not actually protrude in other causes of hyperthyroidism. Also, both conditions may exist at the same time in the hyperthyroid patient with Graves-Basedow disease.

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 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.

Excessive production of thyroid hormone may cause the patient to develop many complaints, including hyperstimulation, restlessness, heat intolerance, tremor, palpitation and heart dysrhythmia, increased bowel activity, and emotionally lability. 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 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 exopthalmos and a cosmetic change in the appearance of her eyes.

Signs and symptoms

Graves-Basedow disease is a disorder characterized by a triad of hyperthyroidism, goitre, and exophthalmos (bulging eyeballs).


Due to the many physiological actions of thyroid hormone, many symptoms and signs are linked to Graves' disease:

Extremely manifested disease that can sometimes be life-threatening is called the thyroid storm.

Diagnosis

On the basis of the signs and symptoms, thyroid hormone (thyroxine or T4, triiodothyronine or T3) and thyroid-stimulating hormone (TSH) are determined in the medical laboratory. Free T4 and Free T3 is markedly elevated, while TSH is suppressed due to negative feedback. An elevated protein-bound iodine level may be detected. A large goiter is sometimes seen on X-rays.

Thyroid-stimulating antibodies may be detected serologically.

Pathophysiology

Grave's disease is an example of a type II hypersensitivity autoimmune disorder. Most features are due to the production of autoantibodies that bind to the TSH receptor, which is present on the follicular cells of the thyroid (the cells that produce thryoid hormone). These antibodies activate the cells in the same fashion as TSH itself, leading to an elevated production of thyroid hormone.

The infiltrative opthalmopathy (thyroid eye disease) that is frequently encountered has been explained by the expression of the TSH receptor on retroorbital tissue.

The exact cause of antibody production is not known. Viral infection may trigger antibodies against its epitopes, which cross-react with the human TSH receptor. 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.

Treatment

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

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 stop the medication and 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 suppletion. 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 opthalmopathy.

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

If left untreated

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.

Epidemiology

There is female predominance (ratio 8:1), and onset is commonly in the third to fifth decades of life. There is a marked family preponderance, which has led to speculation that there may be a genetic cause. To date, no clear genetic defect has been found that would point at a monogenic cause.

History

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

Caleb Hillier Parry (1755-1822) first noted the clinical picture in 1786, and it is reported in his posthumous collection of unpublished writings in 1825. It was also described by the Italians Giuseppe Flajani (1741-1808) in 1802 and Antonio Giuseppe Testa (1756-1814) in 1810. Robert James Graves (1797-1853) of Ireland in 1835, and Karl Adolph von Basedow of Germany in 1840, independently reported the constellation of symptoms. 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.

Bibliography

  • Sayyid Ismail Al-Jurjani. Thesaurus of the Shah of Khwarazm.
  • 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.
  • 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.
  • Parry CH. Enlargement of the thyroid gland in connection with enlargement or palpitations of the heart. Posthumous, in: Collections from the unpublished medical writings of C. H. Parry. London, 1825, pp. 111-129. According to Garrison, Parry first noted the condition in 1786. He briefly reported it in his Elements of Pathology and Therapeutics, 1815. Reprinted in Medical Classics, 1940, 5: 8-30.
  • Graves RJ. New observed affection of the thyroid gland in females.(Clinical lectures.) London Medical and Surgical Journal (Renshaw), 1835; 7: 516-517. Reprinted in Medical Classics, 1940;5:33-36.
  • Marsh H. Dilatation of the cavities of the heart. Enlargement of the thyroid gland. Dublin Journal of Medical and Chemical Science. 1842, 20: 471-474. Abstract.
  • 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 editon, 1945.
  • Von Basedow KA. Die Glotzaugen. [Casper's] Wochenschrift für die gesammte Heilkunde, Berlin, 1848: 769-777.
  • Begbie J. Anaemia and its consequences; enlargement of the thyroid gland and eyeballs. Anaemia and goitre, are they related? Monthly Journal of Medical Science, London, 1849, 9: 496-508.

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