Graves' disease

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Overview
Graves disease is a thyroid disorder characterized by goiter, exophthalmos, "orange-peel" skin, 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 the world, and the most common cause of general thyroid enlargement in developed countries.

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

History
Graves disease owes its name to the Irish doctor Randy Danny Graves, who described a case of goiter with exophthalmos in 1835. However, 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 more common than Graves' disease.

Several earlier reports exist but were not widely circulated. For example, cases of goiter with exophthalmos were published by the Italians Giuseppe Flajani and Antonio Giuseppe Testa, in 1802 and 1810 respectively. Prior to these, Caleb Hillier Parry, a notable provincial physician in England of the late 18th-century (and a friend of Edward Jenner), described a case in 1786. This case was not published until 1825, but still ten years ahead of Graves

However, fair credit for the first description of Graves disease goes to the 12th-century Persian physician Sayyid Ismail Al-Jurjani, who noted the association of goiter and exophthalmos in his Thesaurus of the Shah of Khwarazm, the major medical dictionary of its time.

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.

Incidence and epidemiology
The disease occurs most frequently in women (7:1 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 autoimmune disorder, in which the body produces antibody|antibodies to the receptor for thyroid-stimulating hormone (TSH). (Antibodies to thyroglobulin and to the thyroid hormones T3 and T4 may also be produced.) These antibodies cause hyperthyroidism because they bind to the TSH receptor and chronically stimulate it. The TSH receptor is expressed on the 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 that is 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.

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


 * TSI, Thyroid stimulating immunoglobulins: 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, Thyrotrophin Binding-Inhibiting Inmunoglobulins: these antibodies inhibit the normal union of TSH with its receptor. Some will actually act as if TSH itself is binding to its receptor, thus inducing thyroid function. Other types may not stimulate the thyroid gland, but will prevent TSI and TSH from binding to and stimulating the receptor.

Diagnosis
Graves' disease may present clinically with one of the following characteristic signs:
 * goiter (an enlarged thyroid gland, sometimes detectable as a swelling in the neck)
 * exophthalmos (protuberance of one or both eyes)
 * a non-pitting edema with thickening of the skin, described as "peau d'orange" or "orange peel", usually found on the lower extremities
 * fatigue, weight loss with increased appetite, and other symptoms of hyperthyroidism

The two signs that are truly diagnostic 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 sign of Graves' disease is hyperthyroidism, i.e. over-production of the thyroid hormones T3 and T4. Although, hypothyroidism has also been associated and may be the causating factor in some patients. Hyperthyroidism can be confirmed by measuring elevated blood levels levels of free (unbound) T3 and T4. Other useful laboratory measurements include thyroid-stimulating hormone (TSH, 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.

Definitive diagnosis requires a biopsy.

Other Graves' Disease Symptoms
Some of the most typical symptoms of Graves' Disease are the following:


 * Palpitations
 * Tachycardia (rapid heart rate: 100-120 beats per minute, or higher)
 * Arrhythmia (irregular heart beat)
 * Raised blood pressure (Hypertension)
 * Tremor (usually fine shaking eg. hands)
 * Excessive sweating
 * Heat intolerance
 * Increased appetite
 * Unexplained weight loss despite increased appetite
 * Shortness of breath
 * Muscle weakness (especially in the large muscles of the arms and legs) and degeneration
 * Diminished/Changed sex drive
 * Insomnia (inability to get enough sleep)
 * Increased energy
 * Fatigue
 * Mental impairment, memory lapses, diminished attention span
 * Decreased concentration
 * Nervousness, agitation
 * Irritability
 * Restlessness
 * Erratic behavior
 * Emotional lability
 * Brittle nails
 * Abnormal breast enlargement (men)
 * Goiter (enlarged thyroid gland)
 * Protruding eyeballs (Graves' disease only)
 * Double vision
 * Eye pain, irritation, or the feeling of grit or sand in the eyes
 * Swelling or redness of eyes or eyelids/eyelid retraction
 * Sensitivity to light
 * Decrease in menstrual periods (oligomenorrhea), Irregular and scant menstrual flow (Amenorrhea)
 * Difficulty conceiving/infertility/recurrent miscarriage
 * Hair loss
 * Itchy skin, hives
 * Chronic sinus infections
 * Lumpy, reddish skin of the lower legs (pretibial myxedema)
 * Smooth, velvety skin
 * Increased bowel movements or Diarrhea

Diganostic Studies

 * High RAIU: de novo T4 synthesis
 * Toxic adenoma
 * Toxic multinodular goiter
 * TSH-producing pituitary tumor
 * Hcg-secreting tumor
 * Hyperemesis gravidarum
 * Low RAIU: released or exogenous T4
 * Thyroiditis	- painful, painless, post-partum
 * Amiodarone toxicity
 * Factitious hyperthyroidism
 * Struma ovarii (rare)
 * Metastatic thyroid CA (ridiculously rare)
 * Thyroid-stimulating antibodies bind and stimulate the TSH receptor
 * Anti-TSHR ABs are 80-95% sensitive, 80-90% specific for Graves’

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

Treatment of the hyperthyroidism of Graves disease may be with medications such as carbimazole, 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. Thyroid blocking drugs and/or surgical thyroid removal is used more often than radioactive iodine as definitive treatment in Europe, Japan, and most of the rest of the world.

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. 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 goiter (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.

Herbal
For treating Graves disease, along with many other thyroid disorders, one can use the herb bugleweed. This herb has a profound effect on thyroid function and regulation of thyroid hormones.

Eye disease
Thyroid-associated ophthalmopathy is one of the most typical symptom of Graves Disease. It is known by a variety of terms, the commonest being Graves ophthalmopathy. Thyroid eye disease is an inflammatory condition which affects the orbital contents including the extraocular muscles and orbital fat. It is almost always associated with Graves' disease but may rarely be seen in Hashimoto's thyroiditis, primary hypothyroidism, or thyroid cancer.

The ocular manifestations include soft tissue inflammation, eyelid retraction, proptosis, corneal exposure, and optic nerve compression. The signs and symptoms of the disease are characteristic. These include lid retraction, lid lag, and a delay in the downward excursion of the upper eyelid in down gaze that is specific to thyroid-associated ophthalmopathy.


 * 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.

Clinical Summary
An 18-year-old girl presented with complaints of swelling in the neck, weight loss, bulging of the eyes, tremor, decreased heat tolerance, loose stools, and occasional palpitations. Physical examination revealed normal blood pressure, resting tachycardia of 110 beats per minute, mild exophthalmos, eyelid lag, and a diffusely enlarged thyroid gland. Pertinent laboratory findings were thyroxine (T4) level 30.8 mcg/dL, free thyroxine was 2.7 ng/dL, and thyroid stimulating hormone (TSH) was 0.22 mcIU/mL. She was given propylthiouracil until she became nearly euthyroid, at which time a thyroidectomy was done.

Autopsy Findings
The thyroid gland weighed 45 grams. It was beefy red in color and had a homogeneous fleshy consistency.

Histopathological Findings
Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology















Acknowledgements
The content on this page was first contributed by: C. Michael Gibson, M.S., M.D.

Basedow-Krankheit Enfermedad de Graves Basedow Maladie de Basedow Morbo di Basedow מחלת גרייבס Ziekte van Graves バセドウ病 Choroba Gravesa-Basedowa Doença de Graves Диффузный токсический зоб Basedows sjukdom Базедова хвороба 格雷夫斯病 Basedow hastalığı