What Is Graves' Disease?
Graves' disease is an autoimmune disease characterized by a metabolic imbalance resulting from overproduction of thyroid hormones (thyrotoxicosis). It is characterized by goiter (a diffusely enlarged and hyperactive thyroid gland) exophthalmos (abnormal protrusion of the eyeball), "orange-peel" skin, and hyperthyroidism. It is the most common cause of hyperthyroidism in the world, and the most common cause of general thyroid enlargement in developed countries. Although Graves' disease is known to be caused by an antibody-mediated auto-immune reaction, the trigger for this reaction is still unknown.
History
 Graves' disease owes its name to the Irish doctor Robert James 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, in some parts of Europe, the disease is known as Basedow's disease or Graves-Basedow disease.
Diagnosis
Generally, the symptoms of Graves' disease are identical to the symptoms of hyperthyroidism, a condition that can be caused by Graves' disease. Classic symptoms include an enlarged thyroid gland (goiter), nervousness, irritability, heat intolerance, weight loss with increased appetite , sweating, diarrhea, tremors, palpitations and arrhythmias (particularly tachycardia).
The two signs that are truly diagnostic of Graves' disease (not seen in other hyperthyroid conditions) are exophthalmos (swelling of the tissue behind the eyeballs causing protrusion of the eyeball) and a non-pitting edema with thickening of the skin, described as "peau d'orange" or "orange peel", usually found on the lower extremities
Symptoms
Graves' disease has a multitude of other symptoms, including:
- Hypertension
- Shortness of breath
- Muscle weakness (especially in the large muscles of the arms and legs) and degeneration
- Insomnia
- Increased energy
- Fatigue
- Mental impairment, memory lapses, diminished attention span
- Decreased concentration
- Restlessness, erratic behavior, emotional lability
- Brittle nails
- 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
- Abnormal breast enlargement (men)
- Diminished/changed sex drive
- Decrease in menstrual periods (oligomenorrhea),
- Irregular and scant menstrual flow (amenorrhea)
- Difficulty conceiving/infertility/recurrent miscarriage
- Hair loss
- Itchy skin, hives
- Chronic sinus infections
 Testing for Graves' Disease
 The hyperthyroidism characteristic of Graves' disease is caused by over-production of the thyroid hormones thyroxine (T 4 ) and triiodothyronine (T 3 ), which control body metabolism . Hyperthyroidism can be confirmed by measuring elevated blood levels of free (unbound) T 3 and T 4 . Other useful laboratory measurements include thyroid-stimulating hormone (TSH, low in Graves' disease due to negative feedback from the elevated T 3 and T 4 ), and elevated protein-bound iodine. Thyroid-stimulating antibodies may also be detected serologically. However, definitive diagnosis requires a biopsy, as hyperthyroidism is life threatening.
Physical examination shows an increased heart rate. Examination of the neck may show thyroid enlargement (goiter).
- Serum TSH is decreased
- Serum T 3 , free T 4 are higher than normal
- Radioactive iodine uptake is usually high
This disease may also alter the following test results:
- TSI
- Orbit CT scan or ultrasound
Risk Factors
Other factors that help doctors diagnose Graves' disease include a family history of thyroid problems, premature gray hair, painless white patches on the skin known as vitiligo - or other immune problems such as juvenile diabetes or pernicious anemia.
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 antibodies to the receptor for thyroid-stimulating hormone (TSH). (Antibodies to thyroglobulin and to the thyroid hormones T 3 and T 4 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 T 3 and T 4 . 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.
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.
Ophthalmopathy
 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
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.
The eye problems related to Graves disease usually disappear when medications, radiation, or surgery solve the hyperthyroidism problem. Sometimes use of prednisone (a steroid medication, which suppresses the immune system) is required to reduce eye irritation and swelling. Taping the eyes closed at night to prevent drying may sometimes be required. Sunglasses and eyedrops may lessen irritation of the eyes. Rarely, surgery may be needed to return the eyes to their normal position.
Other Complications
Other possible complications from Graves' Disease include:
 Heart complications, including rapid heart rate, congestive heart failure (especially in the elderly) and atrial fibrillation - Increased risk for osteoporosis
- Inadequate levels of thyroid hormone following surgery or radiation, leading to fatigue, elevated cholesterol levels, mild weight gain, depression, and mental and physical sluggishness
- Complications related to surgery, including:
- Visible scarring of the neck
- Hoarseness due to damage of the nerve leading to the voice box
- Low calcium levels due to damage to the parathyroid glands
A complication of Graves' disease known as thyroid storm may lead to life-threatening heart, liver, or kidney failure. Thyroid storm, a severe worsening of the symptoms of an overactive thyroid gland, begins suddenly and may be caused by a stressful event.
The signs and symptoms of thyroid storm include extreme irritability, high blood pressure, rapid heart rate, vomiting, high fever, delirium and coma. Left untreated, it can be fatal.
Treatment
Medical treatment of Graves' disease includes antithyroid drugs, radioactive iodine, and thyroidectomy (surgical excision of the gland). The purpose of treatment is to control the overactivity of the thyroid gland.
 Antithyroid Drugs
Beta-blockers, such as propranolol, are often used to treat symptoms of rapid heart rate, sweating, and anxiety, until the hyperthyroidism can be controlled. 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 by blocking the binding of iodine and coupling of iodotyrosines.
The most dangerous side-effect of these medications 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.
In order to be effective, antithyroid medications must be administered for six months to two years. 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.
 Radioactive Iodine Therapy
Radioactive iodine therapy is an alternative if drug treatment fails. The patient is given a capsule or a drink of water containing radioactive iodine. After being swallowed, the "radioiodine" is rapidly absorbed by the overactive thyroid cells, which are destroyed by the radiation, so less thyroid hormone is produced. The radioactivity disappears from the body within days.
This modality is suitable for most patients, although some providers prefer to use it mainly for older patients. Indications for radioiodine are: failed medical therapy or surgery or when medical or surgical therapy are contraindicated.
Pregnancy is an absolute contraindication to radioactive iodine therapy. Other contraindications are ophthalmopathy (it can aggravate thyroid eye disease) and solitary nodules. Disadvantages of this treatment are a high incidence of hypothyroidism (up to 80%) requiring hormone supplementation, which acts slowly and has a relapse rate that depends on the dose administered.
The development of radioactive iodine in the early 1940s at the Mallinckrodt General Clinical Research Center and its widespread adoption as a 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.
Therapy with radioactive iodine is the most common treatment for Graves' disease in the United States. Thyroid blocking drugs and/or surgical thyroid removal are used more often than radioactive iodine in Europe, Japan and most of the rest of the world.
Surgery
 Thyroidectomy, or surgical removal of all or part of the thyroid gland, is the third treatment option for Graves' disease. If only a single lump or nodule within the thyroid is producing too much hormone, the surgeon can take out just that small part of the gland. If the entire gland is overactive, which is more often the case, a total thyroidectomy is needed.
Surgery is the preferred treatment for people with a large goiter who chronically relapse after drug therapy, if there are suspicious nodules or suspected cancer, and for patients with ophthalmopathy and people who refuse or are not candidates for radioactive iodine therapy, such as pregnant women. Depending on how much of the gland is left after surgery, subsequent thyroid replacement therapy may be needed.
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. The risks or surgery 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.
Both radiation and surgery result in the need for lifelong use of replacement thyroid hormones, because these treatments destroy or remove the gland.
 Herbal Treatment
The herb bugleweed has a profound effect on thyroid function and regulation of thyroid hormones, and can be used to treat Graves' disease and many other thyroid disorders.
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' 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.
Prognosis
For most people, Graves disease responds well to treatment. However, thyroid surgery or radioactive iodine will sometimes cause hypothyroidism, which can lead to weight gain, depression, and mental and physical sluggishness. Antithyroid medications can also have serious side effects.
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