Graves disease is a organ specific autoimmunity disorder .the self antibodies against the TSH is responsible for the high production of thyroid hormone .Hyperthyroidism is the main cause of graves’ disease. If the disease is unrecognized then it may cause severe symptoms like of thyroid associated ophthalmopathy, myxoedema, and severe cardiac effect. The disease can be diagnosed by blood tests. Different treatments are discussed in this review like usage of thionamides, like Methimazole and Propylthiouracil (PTU), effective radioactive iodine therapy and by total thyroidectomy. The advantage and the drawbacks of the therapy states what treatment is effective. The management of Graves’ disease in children and in pregnant woman are also discussed. The role of thionamides for treating pregnant woman can cause the fetus with severe aplasia cutis. New novel drugs can also be manifested as potential target in the treatment of graves’ disease.
Keywords: Graves’ disease, hyperthyroidism, thyroglobulin, thionamides, radioactive iodine, Methimazole .Propylthiouracil
Originally known as ‘exophthalmic goiter’, .Graves’ disease owes its name to the Irish physician, Robert James Graves, who described the condition in 1835.Graves’ disease is the most common autoimmune disease, affecting 0.5% of the population in the US, and represents 50-80% of cases of hyperthyroidism . It occurs more commonly amongst women, smokers and patients with other autoimmune diseases or a family history of thyroid autoimmunity . Peak incidence occurs between 40 and 60 years of age but any age group may be affected.
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Graves’ disease is an adverse condition that results from abnormal stimulation of the thyroid gland by a material in the blood referred to as thyroid stimulating immunoglobins (TSIs) that bind and activate thyrotropin receptors. The thyroid gland is situated in the lower neck region, below the Adams’ apple. The level of thyroid hormones i.e. thyroxine (T4) and tri-iodothyronine (T3) released from this gland determines the causative agent of Graves’ disease. These hormones are directly released into the blood. When more of these hormones are released leads to hyperthyroidism resulting in Graves’ disease. Iodine plays an important role in synthesis of thyroid hormones. Any alteration in the uptake of iodine can lead to hyperthyroidism. Graves’ disease produces auto-antibodies that bind the receptor for TSH and mimic the normal action of TSH, activating adenylate cyclase and resulting in production of the thyroid hormones. The auto antibodies are not regulated, and consequently they over stimulate the thyroid. Thus these auto-antibodies are called long-acting thyroid-stimulating (LATS) antibodies. [1,4]
CAUSES, SYMPTOMS, AND RISK FACTORS
The main cause of Graves’ disease is hyperthyroidism. Graves’ hyperthyroidism results from the production of unique IgG antibodies that bind to and activate the thyroid-stimulating hormone (TSH) receptor on the surface of thyroid follicular cells. These antibodies are called as THSR antibodies (Tab).This activation stimulates follicular cell growth, causing diffuse thyroid enlargement and increased production of thyroid hormones with an increase in the fraction of triiodothyronine (T3) relative to thyroxine (T4) .
The hyperthyroidism of GD is caused by circulating TSHR antibodies (Tab) that target this receptor on thyroid follicular cells and stimulate excessive production of thyroid
The emergence of this autoimmune process is probably due to an underlying genetic susceptibility with superimposed environmental factors.Particular HLA alleles on chromosome 6, namely HLA-DRB1-08 and DRB3-0202, are known to confer an increased risk of Graves’ disease . Environmental triggers include stressful life events, infection, exposure to high doses of iodine and recent childbirth.
The main characteristic of Graves’ disease are immunologically mediated hyperthyroidism, presence of thyroid associated ophthalmopathy, myxoedema, and severe cardiac effects.
Other symptoms include such as anxiety, breast enlargement in men (possible), double vision , eyeballs that stick out (exophthalmos) , goiter, increased appetite, increased sweating , insomnia , Irregular menstrual periods in women , rapid or irregular heartbeat (palpitations or arrhythmia , weight loss (rarely, weight gain)[4,9].
Risk factors for Graves’ disease are associated with other autoimmune diseases such as vitiligo, rheumatoid arthritis, Addison’s disease, type 1 diabetes, pernicious anemia, and lupus. Untreated Graves’ disease can lead to thyrotoxicosis and its severe form, thyroid storm (death rate is about 20%), heart problems, weak and brittle bones, and death[1,4]. Poorly treated Graves’ disease during pregnancy can cause problems for the woman such as preterm birth, miscarriage, heart failure, and placental abruption. Poorly treated Graves’ disease can cause health problems for a fetus or baby such as preterm birth, low birth weight, thyroid problems.
Blood tests are ideal way of diagnosing Graves ‘ disease .The levels of thyroid hormone are easily determined by blood tests and also whether the hormone production is normal or abnormal. The level of blood TSH can be useful for detection of hyperthyroidism. A hyperthyroidism can be called secondary hyperthyroidism when a pituitary tumor is seen. Thyroid hormone is abnormally high in case of secondary hyperthyroidism. The thyroid cells produce a protein called thyroglobulin when a thyroid cancer is suspected. This is also used as a tumor marker.
TREATMENT OF GRAVE’S DISEASES
The three treatment modalities for Graves’ hyperthyroidism include 
use of thionamides (antithyroid drugs)
radioactive iodine (RAI) therapy
USAGE OF ANTITHYROID DRUGS
Antithyroid drugs are drugs specially used in hyperthyroidism condition. The drug should be chosen under several parameters like choice of drug, dose , duration of therapy to what extent. Some examples of such antithyroid drugs are Carbimazole, Propylthiouracil and Methimazole. These drugs are used for Randomized controlled Trails. The mode of action of these drugs is that they inhibit the synthesis of thyroid hormone. They also act as immunosuppressant and anti inflamanants. Propylthiouracil act more actively of the inhibition activity of T4 to active T3. However Methimazole has its own advantages .it has a longer intrathyriod half life than Propylthiouracil, and less side effects . The dose of thionamides should solely independent on individual, the rate of response to the therapy. Increase in the dose can lead to severe side effects. The duration of the treatment can be extended to 8-18 months . The disadvantage of this therapy is that it has a very high relapse period. (About 30% after the first dose of thionamides)
Other drugs used for therapy
Glucocorticoids can also be used as it helps in the inhibition of conversion of T4 to T3 in the periphery, thus reducing the level of thyroid hormone in case of hyperthyroidism
RADIOACTIVE IODINE (RAI) THERAPY
Prolonged exposure of thionamides has adverse effect to the immune response. To overcome the drawbacks of thionamides radioactive iodine therapy can be used . To have effective RAI treatment the thionamides should be stopped priory . The 131I was used to treat hyperthyroidism since 1942. This treatment was effective in cost and in safety measure. Some relapsed quickly while the others not .hence there was a debate over the use of 131 I. the doses of 131I was selected as per the size of the thyroid gland and the uptake of iodine, alternative radionuclide’s of iodine which can be used is 125I.The RIA therapy might fail because of low uptake of the radioactive iodine or may be due to that the fixed dose of iodine was less to uptake. The side effect of this treatment cause severe eye thyroiditis. Lithium can be used as an adjuvant for 131I . It has been observed that lithium administer a large amount of radiation from a smaller dose.
After a dose of RAI, patients with hyperthyroidism are treated and 80% are recovered as hypothyroidism, 10% with euthyroidism and remaining are given a second dose .The drawback of this method is that they can cause severe throat infection and radiation thyroiditis.
When a patient is not able to recover from thionamides or RAI surgery is a better choice. Even if there is a presence of large, compressive goiter then surgery can be useful. The surgery is called as total thyroidectomy. The thyroid is adversely affected and hence the thyroid gland is removed and replaced by a new thyroid gland.
This method can be useful as it achieves effective remission. The drawback of this therapy is that it may possess recurrent laryngeal nerve palsy and permanent hypothyroidism. Hence this therapy is considered as third line therapy [1,4].
Treatment under specific condition
The thionamides drug Propylthiouracil (PTU) has been regarded safe for pregnant women. The use of Methimazole has adverse effect on the fetal as it causes a rare birth defect called aplasia cutis (a scar like lesion of the scalp) It also can cause severe onset agranulocytosis and hepatotoxicity 
Though it has been seen that PTU is considered, PTU also cause hepatitis during early age of pregnancy. Thus it is recommended to administer PTU only during the first trimester and followed by Methimazole in the second and third trimester. If the pregnant woman with Graves’ disease is given this therapy it would be having a lower risk of hepatitis. A lower risk of fetal hypothyroidism is maintained as the thionamides cross the placenta  along with TSH – receptor anti bodies.
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The children of only 2% are affected from mothers with Graves’ disease. The child is prone to have neonatal autoimmune hyperthyroidism from the mother itself. The possible symptoms that can be faced at the infant stage are cardiac insufficiency, intrauterine growth retardation and eye diseases. The children of 3yrs can be given treatment like very low dose of thionamides .
Graves’ disease has a direct impact on hyperthyroidism. Diagnosing at a early stage is a must to avoid severe complications. The conditions of the people suffering from Graves’ disease are more prone to have protruding large eyes. Therapies are suggested according to the relapse nature of the individual. Early treatments are given to pregnant woman to avoid any circumstances to their children. Children should be given utmost care during the course of treatment.
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