?Graves’ disease is an autoimmune disease. It most commonly affects the thyroid, frequently causing it to enlarge to twice its size or more (goitre), become overactive, with relatedhyperthyroid symptoms such as increased heartbeat, muscle weakness, disturbed sleep, and irritability. It can also affect the eyes, causing bulging eyes (proptosis). It affects other systems of the body, including the skin, heart, circulation and nervous system. It affects up to 2% of the female population, sometimes appears after childbirth, and has a female:male incidence of 5:1 to 10:1.
It has a strong hereditary component; when one identical twin has Graves’ disease, the other twin will have it 25% of the time. Smoking and exposure to second-hand smoke is associated with the eye manifestations but not the thyroid manifestations. Diagnosis is usually made on the basis of symptoms, although thyroid hormone tests may be useful, particularly to monitor treatment.
 Diagnosis Graves’ disease may present clinically with one of the following characteristic signs: exophthalmos (protuberance of one or both eyes) fatigue, weight loss with increased appetite, and other symptoms of hyperthyroidism/thyrotoxicosis rapid heart beats muscular weakness The two signs that are truly ‘diagnostic’ of Graves’ disease (i. e. , not seen in other hyperthyroid conditions) are exophthalmos and non-pitting edema (pretibial myxedema).
Goitre is an enlarged thyroid gland and is of the diffuse type (i. e. ,spread throughout the gland). Diffuse goitre may be seen with other causes of hyperthyroidism, although Graves’ disease is the most common cause of diffuse goitre. A large goitre will be visible to the naked eye, but a small goitre (mild enlargement of the gland) may be detectable only by physical exam.
Occasionally, goitre is not clinically detectable but may be seen only with CT or ultrasound examination of the thyroid. Another sign of Graves’ disease is hyperthyroidism, i. e. , overproduction of the thyroid hormones T3 and T4. Normothyroidism is also seen, and occasionally also hypothyroidism, which may assist in causing goitre (though it is not the cause of the Graves’ disease). Hyperthyroidism in Graves’ disease is confirmed, as with any other cause of hyperthyroidism, by measuring elevated blood levels of free (unbound) T3 and T4.
Other useful laboratory measurements in Graves’ disease include thyroid-stimulating hormone (TSH, usually 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. Biopsy to obtain histiological testing is not normally required but may be obtained if thyroidectomy is performed. Differentiating two common forms of hyperthyroidism such as Graves’ disease and Toxic multinodular goiter is important to determine proper treatment.
Measuring TSH-receptor antibodies with the h-TBII assay has been proven efficient and was the most practical approach found in one study.  Pathophysiology Histopathological image of diffuse hyperplasia of the thyroid gland (clinically presenting as hyperthyroidism) 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 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 goitre. 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 Immunoglobulins: 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. Another effect of hyperthyroidism is bone loss from osteoporosis, caused by an increased excretion of calcium and phosphorus in the urine and stool. The effects can be minimized if the hyperthyroidism is treated early.
Thyrotoxicosis can also augment calcium levels in the blood by as much as 25%. This can cause stomach upset, excessive urination, and impaired kidney function.  Management Treatment of Graves’ disease includes antithyroid drugs which reduce the production of thyroid hormone, radioiodine (radioactive iodine I-131), and thyroidectomy (surgical excision of the gland). As operating on a frankly hyperthyroid patient is dangerous, prior to thyroidectomy preoperative treatment with antithyroid drugs is given to render the patient “euthyroid” (i.e. normothyroid).
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. Therapy with radioiodine is the most common treatment in the United States, whilst antithyroid drugs and/or thyroidectomy is used more often in Europe, Japan, and most of the rest of the world.
?-blockers (such as propranolol) may be used to inhibit the sympathetic nervous systemsymptoms of tachycardia and nausea until such time as antithyroid treatments start to take effect. Pure beta blockers do not inhibit lid-retraction in the eyes, which is mediated by alpha adrenergic receptors. Antithyroid drugs The main antithyroid drugs are carbimazole (in the UK), methimazole (in the US), 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).
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. Lygole is used to block hormone synthesis before surgery. A randomized control trial testing single dose treatment for Graves’ found methimazole achieved euthyroid state more effectively after 12 weeks than did propylthyouracil (77. 1% on methimazole 15 mg vs 19. 4% in the propylthiouracil 150 mg groups).
 A study has shown no difference in outcome for adding thyroxine to antithyroid medication and continuing thyroxine versus placebo after antithyroid medication withdrawal. However two markers were found that can help predict the risk of recurrence. These two markers are a positive Thyroid Stimulating Hormone receptor antibody (TSHR-Ab) and smoking. A positive TSHR-Ab at the end of antithyroid drug treatment increases the risk of recurrence to 90% (sensitivity 39%,specificity 98%), a negative TSHR-Ab at the end of antithyroid drug treatment is associated with a 78% chance of remaining in remission.
Smoking was shown to have an impact independent to a positive TSHR-Ab.  Radioiodine Scan of affected thyroid before and after radioiodine therapy. Radioiodine (radioactive iodine-131) was developed in the early 1940s at the Mallinckrodt General Clinical Research Center. 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.
Hypothyroidism may be a complication of this therapy, but may be treated with thyroid hormones if it appears. Patients who receive the therapy must be monitored regularly with thyroid blood tests to ensure that they are treated with thyroid hormone before they become symptomatically hypothyroid. For some patients, finding the correct thyroid replacement hormone and the correct dosage may take many years and may be in itself a much more difficult task than is commonly understood.
 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 eventual thyroid hormone supplementation in the form of a daily pill(s). The radio-iodine treatment acts slowly (over months to years) to destroy the thyroid gland, and Graves’ disease-associated hyperthyroidism is not cured in all persons by radioiodine, but has a relapse rate that depends on the dose of radioiodine which is administered.
Surgery Further information: Thyroidectomy 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 one 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. Removal of the gland enables complete biopsy to be performed to have definite evidence of cancer anywhere in the thyroid. (Needle biopsies are not so accurate at predicting a benign state of the thyroid). No further treatment of the thyroid is required, unless cancer is detected. Radioiodine treatment may be done after surgery, to ensure that all remaining (potentially cancerous) thyroid cells (i. e., near the nerves to the vocal chords) are destroyed.
Besides this, the only remaining treatment will beSynthroid, or thyroid replacement pills to be taken for the rest of patient’s life. Disadvantages are as follows. A scar is created across the neck just above the collar bone line. However, the scar is very thin, and can eventually recede and appear as nothing more than a crease in the neck. Patient may spend a night in hospital after the surgery, and endure the effects of total anesthesia (i. e. , vomiting), as well as sore throat, raspy voice, cough from having a breathing tube stuck down the windpipe during surgery.