Graves Disease

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Graves' disease is the most common cause of spontaneously occurring thyrotoxicosis, accounting for 60-90% of all cases. Graves' disease also referred to as Basedow's disease or Parry's disease, is an autoimmune disorder with a genetic predisposition that typically affects young women 20-40 years of age. The female to male ratio varies from 4:1 to 10:1. Graves' disease has been linked to certain HLA haplotypes, HLA B8 and HLA DR3 in Caucasian populations, HLA BW35 in the Japanese and HLA BW46 in Chinese populations. It frequently occurs in association with other autoimmune diseases such as: chronic lymphocytic thyroiditis, rheumatoid arthritis, Sjogren's syndrome, vitiligo, pernicious anemia, Type I diabetes mellitus, lupus erythematosis, Addison's disease, myasthenia gravis and idiopathic thrombocytope-nia purpura.2

The specific cause of Graves' disease is unknown. Much of the current research has been directed at the characterization of the autoimmune reaction and determining its etiology. In his review of the pathogenesis of Grave's disease Volpe postulated that the fundamental defect involved reduced activation of suppressor T lymphocytes by specific antigen.2 This occurs as a result of an inherited abnormality in antigen presentation encoded for by histocompatibility genes. The autoimmune dysfunction may also be precipitated by environmental factors such as stress, infection, or trauma. Environmental factors can convert an occult defect in suppressor T lymphocyte function to an overt one. The defect in suppressor T cell function allows for thyroid-directed B lymphocytes, which are normally suppressed, to produce thyroid antibodies directed against the TSH receptor which stimulates the follicular cells in a manner similar to TSH. This leads to cAMP-mediated increases in thyroid hormone synthesis and growth of the thyroid gland. The thyroid receptor antibodies include a predominance of thyroid stimulating immunoglobulins and to a lesser extent, TSH-receptor inhibiting immunoglobulins. Graves' disease is also characterized by thyroid autoantibodies to other antigens including thyroglobulin and thyroid peroxidase. Rastad and Karlsson postulate that cytotoxic lymphocytes and antibody-dependent cytotoxicity may be responsible for lysis of follicular cells and spontaneous remission which has been observed in some patients with Graves' disease.3

The clinical presentation of patients with Graves' disease is characterized by hyperthyroidism, diffuse symmetric goiter, and the variable presence of ophthalm-opathy, dermopathy and acropachy (Fig. 4.2). The extrathyroidal manifestations of Graves' disease are related to tissue deposition of glycosaminoglycans in response to the immune reaction against tissue antigens shared with the thyroid gland or antigens which cross react with the TSH receptor. Patients with Graves' disease have the same symptoms as patients with thyrotoxicosis from other causes (Table 4.2). In addition, patients with Graves' disease typically have a diffuse symmetric goiter (Figs. 4.2 and 4.3) often with an audible bruit or a palpable thrill. Elderly patients typically present with more subtle symptoms and are more likely to have cardiovascular manifestations. Approximately 20% of elderly patients will not have a goiter.

Ophthalmopathy occurs in 5-10% of patients with Graves' disease and is mediated by antibody-induced inflammation which affects the extraoccular muscles, the

Fig. 4.2. A patient with Graves' disease manifested by ophthalmopathy and a diffuse symmetric goiter.

Fig. 4.3. A diffuse, symmetric goiter resected from a patient with Graves' disease with its characteristic absence of nodules.

retroorbital connective tissue and the optic nerve. The etiology is unknown. The retroorbital fibroblast has been suggested as the principle target cell for the antibody-induced inflammation.2 It has also been established that these fibroblasts express TSH receptors.2 A higher prevalence of ophthalmopathy has been reported in patients with higher levels of thyroid receptor antibodies.3 Eyelid retraction, lid lag and stare are nonspecific features that may occur with thyrotoxicosis regardless of its cause and are the consequence of hyperthyroidism-induced sympathetic stimulation of the levater palpebrae superioris muscles of the eyelids. However, periorbital edema, chemosis, exophthalmos, diplopia and decreased visual acuity are more specific for Graves' disease (Fig. 4.2). Graves' ophthalmopathy occurs as a result of edema, gly-cosaminoglycan deposition, leukocyte infiltration and fibrosis of the orbit and the extraoccular muscles.

Dermopathy and acropachy generally occur in patients with ophthalmopathy. Dermopathy, in the form of pretibial myxedema, occurs in 0.5-4% of patients with Graves' disease. It consists of violaceous, plaque-like thickening or induration of the skin of the lower legs and feet. Patients may complain of associated pain and pruritis. Acropachy is rare, occurring in less than 1% of patients with Graves' disease. It is manifested by thickening or clubbing of the fingers or toes, nail changes and peri-osteal new bone formation.

The diagnosis of Graves' disease is usually established by the presence of hyper-thyroidism, a diffuse symmetric goiter and increased thyroidal radioactive iodine uptake. In most patients with Graves' disease, the serum TSH level is below the detectable limits of the assay used. Measurement of thyroid receptor antibodies is not routinely necessary. However, they may be of value in establishing a diagnosis of Graves' disease in an elderly thyrotoxic patient without a palpable goiter. Documentation of high titers of thyroid stimulating immunoglobulins during pregnancy in women with a history of Graves' disease may be important in predicting the risk of fetal and neonatal thyrotoxicosis.2

The thyroid scintiscan is not routinely necessary in the evaluation of patients with Graves' disease. It is used selectively to help differentiate thyrotoxicosis caused by Graves' disease from toxic multinodular goiter or a solitary toxic thyroid nodule (Figs. 4.4, 4.5, and 4.6). It may also be helpful in patients with Graves' disease who have a concomitant dominant thyroid nodule. The thyroid scintiscan in patients with Graves' disease typically reveals increased radioiodine uptake that is diffuse and symmetric (Fig. 4.4).

The management of patients with Graves' disease consists of three therapeutic alternatives: radioiodine, antithyroid drug therapy, or surgery. In the United States the majority of patients with Graves' disease are treated with iodine-131. Iodine-131 emits beta particles which are locally destructive to the follicular cells of the thyroid gland. Nordyke and Gilbert emphasize that delayed hypothyroidism develops in most patients with Graves' disease treated with radioiodine regardless of the dose of iodine-131 used.4 As a result, definitive treatment of hyperthyroidism is the most important consideration. At our institution, a standard 10 mCi dose of iodine-131 is used for treatment of Graves' thyrotoxicosis. Nordyke and Gilbert reported that 90% of their patients with Graves' disease treated with a 10 mCi dose of

Fig. 4.4. Iodine-123 thyroid scintiscan demonstrating diffuse increased uptake characteristic of Graves' disease.

Fig. 4.4. Iodine-123 thyroid scintiscan demonstrating diffuse increased uptake characteristic of Graves' disease.

Fig. 4.5. Iodine-123 thyroid scintiscan demonstrating multiple autonomous functioning nodules and characteristic patchy radioiodine uptake.

iodine-131 were cured.4 Persistent hyperthyroidism was more common in patients with thyroid glands estimated to be greater than 50 grams. A higher dose of iodine-131 may be used in patients with larger thyroid glands. Most patients experience symptomatic improvement 6 to 8 weeks after receiving radioiodine treatment and complications are rare. Serum TSH levels are monitored in all patients and thyroid replacement therapy is begun when TSH levels are elevated. Radioiodine is contraindicated in women who are pregnant or breast feeding. A pregnancy test should be obtained prior to radioiodine administration in all women of child bearing age.

Fig. 4.6. Iodine-123 thyroid scintiscan demonstrating a solitary hyperfunctioning nodule in the superior pole of the right lobe of the thyroid gland. (From McHenry CR, Sandoval BA: Management of follicular and Hürthle cell neoplasms of the thyroid gland. Reprinted with permission from Oncology Clinics of North America (in press)).

Thioamide drugs are used for treatment of Graves' disease in: children, women who are pregnant or breast feeding, elderly patients that have mild to moderate symptoms without a goiter, and for preparation of patients for radioiodine or surgical treatment. The thioamide drugs, propylthiouracil (PTU) and methimazole, both decrease thyroid hormone synthesis by a dose-dependent inhibition of the thyroid peroxidase enzyme. PTU also blocks the peripheral conversion of thyroxine to triiodothyronine. PTU is preferable to methimazole in women who are pregnant or breast feeding because of its greater protein binding which results in less passage across the placenta and the mammary epithelium. PTU has a half life of two hours and is given two to three times per day, whereas methimazole has a half life of six hours and is given one to two times per day. Adverse effects of thioamide drug use can be minor or major. Minor side effects may be dose or agent related and include: skin rash, pruritis, urticaria, nausea, vomiting, myalgias or arthralgias, fever and transient leukopenia. For patients with minor side effects, drug dosage can be reduced or the other thioamide drug can be substituted. However, patients may experience cross sensitivity. Major side effects are idiopathic and include: agranulocytosis, hepatitis, aplastic anemia and vasculitis.

A high thioamide dose is given initially, either 100-200 mg of PTU three times per day or 10-30 mg of methimazole twice a day. Once the free T4 and T3 levels have normalized, the thioamide dose is tapered to the lowest dose that will maintain a euthyroid state. Patients are kept on a maintenance dose usually for one to two years' duration. Remissions are variable and most often last for less than 6 months. Hedley and colleagues reported that 40-80% of patients develop recurrent thyrotoxicosis after discontinuation of antithyroid drugs.5 However, the fact that 20-60% of patients with Graves' thyrotoxicosis become euthyroid after treatment has prompted investigative efforts to try and identify accurate criteria to select patients for antithyroid drug therapy. An anticipated future application of this research will be the development of recommendations for therapy based on the assessment of a patient's risk for recurrence following thioamide treatment.

Surgical treatment of Graves' disease is indicated for: 1) pregnant patients who are intolerant to antithyroid drugs; 2) patients with massive thyroid enlargement and compressive symptoms; 3) patients with a concomitant solitary cold nodule; 4) patients who fail to respond to multiple doses of radioiodine; and 5) patients who prefer surgery. The advantages of surgical treatment of Graves' disease is that patients experience immediate symptomatic improvement. This is in contrast to patients receiving radioiodine who may not experience relief for up to three months from the time they receive their treatment. The standard operation is a bilateral subtotal thyroidectomy leaving a 3 gram remnant of thyroid tissue on either side of the trachea. This operation has traditionally been advocated to try and maintain a euthyroid state postoperatively and reduce the risk of recurrent laryngeal nerve injury and hypoparathyroidism while minimizing the risk of recurrent hyperthyroidism. The incidence of recurrent hyperthyroidism is approximately 10-15% following bilateral subtotal thyroidectomy.

Because it has been demonstrated that a majority of patients become hypothy-roid within ten years of undergoing bilateral subtotal thyroidectomy, near total or total thyroidectomy can be performed preferentially to effectively eliminate the risk of recurrent Graves' disease. However, this is only a suitable alternative if it can be performed without an increase in complication rate. Total thyroidectomy has also been recommended for patients with severe or progressive ophthalmopathy and high TSH receptor antibody titers.3 Total removal of the thyroid gland is advocated to decrease TSH receptor antibodies and other antibodies directed against the extraocular muscles, orbit and optic nerve.3

Prior to elective surgery, patients are rendered biochemically euthyroid using a thioamide drug. A beta adrenergic-blocking agent is also used for symptomatic treatment of thyrotoxicosis as well as to maintain the resting heart rate between 60 and 80 beats per minute. b-blockers inhibit the peripheral conversion of T4 to T3. The use of a thioamide drug and a b-blocker to prepare a patient for surgery is important in eliminating the risk of perioperative thyroid storm. Once the patient's FT4 and T3 levels have been normalized, iodine is administered for 7-10 days prior to surgery, either as Lugol's solution (three drops three times per day) or as a saturated solution of potassium iodide (one drop three times per day). Iodine administration decreases the vascularity of the thyroid gland, reduces operative blood loss and makes the operation easier.

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