Graves disease is a hypermetabolic state caused by circulating immunoglobulin G (IgG) antibodies that bind to and activate the G-protein-coupled thyrotropin receptor. This activation stimulates follicular hypertrophy and hyperplasia, causing thyroid enlargement as well as increases in thyroid hormone production. It affects the thyroid, ocular muscles, and shin. It is characterized by thyrotoxicosis, diffuse goiter, and infiltrative ophthalmopathy (edema and inflammation of the extraocular muscles and an increase in orbital connective tissue and fat); infiltrative dermopathy characterized by lymphocytic infiltration of the dermis; accumulation of glycosaminoglycans; and occasionally edema.

Thyrotoxicosis

• Diffusely enlarged thyroid. Thyroid bruit may be present. Cervical lymphadenopathy also may be present
• Elevated systolic blood pressure with a widened pulse pressure
• Tachycardia, palpitations, tremor, hyperreflexia
• Exophthalmos (50% of patients) (Fig. E1, Fig. E2), lid retraction (lid lag), in which contraction of the levator palpebrae muscles of the eyelids show immobility of the upper eyelid with downward rotation of the eye
• Nervousness, weight loss (weight gain in 10% of patients), heat intolerance, pruritus, muscle weakness, atrial fibrillation
• Increased sweating, brittle nails, clubbing of fingers
• Localized infiltrative dermopathy (1% to 2% of patients) is most frequent over the anterolateral aspects of the legs, commonly over the pretibial area (pretibial myxedema) but can be found at other sites (especially after trauma). It is nonpitting and indurated. It is typically patchy with a peau d’orange appearance to the skin
• Men may have gynecomastia, reduced libido, and erectile dysfunction. Women often have irregular menses

Autoimmune etiology: Thyrotropin receptor antibodies (TRAb) mediated activation of thyroid-stimulating hormone receptor (TSHR). The activity of the thyroid gland is stimulated by the action of T cells, which induce specific B cells to synthesize antibodies against TSHRs in the follicular cell membrane.

• Anxiety disorder
• Premenopausal state
• Thyroiditis
• Other causes of hyperthyroidism (e.g., toxic multinodular goiter, toxic adenoma)
• Other: Metastatic neoplasm, diabetes mellitus, pheochromocytoma

• The diagnosis is made clinically in most instances. The clinical assessment of the patient with Graves orbitopathy is summarized in Table 1.
• The diagnostic workup includes a detailed medical history followed by laboratory and imaging studies and ECG. Patients often present with anxiety, heat intolerance, menstrual dysfunction, increased appetite, and weight loss. Elderly patients can have an atypical presentation (apathetic hyperparathyroidism). For additional information, refer to the topic “Hyperthyroidism.”

• Increased free thyroxine (T₄) and free triiodothyronine (T₃)
• Decreased thyroid-stimulating hormone
• Measurement of thyroid-stimulating antibodies (TSI) and TRAb
• Table E2 summarizes assays of TSHR antibody nomenclature and indications

• 24-h radioactive iodine uptake (RAIU): Increased homogeneous uptake.
• Computed tomography (Fig. E3) or MRI of the orbits (Fig. E4) is useful if there is uncertainty about the cause of ophthalmopathy.

• Patient education and discussion of therapeutic options.
• Smoking cessation: Smoking is associated with an increased risk of progression of Graves ophthalmopathy.

• Advantages and disadvantages of treatment options for Graves hyperthyroidism are summarized in Table E3.
• Antithyroid drugs (thionamides, ATDs) to inhibit thyroid hormone synthesis or peripheral conversion of T₄ to T₃:
  1. Methimazole or propylthiouracil (PTU) are available. Methimazole is generally preferred because it has a longer half-life, allowing for once-daily dosing. PTU is preferred during pregnancy.
  2. Side effects: Skin rash (3% to 5%), arthralgias, myalgias, granulocytopenia (0.5%); rare side effects: Aplastic anemia, hepatic necrosis (PTU), cholestatic jaundice.
  3. Thionamide antithyroid drug therapy results in a remission in 40% to 50% of patients treated for 12 to 18 mo.
• Radioactive iodine (RAI):
  1. Treatment of choice for patients >21 yr and younger patients who have not achieved remission after 1 yr of ATD therapy.
  2. Contraindicated during pregnancy and lactation.
  3. After radioactive therapy there may be an acute elevation of thyroid antibody titers and exacerbation of ocular symptoms in 15% to 20% of patients.
• Surgery: Near-total thyroidectomy. Indications: Obstructing goiters despite RAI and ATD therapy, patients who refuse RAI and cannot be adequately managed with ATDs, and pregnant women inadequately managed with ATDs. Complications of surgery include hypoparathyroidism (4%) and vocal cord paralysis (1%).
• Adjunctive therapy: Beta-adrenergic receptor blockers (e.g., atenolol 50 to 100 mg/day) to alleviate the beta-adrenergic symptoms of hyperthyroidism (tachycardia, tremor); contraindicated in patients with bronchospasm.
• Graves ophthalmopathy: Methylcellulose eye drops to protect against excessive dryness, sunglasses to decrease photophobia, intraocular and systemic high-dose corticosteroids for severe exophthalmos. Worsening of ophthalmopathy after RAI therapy is often transient and can be prevented by the administration of prednisone. Other treatment options include antiinflammatory and immunosuppressive agents, radiation, and corrective surgical procedures. The administration of the antioxidant selenium (100 μg PO bid) has been recently reported as effective in improving quality of life, reducing ocular involvement, and slowing progression of the disease in patients with mild Graves orbitopathy. Its mechanism of action is believed to be an effect on the oxygen free radicals and cytokines that play a pathogenic role in Graves orbitopathy. Inhibition of the insulin-like growth factor I receptor (IGF-IR) is a new therapeutic strategy to combat the underlying autoimmune etiology of ophthalmopathy. Trials with teprotumumab, a human monoclonal antibody inhibitor of IGF-IR, in patients with active, moderate-to-severe ophthalmopathy have shown effectiveness in reducing proptosis.¹
• Dermopathy and acropachy: Topical corticosteroids are often used but are generally ineffective. Trials using rituximab infusion for dermopathy have shown striking improvement.

Patients undergoing treatment with ATDs should be seen every 1 to 3 mo until euthyroidism is achieved and every 3 to 4 mo while they are receiving ATDs.

• ATDs induce sustained remission in <60% of cases.
• The incidence of hypothyroidism after RAI is >50% within the first yr and 2% per yr thereafter.
• Complications of surgery include hypothyroidism (28% to 43% after 10 yr), hypoparathyroidism (4%), and vocal cord paralysis (1%).
• Successful treatment of hyperthyroidism requires lifelong monitoring for the onset of hypothyroidism or the recurrence of thyrotoxicosis.
• RAI therapy is followed by the appearance or worsening of ophthalmopathy more often than is therapy with methimazole, particularly in patients who are cigarette smokers. It can be prevented with the administration of prednisone 0.5 mg/kg body weight per day starting 2 to 3 days after RAI, continued for 1 mo, then tapered off over 2 mo.
• Mild to moderate ophthalmopathy often improves spontaneously. Severe cases can be treated with high-dose glucocorticoids, orbital irradiation, or both. Orbital decompression may be used in patients with optic neuropathy and exophthalmos (see “Hyperthyroidism”).

Graves Disease (Patient Information)

Hyperthyroidism (Related Key Topic)