This often troubling accompaniment of Graves disease results from antibody-mediated inflammation and infiltration of periorbital tissue, affecting about 40% to 50% of patients. Risk factors include radioiodine therapy for hyperthyroidism, smoking, and high serum pretreatment thyroid antibody levels. Antibodies to extraocular muscle and orbital fibroblasts capable of inducing the pathologic changes in vitro have been detected; TSab do not appear to be directly involved, even though onset generally parallels that of the hyperthyroidism.

The inflammatory infiltrate produces swelling of retroorbital tissue, which compresses orbital veins and leads to orbital edema and proptosis. Inflammatory changes of the extraocular muscles may cause diplopia. In general, the eye problems develop concurrently with the onset of hyperthyroidism and change little once established, although up to 20% of patients may experience a gradual worsening with treatment (see later discussion). Approximately 10% of patients show similar eye findings in the absence of Graves disease.

Manifestations range from lid retraction (lid lag) and stare, mild periorbital edema, and conjunctival inflammation to diplopia from extraocular muscle dysfunction, corneal injury, and optic nerve damage. Symptoms include pain, diplopia, proptosis, and blurred vision. The cosmetic changes may be among the most disturbing; the lid lag and stare of hyperthyroidism may make the ophthalmopathy look worse than it actually is.

Thyroid dermopathy is a less common immune-mediated infiltrative process that affects less than 5% of patients with Graves disease. It never occurs alone and almost always occurs in the presence of moderate or severe ophthalmopathy. The condition is characterized by the appearance of nonpitting swelling, indurated nontender plaques with brownish, reddish, dark pink, or purple color and an “orange-skin” appearance primarily limited to the skin of the pretibial area. Rarely, the lower leg can be extensively involved, giving the appearance of elephantiasis. Thyroid acropachy, characterized by clubbing and soft tissue swelling of the distal fingers and toes, is also rare.

The thyroid gland in Graves disease is diffusely enlarged, and a bruit may be heard in severe cases. The classic symptoms and signs of thyrotoxicosis are common. The skin is velvety and the hair silky. Onycholysis, vitiligo, and gynecomastia are found in some cases and may suggest the diagnosis. Cardiac complications are infrequent because of the relative youth of the patient population, but a reversible cardiomyopathy has been identified, manifested by a fall in the ejection fraction with exercise. Heart failure is rare, but impaired exercise tolerance is often reported, perhaps caused by the decreased ejection fraction.

Graves disease usually worsens if it goes untreated, although patients with mild disease may experience remissions of unpredictable duration. After many years, mild hypothyroidism may ensue, especially in patients with small goiters and mild hyperthyroidism at the time of onset.

Triiodothyronine toxicosis is an important entity to consider when patients with clinically apparent hyperthyroidism have
normal T₄ levels. The condition has been reported in association with both diffuse and nodular goiters. The clinical presentation is no different from that of hyperthyroidism caused by elevations in T₄. Isolated elevations in T₃ concentration may also occur in euthyroid patients who have no underlying thyroid disease (see later discussion).

Determination of the serum TSH is the most sensitive way to screen for hyperthyroidism. A marked improvement in the sensitivity of the TSH assay makes it possible to diagnose hyperthyroidism solely on the basis of an absence of detectable TSH. Most patients with overt hyperthyroidism have TSH levels of less than 0.05 µU/mL. As long as the hypothalamic-pituitary axis is intact, an absence of detectible TSH represents the appropriate response to too much circulating thyroid hormone. Undetectable TSH by second- or third-generation assay is diagnostic of hyperthyroidism. A normal TSH level by radioimmunoassay virtually rules out hyperthyroidism, unless a rare TSH-secreting pituitary adenoma is present.

A very low TSH level may result from severe nonthyroidal illness and from the use of drugs that suppress TSH response to thyroid hormone (e.g., glucocorticosteroids). In such circumstances, thyroid hormone levels are usually abnormal. Subclinical hyperthyroidism is suggested by a very low or undetectable TSH and thyroid hormone levels that are normal, often at the upper end of the normal range.

The sensitivity of second- and third-generation TSH assays has markedly reduced the need for thyroid hormone determinations in screening for hyperthyroidism. They can, however, help to confirm the diagnosis and determine the severity of disease and should be obtained when the TSH level is low or undetectable. The free T₄ or free T₄ index (an excellent proxy for the free T₄, calculated by multiplying the serum T₄ by the T₃ resin uptake) is the most useful and consequently the preferred determination of circulating thyroid hormone. The serum total T₃ concentration is elevated along with T₄ in most hyperthyroid states. In the uncommon case of T₃ toxicosis, T₃ is elevated when T₄ levels are normal. Most patients with overt hyperthyroidism caused by Graves disease or nodular goiter have a disproportionate increase in serum T3 relative to T4.

As useful as thyroid hormone levels are for diagnosis, overreliance on them and failure to use the TSH assay can be misleading. Euthyroid hyperthyroxinemia occurs when an increase in thyroidbinding globulin (e.g., pregnancy, estrogen use, liver disease) produces an increase in total T₄, whereas the free T₄ remains normal. More confusing are euthyroid states with increases in both free and total T₄. Patients with autoantibodies against thyroid hormones may manifest surprisingly high levels of free hormone because of interference by these immunoglobulins with the standard radioimmune assays for thyroid hormones. Acute medical, surgical, and psychiatric illnesses, in addition to intake of high doses of propranolol, amiodarone, and gallbladder dyes, can impair the peripheral conversion of T₄ to active T₃ and lead to a rise in free T₄ concentration in conjunction with a reduction in T₃ and an increase in reverse T₃. An unexpectedly normal or low T₃ level in a patient who is clinically euthyroid but has elevated T₄ and free T₄ levels should suggest the possibility of euthyroid hyperthyroxinemia. The T₃ concentration helps in the differentiation.

Antithyroid antibodies (particularly those directed against microsomal peroxidase) are increased in both Graves disease and lymphocytic (Hashimoto) thyroiditis, so their diagnostic utility is limited. Thyroid-stimulating immunoglobulin G antibody (also referred to as thyrotropin receptor antibody and thyroid-stimulating antibody—TSab) can be measured to help in identifying persons with Graves disease and in following disease activity.

Determination serves as an elegant yet simple means of detecting a patient who is surreptitiously taking thyroid hormone—exogenous hormone use results in the suppression of thyroglobulin synthesis. Its other clinical use is in monitoring patients with thyroid cancer.