The term hyperthyroidism refers to an overproduction of hormone by the thyroid gland. The resulting physiologic syndrome of excess thyroid hormone is termed thyrotoxicosis, although the two terms should not be used synonymously. Hyperthyroidism should be used to describe conditions associated with a sustained overproduction of thyroid hormone, such as Graves’ disease or toxic multinodular goiter (TMNG). Several other conditions or situations result in transient increases in circulating thyroid hormone, which may result in thyrotoxicosis, but they do not cause hyperthyroidism in the strict sense of the term (Table 3-1). This chapter reviews the epidemiology, clinical presentation, evaluation, and management of patients with hyperthyroidism, focusing on surgical management.

Hyperthyroidism is present in approximately 0.5% of the population.1,2 An additional 0.8% of the population has mildly suppressed or undetectable serum thyroid-stimulating hormone (TSH) levels but circulating thyroid hormone levels in the normal range.2 Additionally, the rate of development of the various causes of hyperthyroidism varies according to geographic location and is believed to be related to the iodine intake of the population. For example, an epidemiologic survey comparing an area of normal iodine intake to one with insufficient iodine intake found that Graves’ disease accounted for 80% of cases of hyperthyroidism in the iodine-sufficient population but toxic uninodular and multinodular goiter accounted for the majority of cases in the iodine-deficient population.3

The clinical presentation of this disorder involves multiple symptoms that vary depending on the degree of hormone excess, the duration of illness, and the presence of other medical comorbidities. Additionally, the patient’s age may affect the clinical presentation because elderly patients with thyrotoxicosis often have minimal clinical symptoms, a phenomenon termed apathetic hyperthyroidism.4 Thyroid hormones, namely thyroxine (T4) and triiodothyronine (T3), are involved in the production of heat and energy; the development of the nervous system; the regulation of somatic growth and puberty; and the coordination of the synthesis of proteins involved in normal hepatic, cardiovascular, neurologic, and muscular functions. The wide range of actions of T3 and T4 on multiple organ systems accounts for the number and variability of symptoms that may accompany thyrotoxicosis (Table 3-2). Typically, patients complain of nervousness or anxiety, restlessness, palpitations, weight loss, and sensitivity to heat. Women may have irregular menses or problems with decreased fertility, and men may develop painful gynecomastia or reduced libido.5,6

Clinical findings frequently include tachycardia; warm, moist skin; and mild tremor. An enlarged thyroid gland is variably present. Other physical examination findings include “lid lag,” which refers to a slight delay of the eyelid in following the eye itself when having a patient look down; it is caused by increased sympathetic activity. Exophthalmos (protrusion of the eye), pretibial myxedema, and acropachy (clubbing of the fingers and toes) are specific physical examination findings in patients with hyperthyroidism caused by Graves’ disease and are discussed in more detail in subsequent sections.

As previously mentioned, these clinical findings are frequently much more subtle in elderly individuals. These patients may present with congestive heart failure with an arrhythmia. Approximately 25% to 35% of these elderly patients with thyrotoxicosis develop atrial fibrillation, which is resistant to treatment until the thyroid disorder has been treated.7 Additionally, 15% of elderly individuals with atrial fibrillation have underlying thyrotoxicosis.8 Another common clinical presentation of elderly patients with thyrotoxicosis is unexplained weight loss, which is commonly associated with anorexia, rather than the corresponding increase in appetite seen in younger individuals. These findings frequently initiate an exhaustive search for an underlying malignancy before thyrotoxicosis is diagnosed.9

Patients with thyrotoxicosis may also present with a potentially life-threatening constellation of signs and symptoms referred to as thyroid storm. This condition typically occurs in patients with known or undiagnosed thyrotoxicosis after a precipitating event such as surgery, trauma, childbirth, or infection. Signs and symptoms include severe tachycardia, fever, arrhythmias, congestive heart failure, agitation, psychosis, and coma.10

The laboratory diagnosis is relatively unambiguous and typically includes elevated serum concentrations of unbound T3 and T4 with a suppressed TSH hormone level. Measuring levels of the unbound or free fractions of T3 and T4 is preferable to measuring total serum levels because using T3 and T4 levels avoids diagnostic confusion in the setting of changing levels of thyroid-binding proteins. A minority of patients (~1%) have normal serum concentrations of T4 and elevated T3 concentrations known as T3 toxicosis.11 Elevated T3 and T4 levels in the setting of elevated TSH levels may be seen in patients with an inappropriate TSH syndrome, such as a thyrotropin-secreting pituitary tumor or thyroid hormone resistance.12,13

Measurement of thyroid autoantibodies may play a role in elucidating the cause of hyperthyroidism or thyrotoxicosis. Antithyroid microsomal antibodies are antibodies to microsomes that may be released into the circulation with thyroid cell destruction (also known as antimicrosomal or antithyroid peroxidase antibodies). Increased serum levels are usually associated with Hashimoto’s (chronic lymphocytic) thyroiditis but may also be seen in patients with other autoimmune conditions such as hemolytic anemia and Sjögren’s syndrome.14 Antibodies to the TSH receptor (also known as thyroid-stimulating immunoglobulins) are elevated in the majority (80%) of patients with Graves’ disease.15,16

Ultrasonography

All patients with evidence of thyrotoxicosis should undergo thyroid ultrasonography. This simple, noninvasive test may reveal the presence of diffuse thyromegaly, a multinodular goiter, or a solitary nodule. It may also show the characteristic ultrasound findings of thyroiditis, all of which may provide a great deal of information to the clinician concerning the cause of the patient’s thyrotoxicosis. Ultrasonography may be performed in the office and is an extremely useful aspect of the physical examination of patients presenting with symptoms of hyperthyroidism.

Thyroid Scintigraphy

With proven biochemical evidence of hyperthyroidism, thyroid scintigraphy with radioactive iodine (RAI) uptake measurement provides useful information that may direct clinical management. This nuclear medicine test typically uses iodine 123 or technetium-99m pertechnetate as radiopharmaceuticals and is a measure of the iodine avidity of the thyroid gland. Diffusely elevated uptake throughout the thyroid gland suggests Graves’ disease, although focal areas of increased uptake with relative suppression of the remaining thyroid gland are indicative of toxic solitary nodule or TMNG. A diffusely low pattern of uptake is seen in thyrotoxicosis caused by thyroiditis, with excess release of preformed hormone because of cellular destruction. This is different from thyrotoxicosis caused by the excess formation of new hormone, as is the case with hyperthyroidism caused by Graves’ disease, toxic adenoma, and TMNG. Thyroid scintigraphy may also reveal the presence of discrete nodules with low uptake, or “cold” nodules, necessitating additional investigation to rule out malignancy.

The role of fine-needle aspiration biopsy (FNA) in the setting of hyperthyroidism is useful when “cold” nodules, or nodules that do not show any uptake on RAI uptake scans, are present in a patient with Graves’ disease or TMNG who prefers treatment with RAI ablation rather than surgery. Ruling out malignancy in cold nodules in these instances is important before proceeding with ablation therapy. In the absence of cold nodules, FNA is less important because the incidence of malignant nodules that are hyperfunctioning is extremely rare.

A thorough history and physical examination in addition to the previously mentioned biochemical and imaging studies should lead the clinician to the cause of thyrotoxicosis. The following sections go into additional detail about the causes of hyperthyroidism in which surgical resection has a role in treatment.

Epidemiology

Graves’ disease is hyperthyroidism caused by the presence of circulating IgG autoantibodies that bind to and stimulate the G-protein–coupled TSH receptor. Graves’ disease affects approximately 0.5% of the population and is responsible for the majority (50% to 80%) of cases of hyperthyroidism. There is a 5:1 to 10:1 female predominance, and the peak incidence is between 40 and 60 years of age.16,17

A hereditary component appears to confer susceptibility to Graves’ disease; its presence in a maternal relative is associated with an increased incidence of the disease and younger age at onset.18,19 Environmental factors remain important, however, with only a 35% concordance rate between monozygotic twins.19 Events believed to be associated with triggering Graves’ disease in susceptible individuals include the use of sex steroids or immune-modulating drugs such as interferon-α, life stresses, smoking, and dietary iodine intake.20–22

Pathophysiology

Hyperthyroidism caused by Graves’ disease is attributable to an autoimmune process, whereby constitutive stimulation of the TSH receptor by autoantibodies leads to follicular hypertrophy and hyperplasia with enlargement of the thyroid gland. This also leads to thyroid hormone overproduction with a relative increase in the production and secretion of T3 relative to T4 and consequently a suppression of TSH.23 Iodine uptake and clearance are greatly enhanced, and the vascularity of the thyroid gland is significantly increased.