[A] Background

In general, thyrotoxicosis can occur if (i) the thyroid is inappropriately stimulated by trophic factors; (ii) there is constituitive activation of thyroid hormone synthesis and secretion leading to autonomous release of excess thyroid hormone; (iii) thyroid stores of preformed hormone are passively released in excessive amounts owing to autoimmune, infectious, chemical, or mechanical insult; or (iv) there is exposure to extra-thyroidal sources of thyroid hormone, which may be either endogenous (struma ovarii, metastatic differentiated thyroid cancer) or exogenous (factitious thyrotoxicosis).

Subclinical hyperthyroidism (SH) is most often caused by release of excess thyroid hormone by the gland. This condition is defined as a low or undetectable serum thyroid-stimulating hormone (TSH) with values within the normal reference range for both triiodothyronine (T3) and free thyroxine (T4) estimates. Both overt and subclinical disease may lead to characteristic signs and symptoms.

GD is an autoimmune disorder in which thyrotropin receptor antibodies (TRAbs) stimulate the TSH receptor, increasing thyroid hormone production. The natural history of nodular thyroid disease includes growth of established nodules, new nodule formation, and development of autonomy over time (7). In TAs, autonomous hormone production can be caused by somatic activating mutations of genes regulating thyroid hormone systhesis. Germline mutations in the gene encoding the TSH receptor can cause sporadic or familial nonautoimmune hyperthyroidism associated with a diffuse enlargement of the thyroid gland (8). Autonomous hormone production is caused by somatic, activating mutations of genes regulating follicular cell activities. Hormone production may progress from subclinical to overt hyperthyroidism, and the administration of pharmacologic amounts of iodine to such patients may result in iodine-induced hyperthyroidism (9). GD is overall the most common cause of hyperthyroidism in the United States (10,11). Although toxic nodular goiter is less common than GD, its prevalence increases with age and in the presence of iodine deficiency. Therefore, toxic nodular goiter may actually be more common than GD in older patients from regions of iodine deficiency (12). Unlike toxic nodular goiter, which is progressive (unless triggered by excessive iodine intake), remission of GD has been reported in up to 30% of patients without treatment (13).

The mechanism of hyperthyroidism in painless and subacute thyroiditis is inflammation of thyroid tissue with release of preformed hormone into the circulation. Painless thyroiditis is the etiology of hyperthyroidism in about 10% of patients (14), occurring in the postpartum period (postpartum thyroiditis) (15), during lithium (16), or cytokine (e.g., interferonalpha) (17) therapy, and in 5–10% of amiodarone-treated patients (18). Subacute thyroiditis is thought to be caused by viral infection and is characterized by fever and thyroid pain (19).

Thyroid hormone influences almost every tissue and organ system in the body. It increases tissue thermogenesis and basal metabolic rate (BMR) and reduces serum cholesterol levels and systemic vascular resistance. Some of the most profound effects of increased thyroid hormone levels are on the cardiovascular system (20). The complications of untreated thyrotoxicosis include loss of weight, osteoporosis, atrial fibrillation, embolic events, and even cardiovascular collapse and death (21,22).

The cellular actions of thyroid hormone are mediated by T3, the active form of thyroid hormone. T3 binds to nuclear receptor proteins that function as transcription factors to regulate the expression of many genes. Nongenomic actions of thyroid hormone also regulate important physiologic parameters.

The signs and symptoms of overt and mild, or subclinical, thyrotoxicosis are similar, but differ in magnitude. Overt thyrotoxicosis, whether endogenous or exogenous, is characterized by excess thyroid hormones in serum and suppressed TSH (<0.01 mU/L). There are also measurable changes in basal metabolic rate, cardiovascular hemodynamics, and psychiatric and neuropsychological function (23). There is only moderate correlation between the elevation in thyroid hormone concentration and clinical signs and symptoms. Symptoms and signs that result from increased adrenergic stimulation include tachycardia and anxiety and appear to be more pronounced in younger patients and those with larger goiters (24).