Hyperthyroidism and thyrotoxicosis are hypermetabolic conditions that cause significant morbidity and mortality. The diagnosis can be difficult because symptoms can mimic many other disease states leading to inaccurate or untimely diagnoses and management. Thyroid storm is the most severe form of thyrotoxicosis, hallmarked by altered sensorium, and, if untreated, is associated with significant mortality. Thyroid storm should be considered in the differential of any patient presenting with altered mental status. The emergency medicine physician who can rapidly recognize thyrotoxicosis, identify the precipitating event, appropriately and comprehensively begin medical management, and facilitate disposition will undoubtedly save a life.

Keywords

Hyperthyroidism

Thyrotoxicosis

Thyroid storm

Thyroiditis

Graves disease

Key points

Hyperthyroidism is defined as the excess production and release of thyroid hormone by the thyroid gland resulting in inappropriately high serum levels. The disproportionate amount of thyroid hormone leads to an accelerated metabolic state. The most common causes include diffuse toxic goiter (Graves disease), toxic multinodular goiter (Plummer disease), and toxic adenoma.1 Thyrotoxicosis also refers to a hypermetabolic state that results in excessive amounts of circulating thyroid hormone, but includes extrathyroidal sources of thyroid hormone such as exogenous intake or release of preformed stored hormone. Thyroiditis, inflammation of the thyroid gland resulting in release of stored hormone, is a frequent cause of thyrotoxicosis. The clinical presentation of thyrotoxicosis varies from asymptomatic (subclinical) to life threatening (thyroid storm). Thyroid storm is a true endocrine emergency. The diagnosis is based on history, clinical signs and symptoms, and laboratory analyses including thyroid-stimulating hormone (TSH), free T4 (thyroxine), and T3 (triiodothyroxine).

Thyroid hormone affects virtually every organ system and can result in an amalgam of complaints that can be challenging to identify. However, when undiagnosed, serious complications can occur including delirium, insomnia, anorexia, osteoporosis, muscle weakness, atrial fibrillation, congestive heart failure (CHF), thromboembolism, altered mental status, cardiovascular collapse, and death.2,3 Populations that are at increased risk for serious sequelae include pregnant women, children, and the elderly.4 It is essential that the emergency medicine provider has a high clinical suspicion for hyperthyroidism and thyrotoxicosis in patients with a myriad of seemingly unrelated symptoms, especially when coupled with dysautonomia. Thyroid storm needs to be identified rapidly and treated aggressively to avoid multiorgan dysfunction and death.5

Epidemiology

The prevalence of thyrotoxicosis in the United States is estimated at 1.2%, which comprises 0.5% symptomatic and 0.7% subclinical.6 Occurrences are seen at all ages but presentation peaks between 20 and 50 years of age secondary to the higher prevalence of Graves disease. Toxic multinodular goiter typically occurs after age 50 years, as opposed to toxic adenoma, which presents at a younger age. All forms of thyroid disease are more common in women. Graves disease is the most common cause of thyrotoxicosis in the United States, accounting for 60% to 80% of cases, whereas subacute thyroiditis accounts for 15% to 20%, toxic multinodular goiter accounts for 10% to 15%, and toxic adenoma accounts for 3% to 5%.7 Of those with thyrotoxicosis only 1% to 2% develop thyroid storm.8 Although the overall incidence of thyroid storm is low, the morbidity and mortality associated with the diagnosis make it a disease state that all emergency medicine physicians should be adept at identifying and treating.

Pathophysiology

The production and release of thyroid hormones is regulated by a sensitive negative feedback loop involving the hypothalamus, pituitary gland, and thyroid gland (Fig. 1). The hypothalamus releases thyroid-releasing hormone (TRH), which stimulates the pituitary to release TSH, in turn stimulating the thyroid gland to release thyroid hormones, T4 and T3. The increased production of thyroid hormone normally causes inhibition of TRH and TSH release by the hypothalamus and pituitary respectively. Disruption of this delicate system leads to additional production and release of thyroid hormone and subsequent hyperthyroidism.

The production of thyroid hormones in the thyroid gland depends on iodine.3 Dietary iodide is transported into cells and converted to iodine. The iodine is then bound to thyroglobulin by thyroid peroxidase and subsequently forms monoiodotyrosine (MIT) and diiodotyrosine (DIT).9 The MIT and DIT are coupled to form T4 and T3 respectively. T3 is more biologically active and is typically formed in the periphery by conversion of T4 to T3. In the serum, thyroid hormone is typically bound to protein and inactive. Any process that increases the amount of unbound (free) thyroid hormone has the potential to cause thyrotoxicosis.

Causes

Graves disease is the most common cause of hyperthyroidism in developed countries. It is an autoimmune condition in which antibodies against the TSH receptor cause unopposed stimulation of the thyroid gland. The result is excess production of T4 and T3, an enlarged thyroid gland, and increased iodide uptake. The usual negative feedback loop is not effective because the antibody is directed against the TSH receptor. Individuals with a family history of hyperthyroidism or other autoimmune diseases such as pernicious anemia, myasthenia gravis, type I diabetes mellitus, and celiac disease have an increased propensity of developing Graves.3

Toxic multinodular goiter (TMNG) is an important cause of hyperthyroidism. It is caused by unwarranted release of thyroid hormones from multiple autonomously functioning nodules in the thyroid gland. It is more common in areas of dietary iodine deficiency (third-world countries) and in the elderly (poor diet). This condition has an indolent progression and symptoms are typically mild with only slight increase of thyroid hormones above normal. TMNG is more common than Graves disease in the elderly.

Subacute thyroiditis is inflammation of the thyroid gland that typically follows a viral upper respiratory infection and causes additional release of preformed thyroid hormone. Patients typically present with fatigue, sore throat, and upper respiratory symptoms, followed by fever, neck pain, and neck swelling. It is the inflammation of the thyroid gland that causes thyroid hormone to leak into the circulation and subsequent thyrotoxicosis. The disease is usually self-limited but may lead to persistent hypothyroidism.

Toxic nodular goiter (toxic adenoma) is the result of a single nodule in the thyroid gland that is a hyperfunctioning adenoma and produces a surplus of thyroid hormone. Similar to TMNG, this is more common in areas of iodine deficiency. The increased thyroid hormone levels usually decrease TSH, but not to undetectable levels. The normal thyroid gland tissue has no iodine uptake visualized on an iodine uptake study because normal thyroid hormone production is suppressed via the negative feedback loop. However, the adenoma, which functions independently, appears as a single hot nodule with increased iodine uptake.

There are several additional causes of thyrotoxicosis that are rare but deserve consideration. Iodine-induced hyperthyroidism is the result of one or more areas of autonomously functioning thyroid tissue that occur after administration of iodine, classically iodinated contrast material.10 The excess iodine provides increased substrate for production of thyroid hormones. It is more common in areas with endemic goiter and iodine deficiency. It is possible for iodine to act as an immune stimulator leading to autoimmune thyroid disease and subsequent hyperthyroidism. High iodine intake is associated with increased prevalence of Graves disease.3 Patients typically present with a painless goiter.

Postpartum thyroiditis is inflammation of the thyroid gland following delivery. It is a transient form of hyperthyroidism that can develop 6 weeks to 6 months postpartum with a significant chance of recurrence in...