Diagnostics

Disease

Hyperthyroidism

General

Hyperthyroidism and thyrotoxicosis are terms often used interchangeably, however each refers to slightly different conditions.  Hyperthyroidism refers to overactivity of the thyroid gland, with resultant excessive secretion of thyroid hormones and accelerated metabolism in the periphery.  Thyrotoxicosis refers to the clinical effects of an unbound thyroid hormone, regardless of whether or not the thyroid is the primary source.  Thus, while the surreptitious use of exogenous thyroid hormone could cause a thyrotoxicosis, it would not be classified as a primary hyperthyroidism.

There are a number of pathologic causes of hyperthyroidism in children and adults.  These include Grave's disease, toxic adenoma, toxic multinodular goiter, and thyroiditis.  Of these, Grave's disease accounts for approximately 95% of cases of hyperthyroidism.  To understand the pathophysiology of hyperthyroidism, it is necessary to understand the normal physiology of the thyroid gland.

Like the other endocrine glands of the body, the thyroid is controlled by a complex feedback mechanism.  The release of thyroid-stimulating hormone (TSH) from the anterior pituitary is stimulated by low circulating levels of thyroid hormones and is under the influence of thyrotropin-releasing hormone (TRH) from the hypothalamus.  When released, TSH binds to TSH receptors on the thyroid gland setting off a cascade of events within the gland, leading to the release of thyroid hormones (mainly T4 and, to a lesser degree, T3).  Elevated levels of these hormones, in turn, act back on the hypothalamus and anterior pituitary to decrease the synthesis of TRH and TSH, thereby (under normal physiologic conditions) maintaining a tightly regulated level of circulating free hormones.

The particular tests used to evaluate a patient with suspected hyperthyroidism are discussed in the Diagnostics section of this website (see links to left).  A systematic approach to narrowing the differential of hyperthyroidism is shown below.

Distinguishing between Grave's, Toxic Adenoma, and Multinodular Goiter is based on physical exam findings and the appearance of the thyroid scan.  Each is discussed in their respective sections below.

Grave's Disease

Named after Dr. Robert Graves (1797-1853), Grave's disease is the most common cause of hyperthyroidism today.  In this autoimmune disease, elevated levels of thyroid hormone are the result of circulating thyroid-stimulating immunoglobulins (TSI's) of the IgG1 subclass.  These antibodies bind to the extracellular domain of the TSH receptor and activate it, causing follicular growth and the release of thyroid hormones.  The initial stimulus for the formation of the autoantibodies is unknown, but some have implicated bacterial or viral infections of the thyroid gland, which produce cross-reacting antibodies to the TSH receptor.  As such, the thyroid gland, in effect, becomes "ramped up" and no longer maintains its tight regulation under the influence of the pituitary.  Subsequently, circulating levels of TSH by the pituitary decline in response to negative feedback by an abundance of thyroid hormone.

Risk factors for the development of Grave's disease include:

Clinical Presentation

Patients with Grave's disease typically present with a diffuse, non-tender, symmetric enlargement of the thyroid gland, although a goiter is rarely the presenting complaint.  Patient's often complain of the symptoms associated with the hypermetabolic state that is induced by the excessive production of thyroid hormones.  Nervousness, restlessness, heat intolerance, tachycardia, palpitations, anxiety, increased sweating, hair loss, leg swelling, and pretibial myxedema are among the most common complaints.  In addition, patient's may present with a wide range of eye findings such as exophthalmos (or proptosis), lid lag, lid retraction, stare, conjunctival injection, periorbital edema, optic atrophy, and even complete blindness.

Although not well understood, the pathogenesis of eye involvement is thought to be multifactorial.  Some symptoms such as lid lag and lid retraction can be explained by the sympathomimetic effects of the induced thyrotoxicosis.  Other effects, such as exophthalmos or proptosis may be the result of an autoimmune reaction against the muscles or fibroblasts of the eye.

The dermopathy of Grave's disease, pretibial myxedema, consists of thickening of the skin, usually over the lower tibia, such that the skin cannot be picked between the examiner's fingers.  Although relatively rare, it usually occurs in association with ophthalmopathy.

Treatment

There are currently three possible treatments available for Grave's hyperthyroidism.  They include medical blockade of thyroid hormone and its effects (with the use of thionamides which interfere with thyroid hormone synthesis), radioiodine ablation of active thyroid tissue, and surgical resection of the thyroid gland.  As this tutorial deals with the surgical aspects of therapy (as opposed to medical management), the surgical options of total and subtotal thyroidectomy will be discussed.  The following link discusses the surgical therapies currently in use.

Toxic Adenoma and Multinodular Goiter

Toxic Nodular Goiter is the second most common cause of hyperthyroidism after Grave's disease in the Western world.  Originally described by Henry Plummer in 1913 and ascribed the name Plummer's Disease, it refers to a spectrum of disease ranging from a solitary hyperfunctioning nodule (Toxic Adenoma) to multiple areas of hyperfunction (Multinodular Goiter) throughout the gland.

Thought to result from somatic mutations in the human TSH receptor, the autonomously functioning thyroid nodules (both solitary and within a multinodular goiter) result in constitutive activation of the receptor, leading to uncontrolled release of thyroid hormone.

 This excessive release of hormone (no longer under pituitary control), leads to signs and symptoms quite similar to those seen in Grave's disease, however, since these disorders are not due to autoimmune processes, the ophthalmopathy and pretibial myxedema associated with Grave's is not encountered.  Similarly, though, serum thyroid hormone levels show how high T3 and T4 levels, and suppressed TSH.

Because laboratory diagnostics are similar for Grave's and Toxic Nodular Goiters, the differentiation between the two is often made by physical exam and thyroid scan.  Toxic adenomas typically present with a normal to small thyroid, with a prominent, palpable nodule, which is "hot" or hyperfunctional on thyroid scan.  In contrast (as mentioned above), the thyroid of Grave's disease is typically diffusely enlarged and without a distinct nodule.

Treatment

Treatment of toxic nodular goiter is essentially the same as that for Grave's disease.  Therapy is aimed at blocking the production and/or effects of excessive thyroid hormone.  Surgical is considered optimal therapy for both single and multinodular goiter, and can take the form of total or subtotal thyroidectomy, depending on whether which disease is present.  Generally speaking, radioactive iodine ablation is not considered appropriate for either instance, due to the possibility of recurrence in normal thyroid tissue.  As above, the following link discusses the surgical therapies currently in use.