Thyroid Hormone Secretion

As discussed in Chapter 31, the secretion of thyroid hormones is initiated by a hypothalamic hormone called thyrotropin-releasing hormone (TRH), which increases secretion of an anterior pituitary hormone called thyroid-stimulating hormone (TSH, or thyrotropin). TSH is the prime regulator of iodide uptake and thyroid hormone formation by the thyroid gland. It fulfills this role by inducing the expression of three genes involved in iodide uptake and hormone production: (1) the sodium/iodide symporter that transports iodide into the thyroid gland, (2) thyroglobulin, and (3) thyroperoxidase. The secretion of TRH and TSH is regulated, in turn, by feedback inhibition of their secretion by T₄ and T₃ (Fig. 32-1).

Thyroid hormones are synthesized in a process that involves the uptake and organification of iodide and the subsequent coupling of iodotyrosine residues of thyroglobulin. These steps are depicted in Figure 32-2.

After iodide is actively transported into thyroid follicle cells, it diffuses across the cells to the apical membrane, where it is oxidized and attached to tyrosine residues of thyroglobulin. This process is called iodide organification. The iodinated tyrosine residues monoiodotyrosine and diiodotyrosine are then coupled to form T₃ and T₄. Iodide organification and the coupling reactions are catalyzed by thyroperoxidase.

Thyroglobulin is stored as colloid in the follicular lumen. During the release of thyroid hormones, thyroglobulin reenters the follicular cell by endocytosis and undergoes proteolysis. The release of T₄ and T₃ is stimulated by TSH via the formation of cyclic adenosine monophosphate (cAMP) in thyroid follicular cells.

T₄ accounts for about 80% of the hormones secreted by the thyroid, and T₃ accounts for the remainder. These hormones are transported to target organs by thyroid-binding globulin, thyroid-binding prealbumin, and albumin. In peripheral tissues, some of the T₄ is converted to T₃ and reverse T₃ (rT₃) by 5′-deiodinase and 5-deiodinase, respectively. T₃ is about five times more active than T₄, whereas rT₃ is completely inactive. For this reason, the deiodinase enzymes have an important role in controlling the level of thyroid activity. The rate of conversion of T₄ to T₃ is also affected by a variety of other hormones, nutrients, and disease states. T₃ and rT₃ are eventually metabolized by deiodinase and sulfotransferase reactions to diiodothyronine sulfate.

When T₃ enters the nucleus of target cell, it binds to specific receptors that activate gene transcription, leading to increased synthesis of proteins necessary for growth, development, and calorigenesis (heat production).

Hypothyroidism

In infants and children, hypothyroidism causes irreversible mental retardation and impairs growth and development. In adults, hypothyroidism is associated with impairment of physical and mental activity and with slowing of cardiovascular, gastrointestinal, and neuromuscular functions. Hypothyroid patients may note lethargy, cold intolerance, weight gain, and constipation. The skin may become coarse, dry, and cold. Eventually, hypothyroidism causes myxedema, which is described as a dry, waxy swelling of the skin with nonpitting edema. Myxedema coma is characterized by hypothermia, hypoglycemia, weakness, stupor, and shock and is the end stage of long-standing, untreated hypothyroidism.

Many patients with mild hypothyroidism have a T₄ level within the normal range. As the disease progresses, however, the T₄ level usually falls below normal.

The most common cause of hypothyroidism in adults is autoimmune thyroiditis (Hashimoto disease). Other causes include thyroid surgery or radioactive iodine (RAI) treatment for hyperthyroidism; dietary iodine deficiency; and thyroid hypoplasia or enzymatic defects. Pituitary or hypothalamic dysfunction can cause secondary hypothyroidism.

Several types of drugs can induce thyroid disorders. Lithium inhibits the release of thyroid hormones by the thyroid gland (see Fig. 32-1) and can cause hypothyroidism by this mechanism. Amiodarone is an iodine-containing antiarrhythmic drug that can cause either hypothyroidism or hyperthyroidism through a variety of mechanisms that alter multiple thyroid functions.

The treatment for all forms of hypothyroidism is replacement therapy with a thyroid hormone preparation.

Hyperthyroidism

Manifestations of hyperthyroidism, or thyrotoxicosis, can include nervousness, emotional lability, weight loss despite an increased appetite, heat intolerance, palpitations, proximal muscle weakness, increased frequency of bowel movements, and irregular menses.

Most cases of hyperthyroidism are associated with overproduction of thyroid hormones by the thyroid gland, as indicated by the finding of increased RAI uptake. Excessive thyroid hormone production can result from excessive TSH, as occurs in patients with TSH-secreting pituitary adenomas, or it can result from gland stimulation by thyroid antibodies, as occurs in patients with Graves disease.

Graves disease results from the formation of antibodies directed against the TSH receptor on the surface of thyroid cells. These antibodies stimulate the receptor in the same manner as TSH, resulting in overproduction of thyroid hormones. Graves disease is characterized by hyperthyroidism, thyroid enlargement, and exophthalmos (abnormal protrusion of the eyeball). Exophthalmos results from stimulation of orbital muscles by thyroid antibodies.

Excessive thyroid hormone production also occurs in persons with thyroid nodules that are independent of pituitary gland control. Inflammatory thyroid disease (subacute thyroiditis) can cause a transient form of hyperthyroidism that is caused by the release of preformed thyroid hormone from thyroid follicles.

Three treatment modalities are used in hyperthyroidism: antithyroid agents, surgery, and RAI treatment. The goals of therapy are to eliminate excessive thyroid hormone production and to control the symptoms of hyperthyroidism. The choice of treatment depends on the type and severity of hyperthyroidism and on the individual characteristics of the patient. Antithyroid agents are primarily used for the short-term treatment of hyperthyroidism, either to induce remission of Graves disease or to control the symptoms of hyperthyroidism before thyroid surgery or RAI treatment. Surgery or RAI treatment can permanently cure hyperthyroidism. Either of these treatment modalities, however, often results in chronic hypothyroidism, which necessitates lifelong thyroid hormone replacement therapy.