Drugs for thyroid disorders

Thyroid hormones have profound effects on metabolism, cardiac function, growth, and development. These hormones stimulate the metabolic rate of most cells, and increase the force and rate of cardiac contraction. During infancy and childhood, thyroid hormones promote maturation; severe deficiency can produce extreme short stature and permanent mental impairment. Fortunately, most abnormalities of thyroid function can be effectively treated.

We begin our study of thyroid drugs by reviewing thyroid physiology. Next we review the pathophysiology of hypothyroid and hyperthyroid states. Finally, we discuss the agents used for thyroid disorders.

The thyroid gland produces two active hormones: triiodothyronine (T₃) and thyroxine (T₄, tetraiodothyronine). As shown in Figure 58–1, these hormones have nearly identical structures. The only difference is that T₄ contains four atoms of iodine, whereas T₃ contains three. The biologic effects of T₃ and T₄ are qualitatively similar. However, when compared on a molar basis, T₃ is much more potent.

Figure 58–1 Structural formulas of the thyroid hormones.

Preparations of T₃ and T₄ employed clinically, although synthetic, are identical in structure to the naturally occurring hormones. The generic name of synthetic T₃ is liothyronine, and the generic name of synthetic T₄ is levothyroxine. A fixed-ratio mixture of T₃ plus T₄, known as liotrix, is also available.

Synthesis and fate of thyroid hormones

Synthesis.

Synthesis of thyroid hormones takes place in four steps (Fig. 58–2). The circled numbers in the figure correspond with the steps below.

• Step 1. Formation of thyroid hormone begins with the active transport of iodide into the thyroid. Under normal conditions, this process produces concentrations of iodide within the thyroid that are 20 to 50 times greater than the concentration of iodide in plasma. When plasma iodide levels are extremely low, intrathyroid iodide content may reach levels that are more than 100 times greater than those in plasma.

• Step 2. Following uptake, iodide undergoes oxidation to iodine, the active form of iodide. Iodide oxidation is catalyzed by an enzyme called peroxidase.

• Step 3. In this step, activated iodine becomes incorporated into tyrosine residues that are bound to thyroglobulin, a large glycoprotein. As indicated in Figure 58–2, one tyrosine molecule may receive either one or two iodine atoms, resulting in the production of monoiodotyrosine (MIT) or diiodotyrosine (DIT), respectively.

• Step 4. In this final step, iodinated tyrosine molecules are coupled. Coupling of one DIT with one MIT forms T₃ (step 4A); coupling of one DIT with another DIT forms T₄ (step 4B).

Fate.

Thyroid hormones are released from the thyroid gland by a proteolytic process. The amount of T₄ released is substantially greater than the amount of T₃ released. However, much of the T₄ that is released undergoes conversion to T₃ by enzymes in peripheral tissues. In fact, conversion of T₄ to T₃ accounts for the majority (about 80%) of the T₃ found in plasma.

More than 99.5% of the T₃ and T₄ in plasma is bound to plasma proteins. Consequently, only a tiny fraction of circulating thyroid hormone is free to produce biologic effects.

Thyroid hormones are eliminated primarily by hepatic metabolism. Because T₃ and T₄ are extensively bound to plasma proteins, metabolism is slow. As a result, the half-lives of these hormones are prolonged—about 1 day for T₃ and 7 days for T₄.

Thyroid hormone actions

Thyroid hormones have three principal actions: (1) stimulation of energy use, (2) stimulation of the heart, and (3) promotion of growth and development. Stimulation of energy use elevates the basal metabolic rate, resulting in increased oxygen consumption and increased heat production. Stimulation of the heart increases both the rate and force of contraction, resulting in increased cardiac output and increased oxygen demand. Thyroid effects on growth and development are profound: Thyroid hormones are essential for normal development of the brain and other components of the nervous system, and they have a significant impact on maturation of skeletal muscle.

How do thyroid hormones produce their effects? By modulating the activity of specific genes. Furthermore, it appears that most, if not all, of the effects of thyroid hormones are mediated by T₃, not by T₄. There is good evidence that T₃ penetrates to the cell nucleus and binds with high affinity to nuclear receptors, which in turn bind to specific DNA sequences. The result is modulation of gene transcription, causing production of proteins that mediate thyroid hormone effects. Although T₄ also binds with nuclear receptors, its affinity is low, and gene transcription is not altered. Hence it would seem that T₄ serves only as a source of T₃, having little or no physiologic effects of its own.

Regulation of thyroid function by the hypothalamus and anterior pituitary

The functional relationship between the hypothalamus, anterior pituitary, and thyroid is depicted in Figure 58–3. As indicated, thyrotropin-releasing hormone (TRH), secreted by the hypothalamus, acts on the pituitary to cause secretion of thyrotropin (thyroid-stimulating hormone [TSH]). TSH then acts on the thyroid to stimulate all aspects of thyroid function: thyroid size is enlarged, iodine uptake is augmented, and synthesis and release of thyroid hormones are increased. In response to rising plasma levels of T₃ and T₄, further release of TSH is suppressed. The stimulatory effect of TSH on the thyroid, followed by the inhibitory effect of thyroid hormones on the pituitary, constitutes a negative feedback loop.

Figure 58–3 Regulation of thyroid function.
TRH from the hypothalamus stimulates release of TSH from the pituitary. TSH stimulates all aspects of thyroid function, including release of T₃ and T₄. T₃ and T₄ act on the pituitary to suppress further TSH release. (T₃ = triiodothyronine, T₄ = thyroxine, TRH = thyrotropin-releasing hormone, TSH = thyrotropin [thyroid-stimulating hormone].)

Effect of iodine deficiency on thyroid function

When iodine availability is diminished, production of thyroid hormones decreases. The ensuing drop in thyroid hormone levels promotes release of TSH, which acts on the thyroid to increase its size (causing goiter) and ability to concentrate iodine. If iodine deficiency is not too severe, the increased capacity for iodine uptake will restore normal production of T₃ and T₄.

Thyroid function tests

Several laboratory tests can be used to evaluate thyroid function. Three are described below. Values indicating euthyroid (normal), hypothyroid, and hyperthyroid states are summarized in Table 58–1.

TABLE 58–1

Serum Values for Thyroid Function Tests

	Serum Values
Thyroid Test	Normal	Hypothyroid	Hyperthyroid
Total T₄ (mcg/dL)	4.5–12.5	Under 4.5	Over 12.5
Free T₄ (ng/dL)	0.9–2	Under 0.9	Over 2
Total T₃ (ng/dL)	80–220	Under 80	Over 220
Free T₃ (pg/dL)	230–620	Under 230	Over 620
TSH (microunits/mL)	0.3–6	Over 6	Under 0.3

Thyroid pathophysiology

Hypothyroidism

Hypothyroidism can occur at any age. In adults, mild deficiency of thyroid hormone is referred to simply as hypothyroidism. Severe deficiency is called myxedema. When hypothyroidism occurs in infants, the resulting condition is called cretinism.

Hypothyroidism in adults

Clinical presentation.

Signs and symptoms of hypothyroidism depend on disease severity. With mild hypothyroidism, symptoms are subtle and may go unrecognized for what they are. In contrast, with moderate to severe disease, characteristic signs and symptoms emerge. The face is pale, puffy, and expressionless. The skin is cold and dry. The hair is brittle, and hair loss occurs. Heart rate and temperature are lowered. The patient may complain of lethargy, fatigue, and intolerance to cold. Mentation may be impaired. Thyroid enlargement (goiter) may occur if reduced levels of T₃ and T₄ promote excessive release of TSH.

Causes.

Hypothyroidism in the adult is usually due to malfunction of the thyroid itself. In iodine-sufficient countries, the principal cause is chronic autoimmune thyroiditis (Hashimoto’s thyroiditis). Other causes are insufficient iodine in the diet, surgical removal of the thyroid, and destruction of the thyroid by radioactive iodine. Adult hypothyroidism may also result from insufficient secretion of TSH and TRH.

Therapeutic strategy.

Hypothyroidism in adults requires replacement therapy with thyroid hormones. In almost all cases, treatment must continue lifelong. Today, the standard replacement regimen consists of levothyroxine (T₄) alone. Combined therapy with levothyroxine plus liothyronine (T₃) is an option. However, with only three exceptions, all studies to date indicate that combined T₃/T₄ offers no advantage over T₄ alone. (Remember, when we give T₄, much of it is rapidly converted to T₃, the active form of the hormone.) When replacement doses of T₄ are adequate, they can eliminate all signs and symptoms of thyroid deficiency.

Hypothyroidism during pregnancy

Maternal hypothyroidism can result in permanent neuropsychologic deficits in the child. We have long known that congenital hypothyroidism can cause mental retardation and other developmental problems (see below under Hypothyroidism in Infants). However, it was not until 1999 that researchers demonstrated that maternal hypothyroidism—in the absence of fetal hypothyroidism—can decrease IQ and other aspects of neuropsychologic function in the child. The impact of maternal hypothyroidism is limited largely to the first trimester, a time during which the fetus is unable to produce thyroid hormones of its own. By the second trimester, the fetal thyroid gland is fully functional, and hence the fetus can supply its own hormones from then on. Therefore, to help ensure healthy fetal development, maternal hypothyroidism must be diagnosed and treated very early. Unfortunately, symptoms of hypothyroidism are often nonspecific (irritability, tiredness, poor concentration, etc.) or there may be no symptoms at all. Accordingly, some authorities now recommend routine screening for hypothyroidism as soon as pregnancy is confirmed. If hypothyroidism is diagnosed, replacement therapy should begin immediately.

When women taking thyroid supplements become pregnant, dosage requirements usually increase—often by as much as 50%. The need for increased dosage begins between weeks 4 and 8 of gestation, levels off around week 16, and then remains steady until parturition. To ensure adequate hormone levels, some authorities increase T₄ dosage by 30% as soon as pregnancy is confirmed. Further adjustments are based on serum TSH levels, which should be monitored closely.

Hypothyroidism in infants

Clinical presentation.

Hypothyroidism in newborns may be permanent or transient. In either case, congenital hypothyroidism (cretinism) can cause mental retardation and derangement of growth. In the absence of thyroid hormones, the child develops a large and protruding tongue, potbelly, and dwarfish stature. Development of the nervous system, bones, teeth, and muscles is impaired.

Causes.

Cretinism usually results from a failure in thyroid development. Other causes include autoimmune disease, severe iodine deficiency, TSH deficiency, and exposure to radioactive iodine in utero.

Therapeutic strategy.

Hypothyroidism in newborns requires replacement therapy with thyroid hormones. If treatment is initiated within a few days of birth, physical and mental development will be normal. However, if therapy is delayed beyond 3 to 4 weeks, some permanent retardation will be evident, although the physical effects of thyroid deficiency will reverse.

How long should replacement therapy last? In all children, treatment should continue for 3 years, after which it should be stopped for 4 weeks. The objective is to determine if thyroid deficiency is permanent or transient. If TSH rises, indicating thyroid hormone production is low, we know the deficiency is permanent, and hence replacement therapy should resume. If TSH and T₄ normalize, we know the deficiency was transient, and hence further replacement therapy is unnecessary.

Hyperthyroidism

There are two major forms of hyperthyroidism: Graves’ disease and toxic nodular goiter (also known as Plummer’s disease). Of the two disorders, Graves’ disease is more common. Signs and symptoms of both disorders are similar. The principal difference is that Graves’ disease may cause exophthalmos, whereas toxic nodular goiter does not.

Graves’ disease

Graves’ disease is the most common cause of excessive thyroid hormone secretion. This disorder occurs most frequently in women 20 to 40 years of age. The incidence in females is 6 times greater than in males.

Clinical presentation.

Most clinical manifestations result from elevated levels of thyroid hormone. Heartbeat is rapid and strong, and dysrhythmias and angina may develop. The central nervous system is stimulated, resulting in nervousness, insomnia, rapid thought flow, and rapid speech. Skeletal muscles may weaken and atrophy. Metabolic rate is raised, resulting in increased heat production, increased body temperature, intolerance to heat, and skin that is warm and moist. Appetite is increased. However, despite increased food consumption, weight loss occurs if caloric intake fails to match the increase in metabolic rate. Collectively, the above signs and symptoms are referred to as thyrotoxicosis.

In addition to thyrotoxicosis, patients with Graves’ disease often present with exophthalmos (protrusion of the eyeballs). The underlying cause is an immune-mediated infiltration of the extraocular muscles and orbital fat by lymphocytes, macrophages, plasma cells, mast cells, and mucopolysaccharides.

Cause.

Thyroid stimulation in Graves’ disease is caused by thyroid-stimulating immunoglobulins (TSIs), which are antibodies produced by an autoimmune process. TSIs increase thyroid activity by stimulating receptors for TSH on the thyroid gland. That is, TSIs mimic the effects of TSH on thyroid function. TSIs are not responsible for exophthalmos.

Treatment.

Treatment for Graves’ disease is directed at decreasing the production of thyroid hormones. Three modalities are employed: (1) surgical removal of thyroid tissue, (2) destruction of thyroid tissue with radioactive iodine, and (3) suppression of thyroid hormone synthesis with an antithyroid drug (methimazole or propylthiouracil). Radiation is the preferred treatment for adults, whereas antithyroid drugs are preferred for younger patients.

Beta blockers (eg, propranolol) and nonradioactive iodine may be used as adjunctive therapy. Beta blockers suppress tachycardia by blocking beta receptors on the heart. Nonradioactive iodine inhibits synthesis and release of thyroid hormones.

Since exophthalmos is not the result of hyperthyroidism per se, this condition is not improved by lowering thyroid hormone production. If exophthalmos is severe, it can be treated with surgery or with high doses of oral glucocorticoids.

Toxic nodular goiter (Plummer’s disease)

Toxic nodular goiter is the result of a thyroid adenoma. Clinical manifestations are much like those of Graves’ disease, except exophthalmos is absent. Toxic nodular goiter is a persistent condition that rarely undergoes spontaneous remission. Treatment modalities are the same as for Graves’ disease. However, if an antithyroid drug is used, symptoms return rapidly when the drug is withdrawn. Accordingly, surgery and radiation, which provide long-term control, are often preferred.

Thyrotoxic crisis (thyroid storm)

Thyrotoxic crisis can occur in patients with severe thyrotoxicosis when they undergo major surgery or develop a severe intercurrent illness (eg, infection, sepsis). The syndrome is characterized by profound hyperthermia (105°F or even higher), severe tachycardia, restlessness, agitation, and tremor. Unconsciousness, coma, hypotension, and heart failure may ensue. These symptoms are produced by excessive levels of thyroid hormones.

Thyrotoxic crisis can be life threatening and requires immediate treatment. High doses of potassium iodide or strong iodine solution are given to suppress thyroid hormone release. Propylthiouracil is given to suppress thyroid hormone synthesis and peripheral conversion of T₄ to T₃. A beta blocker is given to reduce heart rate. Additional measures include sedation, cooling, and giving glucocorticoids and IV fluids.

Thyroid hormone preparations for hypothyroidism

Thyroid hormones are available as pure, synthetic compounds and as extracts of animal thyroid glands. All preparations have qualitatively similar effects. The synthetic preparations are more stable and better standardized than the animal gland extracts. As a result, the synthetics are preferred to the natural products. Properties of thyroid hormone preparations are summarized in Table 58–2.

TABLE 58–2

Thyroid Hormone Preparations

Generic Name	Trade Names	Dosage Forms	Approximate Equivalent Dosage*	Description
Levothyroxine	Levothroid, Levoxyl, Synthroid, Thyro-Tabs	Tablets, injection	50–60 mcg	Synthetic preparation of T₄ identical to the naturally occurring hormone
Liothyronine	Cytomel, Triostat	Tablets, injection	15–37 mcg	Synthetic preparation of T₃ identical to the naturally occurring hormone
Liotrix	Thyrolar	Tablets	60 mcg	Synthetic T₄ plus synthetic T₃ in a 4:1 fixed ratio
Thyroid	Armour Thyroid, Bio-Throid, Nature-Throid, Thyroid USP, Westhroid	Tablets, capsules	60 mg	Desiccated animal thyroid glands (rarely used today)