CASE 42

A 44-year-old woman presents to the office because of fatigue. She has felt sluggish for months and thinks she may be anemic. She has started taking iron pills but isn’t feeling any better. She has been sleeping well and doesn’t feel depressed. She has noticed some thinning of her hair and feels as if her skin is dry. She takes a multivitamin and iron supplement, otherwise no medications. She has smoked a pack of cigarettes a day for approximately 20 years, occasionally drinks alcohol, and doesn’t exercise. Her mother takes some kind of thyroid pill and has diabetes. On examination, her blood pressure and pulse are normal. Her hair is thinned but there are no focal patches of alopecia or scarring of the scalp. Her skin is diffusely dry. Her thyroid gland feels diffusely enlarged, is nontender, and has no nodules. The remainder of her examination is unremarkable. Lab tests show a normal complete blood count (CBC), glucose, and electrolytes. Her thyroid-stimulating hormone (TSH) level is elevated, and T₄ level is reduced. You diagnose her with hypothyroidism and start her on oral levothyroxine sodium.

What is levothyroxine sodium?

How is triiodothyronine (T₃) produced in the body?

What is the mechanism of action of thyroid hormones?

ANSWERS TO CASE 42:

Thyroid Hormones

Summary: A 44-year-old woman is diagnosed with hypothyroidism and prescribed levothyroxine.

Levothyroxine sodium: Synthetic sodium salt of thyroxine (T₄).

Derivation of T₃ in the body: Approximately 75 percent from the deiodination of T₄; also produced by the coupling of monoiodotyrosine (MIT) and diiodotyrosine (DIT).

Mechanism of action of thyroid hormones: Bind with receptors in nuclei of target cells and alter synthesis rates of specific messenger ribonucleoprotein acids (mRNAs), increasing production of certain proteins including Na⁺, K⁺-ATPase.

CLINICAL CORRELATION

Thyroid hormones have wide-ranging effects of tissues throughout the body. They are involved primarily in the regulation of metabolism. The hypothalamic-pituitary-thyroid axis regulates release of active hormone from the thyroid via a feedback loop. Thyrotropin-releasing hormone (TRH) is produced in the hypothalamus and stimulates the release of TSH from the anterior pituitary. TSH binds to membrane receptors in the thyroid and stimulates the production and release of T₄ and T₃ via a cyclic adenosine monophosphate (cAMP)-mediated system. Synthesis of T₄ exceeds T₃ by approximately fourfold; most circulating T₃ comes from peripheral deiodination of T₄. T₄ and T₃ are almost entirely protein bound, mostly to thyroxine-binding globulin (TBG) and albumin. Unbound thyroid hormone binds to receptors located in the nuclei of target cells. This alters transcription of specific mRNAs, which lead to the increased production of proteins, including Na⁺, K⁺-ATPase. This results in a net increase in ATP and oxygen consumption, raising the metabolic rate. Hypothyroidism occurs when there is inadequate thyroid hormone production and release to meet the body’s metabolic demands. In primary hypothyroidism the thyroid gland is unable to synthesize adequate amounts of thyroid hormone. The pituitary releases increasing amounts of TSH to try to stimulate production, leading to the characteristic laboratory findings of low circulating levels of thyroid hormones with an elevated TSH. Conversely, primary hyperthyroidism is diagnosed by the presence of elevated thyroid hormone levels and a suppressed level of TSH. Hypothyroidism is most often treated by the oral administration of synthetic T₄ in the form of levothyroxine sodium. This replaces both T₄ and, by deiodination, T₃.

APPROACH TO:

Pharmacology of Thyroid Drugs

OBJECTIVES

1. List the hormones involved in the hypothalamic-pituitary-thyroid axis and the synthesis of thyroid hormones.

2. Know the actions of thyroid hormones.

3. List the thyroid hormone preparations, their therapeutic uses, actions, and adverse effects.

4. Describe the antithyroid agents, their mechanisms of action, therapeutic uses, and adverse effects.

DEFINITIONS

Myxedema: The nonpitting edema of the skin and soft tissue that occurs in patients who are hypothyroid. Myxedema coma is an extreme complication of hypothyroidism in which patients exhibit multiple organ abnormalities and progressive mental deterioration. The cardinal manifestation of myxedema coma is a deterioration of the patient’s mental status even without coma.

Thyrotoxicosis: Hyperthyroidism.

DISCUSSION

Class

Thyroid Agonists Thyroid hormones are required for optimum development, growth, and maintenance of function of virtually every tissue of the body. Either hypo- or hyperthyroidism leads to untoward symptoms that need to be treated. The thyroid gland produces both thyroxine (T₄) and triiodothyronine (T₃). Adequate dietary intake of sufficient iodide (I^-) is essential to maintain normal biosynthesis of thyroid hormones. Iodide is transported into the thyroid cell by a sodium-iodide symporter (NIS) and then transported through the apical plasma membrane into the colloid of the thyroid gland. Within the colloid, iodide is oxidized to iodine by thyroidal peroxidase. The process called organification involves the iodination of tyrosine residues of the colloidal protein thyroglobulin to form MIT and DIT. The coupling of two molecules of DIT forms T₄ and the coupling of one molecule of MIT, and one molecule of DIT forms T₃. Under normal circumstances and sufficient iodide, the ratio of T₄ to T₃ is 4:1. T₃ can also be formed by the removal of an iodide molecule from T4 by the action of 5’-deiodinase, which is present within the thyroid gland and in peripheral tissues.

Iodinated thyroglobulin undergoes endocytosis at the apical border and then is extensively degraded within the thyroid cells by proteolysis prior to secretion of T₄ and T₃. Although T₃ is produced with the thyroid, approximately 80 percent of circulating levels of T₃ are produced by the action of 5’-deiodinase in the periphery, especially the liver. Alternatively T₄ can be degraded by the action of deiodinase to reverse T₃, which is an inactive metabolite. Normally approximately 40 percent of T₄ is converted to T₃, 38 percent is converted to rT₃, and the remainder is degraded by other, typically hepatic pathways. Greater than 99 percent of both T₄ and T₃ are bound in the plasma to TBG; T₄ binds to TBG much more avidly. Only the unbound “free” hormone exerts physiologic effects.

Secretion of thyroid hormones is regulated by a classical hypothalamus-pituitary-thyroid negative feedback loop. TRH is produced within hypothalamus. It acts on thyrotrophs in the pituitary to cause the release of thyrotropin (TSH), which in turn stimulates all steps in the biosynthesis and secretion of thyroid hormones. Circulating levels of thyroid hormone decrease the amount of TRH that is released from the hypothalamus, completing the feedback loop. Somatostatin and dopamine reduce TSH release.

Thyroid hormone is critical for normal brain development. The absence of normal thyroid hormone function in the first months of the infant leads to irreversible cretinism. Thyroid hormone induces myelin basic protein, and hypothyroidism leads to decreased production of this protein and defective neuronal myelination. Thyroid hormones have an important effect on oxygen consumption in many tissues including heart, skeletal muscle, kidney, and liver; brain, gonads, and spleen are not affected. This calorigenic effect is important to normal thermogenesis. Thyroid hormones also increase lipolysis.

Thyroid hormone has direct actions on the heart and vascular system. Hyperthyroidism leads to tachycardia, increased stroke volume, increased pulse pressure, and decreased vascular resistance. Hypothyroidism leads to bradycardia, and the opposite of the above effects. Thyroid hormones increase the conversion of cholesterol to bile and increase LDL uptake by the liver and thereby reduce plasma cholesterol concentrations.

Hypothyroidism can be treated effectively by hormone replacement. Common causes of hypothyroidism include autoimmune destruction of the thyroid gland (Hashimoto disease), congenital hypothyroidism, or impaired pituitary or hypothalamic function. Thyroid hormones are indicated for the treatment and prophylaxis of goiter by suppressing abnormal growth of the thyroid gland. Thyroid hormones are also useful in the treatment of TSH-dependent thyroid cancers. Adverse effects of thyroid hormones are a hyperthyroid state with increased calorigenesis and oxygen demand, tachycardia, and increased cardiac workload.

Structure

Synthetic preparations of T₄ (levothyroxine), T₃ (liothyronine) and a 4:1 mixture of T₄/T₃ (liotrix) are preferable to desiccated preparations of thyroid prepared from animals that are more variable in biologic activity.

Mechanism of Action

The actions of the thyroid hormones are mediated by nuclear thyroid receptors that act by increasing or decreasing transcription of target genes. There are three major thyroid receptors: TRβ₁, TRβ₂, and TRα₁. Whereas TRα₁ and TRα₁ are expressed in virtually every tissue, TRβ₂ is expressed exclusively in the anterior pituitary. These receptors bind T₃ in the nucleus. T₄ can bind to the receptors but at much lower affinity and with much less, if any, effect on transcription. Thyroid receptors are bound in the absence of ligand to the promoters of target genes, and in some cases the nonliganded receptor exerts a potent inhibition of basal transcription. T₃ binding to TR results in recruitment of coactivators and subsequent disinhibition and increased rates of transcription. All the above preparations of thyroid hormone can be administered orally. Levothyroxine and liothyronine are also available for parenteral administration. Doses are individualized and monitored by measuring the level of circulating TSH.

Pharmacokinetics

T₄ has a very long half-life (7 days), in large part because of its extensive binding to TBG. The half-life of T₄ is lengthened to 9–10 days in hypothyroidism and decreased to 3–4 days in hyperthyroidism. Thyroid hormones are degraded mostly by the liver and excreted in the bile.

Thyroid Antagonists Hyperthyroidism can be treated with agents that decrease the biosynthesis of thyroid hormones, or destroy of the thyroid gland with radioactive isotopes of thyroid hormones or surgery. The thioamides, methimazole and propylthiouracil (PTU), are the major drugs for treating hyperthyroidism. These drugs act by inhibiting peroxidation of iodide and organification of thyroglobulin. PTU also acts to inhibit the coupling reaction that forms MIT and DIT. PTU is preferred over methimazole in women of child bearing age. Although complications in pregnancy are rare for both agents, PTU has had better safety profile for longer term than methimazole. Methimazole offers the advantage of less frequent dosing.

Adverse effects of thioamides include a maculopapular rash, and less commonly arthralgia, skin rashes, hepatoxicity, cholestatic jaundice, and a lupus-like syndrome. Potentially life-threatening agranulocytosis has occurred with their use.

Historically, iodides were the major antithyroid agents. Large oral doses of iodide inhibit organification and the secretion of thyroid hormones. Iodide is useful in treating acute thyrotoxicosis (thyroid storm), and to reduce the size, vascularity, and fragility of a hyperplastic thyroid preoperatively. Most patients will escape the blocking effects of iodide in 2 to 8 weeks.

Monovalent anions such as perchlorate (CIO₄^-), thiocyanate (SCN^-), and pertechnetate (TCO₄^-) are competitive inhibitors of the iodide transport mechanism, but rarely used compared to thioamides due to adverse effects.

Radioactive iodine-131 is rapidly trapped and concentrated in the colloid of the thyroid gland exactly as occurs with the stable ¹²⁷ I. Radiation is nearly exclusively delivered to the parenchymal cells of the thyroid and leads to a dose-dependent destruction of part or the entire gland. In many circumstances it is considered the treatment of choice for chronic hyperthyroidism. It should not be used in patients who are pregnant because of its action on the thyroid of the fetus.

COMPREHENSION QUESTIONS

42.1 A woman enters your clinic with an enlarged thyroid and you suspect simple adenomatous goiter. The serum TSH is elevated. Which of the following would be the best treatment for this condition?

A. IV infusion of TSH

B. Levothyroxine

C. Propylthiouracil

D. Thyroid ablation with ¹³¹ I

42.2 The mechanism by which thiocyanate reduces synthesis of thyroid hormones is by inhibition of which of the following?

A. Iodine oxidation

B. Iodide transport

C. TSH biosynthesis

D. TRβ

42.3 A 33-year-old man is noted to have tachycardia, heat intolerance, weight loss, and an enlarged thyroid gland. Which of the following is the probable ultimate treatment for this patient?

A. Long-term corticosteroid therapy

B. Propranolol therapy

C. Radioactive iodine

D. Surgical resection

ANSWERS

42.1 B. Hypothyroidism is an indication for thyroid hormone replacement.

42.2 B. Anions such as perchlorate and thiocyanate inhibit the transport of iodide into thyroid cells.

42.3 C. This patient likely has Graves disease, the most common cause of hyperthyroidism in the United States, typically presenting with a painless goiter and symptoms of hyperthyroidism. The treatment of choice is radioactive iodine. Propanalol will help with the symptoms of tachycardia but not the underlying disease process.

REFERENCES

Almandoz JP, Gharib H. Hypothyroidism: etiology, diagnosis, and management. Med Clin North Am. 2012;96:203–21.

Hegedüs L. Treatment of Graves’ hyperthyroidism: evidence-based and emerging modalities. Endocrinol Metab Clin North Am. 2009;38:355–71

Nayak B, Burman K. Thyrotoxicosis and thyroid storm. Endocrinol Metab Clin North Am. 2006;35:663–86.