Thyroid Metabolic Hormones

The thyroid gland, located immediately below the larynx on each side of and anterior to the trachea, is one of the largest of the endocrine glands, normally weighing 15 to 20 grams in adults. The thyroid secretes two major hormones, thyroxine and triiodothyronine, commonly called T4 and T3, respectively. Both of these hormones profoundly increase the metabolic rate of the body. Complete lack of thyroid secretion usually causes the basal metabolic rate to fall 40- 50% below normal, and extreme excesses of thyroid secretion can increase the basal metabolic rate to 60-100% above normal. Thyroid secretion is controlled primarily by thyroid-stimulating hormone (TSH) secreted by the anterior pituitary gland. The thyroid gland also secretes calcitonin, an important hormone for calcium metabolism.

Synthesis and secretion of the thyroid metabolic hormones: About 93% of the metabolically active hormones secreted by the thyroid gland is thyroxine, and 7% triiodothyronine. However, almost all the thyroxine is eventually converted to T3 in the tissues, so that both are functionally important. The functions of these two hormones are qualitatively the same, but they differ in rapidity and intensity of action. T3 is about four times as potent as thyroxine, but it is present in the blood in much smaller quantities and persists for a much shorter time than does thyroxine.

Physiologic anatomy of the thyroid gland: The gland is composed of large numbers of closed follicles (100-300 µm in diameter) filled with a secretory substance called colloid and lined with cuboidal epithelial cells that secrete into the interior of follicles. The major constituent of colloid is the large glycoprotein thyroglobulin that contains the thyroid hormones within its molecule.

Iodine is required for the formation of Thyroxine: To form normal quantities of thyroxine, about 50 mg of ingested iodine in the form of iodides are required each year, or about 1 mg/week. To prevent iodine deficiency, common table salt is iodized with about 1 part sodium iodide to every 100,000 parts sodium chloride.

Fate of ingested Iodides: Iodides ingested orally are absorbed from the GIT into the blood in about the same manner as chlorides. Normally, most of the iodides are rapidly excreted by the kidneys, but only after about one fifth are selectively removed from the circulating blood by the cells of the thyroid gland and used for synthesis of the thyroid hormones.

Iodide Pump (Iodide Trapping): The first stage in the formation of thyroid hormones is transport of iodides from the blood into the thyroid glandular cells and follicles. The basal membrane of the thyroid cell has the specific ability to pump the iodide actively to the interior of the cell. This is called iodide trapping. In a normal gland, the iodide pump concentrates the iodide to about 30 times its concentration in the blood. When the thyroid gland becomes maximally active, this concentration ratio can rise to as high as 250 times. The rate of iodide trapping by the thyroid is influenced by several factors, the most important being the
concentration of TSH; TSH stimulates and hypophysectomy greatly diminishes the activity of the iodide pump in thyroid cells.

Thyroglobulin, and Chemistry of Thyroxine and Triiodothyronine Formation

Formation and Secretion of Thyroglobulin by the Thyroid Cells.

The thyroid cells are typical protein-secreting glandular cells. The endoplasmic reticulum and Golgi apparatus synthesize and secrete into the follicles a large glycoprotein molecule called thyroglobulin, with a molecular weight of about 335,000.

Each molecule of thyroglobulin contains about 70 tyrosine amino acids, and they are the major substrates that combine with iodine to form the thyroid hormones. Thus, the thyroid hormones are formed within the thyroglobulin molecule. That is, the thyroxine and triiodothyronine hormones formed from the tyrosine, remain part of the thyroglobulin molecule during synthesis of the thyroid hormones and even afterward as stored hormones in the follicular colloid.

Oxidation of the Iodide Ion. The first essential step in the formation of the thyroid hormones is conversion of the iodide ions to an oxidized form of iodine, either nascent iodine (I0) or I3, that is then capable of combining directly with the amino acid tyrosine. This oxidation of iodine is promoted by the enzyme peroxidase and its accompanying hydrogen peroxide, which provide a potent system capable of oxidizing iodides.

Iodination of Tyrosine and Formation of Thyroid Hormones—“Organification” of Thyroglobulin     The binding of iodine with the thyroglobulin molecule is called organification of the thyroglobulin. Oxidized iodine even in the molecular form will bind directly but very slowly with the amino acid tyrosine. In the thyroid cells, however, the oxidized iodine is associated with an iodinase enzyme that causes the process to occur within seconds or minutes.

Storage of Thyroglobulin. The thyroid gland is unusual among the endocrine glands in its ability to store large amounts of hormone. After synthesis of the thyroid hormones has run its course, each thyroglobulin molecule contains up to 30 thyroxine molecules and a few triiodothyronine molecules. In this form, the thyroid hormones are stored in the follicles in an amount sufficient to supply the body with its normal requirements of thyroid hormones for 2 to 3 months. Therefore, when synthesis of thyroid hormone ceases, the physiologic effects of deficiency are not observed for several months.

Release of Thyroxine and Triiodothyronine from the Thyroid Gland; Thyroglobulin itself is not released into the circulating blood in measurable amounts; instead, thyroxine and triiodothyronine must first be cleaved from the thyroglobulin molecule, and then these free hormones are released. This process occurs as follows: The apical surface of the thyroid cells sends out pseudopod extensions that close around small portions of the colloid to
form pinocytic vesicles that enter the apex of the thyroid cell. Then lysosomes in the cell cytoplasm immediately fuse with these vesicles to form digestive vesicles containing digestive enzymes from the lysosomes mixed with the colloid. Multiple proteases among the enzymes digest the thyroglobulin molecules and release thyroxine and triiodothyronine in free form. These then diffuse through the base of the thyroid cell into the surrounding capillaries. Thus, the thyroid hormones are released into the blood.

Transport of Thyroxine and Triiodothyronine to Tissues : On entering the blood, over 99 per cent of the thyroxine and triiodothyronine combines immediately with several of the plasma proteins, all of which are synthesized by the liver. They combine mainly with thyroxine-binding globulin and much less so with thyroxine-binding prealbumin and albumin.

Thyroxine and Triiodothyronine are Released Slowly to Tissue Cells. Because of high affinity of the plasma-binding proteins for the thyroid hormones, these substances— in particular, thyroxine—are released to the tissue cells slowly. Half the thyroxine in the blood is released to the tissue cells about every 6 days, whereas half the triiodothyronine—because of its lower affinity—is released to the cells in about 1 day. On entering the tissue cells, both thyroxine and triiodothyronine again bind with intracellular proteins, the thyroxine binding more strongly than the triiodothyronine. Therefore, they are again stored, but this time in the target cells themselves, and they are used slowly over a period of days or weeks.

Thyroid Hormones Have Slow Onset and Long Duration of Action.: After injection of a large quantity of thyroxine into a human being, essentially no effect on the metabolic rate can be discerned for 2 to 3 days, thereby demonstrating that there is a long latent period before thyroxine activity begins. Once activity does begin, it increases progressively and reaches a maximum in 10 to 12 days. Thereafter, it decreases with a half-life of about 15 days. Some of the activity persists for as long as 6 weeks to 2 months. The actions of T3 occur about four times as rapidly as those of thyroxine, with a latent period as short as 6 to 12 hours and maximal cellular activity occurring within 2 to 3 days.

Physiologic Functions of the Thyroid Hormones

Thyroid Hormones Increase the Transcription of Large Numbers of Genes

The general effect of thyroid hormone is to activate nuclear transcription of large numbers of genes. Therefore, in virtually all cells of the body, great numbers of protein enzymes, structural proteins, transport proteins, and other substances are synthesized. The net result is generalized increase in functional activity throughout the body.

Most of the Thyroxine Secreted by the Thyroid is Converted to Triiodothyronine: Before acting on the genes to increase genetic transcription, one iodide is removed from almost all the thyroxine, thus forming triiodothyronine. Intracellular thyroid hormone receptors have a very high affinity for triiodothyronine. Consequently, more than 90 per cent of the thyroid hormone molecules that bind with the receptors is triiodothyronine.

Thyroid Hormones Activate Nuclear Receptors: The thyroid hormone receptors are either attached to the DNA genetic strands or located in proximity to them. The thyroid hormone receptor usually forms a heterodimer with retinoid X receptor (RXR) at specific thyroid hormone response elements on the DNA. On binding with thyroid hormone, the receptors become activated and initiate the transcription process. Then large numbers of different types of messenger RNA are formed, followed within another few minutes or hours by RNA translation on the cytoplasmic ribosomes to form hundreds of new intracellular proteins. However, not all the proteins are increased by similar percentages—some only slightly, and others at least as much as six-fold. It is believed that most, if not all, of the actions of thyroid hormone result from the subsequent enzymatic and other functions of these new proteins.

Thyroid Hormones Increase Cellular Metabolic Activity: The thyroid hormones increase the metabolic activities of almost all the tissues of the body. The basal metabolic rate can increase to 60 to 100 per cent above normal when large quantities of the hormones are secreted. The rate of utilization of foods for energy is greatly accelerated. Although the rate of protein synthesis is increased, at the same time the rate of protein catabolism is also increased. The growth rate of young people is greatly accelerated. The mental processes are excited, and the activities of most of the other endocrine glands are increased.

Thyroid Hormones Increase the Number and Activity of Mitochondria. When thyroxine or T3 is given to an animal, the mitochondria in most cells of the animal’s body increase in size as well as number. Furthermore, the total membrane surface area of the mitochondria increases almost directly in proportion to the increased metabolic rate of the whole animal. Therefore, one of the principal functions of thyroxine might be simply to increase the number and activity of mitochondria, which in turn increases the rate of formation of ATP to energize cellular function. However, the increase in the number and activity of mitochondria could be the result of increased activity of the cells as well as the cause of the increase.

Thyroid Hormones increase Active Transport of Ions Through Cell Membranes: One of the enzymes that increases its activity in response to thyroid hormone is Na+-K+- ATPase. This in turn increases the rate of transport of both sodium and potassium ions through the cell membranes of some tissues. Because this process uses energy and increases the amount of heat produced in the body, it has been suggested that this might be one of the mechanisms by which thyroid hormone increases the body’s metabolic rate. In fact, thyroid hormone also causes the cell membranes of most cells to become leaky to sodium ions, which further activates the sodium pump and further increases heat production.

Regulation of Thyroid Hormone Secretion

To maintain normal levels of metabolic activity in the body, precisely the right amount of thyroid hormone must be secreted at all times; to achieve this, specific feedback mechanisms operate through the hypothalamus and anterior pituitary gland to control the rate of thyroid secretion. These mechanisms are as follows.

TSH (from the Anterior Pituitary Gland) increases Thyroid Secretion. TSH, also known as thyrotropin, is an anterior pituitary hormone, a glycoprotein with a molecular weight of about 28,000. This hormone increases the secretion of thyroxine and T3 by the thyroid gland. Its specific effects on the thyroid gland are as follows:

1. Increased proteolysis of the thyroglobulin that has already been stored in the follicles, with resultant release of the thyroid hormones into the circulating blood and diminishment of the
follicular substance itself.

2. Increased activity of the iodide pump, which increases the rate of “iodide trapping” in the
glandular cells, sometimes increasing the ratio of intracellular to extracellular iodide concentration in the glandular substance to as much as eight times normal.

3. Increased iodination of tyrosine to form the thyroid hormones.

4. Increased size and increased secretory activity of the thyroid cells.

5. Increased number of thyroid cells plus a change from cuboidal to columnar cells and much infolding of the thyroid epithelium into the follicles

In summary, TSH increases all the known secretory activities of the thyroid glandular cells. The most important early effect after administration of TSH is to initiate proteolysis of the thyroglobulin, which causes release of thyroxine and T3 into the blood within 30 minutes. The other effects require hours or even days and weeks to develop fully.

cAMP Mediates the Stimulatory Effect of TSH. In the past, it was difficult to explain the many and varied effects of TSH on the thyroid cell. It is now clear that most, if not all, of these effects result from activation of the “second messenger” cAMP system of the cell. The first event in this activation is binding of TSH with specific TSH receptors on the basal membrane surfaces of the thyroid cell. This then activates adenylyl cyclase in the membrane, which increases the formation of cAMP inside the cell. Finally, the cAMP acts as a second messenger to activate protein kinase, which causes multiple phosphorylations throughout the cell. The result is both an immediate increase in secretion of thyroid hormones and prolonged growth of the thyroid glandular tissue itself. This method for control of thyroid cell activity is similar to the function of cAMP as a “second messenger” in many other target tissues of the body.

Anterior Pituitary Secretion of TSH is Regulated by Thyrotropin-Releasing Hormone from the Hypothalamus: Anterior pituitary secretion of TSH is controlled by a hypothalamic hormone, thyrotropin-releasing hormone (TRH), which is secreted by nerve endings in the median eminence of the hypothalamus. From the median eminence, the TRH is then transported to the anterior pituitary by way of the hypothalamic hypophysial portal blood. TRH has been obtained in pure form. It is a simple substance, a tripeptide amide—pyroglutamyl-histidylproline-amide. TRH directly affects the anterior pituitary gland cells to increase their output of TSH. When the blood portal system from the hypothalamus to the anterior pituitary gland becomes blocked, the rate of secretion of TSH by the anterior pituitary decreases greatly but is not reduced to zero. The molecular mechanism by which TRH causes the TSH-secreting cells of the anterior pituitary to produce TSH is first to bind with TRH receptors in the pituitary cell membrane. This in turn activates the phospholipase second messenger system inside the pituitary cells to produce large amounts of phospholipase C, followed by a cascade of other second messengers, including calcium ions and diacyl glycerol, which eventually leads to TSH release.

Effects of Cold and Other Neurogenic Stimuli on TRH and TSH Secretion. One of the best known stimuli for increasing the rate of TRH secretion by the hypothalamus, and therefore TSH secretion by the anterior pituitary gland, is exposure of an animal to cold. This effect almost certainly results from excitation of the hypothalamic centers for body temperature control. Various emotional reactions can also affect the output of TRH and TSH and therefore indirectly affect the secretion of thyroid hormones. Excitement and anxiety—conditions that greatly stimulate the sympathetic nervous system—cause an acute decrease in secretion of TSH, perhaps because these states increase the metabolic rate and body heat and therefore exert an inverse effect on the heat control center.

Feedback Effect of Thyroid Hormone to Decrease Anterior Pituitary Secretion of TSH
Increased thyroid hormone in the body fluids decreases secretion of TSH by the anterior pituitary. When the rate of thyroid hormone secretion rises to about 1.75 times normal, the rate of TSH secretion falls essentially to zero. Almost all this feedback depressant effect occurs even when the anterior pituitary has been separated from the hypothalamus. So, it is probable that increased thyroid hormone inhibits anterior pituitary secretion of TSH mainly by a direct effect on the anterior pituitary gland itself. Regardless of the feedback mechanism, its effect is to maintain an almost constant concentration of free thyroid hormones in the circulating body fluids.

Antithyroid Substances: Drugs that suppress thyroid secretion are called antithyroid substances. The best known of these substances are thiocyanate, propylthiouracil, and high concentrations of inorganic iodides. The mechanism by which each of these blocks thyroid secretion is different from the others, and they can be explained as follows.

Thiocyanate Ions Decrease Iodide Trapping: The same active pump that transports iodide ions into the thyroid cells can also pump thiocyanate ions, perchlorate ions, and nitrate ions. Therefore, the administration of thiocyanate (or one of the other ions as well) in high enough
concentration can cause competitive inhibition of iodide transport into the cell— that is, inhibition of the iodide-trapping mechanism. The decreased availability of iodide in the glandular cells does not stop the formation of thyroglobulin; it merely prevents the thyroglobulin from becoming iodinated and therefore from forming the thyroid hormones. This deficiency of the thyroid hormones in turn leads to increased secretion of TSH by the anterior pituitary gland, which causes overgrowth of the thyroid gland even though the gland still does not form adequate quantities of thyroid hormones. Therefore, the use of thiocyanates and some other ions to block thyroid secretion can lead to development of an enlarged thyroid gland, which is called a goiter.

Propylthiouracil decreases Thyroid Hormone Formation. Propylthiouracil (and other, similar compounds, such as methimazole and carbimazole) prevents formation of thyroid hormone from iodides and tyrosine. The mechanism of this is partly to block the peroxidase enzyme that is required for iodination of tyrosine and partly to block the coupling of two iodinated tyrosines to form thyroxine or triiodothyronine. Propylthiouracil, like thiocyanate, does not prevent formation of thyroglobulin. The absence of thyroxine and T3 in the thyroglobulin can lead to tremendous feedback enhancement of TSH secretion by the anterior pituitary gland, thus promoting growth of the glandular tissue and forming a goiter.

Iodides in High Concentrations Decrease Thyroid Activity and Thyroid Gland Size: When iodides are present in the blood in high concentration (100 times the normal plasma level), most activities of the thyroid gland are decreased, but often they remain decreased for only a few weeks. The effect is to reduce the rate of iodide trapping, so that the rate of iodination of tyrosine to form thyroid hormones is also decreased.

Because iodides in high concentrations decrease all phases of thyroid activity, they slightly decrease the size of the thyroid gland and especially decrease its blood supply, in contradistinction to the opposite effects caused by most of the other antithyroid agents. For this reason, iodides are frequently administered to patients for 2 to 3 weeks before surgical removal of the thyroid gland to decrease the necessary amount of surgery, especially to decrease the amount of bleeding.

Diseases of the Thyroid

Hyperthyroidism: Causes (Toxic Goiter, Thyrotoxicosis, Graves’ Disease). In most patients with hyperthyroidism, the thyroid gland is increased to two to three times normal size, with tremendous hyperplasia and infolding of the follicular cell lining into the follicles, so that the number of cells is increased greatly. Also, each cell increases its rate of secretion several fold; radioactive iodine uptake studies indicate that some of these hyperplastic glands secrete thyroid hormone at rates 5 to 15 times normal. The changes in the thyroid gland in most instances are similar to those caused by excessive TSH. However, plasma TSH concentrations are less than normal rather than enhanced in almost all patients and often are essentially zero. However, other substances that have actions similar to those of TSH are found in the blood of almost all these patients. These substances are immunoglobulin antibodies that bind with the same membrane receptors that bind TSH. They induce continual activation of the cAMP system of the cells, with resultant development of hyperthyroidism. These antibodies are called thyroid-stimulating immunoglobulin and are designated TSI. They have a prolonged stimulating effect on the thyroid gland, lasting for as long as 12 hours, in contrast to a little over 1 hour for TSH. The high level of thyroid hormone secretion caused by TSI in turn suppresses anterior pituitary formation of TSH. The antibodies that cause hyperthyroidism almost certainly occur as the result of autoimmunity that has developed against thyroid tissue. Presumably, at some time in the history of the person, an excess of thyroid cell antigens was released from the thyroid cells, and this has resulted in the formation of antibodies against the thyroid gland itself.

Thyroid Adenoma. Hyperthyroidism occasionally results from a localized adenoma (a tumor) that develops in the thyroid tissue and secretes large quantities of thyroid hormone. This is different from the more usual type of hyperthyroidism, in that it usually is not associated with evidence of any autoimmune disease. An interesting effect of the adenoma is that as long as it continues to secrete large quantities of thyroid hormone, secretory function in the remainder of the thyroid gland is almost totally inhibited because the thyroid hormone from the adenoma depresses the production of TSH by the pituitary gland.

Symptoms of Hyperthyroidism: (1) a high state of excitability, (2) intolerance to heat,

(3) increased sweating, (4) mild to extreme weight loss (sometimes as much as 100 pounds),

(5) varying degrees of diarrhea, (6) muscle weakness, (7) nervousness or other psychic disorders, (8) extreme fatigue but inability to sleep, and (9) tremor of the hands.

Exophthalmos: Most people with hyperthyroidism develop some degree of protrusion of the eyeball. This condition is called exophthalmos. A major degree of exophthalmos occurs in about one third of hyperthyroid patients, and the condition sometimes becomes so severe that the eyeball protrusion stretches the optic nerve enough to damage vision. Much more often, the eyes are damaged because the eyelids do not close completely when the person blinks or is asleep. As a result, the epithelial surfaces of the eyes become dry and irritated and often infected, resulting in ulceration of the cornea.

Diagnostic Tests for Hyperthyroidism. For the usual case of hyperthyroidism, the most accurate diagnostic test is direct measurement of the concentration of “free” thyroxine (and sometimes triiodothyronine) in the plasma, using appropriate radioimmunoassay procedures. Other tests that are sometimes used are as follows:

1. The basal metabolic rate is usually increased to +30 to +60 in severe hyperthyroidism.
2. The concentration of TSH in the plasma is measured by radioimmunoassay. In the usual type of thyrotoxicosis, anterior pituitary secretion of TSH is so completely suppressed by the large amounts of circulating thyroxine and triiodothyronine that there is almost no plasma TSH.

3. The concentration of TSI is measured by radioimmunoassay. This is usually high in thyrotoxicosis but low in thyroid adenoma.

Physiology of Treatment in Hyperthyroidism. The most direct treatment for hyperthyroidism is surgical removal of most of the thyroid gland. In general, it is desirable to prepare the patient for surgical removal of the gland before the operation. This is done by administering propylthiouracil, usually for several weeks, until the basal metabolic rate of the patient has returned to normal. Then, administration of high concentrations of iodides for 1 to 2 weeks immediately before operation causes the gland itself to recede in size and its blood supply to diminish.

Treatment of the Hyperplastic Thyroid Gland with Radioactive Iodine: Eighty to 90 per cent of an injected dose of iodide is absorbed by the hyperplastic, toxic thyroid gland within 1 day after injection. If this injected iodine is radioactive, it can destroy most of the secretory cells of the thyroid gland. Usually 5 millicuries of radioactive iodine is given to the patient, whose condition is reassessed several weeks later. If the patient is still hyperthyroid, additional doses are administered until normal thyroid status is reached.

Hypothyroidism
The effects of hypothyroidism, in general, are opposite to those of hyperthyroidism, but there are a few physiologic mechanisms peculiar to hypothyroidism. Hypothyroidism, like hyperthyroidism, probably is initiated by autoimmunity against the thyroid gland, but immunity that destroys the gland rather than stimulates it. The thyroid glands of most of these patients first have autoimmune “thyroiditis,” which means thyroid inflammation.This causes progressive deterioration and finally fibrosis of the gland, with resultant diminished or absent secretion of thyroid hormone. Several other types of hypothyroidism also occur, often associated with development of enlarged thyroid glands, called thyroid goiter, as follows.

Endemic Colloid Goiter Caused by Dietary Iodide Deficiency. The term “goiter” means a greatly enlarged thyroid gland. As pointed out in the discussion of iodine metabolism, about 50 milligrams of iodine are required each year for the formation of adequate quantities of thyroid hormone. In certain areas of the world, notably in the Swiss Alps, the Andes, and the Great Lakes region of the United States, insufficient iodine is present in the soil for the foodstuffs to contain even this minute quantity. Therefore, in the days before iodized table salt, many people who lived in these areas developed extremely large thyroid glands, called endemic goiters. The mechanism for development of large endemic goiters is the following: Lack of iodine prevents production of both thyroxine and triiodothyronine. As a result, no hormone is available to inhibit production of TSH by the anterior pituitary; this causes the pituitary to secrete excessively large quantities of TSH. The TSH then stimulates the thyroid cells to secrete tremendous amounts of thyroglobulin colloid into the follicles, and the gland grows larger and larger. But because of lack of iodine, thyroxine and triiodothyronine production does not occur in the Thyroglobulin molecule and therefore does not cause the normal suppression of TSH production by the anterior pituitary. The follicles become tremendous in size, and the thyroid gland may increase to 10 to 20 times normal size.

Idiopathic Nontoxic Colloid Goiter. Enlarged thyroid glands similar to those of endemic colloid goiter can also occur in people who do not have iodine deficiency. These goitrous glands may secrete normal quantities of thyroid hormones, but more frequently, the secretion of hormone is depressed, as in endemic colloid goiter. The exact cause of the enlarged thyroid gland in patients with idiopathic colloid goiter is not known, but most of these patients show signs of mild thyroiditis; therefore, it has been suggested that the thyroiditis causes slight hypothyroidism, which then leads to increased TSH secretion and progressive growth of the noninflamed portions of the gland. This could explain why these glands usually are nodular, with some portions of the gland growing while other portions are being destroyed by thyroiditis. In some persons with colloid goiter, the thyroid gland has an abnormality of the enzyme system required for formation of the thyroid hormones. Among the abnormalities often encountered are the following:

1. Deficient iodide-trapping mechanism, in which iodine is not pumped adequately into the thyroid cells

2. Deficient peroxidase system, in which the iodides are not oxidized to the iodine state

3. Deficient coupling of iodinated tyrosines in the thyroglobulin molecule, so that the final thyroid hormones cannot be formed

4. Deficiency of the deiodinase enzyme, which prevents recovery of iodine from the iodinated tyrosines that are not coupled to form the thyroid hormones (this is about two thirds of the iodine), thus leading to iodine deficiency. Finally, some foods contain goitrogenic substances that have a propylthiouracil-type of antithyroid activity, thus also leading to TSH-stimulated enlargement of the thyroid gland. Such goitrogenic substances are found especially in some varieties of turnips and cabbages.

Physiologic Characteristics of Hypothyroidism. Whether hypothyroidism is due to thyroiditis, endemic colloid goiter, idiopathic colloid goiter, destruction of the thyroid gland by irradiation, or surgical removal of the thyroid gland, the physiologic effects are the same. They include fatigue and extreme somnolence with sleeping up to 12 to 14 hours a day, extreme muscular sluggishness, slowed heart rate, decreased cardiac output, decreased blood volume, sometimes increased body weight, constipation, mental sluggishness, failure of many trophic functions in the body evidenced by depressed growth of hair and scaliness of the skin, development of a froglike husky voice, and, in severe cases, development of an edematous appearance throughout the body called myxedema.

Myxedema: Myxedema develops in the patient with almost total lack of thyroid hormone function. In this condition, for reasons not explained, greatly increased quantities of hyaluronic acid and chondroitin sulfate bound with protein to form excessive tissue gel in the interstitial spaces, and this causes the total quantity of interstitial fluid to increase. Because of the gel nature of the excess fluid, it is mainly immobile, and the edema is the nonpitting type.

Atherosclerosis in Hypothyroidism. As pointed out earlier, lack of thyroid hormone increases the quantity of blood cholesterol because of altered fat and cholesterol metabolism and diminished liver excretion of cholesterol in the bile. The increase in blood cholesterol is usually associated with increased atherosclerosis. Therefore, many hypothyroid patients, particularly those with myxedema, develop atherosclerosis, which in turn results in peripheral vascular disease, deafness, and coronary artery disease with consequent early death.

Diagnostic Tests in Hypothyroidism: The tests already described for diagnosis of hyperthyroidism give opposite results in hypothyroidism. The free thyroxine in the blood is low. The basal metabolic rate in myxedema ranges between -30 and -50. And the secretion of TSH by the anterior pituitary when a test dose of TRH is administered is usually greatly increased (except in those rare instances of hypothyroidism caused by depressed response of the pituitary gland to TRH).

Treatment of Hypothyroidism. Figure 76–4 shows the effect of thyroxine on the basal metabolic rate, demonstrating that the hormone normally has a duration of action of more than 1 month. Consequently, it is easy to maintain a steady level of thyroid hormone activity in the body by daily oral ingestion of a tablet or more containing thyroxine. Furthermore, proper treatment of the hypothyroid patient results in such complete normality that formerly myxedematous patients have lived into their 90s after treatment for more than 50 years.

Cretinism

Cretinism is caused by extreme hypothyroidism during fetal life, infancy, or childhood. This condition is characterized especially by failure of body growth and by mental retardation. It results from congenital lack of a thyroid gland (congenital cretinism), from failure of the thyroid gland to produce thyroid hormone because of a genetic defect of the gland, or from iodine lack in the diet (endemic cretinism). The severity of endemic cretinism varies greatly, depending on the amount of iodine in the diet, and whole populaces of an endemic geographic iodine-deficient soil area have been known to have cretinoid tendencies. A neonate without a thyroid gland may have normal appearance and function because it was supplied with some (but usually not enough) thyroid hormone by the mother while in utero, but a few weeks after birth, the neonate’s movements become sluggish and both physical and mental growth begin to be greatly retarded. Treatment of the neonate with cretinism at any time with adequate iodine or thyroxine usually causes normal return of physical growth, but unless the cretinism is treated within a few weeks after birth, mental growth remains permanently retarded.This results from retardation of the growth, branching, and myelination of the neuronal cells of the central nervous system at this critical time in the normal development of the mental powers. Skeletal growth in the child with cretinism is characteristically more inhibited than is soft tissue growth. As a result of this disproportionate rate of growth, the soft tissues are likely to enlarge excessively, giving the child with cretinism an obese, stocky, and short appearance. Occasionally the tongue becomes so large in relation to the skeletal growth that it obstructs swallowing and breathing, inducing a characteristic guttural breathing that sometimes chokes the child.