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Two types of Thyroid Hormone
- As mentioned earlier, the thyroid gland produces two iodine containing molecules of physiological importance, thyroxine (called T4 because it contains four iodines) and triiodothyronine (T3, three iodines; review Figure 11.3).
- Most T4 is converted to T3 in target tissues by enzymes known as deiodinases.
- We will therefore consider T3 to be the major thyroid hormone, even though the concentration of T4 in the blood is usually greater than that of T3. (You may think of T4 as a sort of reservoir for additional T3.)
- For practical reasons, T4 is typically prescribed in situations where thyroid function is decreased in a person for any reason.
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Thyroid gland location + follicles
- The thyroid gland sits within the neck in front of and straddling the trachea.
 - It first becomes functional early in fetal life.
- Within the thyroid gland are numerous follicles, each composed of an enclosed sphere of epithelial cells surrounding a core containing a protein rich material called the colloid (Figure 11.21b).
- The follicular epithelial cells participate in almost all phases of thyroid hormone synthesis and secretion.
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Synthesis of thyroid hormones- step 1-4
- Step 1: Synthesis begins when circulating iodide is actively cotransported with sodium ions across the basolateral membranes of the epithelial cells, a process known as iodide trapping.
- The Na+ is pumped back out of the cell by Na+/K+-ATPases.
- Step 2: The negatively charged iodide ions diffuse to the apical membrane of the follicular epithelial cells and are transported into the colloid by an integral membrane protein called pendrin (step 2). Pendrin is a sodium-independent chloride/iodide transporter.
- The colloid of the follicles contains large amounts of a protein called thyroglobulin.
- Step 3: Once in the colloid, iodide is rapidly oxidized at the luminal surface of the follicular epithelial cells to iodine, which is then attached to the phenolic rings of tyrosine residues within thyroglobulin (step 3).
- Thyroglobulin itself is synthesized by the follicular epithelial cells and secreted by exocytosis into the colloid.
- The enzyme responsible for oxidizing iodides and attaching them to tyrosines on thyroglobulin in the colloid is called thyroid peroxidase, and it, too, is synthesized by follicular epithelial cells.
- Iodine may be added to either of two positions on a given tyrosine within thyroglobulin.
- A tyrosine with one iodine attached is called monoiodotyrosine (MIT); if two iodines are attached, the product is diiodotyrosine (DIT).
- Step 4: Next, the phenolic ring of a molecule of MIT or DIT is removed from the remainder of its tyrosine and coupled to another DIT on the thyroglobulin molecule (step 4).
- This reaction may also be mediated by thyroid peroxidase.
- If two DIT molecules are coupled, the result is thyroxine (T4).
- If one MIT and one DIT are coupled, the result is T3.
- Therefore, the synthesis of T4 and T3 is unique in that it actually occurs in the extracellular (colloidal) space within the thyroid follicles
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Synthesis of thyroid hormones- step 4-7
- Step 5: Finally, for thyroid hormone to be secreted into the blood, extensions of the colloid-facing membranes of follicular epithelial cells engulf portions of the colloid (with its iodinated thyroglobulin) by endocytosis (step 5).
- Step 6: The thyroglobulin, which contains T4 and T3, is brought into contact with lysosomes in the cell interior (step 6).
- Step 7: Proteolysis [the breakdown of proteins] of thyroglobulin releases T4 and T3, which then diffuse out of the follicular epithelial cell (likely with the aid of membrane-bound transporters) into the interstitial fluid and from there to the blood (step 7).
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Stored iodinated thyroglobulin within the follicles of the thyroid
- There is sufficient iodinated thyroglobulin stored within the follicles of the thyroid to provide thyroid hormone for several weeks even in the absence of dietary iodine.
- This storage capacity makes the thyroid gland unique among endocrine glands but is an essential adaptation considering the unpredictable intake of iodine in the diets of most animals.
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Important example of the general principle of physiology that controlled exchange of materials occurs between compartments and across cellular membranes.
- The processes shown in Figure 11.22 [synthesis of thyroid hormones] are an important example of the general principle of physiology that controlled exchange of materials occurs between compartments and across cellular membranes.
- A pump is necessary to transport iodide from the interstitial space against a concentration gradient across the cell membrane into the cytosol of the follicular cell, and pendrin is necessary to mediate the efflux of iodide from the cytoplasm into the colloidal space.
- These processes can be exploited clinically by administering very low doses of radioactive iodine to a patient suspected of having thyroid disease.
- The radioactive iodine is concentrated in the thyroid gland, allowing the gland to be visualized by a nuclear medicine scan.
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11.10 Control of Thyroid Function
- Essentially all of the actions of the follicular epithelial cells just described are stimulated by thyroid stimulating hormone (TSH), which, as we have seen, is stimulated by Thyrotropin-releasing hormone (TRH).The basic control mechanism of TSH production is the negative feedback action of T3 and T4 on the anterior pituitary gland and, to a lesser extent, the hypothalamus (Figure 11.23).
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- However, TSH does more than just stimulate T3 and T4 production.
- TSH also increases protein synthesis in follicular epithelial cells, increases DNA replication and cell division, and increases the amount of rough endoplasmic reticulum and other cellular machinery required by follicular epithelial cells for protein synthesis.
- Therefore, if thyroid cells are exposed to greater TSH concentrations
- than normal, they will undergo hypertrophy; that is, they will increase in size.
- An enlarged thyroid gland from any cause is called a goiter. There are several other ways in which goiters can occur that will be described later in this section and in one of the case studies in Chapter 19.
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11.11 Actions of Thyroid Hormone
- Receptors for thyroid hormone are present in the nuclei of most of the cells of the body, unlike receptors for many other hormones, whose distribution is more limited.
- Therefore, the actions of T3 are widespread and affect many organs and tissues.
- Like steroid hormones, T3 acts by inducing gene transcription and protein synthesis.
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Actions of T3 on Metabolic Actions
- T3 has several effects on carbohydrate and lipid metabolism, although not to the extent as other hormones such as insulin.
- Nonetheless, T3 stimulates carbohydrate absorption from the small intestine and increases fatty acid release from adipocytes.
- These actions provide energy that helps maintain metabolism at a high rate.
- Much of that energy is used to support the activity of Na+/ K+-ATPases throughout the body; these enzymes are stimulated by T3.
- The cellular concentration of ATP, therefore, is critical for the ability of cells to maintain Na+/K+-ATPase activity in response to thyroid hormone stimulation.
- ATP concentrations are controlled in part by a negative feedback mechanism; ATP negatively feeds back on the glycolytic enzymes within cells that participate in ATP generation.
- A decrease in cellular stores of ATP, therefore, releases the feedback and triggers an increase in glycolysis; this results in the metabolism of additional glucose that restores ATP concentrations.
- One of the by-products of this process is heat. Thus, as ATP is consumed in cells by Na+/K+-ATPases at a high rate due to T3 stimulation, the cellular stores of ATP must be maintained by increased metabolism of fuels.
- This calorigenic action of T3 represents a significant fraction of the total heat produced each day in a typical person.
- This action is essential for body temperature homeostasis, just one of many ways in which the actions of thyroid hormone demonstrate the general principle of physiology that homeostasis is essential for health and survival.
- Without thyroid hormone, heat production would decrease and body temperature (and most physiological processes) would be compromised.
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T3 permissive actions
- Some of the actions of T3 are attributable to its permissive effects on the actions of catecholamines [hormones made by your adrenal glands]
- T3 up-regulates beta-adrenergic receptors in many tissues, notably the heart and nervous system.
- It should not be surprising, therefore, that the symptoms of excess thyroid hormone concentration closely resemble some of the symptoms of excess epinephrine and norepinephrine (sympathetic nervous system activity).
- That is because the increased T3 potentiates the actions of the catecholamines, even though the latter are within normal concentrations.
- Because of this potentiating effect, people with excess T3 are often treated with drugs that block betaadrenergic receptors to alleviate the anxiety, nervousness, and “racing heart” associated with excessive sympathetic activity
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Actions of T3 on Growth and development-
- T3 is required for normal production of growth hormone from the anterior pituitary gland.
- Therefore, when T3 is very low, growth in children is decreased.
- In addition, T3 is a very important developmental hormone for the nervous system.
- T3 exerts many effects on the central nervous system during development, including the formation of axon terminals and the production of synapses, the growth of dendrites and dendritic extensions (called “spines”), and the formation of myelin.
- Absence of T3 results in the syndrome called congenital hypothyroidism.
- This syndrome is characterized by a poorly developed nervous system and severely compromised intellectual function (mental retardation).
- In the United States, the most common cause is the failure of the thyroid gland to develop normally. With neonatal screening, it can be treated with
- T4 at birth which prevents long-term impairment of growth and mental development.
- The most common cause of congenital hypothyroidism around the world (although rare in the United States) is dietary iodine deficiency in the mother. Without iodine in her diet, iodine is not available to the fetus. Thus, even though the fetal thyroid gland may be normal, it cannot synthesize sufficient thyroid hormone.
- If the condition is discovered and corrected with iodine and thyroid hormone administration shortly after birth, mental and physical abnormalities can be minimized.
- If the treatment is not initiated in the neonatal period, the intellectual impairment resulting from congenital hypothyroidism cannot be reversed.
- The availability of iodized salt products has essentially eliminated congenital hypothyroidism in many countries, but it is still a common disorder in some parts of the world where iodized salt is not available.
- The effects of T3 on nervous system function are not limited to fetal and neonatal life. For example, T3 is required for proper nerve and muscle reflexes and for normal cognition in adults.
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11.12 Hypothyroidism
- Hypothyroidism: Any condition characterized by plasma concentrations of thyroid hormones that are chronically below normal.
- Most cases of hypothyroidism—about 95%—are primary defects resulting from damage to or loss of functional thyroid tissue or from inadequate iodine consumption.
- In iodine deficiency, the synthesis of thyroid hormone is compromised, leading to a decrease in the plasma concentration of this hormone.
- This, in turn, releases the hypothalamus and anterior pituitary gland from negative feedback inhibition.
- This leads to an increase in TRH concentration in the portal circulation that drains into the anterior pituitary gland.
- Plasma TSH concentration is increased due to the increased TRH and loss of thyroid hormone negative feedback on the anterior pituitary gland.
- The resulting overstimulation of the thyroid gland can produce goiters that can achieve astounding sizes if untreated (Figure 11.24).
- This form of hypothyroidism is reversible if iodine is added to the diet.
- It is rare in the United States because of the widespread use of iodized salt, in which a small fraction of NaCl molecules is replaced with NaI.
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The most common cause of hypothyroidism in the United
States
- The most common cause of hypothyroidism in the United States is autoimmune disruption of the normal function of the thyroid gland, a condition known as autoimmune thyroiditis.
- One form of autoimmune thyroiditis results from Hashimoto’s disease, in which cells of the immune system attack thyroid tissue.
- Like many other autoimmune diseases, Hashimoto’s disease is more common in women and can slowly progress with age.
- As thyroid hormone begins to decrease because of the decrease in thyroid function due to inflammation of the gland, TSH concentrations increase due to the decreased negative feedback.
- The consequent overstimulation of the thyroid gland results in cellular hypertrophy, and a goiter can develop.
- The usual treatment for autoimmune thyroiditis is daily replacement with a pill containing T4.
- This causes the TSH concentration to decrease to normal due to negative feedback.
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Secondary hypothyroidism
- Another cause of hypothyroidism can occur when the release of TSH from the anterior pituitary is inadequate for long periods of time.
- This is called secondary hypothyroidism and can lead to atrophy of the thyroid gland due to the long-term loss of the trophic effects of TSH.
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Features of hypothyroidism in adults
- The features of hypothyroidism in adults may be mild or severe, depending on the degree of hormone deficiency.
- These include an increased sensitivity to cold (cold intolerance) and a tendency toward weight gain.
- Both of these symptoms are related to the decreased calorigenic actions normally produced by thyroid hormone.
- Many of the other symptoms appear to be diffuse and nonspecific, such as fatigue and changes in skin tone, hair, appetite, gastrointestinal function, and neurological function (for example, depression).
- The basis of the last effect in humans is uncertain, but it is now clear from work on laboratory animals that thyroid hormone has widespread effects on the adult mammalian brain.
- In severe, untreated hypothyroidism, certain hydrophilic polymers called glycosaminoglycans accumulate in the interstitial space in scattered regions of the body.
- Normally, thyroid hormone acts to prevent overexpression of these extracellular compounds that are secreted by connective tissue cells.
- When T3 is too low, therefore, these hydrophilic molecules accumulate and water tends to be trapped with them.
- This combination causes a characteristic puffiness of the face and other regions that is known as myxedema.
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Hyperthyroidism
- There are a variety of ways in which hyperthyroidism, or thyrotoxicosis, can develop.
- Among these are hormone-secreting tumors of the thyroid gland (rare), but the most common form of hyperthyroidism is an autoimmune disease called Graves’ disease.
- This disease is characterized by the production of antibodies that bind to and activate the TSH receptors on thyroid gland cells, leading to chronic overstimulation of the growth and activity of the thyroid gland
- The signs and symptoms of thyrotoxicosis can be predicted in part from the previous discussion about hypothyroidism.
- Hyperthyroid patients tend to have heat intolerance, weight loss, and increased appetite, and often show signs of increased sympathetic nervous system activity (anxiety, tremors, jumpiness, increased heart rate).
- Hyperthyroidism can be very serious, particularly because of its effects on the cardiovascular system (largely secondary to its permissive actions on catecholamines).
- It may be treated with drugs that inhibit thyroid hormone synthesis, by surgical removal of the thyroid gland, or by destroying a portion of the thyroid gland using radioactive iodine.
- In the last case, the radioactive iodine is ingested. Because the thyroid gland is the chief region of iodine uptake in the body, most of the radioactive iodine appears within the gland, where its high-energy radiation partly destroys the tissue.
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