THE THYROID GLAND

UPDATED SECOND EDITION
Walter F. Boron, MD, PhD Professor
David N. and Inez Myers/Antonio Scarpa Chairman Department of Physiology and Biophysics
Case Western Reserve University Cleveland, Ohio
Emile L. Boulpaep, MD Professor
Department of Cellular and Molecular Physiology Yale University School of Medicine
New Haven, Connecticut
AVISO LEGAL: ESTA INFORMACIÓN PUEDE SER UTILIZADA PARA FINES EDUCATIVOS EXCLUSIVAMENTE.
C H A P T E R 4 9
T H E T H Y R O I D G L A N D
Eugene J. Barrett
The thyroid gland is located in the anterior neck, lying like a small bow tie across the front of the trachea. In adults, the normal thyroid weighs ~20 g. It is composed of left and right lobes and a small connecting branch, or isthmus.
The thyroid gland possesses many features unique among endocrine glands, not the least of which is that it is the only endocrine gland that can be easily seen and palpated in the course of a routine clinical examination. At the biochemical level, the thyroid hormones are the only ones that require an essential trace element, iodine, for the production of active hormone. One of the rather unusual features of thyroid hormone physiology is that the hormone is stored in an extracellular site within a highly proteinaceous mate- rial called thyroid colloid. The major protein within this material is thyroglobulin, which contains—as part of its primary structure—the thyroid hormones thyroxine (tet- raiodothyronine or T4) and triiodothyronine (T3). These sequestered hormones are entirely surrounded by thyroid follicular cells, which are responsible for the synthesis of thyroid hormones (Fig. 49-1).
The physiological actions of thyroid hormones also display several unique aspects. Although, like most peptide hormones, T4 and T3 are made as part of a larger protein, unlike peptide hormones, no cell-membrane receptors exist for these hormones. Instead, like the steroid hormones, thyroid hormones act by binding to nuclear receptors (see Chapter 3) and regulate the transcription of cell proteins. The hormones secreted by the thyroid act on multiple tissues and are essential for normal development, growth, and metabolism. The thyroid makes another hormone, calcito- nin, which is synthesized by thyroid C cells (parafollicular cells); these C cells are not part of the follicular unit (Fig. 49-1). Calcitonin may play a role in Ca2+ and phosphate homeostasis. The physiology of calcitonin is discussed along with that of parathyroid hormone in Chapter 52.
SYNTHESIS OF THYROID HORMONES
Thyroid hormones are made by iodinating tyrosine residues on thyroglobulin and are stored as part of thyroglobulin molecules in thyroid follicles
The structures of T4 and T3, the two active thyroid hor- mones, are shown in Figure 49-2. T3 is far more active than
T4. Also shown is reverse T3 (rT3), which has no known biological activity. It has two iodines on its outer benzyl ring, rather than two on its inner ring, as is the case for T3. All three compounds derive from the ether linkage of a tyrosine molecule to the benzyl group of a second tyrosine molecule; one or two iodine atoms are attached to each benzyl group. The bottom panel of Figure 49-2 shows T4 as part of the thyroglobulin molecule.
The synthesis of thyroid hormones begins with the trap- ping of iodide by the thyroid gland. Iodine is essential for the formation of thyroid hormones. It exists in nature as a trace element in soil and is incorporated into many foods. The iodide anion (I−) is rapidly absorbed by the gastrointes- tinal tract and is actively taken up by the thyroid gland. A specialized Na/I cotransporter (NIS) is located at the baso- lateral membrane (i.e., facing the blood) of the thyroid fol- licular cell (Fig. 49-3). NIS (for Na Iodide Symporter) is a 65-kDa integral membrane protein that is believed to have 12 membrane-spanning segments. NIS moves I− into the follicular cell against the I− electrochemical gradient, fueled by the energy of the Na+ electrochemical gradient (see Chapter 5). Several other anions (e.g., perchlorate, pertech- netate, and thiocyanate) can compete with I− for uptake by the thyroid. Iodide leaves the follicular cell and enters the lumen of the follicle across the apical membrane. Pendrin, a member of the SLC26 family of anion exchangers (see Chapter 5), is present on the apical membrane and may contribute to I− secretion. Mutations in this protein can lead to a congenital syndrome typically characterized by a large thyroid gland (goiter) and hearing loss. The thyroid enlarges because of defi cient I− uptake, just as it would with an I−- defi cient diet (see the box titled Iodine Defi ciency).
In parallel with the secretion of I− into the follicle lumen, the follicular cell secretes thyroglobulin into the lumen; thy- roglobulin contains the tyrosyl groups to which the I− will ultimately attach. The thyroglobulin molecule is a glycopro- tein synthesized inside the follicular cell, following the secre- tory pathway (see Chapter 2). Thyroglobulin is a very large protein (>600 kDa), and it accounts for approximately half of the protein content of the thyroid gland. It has relatively few tyrosyl residues (~100/molecule of thyroglobulin), and only a few of these (<20) are subject to iodination. The secre- tory vesicles that contain thyroglobulin also carry the enzyme thyroid peroxidase on their intravesicular surfaces. As the secretory vesicles fuse with the apical membrane, this enzyme faces the follicular lumen and catalyzes the oxidation of I− to
1044
1045Chapter 49 • The Thyroid Gland
Isthmus
Red blood cell
Figure 49-1 Structure of the thyroid gland. The thyroid gland is located anterior to the cricoid cartilage in the anterior neck. The gland comprises numerous follicles, which are fi lled with colloid and lined by follicular cells. These follicular cells are responsible for the trap- ping of iodine, which they secrete along with thyroglobulin—the major protein of the thyroid colloid—into the lumen of the follicle.
HO O C C
B A
B A
HO C
AA
AA
Later, inside the lysosomes of the follicular cell, enzymes will cleave the two peptide bonds shown, releasing T4.
Peptide backbone of thyroglobulin molecule
Figure 49-2 The structure of T4, T3, and rT3. T4, T3, and rT3 all are products of the coupling of two iodinated tyrosine derivatives. Only T4 and T3 are biologically active, and T3 is far more active than T4 because of a higher affi nity for TRs. rT3 forms as an iodine is removed from the inner benzyl ring (labeled A) of T4; rT3 is present in approxi- mately equal molar amounts with T3. However, rT3 is essentially devoid of biological activity. As shown in the bottom panel, T4 is part of the peptide backbone of the thyroglobulin molecule, as are T3 and rT3. Cleavage of the two indicated peptide bonds would release T4.
I0. As the thyroglobulin is entering the lumen of the thyroid follicle by the process of exocytosis, its tyrosyl groups react with I0.
One or two oxidized iodine atoms incorporate selectively into specifi c tyrosyl residues of thyroglobulin. Within the thyroglobulin molecule, an internal rearrangement occurs, resulting in the conjugation of two iodinated tyrosyl residues to form a single iodothyronine, as well as a remnant dehy- droalanine. Both remain as part of the primary structure of the iodinated thyroglobulin until it is later degraded inside the follicular cell. This coupling of two tyrosines, catalyzed by thyroid peroxidase, does not occur unless they are iodin- ated. Because only a few tyrosyl groups become iodinated, something specifi c about the structure of the protein near these residues probably facilitates both iodination and con- jugation. The thyroid hormones, although still part of the thyroglobulin molecule, are stored as colloid in the thyroid follicle.
Follicular cells take up iodinated thyroglobulin, hydrolyze it, and release T4 and T3 into the blood for binding to thyroid-binding globulin and other proteins
While they are attached to thyroglobulin in the thyroid fol- licular lumen (Fig. 49-1), thyroid hormones remain inactive until the iodinated thyroglobulin is hydrolyzed. Before this
US O DI DÁ CT IC O
1046 Section VIII • The Endocrine System
proteolysis can begin, the follicular cells must resorb thyro- globulin from the follicular lumen by fl uid-phase endocyto- sis (see Chapter 2). As the endocytic vesicle containing the colloid droplet moves from the apical toward the basolateral membrane, it fuses with lysosomes to form a lysoendosome. Inside this vesicle, lysosomal enzymes hydrolyze the thyro- globulin and form T4 and T3, as well as diiodothyronine (DIT) and monoiodothyronine (MIT). The vesicle releases both T4 and T3 near the basolateral membrane, and these substances exit the cell into the blood by an unknown mech- anism. Approximately 90% of the thyroid hormone secreted by the thyroid is released as T4, and 10% is released as T3. The thyroid releases very little reverse T3 into the blood. As
discussed in the next section, nonthyroidal tissues metabo- lize the T4 released by the thyroid into T3 and rT3. Approxi- mately three fourths of circulating T3 arises from the peripheral conversion of T4, which occurs principally in the liver and kidneys.
In the circulation, both T4 and T3 are highly bound to plasma proteins. Thyroid-binding globulin (TBG), albumin, and transthyretin (TTR) account for most of this binding. The affi nity of these binding proteins is suffi ciently high that, for T4, more than 99.98% of the hormone circulates tightly bound to protein. T3 is bound only slightly less: ~99.5% is protein bound. Because the free or unbound hormone in the circulation is responsible for the actions of the thyroid hor-
Pendrin
te rs
tit ia
I–
I–
(Iodide)
I–
I0
(Iodine)
Trapping: TSH increases the activity of a Na/I cotransporter (NIS) on the basolateral membrane of the thyroid follicular cell. The result is increased iodine trapping: the ratio of follicular-cell iodine to plasma iodine (the so-called thyroid/serum or T/S ratio) increases under conditions of high TSH.
1
Iodide leaves the cell, probably via pendrin, and enters the lumen. The follicular cell also secretes thyroglobulin. Thyroid peroxidase, on the luminal surface of secretory vesicle, oxidizes I– to I 0.
2
Endocytosis: TSH stimulates the endocytosis of iodinated thyroglobulin into the follicular cells from thyroid colloid.
5
6
Secretion: TSH stimulates the secretion of T4 and T3 into the circulation.
7
NIS
T4 T3
DIT MIT
Conjugation: TSH stimulates the conjugation of iodinated tyrosines to form T4 and T3 linked to thyroglobulin.
4
Iodination: TSH also stimulates iodination of thyroglobulin in the follicular lumen.
3
Iodine
Blood
Deiodinase
Figure 49-3 The follicular cell and its role in the synthesis of T4 and T3. The synthesis and release of T4 and T3 occurs in seven steps. Inside the follicular cell, a deiodinase converts some of the T4 to T3. Thyrotropin (or TSH) stimulates each of these steps except step 2. In addition, TSH exerts a growth factor or hyperplastic effect on the follicular cells.
US O DI DÁ CT IC O
1047Chapter 49 • The Thyroid Gland
mones on their target tissues, the large amount of bound hormone has considerably confounded our ability to use simple measurements of the total amount of either T4 or T3 in the plasma to provide a reliable index of the adequacy of thyroid hormone secretion. For example, the amount of TBG in the serum can change substantially in different phys- iological states. Pregnancy, oral estrogen therapy, hepatitis, and chronic heroin abuse can all elevate the amount of TBG and hence the total concentration of T4 and T3. Decreased levels of TBG, associated with diminished concentration of total T4 and T3, can accompany steroid usage and the nephrotic syndrome. However, despite the marked increases or decreases in the amounts of circulating TBG, the concen- trations of free T4 and T3 do not change in the aforemen- tioned examples. The box titled Free Versus Bound Thyroxine indicates how one can calculate levels of free T4 or T3, knowing the concentration of TBG and the concentration of total T4 or total T3.
The liver makes each of the thyroid-binding proteins. TBG is a 54-kDa glycoprotein consisting of 450 amino acids. It has the highest affi nity for T4 and T3 and is responsible for most of the thyroid-binding capacity in the plasma. The extensive binding of thyroid hormones to plasma proteins serves several functions. It provides a large buffer pool of
thyroid hormones in the circulation, so that the active con- centrations of hormone in the circulation change very little on a minute-to-minute basis. The binding to plasma pro- teins markedly prolongs the half-lives of both T4 and T3. T4 has a half-life of 8 days, and T3 has a half-life of ~24 hours; each is longer than the half-life of the steroid or peptide hormones. Finally, because much of the T3 in the circulation is formed by the conversion of T4 to T3 in extrathyroidal tissues, the presence of a large pool of T4 in the plasma pro- vides a reserve of prohormone available for synthesis of T3. This reserve may be of particular importance because T3 is responsible for most of the biological activity of thyroid hormones.
Peripheral tissues deiodinate T4 to produce T3
The thyroid synthesizes and stores much more T4 than T3, and this is refl ected by the ~10 : 1 ratio of T4/T3 secreted by the thyroid. However, certain tissues in the body have the capacity to selectively deiodinate T4, thereby producing either T3 or rT3. T3 and rT3 can each be further deiodinated
Iodine Defi ciency
In areas where soil is relatively iodine defi cient, human iodine defi ciency is common. Because seawater and seafood contain large amounts of iodide, iodine defi -
ciency is more common in inland areas, particularly in locales that rely on locally grown foods. For example, in inland areas of South America along the Andes Mountains, in central Africa, and in highland regions of Southeast Asia, iodine defi ciency is common. In the early 1900s, investiga- tors fi rst recognized that iodide was present in high concen- trations in the thyroid and that iodine defi ciency promoted goiter formation. These observations led to efforts to supple- ment dietary iodine. Iodine defi ciency causes thyroid hormone defi ciency. The pituitary responds to this defi cit by increasing the synthesis of thyrotropin (or TSH), which, in turn, increases the activity of the iodine-trapping mechanism in the follicular cell in an effort to overcome the defi ciency. The increased TSH also exerts a trophic effect that increases the size of the thyroid gland. If this trophic effect persists for suffi cient time, the result is an iodine-defi cient goiter. The word goiter is simply a generic term for an enlarged thyroid. If this effort at compensation is not successful (i.e., if insuffi cient thyroid hormone levels persist), the person will develop signs and symptoms of goitrous hypothyroidism. When iodine defi ciency occurs at critical developmental times in infancy, the effects on the CNS are particularly devastating and produce the syndrome known as cretin- ism. Persons so affected have a characteristic facial appear- ance and body habitus, as well as severe mental retardation. Dietary supplementation of iodine in salt and bread has all but eliminated iodine defi ciency from North America. In many nations, especially in mountainous and landlocked regions of developing nations, iodine defi ciency remains a major cause of preventable illness.
Free Versus Bound Thyroxine
Most of the T4 and T3 in the serum is bound to pro- teins, the most important of which is TBG. For the binding of T4 to TBG, the reaction is as follows:
T TBG T TBGK 4 4+ ← →
K T TBG
4
4
[ ] [ ]
FREE4 4=
[ ] ( )
( ) ( )
.
= × ⋅
= × =
−
−
Because the bound T4 in this example is 100 nM, and the free T4 is only 20 pM, we can conclude that only ~0.02% of the total T4 in the plasma is free. Because 99.98% of the total T4 in the plasma is bound, moderate fl uctuations in the rate of T4 release from the thyroid have only tiny effects on the level of free T4. To simplify, we have not included the minor contribution of albumin and TTR in this sample calculation.
US O DI DÁ CT IC O
1048 Section VIII • The Endocrine System
to various DITs and MITs (Fig. 49-4); both DITs and MITs are biologically inactive. Both iodine atoms on the inner ring, and at least one iodine atom on the outer ring, appear essential for biological activity. Similarly, the loss of the amino group renders T4 or T3 inactive. The importance of the peripheral deiodination of T4 to T3 can be readily appre- ciated from the observation that persons whose thyroids have been removed have normal circulating concentrations of T3 when they receive oral T4 supplementation.
Inasmuch as T3 is biologically much more active than the far more abundant T4, the regulation of the conversion of T4 to T3 in peripheral tissues assumes considerable importance. Two distinct deiodinases convert T4 to T3 (Fig. 49-4): The 5′/3′-deiodinase removes an I from the outer ring, thus pro- ducing T3, whereas the 5/3-deiodinase removes an I from the inner ring, thereby producing the inactive rT3. Because the 3′ and 5′ positions in T4 are equivalent stereochemically, removal of either of these yields T3. Similarly, removing the I from either the 3 or the 5 position of the inner ring of T4 yields rT3. Further deiodination by these two enzymes ulti- mately yields T0 (i.e., thyronine).
The 5′/3′-deiodinase, which acts on the outer ring, comes in two forms. Type 1 is present in high concentrations in the liver, kidneys, and thyroid. It appears to be responsible for generating most of the T3 that reaches the circulation. Type 2 is found predominantly in the pituitary, central nervous system (CNS), and placenta and is involved in supplying those tissues with T3 by local generation from plasma-derived T4. As shown later, the type 2 enzyme in the pituitary is of particular importance because the T3 that is generated there is responsible for the feedback inhibition of the release of thyrotropin (or thyroid-stimulating hormone, TSH).
The relative activity of the deiodinases changes in response to physiological and pathologic stimuli. Caloric restriction or severe stress inhibits the type 1 outer ring deiodinase; this process decreases the conversion of T4 to T3—and thus
reduces the levels of T3. In contrast, levels of rT3 rise by default in these situations, in part because of reduced con- version to DITs. These decreases in T3 levels are accompa- nied by a decline in metabolic rate. You may think that because plasma levels of T3 fall, there would be a compensa- tory rise in TSH, the secretion of which is inhibited by T3. However, because type 2 deiodinase mediates the conversion of T4 to T3 within the pituitary and CNS, and because caloric restriction does not affect this enzyme, local T3 levels in the pituitary are normal. Thus, the thyrotrophs in the pituitary continue to have adequate amounts of T3, and no compensa- tory rise in TSH occurs. Teleologically, the rationale to restrain calorie expenditure in settings of decreased caloric intake is appealing.
ACTION OF THYROID HORMONES
Thyroid hormones act through nuclear receptors in target tissues
Thyroid hormones act on many body tissues to exert both metabolic and developmental effects. Most, if not all, of the actions of thyroid hormones occur as thyroid hormones bind to and activate nuclear receptors (see Chapter 3). These receptors, in turn, are bound to chromatin and alter the transcription of specifi c genes. The multitude of thyroid hormone actions is mirrored by the ubiquitous expression of thyroid hormone receptors (TRs) throughout the body’s tissues. Once T4 and…