Delbert A. Fisher
EMBRYOLOGY
The thyroid gland develops as an endodermal diverticular outpouching from the floor of the pharynx during the third week of gestation, at a site that persists as the foramen cecum at the base of the tongue in adults. The medial thyroid anlage descends in the neck anterior to structures that form the hyoid bone and larynx. During its descent, the anlage remains connected to the foramen cecum via an epithelial-lined tube known as the thyroglossal duct. The epithelial cells making up the anlage give rise to the thyroid follicular cells. Paired lateral anlages originate from the fourth branchial pouch and fuse with the median anlage at approximately the fifth week of gestation. The lateral anlages are neuroectodermal in origin (ultimobranchial bodies) and provide the calcitonin-producing parafollicular or C cells, which come to lie in the superoposterior region of the gland. Thyroid follicles are initially apparent by 8 weeks, and colloid formation begins by the 11th week of gestation. The growth and descent of the thyroid into the neck requires the coordinated action of multiple transcription factors. TTF-1, TTF-2, and PAX-8 are expressed just before and after the appearance of the thyroid diverticulum. Targeted disruption of the TTF-1 gene in mice results in complete absence of the thyroid gland, whereas disruption of PAX-8 results in a small thyroid that lacks follicles.
The thyroid forms bilateral lobes connected by an isthmus in the middle, typically just below the cricoid cartilage. In about 50% of individuals, there is a pyramidal lobe in the midline that represents the most caudal end of the thyroglossal duct. Persistence of the thyroglossal duct results in formation of a thyroglossal cyst. Lack of descent leads to a lingual thyroid.
THYROID HORMONE
Metabolism of Dietary Iodine
The major substrates for thyroid hormone synthesis are iodide and the amino acid tyrosine. Iodine is absorbed from the upper gastrointestinal tract, where it is distributed within the extrathyroidal iodide pool.1,2 The rate of thyroid iodide trapping is inversely related to the rate of renal iodide excretion. Iodide is excreted largely in urine through glomerular filtration.
Biosynthesis of Thyroid Hormone
Iodide is transported across the cell membrane into the thyroid follicular cell by a sodium-iodide symporter (NIS). The symporter normally generates a thyroid to a serum concentration gradient of 30- to 40-fold. This gradient can reach several hundredfold when the thyroid gland is stimulated by a low iodine diet, by thyroid-stimulating hormone (TSH), or by thyroid-stimulating immunoglobulins in Graves disease. The iodide traverses the cell from the plasma membrane to the apical membrane, where it is transported out of the cell by a chloride-iodide transport protein referred to as Pendrin.1,2 Pendrin is localized to the apical membrane near the complex of thyroid peroxidase (TPO) and two nicotinamide adenosine dinucleotide phosphate (NADPH) oxidases (THOX1 and THOX2), which catalyze iodine organification (Fig. 526-1). Thyroglobulin is the essential substrate for iodide organification. Iodide is oxidized to an active intermediate followed by iodination of thyroglobulin-bound tyrosyl residues to form monoiodinated and diiodinated tyrosine (MIT and DIT). Both iodide oxidation and organification are catalyzed by the TPOTHOX complex.
FIGURE 526-1. Steps in the biosynthesis, storage (as follicular colloid), and secretion of thyroid hormones. The synthesis, organification, and degradation of thyroglobulin occur within the same thyroid follicular cell. Thyroid-stimulating hormone (TSH) via the G-protein–coupled TSH receptor stimulates iodide trapping via the sodium-iodide symporter in the basal membrane, thyroglobulin synthesis, and thyroglobulin endocytosis and degradation. Organ-ification of iodide within thyroglobulin occurs at the apical membrane where the chloride-iodide transporter Pendrin (Pen) delivers iodide to the thyroid peroxidase (TPO) nicotinamide adenosine dinucleotide phosphate (NADPH) oxidase (THOX) complex. Iodide, derived from iodotyrosine deiodinase–mediated deiodination of mono- and diiodotyrosine (MIT, DIT), is recycled within the gland. Secretion products include thyroxine (T4), triiodothyronine (T3), MIT, and DIT. Thyroglobulin also reaches the circulation, probably largely via the thyroid lymphatics.
Secretion of Thyroid Hormones
Thyroglobulin is stored in colloid, and before thyroid hormones are released, the colloid must be ingested by the follicular cell.1,3-6 Ingested colloid droplets fuse with proteolytic enzyme-containing lysosomes to form phagolysosomes, where thyroglobulin hydrolysis occurs. The free monoiodinated tyrosine (MIT), diiodinated tyrosine (DIT), T3, and T4 within the phagolysosomes are released into the cytoplasm and diffuse into blood (Fig. 526-1). The MIT and DIT released during hydrolysis of thyroglobulin are largely deiodinated under the influence of an iodotyrosine deiodinase.1,3-5 Most of the released iodide is reused for new hormone synthesis. The loss from the thyroid gland of this normally recycled iodine, amounting to 70% to 80% of the daily thyroidal iodine supply, can cause iodine deficiency and variable degrees of hypothyroidism.
Regulation of Thyroid Function
Thyroid gland biosynthesis and secretion are regulated by thyroid-stimulating hormone (TSH).1,7-9 TSH activates follicular cell adenylate cyclase and stimulates production of intracellular cyclic adenosine monophosphate (cAMP), which mediates iodide trapping, iodothyronine synthesis, thyroglobulin synthesis, glucose oxidation, pinocytosis, hormone release, and thyroid growth.1,7,8
The hypothalamus controls the secretion of TSH by the pituitary gland. Removal of the pituitary gland causes thyroid atrophy, but thyroid cell integrity and function are maintained at a basal level. Secretion of TSH is regulated by thyrotropin-releasing hormone (TRH), a tripeptide synthesized in the hypothalamus and secreted into the pituitary portal vascular system for transport to the anterior pituitary thyrotroph cell. TRH production is regulated by environmental temperature; decreasing environmental and body temperatures increase TRH secretion and increase the tonic level of TSH release. Somatostatin and dopamine can inhibit TSH release by actions at the pituitary level. Norepinephrine, glucocorticoids, and serotonin can also inhibit TSH release.
TSH secretion is characterized by centrally mediated pulsatile and circadian variation. Low amplitude pulsatile peaks occur at 1- to 2-hour intervals. The diurnal variation in children is characterized by a peak in serum TSH at 10 to 11 pm with nadir values at 2 to 6 pm. The absence of the nocturnal TSH surge in children is associated with an approximate 30% reduction in serum T4, T3, and FT4 levels.1,9Superimposed on the central hypothalamic control is a negative feedback action of thyroid hormones to maintain the normal resting levels of free thyroid hormones within narrow limits. Hypothalamic and pituitary iodothyronine monodeiodinase (MDI) deiodinates T4 to T3, which, with circulating free T3 acts via thyroid hormone receptors in the TRH neurons and pituitary thyrotroph cells to continually modulate TRH, TSH, and thyroid hormone secretion to maintain free hormone levels at or near the individual “set pointî” Fig. 526-2).
Transport and Distribution of Thyroid Hormones
Both T3 and T4 are present in blood in association with plasma proteins. The thyroid gland is the sole source of T4, but most of the T3 in blood is derived from nonglandular sources through monodeiodination of T4 in peripheral tissues.1,3-5 The concentration of T4 in human blood is 50 to 100 times greater than that of T3. The concentrations of both are relatively constant in the steady state. Average values for children relative to age are shown in Table 526-1. The circulating thyroid hormone-binding proteins include thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (transthyretin), and albumin. The binding reactions are such that the euthyroid steady-state concentrations of free T4 and free T3 approximate 0.03% and 0.30%, respectively, of the total hormone concentrations. Absolute mean free T4 and T3concentrations approximate 2.0 and 0.30 ng/dL, respectively (25.7 and 4.6 pmol/L).
Metabolism of Thyroid Hormones
Deiodination is the main pathway of thyroid hormone metabolism mediated by iodothyro-nine monodeiodinase (MDI) enzymes.1,3,10,11 Circulating free T4 enters peripheral tissues where it is enzymatically monodeiodinated (Fig. 526-3). Three iodothyronine monodeiodinase enzymes (MDI-1, MDI-2, and MDI-3) are involved in the progressive deiodination of T4: two hydroxyl or outer-ring deiodinases (types 1 and 2), and one alanine side chain or inner-ring deiodinase (type 3). The first step in T4 metabolism is deiodination either to active T3 or to reverse T3 (rT3), which is inactive metabolically. Under normal circumstances, T3and rT3 are produced at approximately similar rates. The alanine side chain of the inner ring of the iodothyronines is subject to degradative reactions, including transamination, deamination, and decarboxylation. Sulfation at the outer-ring hydroxyl site produces inactive iodothyronine sulfates (Fig. 526-3).
FIGURE 526-2. The hypothalamic-pituitary-thyroid control axis. Pituitary thyrotropin (thyroid-stimulating hormone [TSH]) secretion is regulated by hypothalamic thyrotropin-releasing hormone (TRH) secretion by TRH neurons. Major regulatory factors modulating TRH secretion include environmental temperature, somatostatin and dopamine (not shown). TSH stimulates thyroidal T4 and T3 secretion by thyroid follicular cells. T4 and T3 are largely bound to circulating binding proteins. Circulating free T4 and T3 feedback inhibits TRH and TSH secretion. Hypothalamic and pituitary iodothyronine monodeiodinase 2 (MDI-2) deiodinate T4 to T3, which, with circulating T3, acts to modulate TRH and TSH secretion to maintain free hormone levels near the individual ‘set point.’ Thyroid hormone effects in peripheral tissues, here represented as liver, are largely mediated by T3-derived MDI-1–or MDI-2–mediated deiodination of circulating T4.
Actions of Thyroid Hormones
Thyroid hormones influence brain maturation; growth and development; oxygen consumption and heat production; nerve function; and metabolism of lipids, carbohydrates, proteins, nucleic acids, vitamins, and inorganic ions. They also have important effects on other hormone actions. T3 is the active hormone and binds to nuclear receptors with approximately 10 times the affinity of T4. T3 also binds to plasma membrane and mitochondrial inner-membrane receptors. The major effects of thyroid hormones are mediated by the nuclear T3 receptors, which are members of the steroid hormone-retinoic acid receptor superfamily and function as DNA transcription factors. In humans, two genes code for thyroid hormone nuclear receptors: one on chromosome 3, designated TRβ, and one on chromosome 17, designated TRα. Alternative splicing of expressed mRNA species leads to production of the major active thyroid hormone-binding transcripts, TRα1, TRβ1, TRβ2, and TRβ3. The TRs exist as monomers, homodimers, and heterodimers with other nuclear receptor family members such as the retinoid X receptors (Fig. 526-4).
Table 526-1. Normal Values for Serum Thyroid Hormones, Thyroglobulin, and Thyroid-Binding Globulin Concentration
FIGURE 526-3. Structure of T4 and T3. T4, tetraiodothyronine, serves largely as a prohormone. Thyroid hormone actions are largely mediated by T3, triiodothyronine, which is derived by monodeiodination from T4 via two monodeiodinase enzymes, iodothyronine monodeiodinase (MDI)-1 and MDI-2. Both T4 and T3 are inactivated by MDI-3, which deiodinates T4 to inactive reverse T3 (rT3) and T3 to inactive T2. The iodothyronines are also metabolized to inactive glucuronides and sulfates, shown here as T4G and T4S. The alanine (Ala) side chain is subject to transamination forming acetic acid analogs, here shown as tetrac or T4Ac, which have some activity but are rapidly degraded. T3Ac (not shown) has been used to treat thyroid hormone resistance.
FETAL AND NEWBORN THYROID FUNCTION
Fetal Thyroid Function
The fetal thyroid and pituitary glands are well formed by 10 to 12 weeks’ gestation.1,3,15 The thyroid gland can accumulate iodide and synthesize hormone, and the pituitary gland contains thyroid-stimulating hormone (TSH) by this time. Nevertheless, fetal serum TSH, T4, and T3 concentrations are either undetectable or very low before midgestation. The placenta is impermeable to TSH and relatively impermeable to thyroid hormones. Most of the thyroid hormone that crosses the placenta is deiodinated, but there is limited transfer of intact T4 from mother to fetus, and there are low levels of T4 in the cord blood of an athyroid fetus (range 30–70 nmol/L; 2.3–5.4 τg/dL). The placenta contains an active inner-ring iodothyronine deiodinase that inactivates T4 to rT3 and T3 to diiodothyronine (T2). Between 18 and 24 weeks’ gestation, there is a progressive increase in fetal pituitary TSH content and concentration, and by 24 weeks, fetal serum levels of TSH exceed paired maternal values. There is a parallel increase in fetal thyroid uptake of radioiodine. This midgestation increase in TSH secretion correlates with maturation of the hypothalamic-pituitary portal blood vascular system and an increase in hypothalamic production of thyrotropin-releasing hormone (TRH) (Fig. 526-5).
FIGURE 526-4. Thyroid hormone acts by binding to specific nuclear thyroid hormone receptors (TR). T3 and T4 are transported into the cell. Iodothyronine monodeiodinase (MDI) deiodinates T4 to T3, and the T3 enters the nucleus interacting with the nuclear T3receptor, here bound as a heterodimer with retinoid X receptor (RXR) to the thyroid hormone response element (TRE) of a T3 responsive gene. This causes either an increase or decrease in gene transcription of messenger RNA (mRNA) and protein, mediating the thyroid response of a given cell.
Between midgestation and term, fetal serum TSH concentrations remain relatively high and stimulate a progressive increase in fetal serum T4 concentration. There is also a progressive increase in serum thyroxine-binding globulin (TBG) concentration peaking at 30 to 35 weeks’ gestation, but the progressive increase in T4 secretion produces saturation of protein-binding sites and a progressive increase in circulating free T4. T4 in the fetus is metabolized largely to inactive iodothyronines and inactive sulfated iodothyronine analogs. Iodothyronine monodeiodinase 3 (MDI-3) in fetal liver, skin, and placenta degrades T4 to rT3 and T3 to T2. The low fetal serum T3 levels result from low levels of hepatic MDI-1 activity in fetal liver. Fetal blood rT3 and rT3sulfate (rT3S) levels are high by 20 to 24 weeks’ gestation because of increased rT3production. Fetal pituitary, brain, and brown adipose tissues contain an active MDI-2 isoenzyme, capable of local T3 production from T4. MDI-2 in brain and brown adipose tissue is inhibited by thyroid hormone, and activity increases in the hypothyroxinemic fetus. The liver enzyme is stimulated by thyroid hormone, and activity is reduced in the T4-deficient fetus. Both effects serve to augment availability of T3 to brain tissue in the event of fetal T4 deficiency. Inactive sulfated iodothyronines are the major hormone metabolites circulating in the fetus.
FIGURE 526-5. Maturation of thyroid function in the fetal and neonatal periods. Thyrotropin-releasing hormone (TRH) is produced in the fetal environment from placenta and fetal gut tissues, largely pancreas. Serum levels are relatively high due to this extrahypothalamic production and lack of degrading enzymes in fetal plasma. There is a progressive increase in fetal hypothalamic TRH concentrations beginning at midgestation associated with a progressive increase in fetal serum thyroid-stimulating hormone (TSH). Fetal serum thyroxine (T4) levels increase progressively during the latter half of gestation due largely to increased fetal hepatic production of thyroid-binding globulin (TBG). Fetal serum T4 concentrations also increase progressively in response to the increasing TSH secretion and progressive maturation of fetal thyroid TSH responsiveness. Most fetal T4 is converted in peripheral tissues to inactive reverse triiodothyronine (rT3) and inactive sulfated iodothyronines (represented by rT3 sulfate [rT3S]). At 28 to 32 weeks’ gestation, decreasing production of rT3 and sulfated analogs and increased production and/or decreased degradation of T3 lead to decreasing serum rT3 and rT3S levels and increasing T3 concentrations. At the time of parturition, a cold-stimulated TSH surge peaks at 30 minutes followed by increased T4and T3 secretion and serum concentrations of T4 and T3. Serum T3 levels after birth remain elevated due to increased T4 to T3 conversion and loss of placental deiodination.
Newborn Thyroid Function
With extrauterine exposure, the serum concentration of thyroid-stimulating hormone (TSH) increases rapidly to a mean peak level of 80 to 90 μU/mL (80–90 U/L) by 30 minutes, largely stimulated by cooling of the neonate in the extrauterine environment.3 In response, serum T3, T4, free T4, and free T3 levels increase briskly. The serum concentration of thyroxine-binding globulin (TBG), in contrast, remains unchanged, and the high serum hormone levels decrease only gradually to childhood values during the first month after birth. The levels of iodothyronine sulfate conjugates decrease rapidly after birth because of the increased activity of tissue iodothyronine monodeiodinase 1 (MDI-1). Local T3 production from T4 in brown adipose tissue potentiates norepinephrine-stimulated brown fat thermogenesis, which is essential for extrauterine survival.