Chapter 526. The Thyroid

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.

Metabolism of Dietary Iodine

The thyroid gland concentrates iodide from the blood and returns it to peripheral tissues in a hormonally active form. 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; 1% to 2% may be excreted in sweat under basal conditions and as much as 10% with severe sweating. There is continuous secretion of iodide by the salivary and digestive glands, but this is reabsorbed; there is no substantial fecal excretion.

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 TPO-THOX complex.

A normal thyroid gland contains 50 to 100 mg thyroglobulin for every 1 g of gland. MIT, DIT, triiodothyronine (T3), and thyroxine (T4) are present within thyroglobulin as iodoaminoacyl residues that can be cleaved by proteolytic enzymes. Thyroglobulin is a large 650,000-dalton glycoprotein composed of two monomeric 2767 amino acid polypeptide chains, each containing 67 tyrosine residues.1,3-6 Approximately one third of the tyrosines are spatially oriented to be susceptible to iodination, most at the extreme ends of the monomers. TPO catalyzes the coupling of iodotyrosines (MIT and DIT) within the thyroglobulin molecule to form T3 and T4. DIT and MIT couple, with loss of an alanine side chain, to form T3; DIT and DIT couple to form T4. The relative proportions of T3 and T4 formed depend on the amount of available iodide and the extent of thyroglobulin iodination. With adequate iodine intake, 70% of the iodoprotein is iodotyrosine; the rest is iodothyronine with a T4-to-T3 ratio ranging from 10:1 to 20:1.

An outer-ring iodothyronine monodeiodinase (MDI) in the follicular cell catalyzes monodeiodination of T4 to T3. MDI activity is stimulated by TSH, with the result that the ratio of T3 to T4 secreted from the thyroid gland increases with increasing TSH stimulation.

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 T3 concentrations 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 iodothyronine monodeiodinase (MDI) enzymes.1,3,10,11Circulating 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, T3 and 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).

In most tissues, particularly liver, and excluding brain and brown adipose tissue, T3 and rT3 generated through T4 monodeiodination diffuse rapidly from tissue to interstitial fluid to plasma. Thus, circulating levels of T3 and rT3 reflect both secretion and peripheral production. From 70% to 90% of circulating T3 is derived from peripheral conversion and 10% to 25% from the thyroid gland; respective values for rT3 are 96% to 98% and 2% to 4%. Progressive tissue monodeiodination reactions degrade T3 and rT3 to diiodo-, monoiodo-, and noniodinated thyronine.

The acetic acid analogs in tissue, bile, and urine have some activity, but are rapidly degraded. Pyruvic acid analogs and small amounts of lactic acid analogs that have been observed in urine and bile have minimal biologic activity. Thyroid hormones are excreted in urine and stool in both free and conjugated forms. The conjugation reactions involve both glucuronide and sulfoconjugation. Glucuronide conjugation occurs mainly in liver through microsomal glycuronyl transferase. Sulfoconjugation is also prominent in the liver and may be an obligatory step for hepatic monodeiodination reactions. Iodothyronine sulfation markedly augments outer-ring deiodination in the liver. In the fetus, where outer-ring deiodinase activity is developmentally low, the major thyroid hormone metabolites are sulfate conjugates, which are biologically inactive.

Actions of Thyroid Hormones

The free thyroid hormones are transported into peripheral cells via plasma membrane iodothyronine transporters.1,3,12-14 These belong to several families of integrin, organic anion, amino acid, and monocarboxylate solute carriers. The relative significance of these transporter types is not yet clear. αVβ3 integrin binds T4 with high affinity, and this or similar membrane receptors appear to trigger the reported nongenomic actions of thyroid hormones, including solute transport, signal-transducing kinase activation, posttranslational modifications of nucleoproteins, actin polymerization, and mitochondrial activity; these effects have been triggered by rT3 and T2, as well as T4 and T3, so that several membrane transporters may be involved. The regulation of actin polymerization by thyroid hormone in developing brain provides a nongenomic mechanism to influence neuronal migration.

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).

Other receptor transcripts, including TRα2, TRΔα1, and TRΔα2, have been characterized. These do not bind T3 or DNA but can inhibit TR and retinoid receptor activities. The TRα receptors are expressed in most tissues. TRβ1 is expressed in liver, kidney, heart, lung, brain, cochlea, and pituitary, and TRβ2 in the hypothalamus, pituitary gland, retina, and cochlea. The receptors function redundantly, as indicated by knockout studies in mice, but predominant effects of one or another TR have been described. T3 binding by the TR leads to transcriptional regulation of responsive gene activity, modulating synthesis of RNA and proteins that mediate thyroid hormone actions in various tissues (Fig. 526-4). Thyroid hormone receptor inactivation studies in mice have led to the view that TRβ receptors are more involved with feedback regulation of thyroid hormone and cochlear development, whereas energy metabolism and cardiac function are more likely TRα regulated.

Fetal Thyroid Function

The fetal thyroid and pituitary glands are well formed by 10 to 12 weeks’ gestation.1,3,15The 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 μg/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).

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 rT3 production. 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.

Sulfokinase enzymes are present early in fetal life. Sulfation of the phenolic hydroxyl group of the iodothyronine molecule may be a normal prerequisite step for enzymatic monodeiodination. The sulfated iodothyronines are preferred substrates for MDI-1, and concentrations are high in fetal serum in part because of the low type 1 activity. However, increased production of sulfated metabolites is also involved. In the fetal sheep during the last trimester of gestation, nearly 75% of the daily T4 production is metabolized to inactive sulfated analogs and 10% to 15% to inactive reverse T3. Only 5% of daily iodothyronine production is T3. The low production and low levels of the active T3 and the predominant metabolism of T4 to inactive metabolites suggest that fetal thyroid hormone metabolism is oriented to inactivation of T4, presumably to avoid tissue thermogenesis and potentiate an anabolic state of the rapidly growing fetus.

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.