Which of the following is involved in the regulation of thyroid hormone levels

Pathophysiology

Thyroid hormone secretion is tightly regulated by the hypothalamic-pituitary-thyroid axis. Thyrotropin-releasing hormone (TRH) is released from the hypothalamus and stimulates the synthesis and secretion of thyroid-stimulating hormone (TSH). TSH, in turn, controls the synthesis and secretion of the thyroid hormones, thyroxine (T4) and triiodothyronine (T3). More than 99.5% of T4 and T3 are protein bound in the serum and are, thus, metabolically inactive. The small percentage of free T4 and T3 influences metabolic function and modulates the release of both TRH and TSH using a negative-feedback system.47

Interestingly, although the thyroid gland primarily produces T4, this is a biologically inactive hormone. To gain biologic function, T4 must be converted to the active hormone T3 in peripheral tissues such as the kidney and liver. More than 80% of the available T3 is synthesized through this extrathyroidal deiodination process. Thyroid hormone exerts cellular control when T3 directly binds to cytoplasmic thyroid hormone receptor complexes. In the presence of additional regulatory elements, these complexes migrate to the nucleus and directly activate or inhibit transcription of genes that modulate cellular metabolism, adrenergic responsiveness, and thermoregulation.48

The excessive levels of T4 and T3 seen in hyperthyroidism typically result from an overproductive thyroid nodule or gland. Less commonly, excessive pituitary secretion of TSH or the overingestion of thyroid hormone can result in hyperthyroidism.49

The pathologic transition from hyperthyroidism to thyroid storm is not fully understood but usually is associated with a precipitating event such as surgery, sepsis, injury, or other acute medical illness.50 Although total thyroid hormone levels may not be significantly higher than those observed in uncomplicated thyrotoxicosis, higher levels of free thyroid hormone and lower levels of binding protein have been demonstrated.51 Elevated catecholamines in acute illness or trauma may further stimulate the synthesis and release of thyroid hormone, which in turn promotes the upregulation of β-adrenergic receptors and enhances the catecholamine effect.52

Introduction

Thyroid hormone (TH) synthesis and release is under feedback regulation from the hypothalamic input to the pituitary via thyroid stimulating hormone (TSH) releasing hormone (TRH). Clinicians generally diagnose thyroid disease based on the serum levels of the THs (L-3,3′,5-triiodothyronine [T3] and L-3,3′,5,5′-tetraiodothyronine thyroxine, [T4]) in conjunction with the measurement of serum TSH. Patients with hypothyroidism have low serum THs and high TSH serum concentrations. This is usually a result of reduced production of TH due to gland destruction (such as in autoimmune thyroid disease) or impaired biosynthesis of thyroid hormone (such as in organification defects). On the other hand, hyperthyroidism is usually diagnosed when the T4 and T3 are high and the TSH is low. The latter is commonly seen in autoimmune hyperthyroidism or autonomous TH secreting nodules of the thyroid. When there is loss of the inverse relationship between TH levels and TSH concentrations or when T4 and T3 levels are markedly different (for example high T3 and low T4 in a TH transporter defect, see below), the clinician must consider a broad differential diagnosis. Correct diagnosis can be made from clinical observations and confirmed by appropriate genetic testing, as discussed in this chapter. The correct diagnosis will lead to a rational therapy avoiding inappropriate thyroid gland ablation or TH supplementation.

It is important to appreciate that the centrally regulated system described above, is not affected by TH demands in cells not directly involved in the feedback control. Local requirement for TH is adjusted through additional mechanisms. One such system is the control of TH entry into the cell through active transmembrane transporters [1]. Another is the activation of the precursor T4 by removal of the outer ring iodine (5′-deiodination) to form T3, or inactivate T4 and T3 by inner ring (5-deiodination) to form L-3,3′,5′-triiodothyronine or reverse T3 (rT3) and L-3,3′-diiodothyronine (T2), respectively (Fig. 10.1). Changing concentrations of deiodinases in various cell types allows an additional local regulation of hormone supply [2].

Finally, the presence and abundance of TH receptors (TRs), through which TH action is mediated, determines the type and degree of hormonal response. Action takes place in the cytosol as well as in the nucleus [3]. The latter, known as the genomic effect, has been more extensively studied [4, 5] (Fig. 10.1). TRs are transcription factors that are associated with the DNA of genes whose expression they regulate.

The syndromes of reduced sensitivity to thyroid hormone include a group of disorders with apparent discordance between serum TSH and TH levels. Resistance to thyroid hormone (RTH), a syndrome of reduced end-organ responsiveness to thyroid hormone (TH), was identified in 1967 [6]. With the recognition of TRβ gene mutations [7, 8] the term RTH become synonymous with defects in TR [9]. Recent discoveries of genetic defects that reduce the effectiveness of TH through altered cell membrane transport [10, 11] and metabolism [12] broadened the definition of resistance to TH to include all defects that interfere with the biological activity of an authentic hormone secreted in normal amounts. It is suggested that use of the acronym RTH be limited to the syndrome produced by reduced intracellular action of the active TH, T3. Reduced sensitivity to TH (RSTH) is used to describe impaired effectiveness of TH in the broader sense. While the clinician considers these defects when confronted with thyroid function tests that show a discordance of serum TH and TSH concentrations, each defect has its own constellation of test abnormalities and different clinical presentation.

Thyroid Hormone Biochemistry

An overview of thyroid hormone biosynthesis and secretion is provided in Figure 77-12.10 In this schematic diagram, iodide is transported into the thyroid follicular cell by the action of the sodium-iodide symporter. Subsequently this iodide diffuses passively through the iodide channel, termed pendrin. Thyroglobulin (TG) is synthesized within the rough endoplasmic reticulum and subsequently is packaged by the Golgi apparatus into TG secretory vesicles that are released into the follicular cell lumen. Thyroid oxidase produces hydrogen peroxide that is subsequently utilized by thyroid peroxidase to oxidize iodide to iodine. Iodine then reacts with the tyrosine residues within TG to produce monoiodotyrosine and diiodotyrosine residues within the TG peptide.

Thyroid peroxidase also catalyzes coupling of adjacent iodotyrosines to form thyroxin (T4), as well as lesser amounts of triiodothyronine. Secretion of T4 from the thyroid follicular cell begins with TG phagocytosis and formation of TG endosomes that then fuse with lysosomes containing proteolytic enzymes capable of digesting TG into peptide fragments, as well as monoiodotyrosine, diiodotyrosine, and tT4. T4 is released from the cell at the basal membrane, and both monoiodotyrosine and diiodotyrosine are deiodinated by iodotyrosine deiodinase and recycled.

T4 is transported to peripheral tissues via the transport hormones T4-binding globulin, transthyretin, and albumin. Because all of the T4 transport proteins are of at least moderate size, T4 is not filtered by the kidney. In peripheral tissues, T4 is metabolized to triiodotyrosine (T3) and reverse T3 (rT3) by the action of various isoforms of iodotyrosine deiodinases. Transcription and translation of this enzyme is highly dependent upon cytokine stimulation. If monodeiodination occurs on the outer tyrosine ring the product is T3, and if the monodeiodination occurs on the inner tyrosine ring the resultant product is rT3 (Figure 77-3).10

In peripheral tissues, T3 binds to thyroid hormone receptors that can bind to specific nucleotides sequences termed thyroid responsive elements within promoter regions of genes that they regulate, whether or not the thyroid hormone is present. The presence or absence of T3 on the thyroid receptor dictates a corepressor or coactivator activity.162

Synthesis, storage and release of thyroid hormones

Synthesis of T4 and T3 occurs on thyroglobulin (Tg), a glycoprotein of molecular weight 660 000 Da that contains many tyrosyl residues. Thyroglobulin is synthesized by the thyrocytes and exported to be stored within the colloid of the follicular lumen. Incorporation of iodide into Tg requires hydrogen peroxide and thyroid peroxidase (TPO), an enzyme that is synthesized within the follicular cell and transported to the apical membrane. Thyroid hormones are synthesized at the interface between the apical membrane of the thyrocyte and the colloid of the follicular lumen.

The process of thyroid hormone synthesis, storage and secretion requires a series of highly regulated steps (Fig. 19.3).

Trapping of iodide. Iodide from plasma is actively transported by a sodium-iodine symporter situated in the basal membrane of the thyrocyte. This process allows iodide to be actively taken up against a steep concentration gradient. At the apical membrane of the cell, pendrin, a relatively non-specific anion transporter, mediates iodide efflux. The sodium-iodide symporter is competitively inhibited by anions of similar size to iodide. Pertechnetate is also transportable and thus is used for radioactive imaging of the gland. Perchlorate is used to block the uptake of iodide, for example after accidental exposure to radioactive iodide. Thiocyanates (found in certain foods, e.g. cassava) competitively inhibit the iodide pump but are not taken up into the gland.

Oxidation of iodide to iodine by thyroid peroxidase. This occurs on the luminal side of the apical membrane and requires TPO and hydrogen peroxide, which is generated by a calcium-dependent flavoprotein enzyme system situated at the apical membrane.

Recently, the dual oxidase molecules DUOX1 and DUOX2, which contain peroxidase-like and NADPH oxidase-like domains have been identified as essential for H2O2 production. They require maturation or activation factors (DUOXA1 or 2) for translocation of DUOX from the endoplasmic reticulum to the apical plasma membrane where H2O2 production occurs. Mutations in DUOX2 and DUOXA2 have both recently been identified as causes of hypothyroidism, resulting from diminished H2O2 production.

Halogenases collect the iodide removed from thyroglobulin as it is broken down in the cell.

Antithyroid drugs such as propylthiouracil and mercaptoimidazoles (methimazole and carbimazole) exert their action through inhibiting the action of TPO.

Incorporation of iodine into tyrosyl residues on thyroglobulin. Mono-iodotyrosine and di-iodotyrosine (MIT and DIT) are formed through the actions of TPO (organification).

Coupling of two iodotyrosyl residues in the thyroglobulin molecule. This is also catalysed by TPO and produces T3 and T4 that remain linked to Tg. When iodine supply is limited, the proportion of T3 produced on Tg increases. Iodinated Tg is stored in the follicular lumen.

Internalization of Tg and release of T4 and T3. When there is a demand for thyroid hormone, this is signalled by an increase in plasma thyroid stimulating hormone (thyrotrophin; TSH) concentration. Thyroglobulin is then internalized by pinocytosis and appears as colloid droplets that fuse with lysosomes and undergo proteolytic degradation to release T3 and T4. Any MIT and DIT is deiodinated and the iodine conserved.

Delivery of T4 and T3 into the circulation. This is probably achieved by thyroid hormone transporters. The large stores of T4 and T3 incorporated into thyroglobulin allow secretion of T4 and T3 more quickly when required than if it had it had to be synthesized.

Thyroid stimulating hormone appears to stimulate each of the above processes. It also stimulates the expression of many genes in thyroid tissue including thyroglobulin, sodium iodide symporter (NIS) and interleukin-8. It also causes thyroid hyperplasia and hypertrophy.

Control of Thyroid Hormone Production

The pattern of perinatal thyroid hormone secretion in the human is shown in Figure 92-1. Maturation of thyroid system control can be considered in three phases: hypothalamic, pituitary, and thyroidal. Changes in these systems are complex and superimposed on the increasing production and increasing serum concentration of serum thyroid hormone–binding globulin (TBG) as well as the changing pattern of fetal tissue iodothyronine deiodination during gestation. Maturation of these latter systems is described in the following section.

Although the fetal thyroid gland is able to concentrate iodide and synthesize thyroglobulin at 70 to 80 days of gestation, little thyroid hormone synthesis occurs until about 18 weeks of gestation. At this time, thyroid follicular cell iodine uptake increases, and T4 becomes measurable in the serum. Both total and free T4 concentrations then increase steadily until the final weeks of pregnancy (Fisher, 1985). This pattern differs from the development of serum T3 levels in the fetus. The fetal serum T3 concentration is low (less than 15 μg/dL) until 30 weeks of gestation and then increases slowly in two distinct phases, a prenatal and a postnatal phase. Prenatally, serum T3 increases slowly after 30 weeks of gestation to reach a level of approximately 50 μg/dL in term cord serum (Fisher and Klein, 1981). Postnatally, both T3 and T4 serum concentrations increase fourfold to sixfold within the first few hours of life, peaking at 24 to 36 hours after birth. These levels then gradually decline to adult values over the first 4 to 5 weeks of life. The prenatal increase in serum T3 seems to be due largely to progressive maturation of hepatic type I (phenolic) outer-ring iodothyronine deiodinase activity and increasing hepatic conversion of T4 to T3, although other tissue sources of deiodinase, such as brown fat and kidney, may be involved.

Fetal serum TSH increases rapidly from a low level at 18 weeks of gestation to a peak value at 24 to 28 weeks and then gradually declines until term. At the time of parturition, partly in response to cold stress, an acute release of TSH occurs, resulting in an elevated level by 30 minutes of life. The level of circulating TSH remains modestly elevated for 2 to 3 days after birth. The increases in thyroid hormone that occur immediately after birth are not totally dependent on TSH and may represent other influences in the thyroid gland at the time of parturition. The high postnatal T3 levels in the days following birth are due to both TSH stimulation of thyroidal T3 secretion and further rapid maturation of tissue outer-ring monodeiodinase activity.

Fetal thyroid gland function develops under the influence of a moderately elevated TSH level during the last half of gestation. The increase in serum T4 that occurs during the last trimester is accompanied by a progressive decrease in serum TSH, suggesting that changes in both thyroid follicular cell sensitivity to TSH and pituitary thyrotroph sensitivity to the negative feedback effect of thyroid hormones occur during this period. The pituitary gland contains a type II outer-ring iodothyronine deiodinase, which converts T4 to active T3, which in turn modulates TSH production. In most circumstances, it is circulating T4 that is most important in TSH control. Thus, even when the circulating T3 level is low (as in midgestation), there may be significant negative feedback control (by T4) of pituitary TSH secretion.

The ontogeny of TRH secretion and function in the fetus remains somewhat obscure. TRH immunoactivity is detectable in the hypothalamus by midgestation, increasing markedly in the third trimester after the peak in serum TSH activity is noted. The premature infant (born before 30 to 32 weeks) is characterized by low levels of T4 and free T4, a normal or low level of TSH, and a normal or prolonged TSH response to TRH indicating a state of physiologic TRH deficiency. The full-term human fetus responds to pharmacologic maternal doses of TRH with a somewhat prolonged increase in TSH, suggesting a degree of relative hypothalamic (tertiary) hypothyroidism (Roti et al, 1981). Fetal sources of nonhypothalamic TRH (placenta and pancreas) probably contribute to the elevated circulating levels of fetal and cord blood TRH and presumably account for the high circulating TSH level characteristic of the midgestation fetus. However, the significance of ectopic TRH to the development of thyroid system control remains to be investigated.

In summary, the control of fetal thyroid hormone secretion can be characterized as a balance among increasing hypothalamic TRH secretion, increasing thyroid follicular cell sensitivity to TSH, and increasing pituitary sensitivity to thyroid hormone inhibition of TSH release. The fetus progresses from a state of both primary (thyroidal) and tertiary (hypothalamic) hypothyroidism in midgestation through a state of mild tertiary hypothyroidism during the final weeks of pregnancy and to fully mature thyroid function in the perinatal period.

What is involved in the regulation of thyroid hormone levels?

What are the 2 main hormones associated with the formation of thyroid hormone?

Which of the following is important for thyroid hormones synthesis?