Hormone Kinetics and Production

Deiodination at the 5′ or 5 position accounts for approximately 80% of the daily disposal of T₄, with the other processes shown in Fig. 4-1 responsible for the remaining metabolism of this compound.⁵ Such approximations may underestimate the role of both deiodinative and nondeiodinative pathways, however. Many of the products of these reactions, including T₃ and rT₃, are present primarily in the intracellular compartment and may undergo degradation before they have a chance to exchange with the plasma pool. It thus is difficult in human kinetic studies that use plasma sampling techniques alone to assess the contribution of these processes to overall thyroid hormone metabolism. For example, it has been demonstrated that most of the thyronine (T₀) excreted in the urine is in the form of its acetic acid analogue,¹⁷ thus suggesting that deamination plays a more prominent role in thyroid hormone metabolism than is apparent from the very low circulating levels of Tetrac and Triac. Such concerns have led to the concept that “hidden pools” of thyroid hormone metabolites may be present in tissues.¹⁸

Table 4-1^19–21 provides estimates of various kinetic parameters of thyroid hormone production and metabolism in humans.^5,22,23 The high affinity of T₄ for plasma binding proteins, along with its greater production rate, accounts for its relatively high concentration in serum, as well as its long serum half-life. In contrast, T₃ and rT₃ are present at much lower serum concentrations because of their lower production rates, greater metabolic clearance rates, and lower affinity for thyroxine-binding globulin (TBG). In addition, these two triiodothyronines appear to reside primarily within the intracellular compartment; thus their volumes of distribution are significantly greater than that of T₄.

The rate of T₄ production remains remarkably constant in healthy adults, with alterations noted only during pregnancy and in the aged. Although not well documented, increased T₄ secretion probably occurs during pregnancy in response to several factors, including thyroidal stimulation by human chorionic gonadotropin, an increase in the size of the extrathyroidal T₄ pool resulting from increased TBG levels, and an increase in the rate of T₄ and T₃ degradation because of high levels of 5-deiodinase activity in the pregnant uterus and placenta.24,25 One clinical consequence is the need to increase the replacement dose of T₄ by 25% to 50% in hypothyroid women during pregnancy.²⁶ Thyroid function appears to be well preserved through age 80 in healthy individuals, although a slight decrease in T₄ production and clearance is noted after the age of 60 years, and free T₃ levels are lower in centenarians.^27,28 That being the case, the decreased T₄ requirements of elderly hypothyroid patients probably result more from the presence of chronic illness and the use of concurrent medications than from the aging process per se.^29,30

Deiodination and The Iodothyronine Deiodinases

The potential importance of deiodination to thyroid hormone action was first recognized nearly 50 years ago when Gross and Pitt-Rivers demonstrated that although T₃ was considerably more potent than T₄,³¹ it was present in the thyroid in much lower amounts.³² This observation suggested that T₃ was derived largely from T₄ by metabolism in extrathyroidal tissues. This thesis was later proved by Braverman et al., who demonstrated the presence of T₃ in the serum of athyreotic subjects injected with T₄.³³ Research over the past three decades has confirmed the physiologic importance of the 5′- and 5-deiodination processes, has defined the biochemical parameters of these enzymatic reactions, has determined important regulatory factors that influence deiodinase activities, and has identified key structural determinants of the proteins that catalyze these reactions.^34,35

Three deiodinase isoforms, termed D1, D2, and D3, are present in vertebrate species. These differ in their catalytic properties, patterns of tissue expression, and mechanisms of regulation.34,36,37 The 5′- and 5-deiodination reactions catalyzed by these enzymes can be considered broadly as activating and inactivating processes, respectively.

Biochemical Characteristics

The biochemical properties of the deiodinases are outlined in Table 4-2.^38–45 They are in essence oxidoreductases in that they catalyze the substitution of hydrogen for iodine on the iodothyronine substrate. No other catalytic properties of these enzymes have yet been identified, nor do other known enzymes possess deiodinase activity. The enzymes are remarkable in terms of their substrate specificity and the precise location of the iodine removed.¹⁶ D1 is unique in that it can catalyze either 5′- or 5-deiodination, depending on the reacting substrate. Thus rT₃ is efficiently deiodinated only at the 5′ position by D1. In contrast, T₄ and T₃ are poor substrates for this enzyme unless they are first sulfated. This reaction markedly enhances their rate of 5-deiodination and further reduces their susceptibility to 5′-deiodination.⁴⁶ That D1 is relatively inefficient in converting T₄ to T₃ presents a considerable paradox, given that a significant proportion of T₃ production has traditionally been believed to occur in the liver and other D1-expressing tissues (vide infra).

D2 catalyzes only 5′-deiodination and very efficiently converts T₄ to T₃.¹⁶ The T₃ thus formed is a poor substrate for 5′-deiodination and is not further metabolized by this enzyme. In contrast, rT₃ is a good substrate for D2 as well as D1 and frequently is used in research assays to quantitate 5′-deiodinase activity. D3 exclusively catalyzes 5-deiodination¹⁶ and thus serves to convert T₄ and T₃ to rT₃ and 3,3′-T₂, respectively—metabolites with little affinity for the nuclear thyroid hormone receptors.

The deiodinases all require the availability of reduced thiol cofactors for efficient catalytic cycling.³⁹ These cofactors presumably function to displace iodine from an enzyme intermediate formed during the reaction and thus to regenerate the active deiodinase.⁴⁷ In in vitro assay systems using tissue homogenates or cellular subfractions, dithiothreitol typically is added as a cofactor. This small, nonnative four-carbon dithiol efficiently supports deiodination of all three enzymes. Kinetic data derived from broken cell preparations using dithiothreitol as cofactor have demonstrated a Michaelis-Menten constant (K_m) value for D1 of approximately 2.3 µmol/L (for T₄ 5′-deiodination), whereas D2 and D3 manifest much lower K_m values in the nanomolar range (see Table 4-2).³⁹ Based on this analysis, D1 sometimes is referred to as a “high K_m” enzyme, whereas D2 is said to catalyze a “low K_m” 5′-deiodination process. This distinction is somewhat spurious, however, because the kinetic properties of the deiodinases are clearly dependent on the thiol cofactors used in the assay system.⁴⁸ Thus, when the native thiol cofactor glutathione or thioredoxin is used, K_m values for D1 in the nanomolar range are obtained. Unfortunately, the cofactor system supporting deiodination in intact cells remains unknown,⁴⁹ and evidence suggests that glutathione and thioredoxin may not serve this role.⁵⁰ Thus the physiologic significance of the kinetic parameters derived in vitro remains uncertain.

Inhibitors

In addition to differences in their catalytic properties, the deiodinases show differential susceptibilities to certain inhibitors³⁹ (see Table 4-2). Most notable is the marked sensitivity of D1 to the antithyroid drug propylthiouracil (PTU). This agent forms an inactive complex with D1 by binding covalently to its active site. Notably, D2 and D3 show little or no susceptibility to inhibition by PTU. The related thioureylene drugs carbimazole and methimazole have no inhibitory effect on deiodination.⁴⁷

Gold compounds such as aurothioglucose are known to react with the active site selenocysteine residue in glutathione peroxidase and impair its activity.⁵¹ This compound also inhibits all three deiodinase isoforms, with D1 again showing a significantly greater sensitivity to this effect.^52–54 Other drugs that affect thyroid hormone metabolism include the iodinated radiographic contrast agents iopanoic acid (Telepaque) and sodium ipodate (Oragrafin). These small phenolic compounds act as substrate analogues and inhibit all three deiodinases in a competitive manner. To date, no selective inhibitors of D2 or D3 have been described—a situation that has significantly limited experimental investigations into their physiologic roles.

Tissue Patterns of Expression

An intriguing feature of the deiodinases is their pattern of tissue expression (see Table 4-2). The liver, kidney, thyroid gland, and pituitary gland express high levels of D1, with lesser amounts found in the brain.^16,55,56 In contrast, D2 is most abundant in the pituitary gland and brown adipose tissue (in rodents), with significant amounts also noted in the central nervous system.¹⁶ Studies using in situ hybridization and immunocytochemistry have demonstrated that D2 expression in the brain appears to be confined to certain subpopulations of astroglial cells, such as the tanycytes lining the third ventricle of the hypothalamus, which suggests that they serve as the principal site of T₃ production in this tissue.^57–59 In humans, D2 expression appears more widespread; the mRNA for this enzyme has been noted in the heart, skeletal muscle, and thyroid gland,^54,60 as well as in coronary artery smooth muscle cells.⁶¹

In adult mammals, D3 expression occurs primarily in the brain, with significant amounts also present in the skin.62,63 The brain is thus the only tissue that expresses all three deiodinases, although these are generally found in different subregions of this tissue and in different cell types. Thus, as opposed to the expression of D2 by glial cells, D3 is expressed primarily in neurons.^64,65

Finally, as detailed below, deiodinase expression patterns during pregnancy and development are of critical importance, with high levels of D3 activity present in the uterus, the placenta, and several fetal tissues.66,67

Structural Characteristics

Important structural features of the deiodinases have been deduced from the results of molecular cloning experiments.³⁷ All the enzymes have a molecular mass of approximately 29 to 32 kDa, function as homodimers,^43–45 and are selenoproteins in that they contain the uncommon amino acid selenocysteine as the reactive residue in the catalytic cleft (Fig. 4-2).⁶⁸ The importance of this amino acid to enzymatic activity is demonstrated by experiments in which selenocysteine has been replaced by cysteine. Such a substitution decreases the catalytic efficiency of the mutant protein to less than 1% of that of the native enzyme.⁶⁹ In the case of D3, the cysteine mutant also demonstrates an altered substrate preference.⁷⁰ It is remarkable that substitution of selenocysteine for a serine residue in a monoclonal antibody raised against T₄ confers on the protein deiodinase activity with catalytic properties similar to the D1, including sensitivity to PTU inhibition.⁷¹

The importance of selenocysteine to deiodination likely derives from its being ionized at physiologic pH, thus serving as a much more potent nucleophile than cysteine.⁷² Incorporation of selenocysteine into the deiodinases and other selenoproteins occurs at the time of translation and is directed by a specific stem-loop structure in the 3′-untranslated region of the mRNA termed a selenocysteine insertion sequence.⁷³ A unique tRNA (Sec-tRNA[Sec]), a specific RNA binding protein, and a specialized elongation factor also are required for efficient synthesis of selenoproteins.^74,75

In earlier studies, it was suggested that a 29 kDa (p29) nonselenoprotein, almost identical in sequence to a member of the Dickkopf protein family (Dkk3), was a substrate binding subunit of the D2.⁷⁶ However, Montero-Pedrazuela et al. have demonstrated a marked difference in spatial expression patterns in the brain of the p29 and the D2 selenodeiodinase,⁷⁷ and as recently reported, mice deficient in the Dkk3 protein do not have any consistent alterations in thyroid hormone status or D2 activity in their tissues.⁷⁸ These findings strongly suggest that the p29 protein is not relevant to D2 activity or to thyroid hormone homeostasis.

The overall amino acid identity of the three deiodinase isoforms is less than 30%. However, a high degree of homology is present in the regions of the selenocysteine and a conserved histidine residue (Fig. 4-3A). These areas show significant structural similarities to the thioredoxin-fold family of proteins and to α-l-iduronidase, respectively.⁷⁹ Based on these structural homologies, Callebaut et al.⁷⁹ and others have reported mutagenesis studies that define further the structure-function correlates of the deiodinase isoforms, including the identification of a key serine residue in the D1 active catalytic site that appears to confer sensitivity to PTU.⁸⁰

In addition, all deiodinases contain a hydrophobic region near the N-terminus,⁸¹ and subcellular fractionation studies have confirmed that these enzymes are integral membrane proteins.^82,83 Such studies, along with fluorescent microscopy of epitope-tagged enzymes, have demonstrated that the D2 is located in the endoplasmic reticulum,^82,84 whereas a significant fraction of the D3 has been reported to be in the plasma membrane.⁸⁵ The location of the D1 may vary in different tissues; in renal epithelial cells, the D1 has been localized to the basolateral plasma membranes,⁸⁶ whereas in the liver, it appears to reside in the endoplasmic reticulum (Pallud, Croteau, and St. Germain, unpublished observations). Studies by Friesema et al.⁸⁷ demonstrate that the catalytic effectiveness of all three deiodinases is markedly increased when specific thyroid hormone transporters are coexpressed with the deiodinases in cultured cells. This finding indicates that the active catalytic sites of these enzymes are located in the intracellular compartment.

Genetic Considerations and Knockout Mouse Models

The three deiodinase isoforms are coded in mammals by three different genes located in humans on chromosomes 1 (D1) and 14 (D2 and D3), as indicated in Table 4-2.^40–42 Although their genetic structure appears relatively simple in that they contain only four, three, and a single exon, respectively (Fig. 4-3B),^40,88,89 surprising complexities that may influence expression patterns have been identified.^90,91 For example, the DIO3 gene locus also expresses antisense transcripts from the DIO3os gene coded on the opposite DNA strand, and in the mouse fetus, the D3 is imprinted; transcription preferentially occurs from the paternal allele.⁹¹ In humans the DIO3 is also located within an imprinted region of chromosome 14.⁹¹ This pattern of organization and expression of the D3 often is observed for genes important in development.⁹²

To enhance our understanding of the physiologic roles of the deiodinases, genetic knockout models of each of the isoforms have been developed and partially characterized (Table 4-3).^93–100 D1-deficient mice show no general phenotypic abnormalities, although serum T₄ and rT₃ levels are modestly elevated, and the excretion patterns of iodothyronines in the feces and of iodine in the urine are significantly altered.⁹³ D2-deficient mice are viable and fertile in a protected laboratory setting. However, observed impairments in hearing,⁹⁶ thermogenesis,⁹⁵ and neurocognition⁹⁷ in these mutants would likely result in lethality in the wild. These animals also manifest elevated T₄ and thyroid-stimulating hormone (TSH) levels and show a marked selective resistance to the feedback effects of T₄, demonstrating the importance of D2 in pituitary thyrotroph regulation.⁹⁴ This contrasts with D1-deficient mice, in which TSH levels are normal.⁹³ This implies that the D1 expressed in the pituitary is not involved in TSH regulation.

A striking finding in the D1- and D2-deficent mouse models is that serum T₃ levels are normal.93,94 Indeed, in mice cross-bred to yield a combined D1 and D2 deficiency, the serum T₃ level is only minimally decreased (V. A. Galton, unpublished observations).¹⁰¹ This finding is both unexpected and difficult to explain, given that 5′-deiodination in peripheral tissues is supposed to contribute 80% of the T₃ production in humans and 45% in rats, with the remainder secreted directly from the thyroid.^34,102 Given that the combined D1/D2 knockout mouse has been unequivocally shown to lack all 5′-deiodinating capacity, it is clear that at least in the rodent, thyroidal production and secretion of T₃, perhaps combined with a decreased rate of T₃ clearance from D1 deficiency, can compensate and maintain serum T₃ levels that are essentially normal in the face of an inability to convert T₄ to T₃ in all tissues. A surprising corollary to this observation is that a D1 deficiency does not appear to significantly compromise T₃ secretion from the rodent thyroid, a tissue in which this enzyme is highly expressed and previously was thought to be essential for T₃ production.^102,103 This suggests that under physiologic conditions, D1 acts primarily as a “scavenger” enzyme that prevents the buildup of lesser iodothyronines (rT₃, T₂s, T₁) and sulfated derivatives in the thyroid gland, blood, and tissues.

The extent to which humans may be able to compensate for at least a partial impairment in 5′-deiodinating capacity has recently been reported. Although to date no mutations in the deiodinase genes in humans have been described, Dumitrescu et al.¹⁰⁴ have described two families with partially inactivating mutations in the selenocysteine insertion sequence-binding protein2 (SBP2), which is essential for the synthesis of selenoproteins, including the deiodinases.⁷⁴ Affected individuals demonstrate short stature and delayed bone age along with modest abnormalities in serum thyroid hormone levels, including increases in total T₄ and rT₃.¹⁰⁴ Notably, total serum T₃ levels were only minimally reduced, whereas TSH levels were at the upper part of the reference range and proved relatively resistant to suppression by administered T₄, but not T₃. These findings are very similar to those observed in knockout mice with a combined deficiency in D1 and D2, as noted previously. Indeed, a deficiency in D2 activity was demonstrated in cultured skin fibroblasts from affected patients.¹⁰⁴

Mice deficient in D3 present the most severe phenotype, likely as a result of the importance of this enzyme during the developmental period. Observed abnormalities include significant perinatal mortality, growth retardation, impaired fertility, and altered systemic thyroid hormone levels during the perinatal period (transient hyperthyroidism) and in adulthood (moderate hypothyroidism).99,100 Multiple abnormalities, including impaired response of the thyroid gland to TSH and of the pituitary to TRH, have been observed at all levels of the thyroid axis in the D3-deficient adult mouse. The response to hypothyroidism of TRH mRNA production in the hypothalamus and of pituitary TSH production is also markedly impaired. Many of these abnormalities are similar to those observed in human infants born to mothers with poorly controlled hyperthyroidism during pregnancy^105,106 or to rodents treated with large doses of thyroid hormone during the perinatal period.^107,108 These findings demonstrate that strict control of thyroid hormone levels during development by D3 is critical for proper development of the thyroid axis.

Regulation

The deiodinases are regulated by multiple hormones, growth factors, and environmental and nutritional factors.³⁴ Foremost among these are the thyroid hormones themselves; alterations in thyroid status induce profound changes in enzyme activity (see Table 4-2). Hypothyroidism is associated with a marked decrease in D1 and D3 levels, whereas D2 activity increases severalfold. Opposite changes occur in hyperthyroidism. These changes result from both pretranslational and posttranslational mechanisms.³⁴ For example, D1 and D3 mRNA levels are increased in the hyperthyroid state,^53,109 and D2 mRNA is decreased.⁵⁴ Hyperthyroidism also results in rapid downregulation of D2 activity by ubiquitination of the D2 protein.^110,111 This induces a reversible conformational change in the enzyme’s dimerization structure, which results in reversible loss of activity and eventually may target the enzyme for proteasomal degradation.¹¹² Considerable progress has been made in defining the molecular mechanisms involved in transcriptional control of the deiodinases; this topic has been reviewed recently by Gereben et al.³⁷ Of particular interest has been the observation by Simonides et al.¹¹³ that hypoxia induces D3 expression in several cell culture systems, as well as in ischemic myocardium.

Other important regulatory effects on deiodinase activity are noted in the thyroid gland, where TSH and thyroid-stimulating immunoglobulins stimulate both D1 and D2 activity⁶⁰; in brown adipose tissue, where cold exposure,¹¹⁴ bile acids,¹¹⁵ or intracerebroventricular administration of leptin¹¹⁶ markedly stimulates D2 activity; and in the liver, where nutritional deprivation, diabetes, tumor necrosis factor, and other cytokines decrease D1 activity (see also below).^109,117,118 In addition, D2 activity in the brain displays a significant diurnal variation.¹¹⁹ Although the physiologic significance of this remains to be determined, in some seasonal breeding species, rhythmic alterations in D2 and D3 activity in the central nervous system, perhaps mediated by melatonin,¹²⁰ appear to be integral responses to changes in the photoperiod.^121,122

Altered Thyroid States

Several examples of these principles can be cited, starting first with the response to alterations in thyroid hormone status. Experimental studies, as well as clinical experience, indicate that serum T₃ levels tend to be maintained within the normal range in patients with moderate degrees of hypothyroidism despite the attendant hypothyroxinemia.142,143 Several factors, including an increase in the relative proportion of T₃ secreted from the thyroid gland and an increase in the proportion of T₄ converted to T₃ in extrathyroidal tissue, appear to be responsible for this finding¹⁴⁴ (Fig. 4-4). Both of these effects result from increased rates of 5′-deiodination. Thus in the thyroid gland, D1 and D2 activities are stimulated by the increase in TSH that accompanies hypothyroidism.⁶⁰ In peripheral tissues, T₄ to T₃ conversion mediated by D2, which recently has been postulated to be the major source of plasma T₃ in euthyroid humans,¹⁴⁵ is also relatively enhanced by increased D2 activity.⁵⁴ As a result, T₄ is used more efficiently for T₃ production. In addition, the rate of T₃ clearance in extrathyroidal tissues is decreased. This decrease probably results in part from diminished 5-deiodination caused by the decreases in D1 and D3 activity that have been observed in the hypothyroid state. The physiologic importance of these extrathyroidal mechanisms, which in essence act as a form of peripheral autoregulation to help maintain T₃ levels, is easily demonstrated by the administration of varying doses of T₄ to athyreotic individuals. Under such circumstances, the circulating T₃/T₄ ratio is highest when low doses of T₄ are given, and the ratio progressively declines as full replacement and then supraphysiologic doses are provided.^142,143 Alterations in the rates of nondeiodinative pathways may contribute to this response. The net effect of these metabolic adaptations is to minimize the decrease in circulating T₃ levels in the face of impaired secretion from the thyroid gland.

In the hyperthyroid state that occurs with Graves’ disease, D1 activity is markedly increased both in peripheral tissues (as a result of the thyrotoxic state) and in the thyroid gland (because of thyroid-stimulating immunoglobulins that mimic the D1-stimulating effects of TSH).³⁴ Although relatively inefficient in converting T₄ to T₃, this enhanced D1 activity has been shown recently to be the major source of circulating T₃ in this condition, as well as in toxic multinodular goiter, with much of the D1-mediated T₃ production occurring in the hyperactive thyroid gland itself.¹⁰³ However, given the marked increase in thyroidal T₄ and T₃ production in the hyperthyroid state, the increase in D1 expression in extrathyroidal tissues appears to be paradoxical in that it would serve to further increase serum T₃ levels. But such may not be the case; the administration of high doses of T₃ to D1-deficient mice results in both higher serum T₃ levels and a greater degree of tissue thyrotoxicosis as compared with thyrotoxic wild-type animals.⁹³ Thus, enhanced expression of D1 in the liver and kidney of hyperthyroid animals may serve to actually mitigate the increase in serum T₃, and thus the degree of thyrotoxicosis, presumably as a result of the inactivating 5-deiodinating capability of this enzyme.

The changes in D2 and D3 activity observed in hypothyroidism and hyperthyroidism have important additional effects. In organs that express these enzymes, alterations in activity provide a local mechanism for the maintenance of T₃ concentrations at the cellular level. Thus in the hypothyroid rat infused with increasing doses of T₄, normalization of the T₃ content of D2-expressing tissues, such as the cerebral cortex, cerebellum, and brown adipose tissue, is attained at much lower infusion rates than are required by other tissues.¹⁴⁶ This presumably reflects an enhanced rate of T₄ to T₃ conversion in these tissues by the elevated D2 activity. In contrast, the increased level of D3 expression in the brain that accompanies hyperthyroidism may explain why nuclear T₃ levels are observed to be normal in most regions of this organ under this abnormal condition.¹⁴⁷ The deiodinases thus appear to provide an additional level of autoregulation in tissues where thyroid hormone effects are especially critical.

Development

Thyroid hormones are of unquestioned importance to the developing fetus and during the neonatal period; hypothyroidism at this time can result in the clinical syndrome of cretinism characterized by severe neurologic impairment.¹⁴⁸ However, exposure during development to excessive levels of thyroid hormones promotes premature differentiation of fetal tissues and thus is also detrimental.^149,150 Throughout most of gestation, circulating levels of total T₄ and total T₃ in the mammalian fetus are extremely low,¹⁵¹ although significant amounts of free hormone have been demonstrated in amniotic fluid and fetal serum.¹⁵² Thus a key role of the uteroplacental unit is to limit access of the large pool of maternal thyroid hormones to the fetus while at the same time allowing small, but appropriate amounts of hormone to reach the developing embryo.¹⁵³ This is accomplished by expression in the pregnant uterus^25,154 and in the placenta⁶⁷ of exceedingly high levels of D3 activity. (D2 is also expressed in these tissues, although its role remains undefined.^66,155) Uterine D3 and D2 activities are regulated in a complex fashion by estrogens, progesterone, and probably other factors.^156,157 However, the marked rise in uterine D3 expression observed during pregnancy is induced immediately and directly by implantation and represents an integral aspect of the uterine decidualization reaction.¹⁵⁶ As implied above, high levels of D3 in the pregnant uterus and subsequently in the placenta do not result in a complete barrier to the transfer of maternal thyroid hormones to the fetus, as evidenced by the finding of significant levels of T₄ and T₃ at term in the serum of athyreotic infants.¹⁵⁸ Transporter proteins such as MCT8 likely also play an important role in thyroid hormone homeostasis in the fetal-placental unit.¹⁵⁹

Most mammalian fetal tissues, including the human fetal brain,160,161 also express deiodinases, with D3 activity largely predominating in the early and mid stages of development.⁶⁶ During the later stages of gestation and in the neonatal period, after fetal thyroid function has been initiated, expression of 5′-deiodinases becomes more prevalent. In this regard, expression of D2 in the fetal and neonatal brain appears to be critically important for supplying T₃ for the normal development of this tissue.¹⁶² This concept has been verified directly with regard to cochlear development; failure of the normal induction of D2 expression in the rodent cochlea shortly after birth results in marked hearing impairment.^96,163 However, D2 expression in the developing brain may not be essential, or even important, in all brain regions, as demonstrated by the observation that the neurologic phenotype of the D2KO mouse is relatively mild compared with the rodent with developmental hypothyroidism.⁹⁷ This observation points to an important role of T₃ derived from the serum, which is the sole source of brain T₃ in the developing D2KO mouse, in neurologic development.

The ordered and timely expression of the deiodinases during development is also critically important in lower species such as the metamorphosing tadpole.164–167

An important aspect of thyroid hormone metabolism during development relates to the very high levels of sulfated iodothyronines that circulate in the fetus, most likely as a result of the low D1 levels that occur during development and the fact that these metabolites are not efficiently degraded by D3.¹⁶⁸ This observation has led to speculation that fetal T₃S could serve as a reservoir of T₃ that becomes available later in pregnancy through the actions of tissue sulfatases.¹⁶⁹

Fasting and Illness

Profound changes occur in thyroid hormone economy during states of fasting and severe systemic illness, as detailed elsewhere in this volume. In humans, as well as in various animal models, the hallmark features induced by these conditions consist of marked decreases in the serum levels of total and free T₃, accompanied by an inappropriately normal or reduced serum TSH level.170,171 Serum T₄ levels are also reduced in fasted rodents and in critically ill humans. These alterations in circulating thyroid hormone levels are accompanied by reduced tissue levels of T₃,¹⁷² and the severity of these changes in acute illness correlates closely with patient mortality rates.¹⁷³ This generalized suppression of the thyroid axis is hypothesized by some observers to be of adaptive benefit in that it is associated with a significant decline in basal metabolic rate (BMR) in both humans and rodents,^174,175 and it appears to lessen protein and fat catabolism.^176,177

The triggering and homeostatic mechanisms that underlie this response of the thyroid axis are complex and remain poorly understood despite decades of experimental observations. Given the importance of the deiodinases in the maintenance of peripheral and tissue thyroid hormone levels, alterations in the expression and activity of these enzymes have been postulated to play important roles in the development of this syndrome.¹⁷¹ In particular, decreases in serum and tissue T₃ levels observed in nutritional deprivation and illness have been attributed, at least in part, to the decreases in D1 activity and/or increases in D3 activity observed experimentally in the liver, muscle, heart, and other tissues of humans and experimental animals.^{109,113,173,178–180} In fasted or ill rodents, increased activity of D2 and decreased activity of D3 locally in the hypothalamus have been postulated to result in increased T₃ levels in this tissue, thereby preventing or blunting the rise in TRH, and subsequently TSH, that otherwise would be expected to result from decreased serum T₃ and T₄ levels.^181–183

However, it is important to note that these concepts are based entirely on indirect evidence. For example, the current concept that peripheral T₃ production rates are diminished in fasting and illness is derived largely from in vivo kinetic studies that attempt to define rates of T₄ and T₃ production and clearance from serum measurements alone.¹⁸⁴ Unfortunately, such studies are prone to misinterpretation. Thus, in the only two studies in which the in vivo rate of T₄ to T₃ conversion was measured directly in whole animals subjected to fasting, by injecting animals with ^[125]I-T₄ and quantifying ^[125]I-T₃ appearance, the fraction of T₄ converted to T₃ was approximately doubled, and total T₃ production was unchanged.^185,186 It thus appears that much of the T₃ produced during fasting remains in the tissues, where it may be metabolized via other pathways, and is not exchanged with the plasma T₃ pool.¹⁸⁶ Such results serve to highlight the methodologic shortcomings inherent in kinetic studies of thyroid hormone metabolism in humans or rodents, where sampling is limited to the plasma compartment.

Caution should also be exercised in inferring causality between in vitro–determined deiodination rates in tissue homogenates and observed alterations in systemic thyroid hormone parameters.¹⁷³ Studies conducted in deiodinase-deficient animals call into question the validity of such correlations. Thus, the changes in serum T₄, T₃, and TSH observed in fasted D1/D2KO mice are virtually identical to those in fasted wild-type mice (Galton/St. Germain, unpublished observations), and D3KO mice subjected to bacterial infection develop a nonthyroidal illness–type syndrome to the same extent as do infected wild-type mice.¹⁸⁷ Notably, however, changes in deiodinase activities could affect T₃ availability in selected cells or tissues and therefore could be important in the local response to nutritional deprivation, hypoxia, or inflammation, as suggested by Simonides et al.¹¹³

Thermogenesis

T₃ and other thyroid hormone derivatives (e.g., 3,5-T₂, 3-iodothyronamine) have been implicated in the control of metabolic rate and thermogenesis by both genomic and nongenomic mechanisms11,188 (vide supra). D2 has been demonstrated to be a key modulator of T₃ availability and thus thermogenesis in brown adipose tissue (BAT) and other organs.⁹⁵ The importance of D2 in energetic pathways has been highlighted recently by the report that in mice, the induction of D2 in BAT by bile acids, working through a unique G protein–coupled receptor (TGR5), protects against diet-induced obesity and insulin resistance.¹¹⁵ This suggests that the selective induction of D2 in thermogenic tissues could have therapeutic value in the treatment of obesity and diabetes. In this regard, da Silva et al.¹⁸⁹ recently demonstrated that the small polyphenolic molecule kaempferol stimulates D2 activity and energy expenditure in cultured human skeletal muscle myoblasts.

Effects of Selenium

Nutritional selenium deprivation in experimental animals leads to characteristic changes in deiodinase activities and serum thyroid hormone levels.⁶⁸ The most profound changes are noted in the liver and kidney, where marked decreases in D1 activity are noted secondary to impaired translation of selenoproteins.¹⁹⁰ In tissues where selenium levels are better preserved, such as the thyroid gland and brain, deiodinase activities are altered to a lesser extent or not at all.^102,191,192 Thus changes in serum thyroid hormone levels in selenium deficiency resemble those observed in other model systems where D1 activity is impaired, namely, T₄ is increased and little change occurs in T₃ or TSH.¹⁹³ Similar observations in circulating hormone levels have been noted in human populations susceptible to selenium deficiency.^194,195 In these circumstances, dietary selenium supplementation results in small but significant decreases in serum T₄ levels and increases in the T₃/T₄ ratio, thus suggesting restoration of D1 activity. The clinical consequences of these changes have not been determined. It is notable that a recently reported randomized control trial of selenium supplementation in patients in an intensive care unit with severe sepsis found no direct effect of selenium on free and total serum thyroid hormone levels, although patient morbidity seemed to be lessened.¹⁹⁶

Of note are reported cases of worsening hypothyroidism developing in individuals with combined selenium and iodine deficiency who were given selenium supplements alone.¹⁹⁷ It is postulated that under such circumstances, restoration of D1 activity enhances T₄ metabolism and thereby worsens the iodine-induced hypothyroxinemic state. Thus concurrent iodine and selenium supplementation is required to restore thyroid hormone economy in this situation.

Drug Effects

Numerous drugs are known to affect the metabolism of thyroid hormones by directly interfering with enzymatic mechanisms or by altering the regulation of these processes.¹⁹⁸ The effect of PTU in inhibiting D1 activity provides it with a theoretical advantage over methimazole for use in the treatment of hyperthyroidism. In this condition, the increased expression of D1, combined with elevations in T₄ levels, probably contributes to the overproduction of T₃ in the thyroid gland.¹⁰³ However, this effect of PTU is noted only with relatively high doses of the drug (>1000 mg/day). At the usual doses prescribed for treating hyperthyroidism, methimazole (10 mg three times daily) actually results in more rapid restoration of the euthyroid state than does PTU (100 mg three times daily).¹⁹⁹

As noted previously, oral radiographic contrast dyes (e.g., iopanoic acid, sodium ipodate) are potent competitive inhibitors of all three deiodinase isoforms. Although they now are rarely used in clinical medicine as diagnostic agents, the rapidity with which they lower circulating T₃ levels makes them extremely useful in the treatment of severe hyperthyroidism. For example, treatment of patients with Graves’ disease with sodium ipodate (1 g daily per os) has been noted to lower serum T₃ levels by 58% within 24 hours of initiation of therapy—a decrease that is much greater than that noted with PTU (200 mg three times daily)²⁰⁰ or a saturated solution of potassium iodide (12 drops SSKI daily).²⁰¹ Of importance, these decreases in serum T₃ levels are associated with rapid improvement in cardiovascular complications, with beneficial effects on systemic resistance and cardiac output noted within 3 to 6 hours after treatment initiation.²⁰² However, because of the high iodine content of these drugs, escape from their T₃-lowering effects and exacerbation of hyperthyroidism may occur after several days of therapy.²⁰¹ It thus is important that PTU or methimazole be administered concurrently to impair thyroidal secretion, and that use of the contrast agent be discontinued when thyrotoxicosis has been adequately controlled. It is notable that iopanoic acid (1 g daily per os for 13 days) has been used successfully to rapidly control the hyperthyroid state prior to thyroidectomy in patients with severe amiodarone-induced thyrotoxicosis.²⁰³ (Iopanoic acid is currently available only from compounding pharmacies.)

Propranolol, in relatively modest doses (80 mg/day), also blocks the conversion of T₄ to T₃ by acting as a competitive inhibitor of 5′-deiodinase activity.²⁰⁴ This drug therefore results in a 20% to 30% decrease in serum T₃ levels and a slight elevation in serum T₄ in hyperthyroid patients. Other commonly used β-blockers do not have this effect. High doses of glucocorticoids (e.g., 2 mg of dexamethasone four times daily) have been demonstrated to lower T₃ levels within 24 hours in hyperthyroid patients with Graves’ disease,²⁰⁵ as well as in euthyroid individuals.²³ This activity provides part of the rationale for the use of these agents in severe thyrotoxicosis. Animal studies have demonstrated that this effect is due, at least in part, to diminished total body production of T₃, and indeed, decreased D1 activity has been observed in the liver of dexamethasone-treated rats.²⁰⁶ In addition, D2 activity in the brain of experimental animals is altered by several neuropharmacologic agents.²⁰⁷

Finally, the antiarrhythmic agent amiodarone is another iodine-rich compound that competitively inhibits the conversion of T₄ to T₃ and thus frequently causes a rise in serum T₄ levels and a modest decrease in serum T₃.²⁰⁸ Although most patients who take this drug remain euthyroid as judged by normal serum TSH levels, the large quantities of iodine liberated during the course of its metabolism can result in hypothyroid or hyperthyroid states, with the latter at times being extremely difficult to treat.²⁰⁹

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