Werner & Ingbar's The Thyroid: A Fundamental & Clinical Text, 9th Edition

38.Thermogenesis and the Sympathoadrenal System in Thyrotoxicosis

J. Enrique Silva

OVERVIEW OF THERMOGENESIS

Living organisms are open systems wherein multiple energy transformations take place. Heat is constantly generated simply by virtue of the fundamental laws of thermodynamics. The energy contained in food is captured largely in the form of adenosine triphosphate (ATP), and this is used to sustain other biochemical processes, as well as physical processes such as movement or creation of ion or chemical gradients. In all these energy transformations, a fraction is lost as heat. Heat production or thermogenesis is thus the obligatory consequence of the multiple energy transformations that occur in living cells. Homeothermic species, however, must produce more heat than poikilothermic species because they must maintain the core temperature in environments usually colder than the body. To produce sufficient heat, homeothermic species (mammals and birds) had to increase the energy cost of living. Metabolic rate, as judged by oxygen consumption (QO2), is clearly greater in mammals than in reptiles, whether measured in the whole animal or individual tissues (1). In addition to sustaining more energy transactions, the homeothermic machine has a lower thermodynamic efficiency; that is, for any given amount of work (chemical, mechanical), a larger amount of energy is dissipated as heat (2). The sum of the heat resulting from the minimal energy cost of living plus this extra thermogenesis derived from the vital process traditionally has been called obligatory thermogenesis, although it is probably more accurate to call it basal thermogenesis, because a fraction of it is not obligatory and can be reduced (Table 38.1). Indeed, most, if not all, this reducible fraction is thyroid hormone (TH) dependent and subject to regulation. In addition, homeothermic species can produce extra heat in response to cold or to dissipate energy when overfed. This is the so-called facultative or adaptive thermogenesis. This is activated when obligatory thermogenesis is not sufficient to maintain body temperature in colder environments. In such a situation, the body defends its temperature by reducing heat dissipation (vasoconstriction, piloerection) and by recruiting facultative thermogenesis in the form of shivering and increased metabolic heat. Shivering is the most acute response and is rapidly replaced by the production of metabolic heat. In small mammals, including the human newborn and infant, the main site of nonshivering facultative thermogenesis is the brown adipose tissue (BAT). In birds and larger mammals, including probably the adult human, skeletal muscle may be an important site of facultative thermogenesis (3,4,5). Not only is vasoconstriction a way to reduce heat dissipation, but it also constitutes a signal to activate thermogenic mechanisms. The reduction of blood flow to the skin in a cold environment makes it become rapidly colder, and temperature sensors bring this information to the hypothalamus, which coordinates the homeostatic responses.

TABLE 38.1. THERMOGENESIS IN HOMOTHERMIC SPECIES


Obligatory or basal thermogenesis

1. Heat derived from the minimal energy cost of living

2. Additional heat produced from

   a. Higher number of energy transactions (more active, more complex metabolism)

   b. Reduced fuel efficiency of at least some functions

Facultative or adaptive thermogenesis

1. Shivering thermogenesis

2. Nonshivering facultative thermogenesis


The cold and heat intolerance of patients with hypothyroidism and thyrotoxicosis are well known even to the layperson. TH is present in all vertebrates, in which it plays an important developmental function and regulates the operation of specific genetic programs, but only in homeothermic species (birds and mammals) does TH stimulate obligatory thermogenesis. I have recently reviewed this topic (6). How TH acquired this new function with the advent of homeothermy is simply a matter of speculation.

In considering the thermogenic effects of TH, it is important to distinguish those that directly generate the heat from those that play an ancillary role to provide the fuel for thermogenesis. Even today we are not sure what biochemical mechanisms are used by TH to produce heat. In general, TH induces heat production by increasing ATP turnover and by reducing the thermodynamic efficiency of the biologic machine. This is schematically illustrated in Figure 38.1. This view has experimental support. For example, the ATP cost to produce a given amount of glycogen from gluconeogenic precursors is greater in euthyroid rat hepatocytes than in the hypothyroid counterpart (7); also, for any amount of mechanical work, the amount of energy dissipated as heat is greater in the euthyroid than in the hypothyroid skeletal muscle (8). In terms of thermogenesis, increased energy transformations and reduced thermodynamic efficiency is exactly what differentiates the homeothermic from the poikilothermic species. One may thus consider TH as essential to realize such differences.

Basal metabolic rate could decrease 30% or more in severe hypothyroidism, indicating that heat production is reduced by the same amount, or probably more, because TH normally reduces fuel efficiency. Observations made in hepatocytes from hypothyroid, euthyroid, and thyrotoxic rats support this view. The difference in QO2 between hypo- and euthyroid hepatocytes was greater than the difference in ATP turnover (9), meaning that a larger fraction of the energy contained in the fuel oxidized was dissipated as heat in the euthyroid than in the hypothyroid condition.

FIGURE 38.1. Schematic representation of energy transformations and heat generation in aerobic living cells. The energy contained in substrates is largely released in the mitochondria, where a fraction is captured in form of adenosine triphosphate (ATP) and a fraction is lost as heat. The energy contained in ATP is then used to sustain vital functions. Although a fraction of energy is also dissipated as heat when ATP is utilized, it is estimated that it is less than that dissipated in ATP synthesis and probably not subject to homeostatic regulation. Thermogenesis can increase by augmenting ATP demands, hence synthesis and utilization, as well as by lowering the efficiency of ATP synthesis. Thyroid hormone utilizes both types of mechanisms to augment obligatory thermogenesis. Facultative thermogenesis in brown adipose tissue largely results from uncoupling phosphorylation. This is stimulated by the sympathetic nervous system and amplified by thyroid hormone. (Adapted from Silva JE. The thermogenic effect of thyroid hormone and its clinical implications. Ann Intern Med 2003;139:205–213, with permission.)

Thermogenesis obviously increases energy needs. Essential to support TH thermogenesis is the provision of extra energy. It makes teleologic sense, therefore, that TH also stimulates food intake and lipogenesis (see references 6 and 10, and references therein). The former provides additional energy; the latter, a mechanism to store it in a high caloric density form, fat. Hepatic de novo synthesis of fatty acids and of triacylglycerols (triglycerides) is increased (11), and these are rapidly mobilized to white adipose tissue and muscle, where TH stimulates lipoprotein lipase (12,13). In addition, TH enhances the lipolytic responses to catecholamines in white adipose tissue (14,15,16). Increased thermogenesis also demands additional oxygen supply to tissues, and TH clearly stimulates cardiac function, increasing cardiac performance and output as well as the capacity of blood to transport oxygen (17). Such an increase in myocardial efficiency and cardiac output would not be necessary if TH did not increase metabolic rate and heat production.

In many of these actions, but particularly those involving fuel and oxygen delivery, TH interacts with the sympathoadrenal system. Such interaction is also particularly important in facultative thermogenesis. TH is essential for BAT to express all its thermogenic potential, as discussed later. Such synergistic interaction takes place at several levels, namely potentiation of the norepinephrine signal at various steps, increase in enzyme activities needed for the thermogenic function, and a synergism with cyclic adenosine monophosphate (cAMP) at the gene expression level (18). On the other hand, sympathetic stimulation of BAT is affected by the thyroid status. By affecting basal thermogenesis, TH changes the need of facultative thermogenesis to maintain body temperature, hence sympathetic stimulation of BAT.

OVERVIEW OF THE SYMPATHOADRENAL SYSTEM

The sympathoadrenal system includes the sympathetic nervous system (SNS) and the adrenal medulla, the activity of which is centrally controlled at the level of the hypothalamus and brainstem. Both limbs of the sympathoadrenal system may be activated together, as in severe cold exposure and strenuous exertion, or independently, as in hypoglycemia, in which the adrenal medulla is stimulated and the activity of the SNS is suppressed. Norepinephrine, the main SNS neurotransmitter, is synthesized and stored in peripheral sympathetic nerve endings and released in response to coordinated nerve impulses targeted to specific tissues or organs. Epinephrine, in contrast, is a hormone secreted by the adrenal medulla in response to impulses carried in the splanchnic nerves and which influences processes throughout the body.

Catecholamines initiate their effects by interacting with cell surface receptors. Early pharmacologic and physiologic studies distinguished several types and subtypes of adrenergic receptors (19). With modern molecular cloning approaches, we have learned that this functional variability reflects the existence of different genes and variations in posttranscriptional processing (19,20,21). The α-adrenergic receptors mediate effects such as vasoconstriction, inhibition of insulin secretion (22), and stimulation of BAT type II thyroxine 5′deiodinase (23). The β-adrenergic receptors, on the other hand, mediate a variety of other processes, including cardiac stimulation, lipolysis, bronchodilation, vasodilation, and the production of metabolic heat. Both α2- and β-adrenergic receptors are coupled to adenylyl cyclase by means of guanosine phosphate–binding proteins (G proteins). Whereas β-adrenergic receptors stimulate the production of cAMP by interacting with stimulatory G proteins (Gs), α2 receptors interact with inhibitory G proteins (Gi) to inhibit adenylyl cyclase. Cyclic AMP activates protein kinases, generically called protein kinase A (PKA), which phosphorylates a wide variety of proteins, ultimately leading to end effects. The α1-adrenergic receptor second messengers are inositol triphosphate (IP3) and diacyl glycerol, both released from the hydrolysis of phosphatidyl-inositol. Diacyl glycerol directly stimulates protein kinase C (PKC), which in turn phosphorylates several proteins mediating a variety of end effects, and IP3 elevates cytosolic Ca2+, which influences cellular processes either directly or indirectly through the activation of Ca2+-calmodulin-dependent protein kinases.

INTERACTIONS BETWEEN THYROID HORMONES AND THE SYMPATHOADRENAL SYSTEM: AN OVERVIEW

The sympathoadrenal system and TH normally interact in a coordinated manner in a number of responses to the environment. Whereas the adaptive role of the sympathoadrenal system is more readily evident, providing the means for rapid adjustments, TH increases the capacity of the cells to respond to most actions of catecholamines and maintains a metabolic rate appropriate for the availability and mobilization of substrates essential to ensure vigorous adrenergic responses. On the other hand, catecholamines increase thyroxine (T4) to triiodothyronine (T3) conversion in selected tissues and may increase the retention of the TH receptor in the nucleus or the recognition of DNA sequences through PKA-mediated phosphorylation of the T3 receptor (24,25,26), the significance of which is yet to be defined. The synergistic interaction of both systems is essential, for example, in the response to cold exposure, when they interact to increase heat production. In general, a synergistic interaction is needed in states when the delivery of substrate or release of energy is required, such as during cold adaptation or overeating. In opposite situations, for example, starvation, both systems are turned down independently, at separate levels: sympathetic outflow decreases (27), and thyroidal secretion as well as T4 to T3 conversion are reduced (see Chapters 4B and 7).

In thyrotoxicosis and hypothyroidism, the interactions between the two systems are dominated by the fixation of one of them, the thyroid, at an abnormally high or low level. For example, in thyrotoxicosis, both obligatory thermogenesis and the responsiveness to catecholamines are increased, whereas the opposite occurs in hypothyroidism. The main response to these situations consists of a reduction or an increase, respectively, of sympathetic activity, as measured by norepinephrine turnover, in organs or tissues such as the heart and BAT (28,29,30). In patients with thyrotoxicosis, plasma and urinary levels of norepinephrine have been reported as either normal or diminished (31,32), whereas in hypothyroid patients urinary norepinephrine excretion is increased and plasma norepinephrine levels are significantly elevated (32,33), reflecting proportional increases in production rate (34,35) (Chapter 60). As discussed later, the type II 5′deiodinase (D2) is stimulated by norepinephrine and inhibited by T4. In thyrotoxicosis, therefore, the activity of D2 in BAT will be reduced and so will the generation of T3 in this tissue, limiting heat generation. Studies in animals show that in T4-induced thyrotoxicosis, the activity and the responses of BAT to cold are reduced (36,37). The opposite will occur in hypothyroidism, which enhances the activation of TH in BAT and helps to maintain its thermogenic function even in the presence of reduced plasma T4 (38).

It follows from the preceding that the sympathomimetic features of thyrotoxicosis cannot be explained by increased sympathetic activity or epinephrine secretion, nor can the bradycardia or impaired thermogenesis of hypothyroidism be accounted for by reduced sympathetic activity. It is the exaggerated or the reduced response to catecholamines that explains these manifestations of thyrotoxicosis or hypothyroidism. In addition, some effects of TH are similar to those of sympathoadrenal activation, particularly in the cardiovascular and central nervous systems.

EFFECTS OF THYROID HORMONE ON PHYSIOLOGIC RESPONSES TO CATECHOLAMINES

TH clearly enhances the β-adrenergic receptor–mediated effects of catecholamines, and this action is important both physiologically and medically. Regarding the α-adrenergic signaling pathways, the effect of TH is neither as clear nor (seemingly) as physiologically important as on the β-adrenergic pathways. In part, this may result from TH acting at different levels downstream of the α-adrenergic receptor, often in the opposite direction. For example, T3 reduces the expression of these receptors in liver and other organs (39) and enhances Ca2+-mediated processes, but not PKC-mediated processes, whereas it directly stimulates gluconeogenesis and glycogenolysis and has a net stimulating effect on liver respiration (40).

MECHANISMS WHEREBY THYROID HORMONE ENHANCES β-ADRENERGIC RECEPTOR–MEDIATED RESPONSES TO CATECHOLAMINES

The mechanisms whereby TH enhances the β-adrenergic effects are varied both qualitatively and quantitatively, in a tissue- and species-specific manner. They can be grouped into those whereby T3 increases the accumulation of cAMP in response to adrenergic stimulation and those in which T3 potentiates or enhances the effects of cAMP.

Amplification of the cAMP Response to β-Adrenergic Receptor Stimulation

TH can indeed markedly increase cAMP production. Plasma levels of cAMP are reduced in hypothyroid patients and are increased in hyperthyroid patients (41,42). In the latter group, the increase was diminished by the β-receptor antagonist, propranolol, whereas the infusion of epinephrine markedly increased urinary cAMP excretion in these patients (43). An increase of the number of β-adrenergic receptors, as well as a reduction in the number of α-adrenergic receptors by TH, has been documented in a number of tissues and cell systems from several species (see reference 39 for a review). For example, TH augments the density of β-adrenergic receptors in the heart (39,44), brown fat (45), and white adipose tissue (39) of rats. In humans, T3 administration increases the density of β-receptors on circulating monocytes (46), and thyrotoxicosis is associated with about doubling the density of β2-adrenergic receptors in white adipocytes (15). In general, the gain in receptor number in the transition from hypothyroidism to thyrotoxicosis is modest, rarely more than twofold, and additional mechanisms have to be invoked to explain the much larger increase in cAMP and some responses to catecholamines (15,16,47).

Thyroid hormones increase adenylyl cyclase activity in the rat epididymal fat pad (48) and brown adipocytes (47) and potentiate cAMP accumulation in response to catecholamines in isolated adipocytes from thyrotoxic human subjects or T3-treated rats (16,49). In addition, TH affects the expression of adenylyl cyclase isoforms (50,51,52). Probably the most important postreceptor mechanism whereby thyroid hormones enhance cAMP responses is by decreasing the level of certain G-protein subunits. Several studies, using different systems, indicate that T3 down-regulates some species of Gαi and Gβsubunits (53,54,55,56). The former leads to less Gi-mediated inhibition of adenylyl cyclase, whereas the latter makes more GαS subunits available to mediate stimulation of the cyclase. There is also evidence that TH may limit cAMP degradation by down-regulating some phosphodiesterases in adipose tissue (57). By other mechanisms less well characterized, such as an increase in cytosolic Ca2+, thyroid hormones could contribute to amplifying cAMP accumulation in response to catecholamines (40).

Enhancement of cAMP Effects by Thyroid Hormone

In addition to increasing the availability of cAMP, TH may enhance the effects of cAMP. Examples of this level of action of TH are the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) and BAT uncoupling protein 1 (UCP1). Given the growing list of genes regulated by cAMP (58), some of them also regulated by TH, this novel mechanism may well turn out to be common.

The enzyme PEPCK is a rate-limiting enzyme in gluconeogenesis. PEPCK gene transcription is stimulated by cAMP (produced in response to glucagon or epinephrine) through cAMP response elements (CREs) identified and characterized in the gene sequence (59). TH stimulates gluconeogenesis and the activity of PEPCK (60) interacting in a synergistic manner with cAMP at the gene level through a thyroid hormone response element (TRE) (61).

BAT is an important site of facultative thermogenesis regulated by catecholamines, a unique heat-producing organ in mammals (62,63). This tissue plays an important role in temperature regulation and diet-induced thermogenesis in small animals and during the newborn period in larger species, including humans (62,63). UCP1 is the key molecule in BAT thermogenesis. Norepinephrine (via cAMP) and T3 synergistically stimulate the expression of the UCP1 gene; each separately induces a twofold to threefold increase in gene expression, whereas together the induction is about 20-fold (64). The synergistic interaction also takes place at the gene level. Two TREs have been found high upstream in a critical enhancer element. Of the two, the downstream TRE and an adjacent downstream sequence seem essential for the synergism between cAMP and T3, both of which interact with an additional, less well-defined downstream cAMP response sequence located near the minimal promoter of the gene (see reference 18 and references therein).

EFFECTS OF CATECHOLAMINES ON EXTRATHYROIDAL T4 CONVERSION TO T3

Catecholamines stimulate T4 5′deiodination to T3. Because T3 is intrinsically 10 or more times more potent than T4, this is a mechanism whereby catecholamines enhance the potency of thyroidal secretion. Interestingly, this activation may occur in a tissue-specific manner.

Biochemical and physiologic studies of T4 to T3 conversion have defined the existence of two pathways for the generation of T3 (65,66). These two pathways correspond to two separate selenoproteins with iodothyronine 5′-deiodinating activity, type I (D1) and type II (D2) deiodinases encoded by two separate genes (comprehensively reviewed in reference 67) (see also Chapter 7B). D1 is largely present in the liver, kidney, and thyroid, and it is believed to be the main source of extrathyroidally generated plasma T3, whereas D2 has been demonstrated in pituitary, central nervous system, placenta, and BAT, and, following its cloning, in human skeletal muscle and heart (68). The D2 is believed to provide, predominantly, a local source of T3 that is subject to tissue-specific regulation (69,70,71).

Catecholamines and D1

The possibility of a significant effect of catecholamines on peripheral conversion of T4 to T3 was raised by studies demonstrating that β-adrenergic blockade, both in hyperthyroid and in hypothyroid patients maintained on a fixed dose of T4, decreased the circulating level of T3 (see reference 72 for review). Nevertheless, subsequent work suggests, without excluding a minor in vivo stimulatory effect of catecholamines on D1, that inhibition by β-adrenergic antagonists is largely the result of a direct effect of these agents on D1. Thus, β-adrenergic blocking agents can actively block T4 to T3 conversion in crude homogenates of the liver, and catecholamines do not stimulate T3 formation in whole-cell preparations. D- and L-propranolol are equally potent for inhibiting D1, and the inhibitory potency of various other compounds correlates better with the lipid solubility and membrane stabilizing properties than with their β-blocking potency (73,74).

Catecholamines and D2

In the BAT of rats (23,69) and other species (75,76), D2 can be vigorously stimulated by catecholamines. The α1-receptor agonists suffice to stimulate D2 in vivo, and the stimulation by norepinephrine, a nonselective agonist, can be obliterated by prazosin, a specific α1-receptor antagonist (23,77). However, experiments in isolated brown adipocytes show the need for both the α1-pathway and cAMP for full stimulation (78) and suggest that the α1-pathway somehow amplifies a cAMP-dependent signal. The brain is another tissue in which the local D2 is the major source of T3 (71). An old report showing that the injection of epinephrine significantly increased the amount of tracer T3 in the brains of mice after the injection of radiolabeled T4 without detectable radiolabeled T3 in the serum (79) indicated that catecholamines could stimulate the D2 in the brain. It was found later that this enzyme can be activated by cAMP, at least in astrocytes (80), and a CRE was identified on the 5′-flanking sequence of the D2 gene (81,82).

In the rat, acute or sustained adrenergic stimulation of BAT results in a striking increase in local T3 generation, which can nearly saturate the T3 receptors of this tissue (83) as well as contribute to the plasma pool of T3 (77). The increase in local T3 and the high level of nuclear T3 occupancy have proved essential for a full response of uncoupling protein, α-glycerophosphate dehydrogenase, and other enzymes to adrenergic stimulation (70,84), which now has the support of observations in transgenic D2-deficient mice (85). This level of T3 receptor occupancy in the absence of T4 is possible only with more than a 10-fold elevation of the plasma T3 levels (84). As mentioned earlier, in addition to its responsiveness to norepinephrine and cAMP, D2 activity is increased in hypothyroxinemia and is promptly and powerfully inhibited by T4 (69,86), by virtue of which this enzyme plays a key role in coordinating the synergism between norepinephrine and T3 in brown fat and possibly other tissues.

Early investigations suggested that a significant fraction of plasma T3 in humans could derive from the activity of D2 (87). The recent finding of D2 messenger RNA (mRNA) and activity in human skeletal muscle (88) lends further support to this possibility. Furthermore, even though normal thyroid largely contains D1, the hyperactive thyroid gland of Graves' disease contains large amounts of D2 (89); however, because this enzyme is so sensitive to T4 inhibition (69,86), it is not yet clear to what extent D2 could contribute to the extrathyroidal T3 pool in thyrotoxicosis.

PHYSIOLOGIC AND CLINICAL CONSEQUENCES OF CATECHOLAMINE-THYROID HORMONE INTERACTIONS IN THYROTOXICOSIS

Cardiovascular Responses

The fact that the β-receptor blockade ameliorates some of the cardiovascular manifestations of thyrotoxicosis suggests that catecholamines play a role in their genesis. Because levels of catecholamines are not elevated and there is a reduction in the sympathetic input to the heart (90), the sympathetic component of the cardiovascular manifestations of thyrotoxicosis largely reflects an enhanced heart sensitivity, responsiveness, or both to catecholamines by virtue of mechanisms discussed previously. In humans, most studies [with a few exceptions (91,92)] demonstrated exaggerated heart rate responses to catecholamines in thyrotoxicosis (93). It is likely that the extent of participation of the SNS in the hyperdynamic cardiovascular state of thyrotoxicosis varies, depending on the physiologic status and the extent to which the sympathetic outflow in thyrotoxicosis is reduced (29). Even if lower than normal, the adrenergic stimulation of the heart, such as in stressful situations or exercise, will result in exaggerated cardiovascular responses. This exaggerated responsiveness of the thyrotoxic heart to adrenergic stimulation, on the other hand, may be advantageous at high load rates, as suggested by the negative effect of β-adrenergic blockade in the left ventricular ejection fraction during exercise in hyperthyroid persons (94).

It is important to emphasize that T3 directly affects biochemical changes in the myocardium, leading to tachycardia, increased contractility, and accelerated relaxation (95,96) (see also Chapter 31). The problem of the extent to which enhanced catecholamine responsiveness and sensitivity participate in the generation of hemodynamic changes in thyrotoxicosis, namely, the direct effects of TH, has been approached by studying the hemodynamic effects of β-blockers in thyrotoxicosis (see reference 17 for review). In general, results show that β-adrenergic blockade reduces, but does not normalize, heart rate and cardiac output. Most researchers agree that β-blockade does not significantly decrease the enhanced contractility characteristic of the thyrotoxic heart, in agreement with the observation that the reduction in cardiac output obtained with β-blockers is proportional to the drop in heart rate.

An important factor in the elevated cardiac output and hyperdynamic circulation of thyrotoxicosis is the reduction in peripheral vascular resistance (17). This reduction is thought to be mediated by a globally reduced sympathetic tone to skeletal muscle (29), along with decreased responses to contractile stimuli mediated by α1-adrenergic receptors and enhanced responsiveness to β2-adrenergic receptor–mediated dilatation (97,98). Indeed the contribution of β2-adrenergic receptor in vascular peripheral resistance, particularly at the skeletal muscle level, has become more evident in recent times, and seems to be important in hyperthyroidism (17,99,100). Actually, β-adrenergic antagonists have been reported to increase peripheral vascular resistance (see references 93 and 101 and references therein), and this should be a reason to be cautious in the use of β-blockers in certain patients with severe hyperthyroidism (102), as discussed later.

Metabolic Responses

Lipolysis

TH accentuates the lipolytic effect of catecholamines in experimental animals and humans. T3 not only enhances the strength of the norepinephrine signal by a variety of mechanisms, but it also may stimulate lipolysis by other, post–adenylyl cyclase mechanisms that as yet are not well defined. Increased sensitivity, responsiveness, or both to catecholamines in thyrotoxicosis has been documented in vivo and in vitro, in adipose tissue or adipocytes of several species, including humans (15,16,103). The mechanisms that strengthen the norepinephrine signal vary with the species. In rats, for example, it has been convincingly documented that TH inhibits the expression of Gb subunit (104) and Gi subunits (105,106). These proteins are underexpressed in adipocytes exposed to excess TH, whereas they are overexpressed in hypothyroidism. Recent studies in human white adipocytes from patients with hyperthyroidism, before and after treatment, as well as from euthyroid controls, suggest that an increase in β2-adrenergic receptors occurs. This is associated with increased responsiveness to β2, but not β1 or α2, agonists, as well as increased response to cAMP analogues or direct stimulation of adenylyl cyclase, suggesting a dual mechanism operating at both the receptor and postreceptor levels (15). The up- and down-regulation of several genes relevant to the lipolytic response has been documented in primary cultures of human subcutaneous adipocytes (107). There is indeed a coordinated increase in agonistic and decrease in antagonistic genes, such as α2-adrenergic receptors, Gi protein, and phosphodiesterase, resulting in enhanced responses to norepinephrine via the β2-adrenergic receptor. These observations are consistent with a much greater increase in lipolytic responses to norepinephrine (>10-fold) than in the number of β2-adrenergic receptors (by twofold to threefold) in adipocytes from thyrotoxic persons. Pharmacologic approaches in the past, though, failed to support a major role for α2-adrenergic receptors, which inhibit adenylyl cyclase through Gi proteins in the increased lipolytic responses (15,108). Lastly, TH also directly stimulates lipogenesis and fatty acid oxidation (109), contributing to accelerated fatty acid turnover.

Thermogenesis

As explained earlier, TH plays a critical role in thermogenesis. At least 30% of the heat produced from basal metabolic rate, so-called obligatory or basal thermogenesis (Table 38.1), is TH-dependent, and TH is essential for full facultative or adaptive thermogenesis responses. The relationship between catecholamines and thyroid hormones in the regulation of metabolic heat production in mammalian organisms is complex. Both thyroid hormones and the SNS participate in thermogenesis (reviewed in references 6 and 110). The SNS is concerned chiefly with rapid adjustments in heat production above basal rates in response to low environmental temperature or dietary intake (111) (facultative thermogenesis), whereas TH has the double role of being the main controller of basal thermogenesis and potentiating catecholamine-induced facultative thermogenesis.

TH increases basal thermogenesis, seemingly by a dual mechanism: by increasing ATP demands and by reducing the thermodynamic efficiency of ATP synthesis (Fig. 38.1). There is normally a fraction of energy dissipated as heat in the process of ATP synthesis as well as in the utilization in vital processes of the energy stored in ATP. Simply by increasing ATP demands and hence turnover, TH augments heat production, but this mechanism accounts for only a fraction, roughly 50%, of the increase in energy expenditure resulting from TH action (see reference 6 and references therein). The other part is probably the result of a decrease in the energy efficiency of vital processes, particularly in the synthesis of ATP. The fraction of energy dissipated as heat in ATP synthesis is greater than that lost in the utilization of ATP and is subject to regulation. The concept that TH could reduce the efficiency of ATP synthesis is quite old but remained dormant for many years, and it was only recently revived (112) as a result of the analysis of the oxygen consumption as a function of the proton gradient across the inner mitochondrial membrane. Harper et al. have demonstrated that TH treatment of animals or cells results in increased proton leak in the mitochondria (9,113). Based on studies in rat hepatocytes, this mechanism is more important in the transition from hypothyroidism to euthyroidism than in thyrotoxicosis (9). These results support the concept that sustaining thermogenesis is a primary physiologic role of TH, rather than the mere consequence of increasing metabolic rate. While still significant in thyrotoxicosis, this mechanism is less important than increased ATP turnover as source of heat. The mechanism of the proton leak remains speculative. The novel uncoupling proteins UCP2 and UCP3 (see reference 114 for review) have the potential to account for the proton leak. It was recognized early on that UCP3 was stimulated by TH and adrenergic receptor activation (115). The major problem derives from the observation that transgenic UCP3 knockout mice do not respond differently from the cognate controls to T3 (116), and neither this model nor the UCP2 knockout mice shows evidence of a thermogenic defect (116,117,118). Although this evidence is compelling, it is not definitive. TH can possibly utilize other thermogenic mechanisms that may be recruited as the level of TH increases, and the doses of T3 injected in those experiments (116) were many times the daily production rate of this hormone.

Looking for alternative thermogenic mechanisms, we have investigated the mitochondrial glycerol-3-phosphate dehydrogenase (mGPD; EC 1.1.99.5), because this enzyme has long been known to be stimulated by TH (119). Moreover, mGPD is stimulated by TH only in tissues and species where TH increases thermogenesis (119,120,121). mGPD is the rate-limiting enzyme in the glycerol-3-phosphate (G3P) shuttle. This and the malate-aspartate shuttle transfer reducing equivalents (H+, e-) from cytoplasm to mitochondria to produce H2O and capture the energy released as ATP. These shuttles are present in most cells, but their activity in absolute and relative terms varies substantially. For example, the G3P shuttle is very active in skeletal muscle, whereas the malate-aspartate shuttle is of minor importance (122). The other enzyme in the G3P shuttle is the cytoplasm glycerol-3-phosphate dehydrogenase (cGPD; EC 1.1.1.8). This enzyme reduces dihydroxyacetone-3-phosphate (DHAP) to G3P that can be used for lipid synthesis or reoxidized to DHAP by mGPD, which then transfers the reducing equivalents to the complex III of the mitochondrial respiratory chain. Depending on the tissues and prevailing conditions, the G3P shuttle can thus generate ATP or store energy as fat. Because the electrons enter the respiratory chain in complex III, only two ATPs are generated per pair of electrons or per atom of oxygen, as opposed to three ATPs when the electrons enter in complex I, as occurs with the use of the malate-aspartate shuttle. The G3P shuttle then allows for the rapid generation of ATP but with less efficiency. The G3P shuttle is, not surprisingly, quite active in cells that require rapid ATP generation such as flight muscle of insects, pancreatic islets, β cells, sperm cells, and muscle. Interestingly, mGPD is also abundant in BAT (123), although its role in this tissue has not been defined.

For the reasons briefly outlined, we have been investigating the phenotype of a mouse with targeted disruption of the mGPD gene (124). Mice with deletion of both alleles (mGPD–/–) had lower energy expenditure as judged by oxygen consumption and food intake (125). A compensated thermogenic defect was evident by the signs of chronic BAT stimulation and elevation of the plasma T4 and T3 concentrations. The elimination of these two responses made evident the thermogenic defect of mGPD–/– mice (125). They also have a twofold increase in UCP3 mRNA level in muscle, but the compensatory value of this change awaits confirmation. These results indicate that mGPD plays a role in the physiologic stimulation of obligatory thermogenesis by TH. Indeed, the increase in oxygen consumption caused by high doses of T3 was not different between the mGPD–/– mice and the littermates of wild-type genotype.

It has been mentioned that BAT is an important site of facultative thermogenesis, where the synergism between the SNS and TH is essential to the realization of BAT thermogenic potential and where D2 plays a pivotal role. In thyrotoxicosis, the mechanisms regulating this deiodinase may serve the function of preventing an unwanted thermogenic synergism between TH and catecholamines because this enzyme is highly sensitive to inhibition by elevated plasma T4levels (69,86) and very dependent on continued adrenergic stimulation (64). Indeed, it has been found that brown-fat responses to cold are blunted in rats with T4-induced thyrotoxicosis (36,37). Another locus of coordinated interaction between SNS and TH is the β3-adrenergic receptor. These receptors are expressed predominantly in BAT and white adipose tissue of several species, including humans (see reference 126 for review). They are G protein–coupled receptors mediating metabolic responses, such as thermogenesis and lipolysis. Interestingly, the expression of β3-adrenergic receptors is increased in hypothyroid BAT and is rapidly reversed by an injection of T3, whereas the opposite occurs in white fat (127). This powerful effect of T3 over BAT β3-adrenergic receptors may be yet another mechanism for curbing facultative thermogenesis in thyrotoxicosis (127).

Skeletal muscle is likely an important site of facultative thermogenesis in adult humans (128) and in birds (see references 96 and 129 and references therein), who have little or no BAT. Muscle facultative thermogenesis is directly or indirectly (e.g., through fatty acids) stimulated by catecholamines (5) in a TH-dependent manner (8). It is conceivable that facultative thermogenesis in these sites also is reduced in human thyrotoxicosis and, furthermore, that the hyperthermia of thyroid storm represents the failure of the body to suppress the sympathetic activity in such sites. This view is supported by observations that thyroid storm may be triggered by stressful situations or by sympathomimetic agents (130). Moreover, propranolol has a beneficial effect on thyroid storm hyperthermia, but it does not reduce resting energy expenditure in uncomplicated thyrotoxicosis (131), in agreement with a suppressed adrenergic contribution to thermogenesis in this state.

Other Metabolic Responses

Muscle-protein loss (Chapter 41) associated with thyrotoxicosis is not likely to be mediated by catecholamines because muscle sympathetic activity is frequently reduced in thyrotoxicosis (29), and β-blocking agents have no effects on protein degradation in thyrotoxicosis in either rats or humans, as judged by 3-methylhistidine excretion (132,133).

Thyrotoxicosis also appears to modify the effect of catecholamines on insulin secretion in rats and in human subjects (134,135,136). Depending on the circumstances, catecholamines may either suppress or stimulate insulin secretion; suppression is mediated by an α-adrenergic mechanism (22), and stimulation involves the β-adrenergic receptor (137). In both experimental and clinical thyrotoxicosis, β-receptor-mediated stimulation of insulin secretion is enhanced (134).

Catecholamines are known to increase calcium mobilization from the skeleton (138), which is believed to be mediated by β-adrenergic receptors, as recently described in human and rat osteoblasts (139). That the stimulation of calcium release from bone in thyrotoxicosis may be mediated at least in part by catecholamines finds support in the observation that β-blockers may significantly reduce serum calcium in hypercalcemic but not in normocalcemic thyrotoxic patients or in normal subjects (140,141).

ADRENERGIC BLOCKADE IN HYPERTHYROIDISM

It follows from the foregoing discussion that, in view of the enhanced tissue responses to catecholamines, it may be beneficial in thyrotoxicosis to protect the body against residual sympathetic activity or during the derepression of SNS that may follow stimuli such as emotion, stress, and exercise. Reserpine, guanethidine, and propranolol all reverse

some of the alterations that accompany the thyrotoxic state (101). Because most of the catecholamine effects enhanced by TH are mediated by β-adrenergic receptors, β-adrenergic antagonists probably represent the most specific way to accomplish the sympathetic blockade. The efficacy of propranolol in the symptomatic management of thyrotoxicosis was demonstrated in several studies (101). β-adrenergic blockade does not reduce thyroidal secretion, and although several β-blockers induce a modest decrease in plasma T3 levels (72), these actions of β-blockers are believed to play a minor role in the beneficial effects of sympathetic blockade. Studies on the levels of cAMP (42) suggest that most of the clinical effect, particularly in lower doses, is due to β-adrenergic receptor blockade. Even though some reports comparing D- and L-propranolol (142) suggest that part of the beneficial effects of this drug may be independent from β-adrenergic antagonism, such a mechanism does not seem clinically important.

Clinical and Physiologic Effects of Adrenergic Blockade

The most dramatic effects of adrenergic blockade in uncomplicated thyrotoxicosis are symptoms derived from exaggerated responses to catecholamines and the hemodynamic changes associated with thyrotoxicosis. The hemodynamic effects of adrenergic blockade in experimental and spontaneous thyrotoxicosis have been the subject of repeated studies. Heart rate, cardiac output, systolic blood pressure, and pulse pressure are decreased, whereas circulation time is prolonged and peripheral vascular resistance is increased (17,93,101,143) by adrenergic blockade. This latter effect is probably due to the cancellation of β2-adrenergic receptor activity, which is thought to mediate the peripheral vasodilatation of thyrotoxicosis, particularly in muscle (99). As mentioned earlier, the reduction in cardiac output following sympathetic blockade in hyperthyroidism closely corresponds to the decrease in heart rate with little or no effect on myocardial contractility (92,144,145), supporting the idea that most of the enhanced contractility reflects a direct action of T3 on the myocardial Ca2+-dependent- and myosin heavy-chain ATPases (95,144). It is important to recall that in exercise, in conditions of overload, or in impending congestive failure, the SNS contributes significantly to maintain cardiac output; in such conditions, the indiscriminate use of adrenergic blocking agents is likely to be detrimental (94,146,147). In such cases it is preferable to use selective β1-adrenergic receptor blocking if β-adrenergic receptors are deemed necessary to reduce heart rate and restlessness.

Lid lag, lid retraction, widened palpebral fissure, as well as tremor and hyperreflexia, all expressions of increased adrenergic responses, are correspondingly reduced by sympathetic blockade (148,149,150,151). Interestingly, the tremor is a β2-mediated effect, as may be the hypokalemia seen in a few patients (24). Nervousness and irritability also are diminished (152). Some of the more unusual but dramatic neurologic manifestations of thyrotoxicosis also are ameliorated by β-adrenergic blockade. Thyrotoxic periodic paralysis (24–153), choreoathetosis (154), and upper motor neuron weakness and spasticity (155) have been reported to improve with β-receptor blocking agents. Beta-adrenergic blockade also has been reported to reduce the hypercalcemia associated with hyperthyroidism (141,156,157).

Adrenergic blockade may reduce weight loss in hyperthyroid subjects at high doses (158), but it does not restore weight to normal (101,159). The reported improvement in nitrogen balance induced by β-blockers (159) probably is the result of a reduction in intestinal hypermotility and improved absorption (160) rather than from blocking catabolic effects of catecholamines. Although the clinical correlates of increased metabolic rate, heat intolerance, and sweating are ameliorated by β-blockade (101,161), β-blockade does not seem to reduce hypermetabolism to a clinically significant extent (131), except probably in thyroid storm, as discussed earlier.

Clinical Usefulness of Adrenergic Blockade in the Treatment of Thyrotoxicosis

Beta-blockers have significantly improved the management of the symptomatic thyrotoxic patient. In mild to moderate thyrotoxicosis, subjective symptomatic improvement often can be achieved with 40 to 80 mg of propranolol per day. Although thyrotoxicosis increases plasma clearance of propranolol (158,162,163), clinical goals can be attained with relatively low doses empirically determined. A reduction in pulse rate, particularly after mild exercise in the office, such as a few squattings, often provides a useful guide. In my experience, 40 mg of nadolol, a non-β-selective antagonist, at bedtime is an easy, effective way to obtain symptomatic relief.

Probably because of direct, unrestrained participation of the SNS, the effect of these agents in the thyroid storm is often dramatic (101). In these patients, doses of propranolol in excess of 160 mg per day may be necessary. A sensible approach is to control the acute manifestations with up to 5 to 10 mg of intravenous propranolol, at 1 mg per minute, followed by oral maintenance doses commenced 4 to 6 hours later and titrated to maintain reasonable control of the symptoms and tachycardia. When congestive failure, pressure, or volume overload is an issue, it is better to use short-acting β-blockers (102) and preferably β1-adrenergic receptor selective agonists because blocking β2-adrenergic receptors may be associated with increases in vascular peripheral resistance (99).

β-adrenergic blockade is also useful in thyrotoxic patients undergoing emergency surgery. Severely thyrotoxic patients undergoing surgery frequently have tachycardia and high temperature in the postoperative period, probably reflecting the sympathetic activation in response to the surgical stress (164). Propranolol, with or without concomitant inorganic iodides (164,165,166), or even with dexamethasone (167), has been used safely in hyperthyroid patients in preparation for thyroidal or nonthyroidal emergency surgery. Even though the metabolic and endocrine responses to surgical stress appear to be diminished by propranolol (168,169), β-blockers do not significantly antagonize the catabolic effects of the excess thyroid hormones or their direct thermogenic effects (159,170,171,172,173), as described in reports of failure of propranolol to prevent thyroid storm (174,175). In cases of untoward effects of thionamides, there is consensus that it is safer to include iodides to reduce thyroidal secretion (166,168) or dexamethasone (167) to counteract some effects of TH by inhibiting conversion of T4 to T3. Also, the higher doses of β-blocker used in these patients will eliminate completely the sympathetic stimulation of the heart, which may precipitate congestive heart failure in patients with limited reserve resulting from preexisting heart problems or pressure or volume overloads (94,146).

Propranolol also has been used in the treatment of thyrotoxicosis during pregnancy (176,177) and in the preoperative preparation of pregnant women for thyroidectomy (178). Although propranolol is effective for controlling the symptoms of thyrotoxicosis in the mother, it has potential adverse effects on the fetus and on the course of labor. Neonatal apnea, bradycardia, hypoglycemia, polycythemia, hyperbilirubinemia, and premature labor all have been described (176,179). Congestive heart failure in the newborn is a dreaded potential complication (180). In the thyrotoxic patient who is pregnant and in parturition or in need of cesarean section, propranolol may be life saving, but potential adverse effects on the fetus should be anticipated and call for an expectant attitude. Propranolol actually may play an important role in the management of neonatal thyrotoxicosis (181,182,183), but, as is the case of the transplacental passage route, it also may cause severe side effects (184) and should be used with extreme care.

Sympathetic blockade, particularly β-adrenergic blockade, certainly has an important place in the management of thyrotoxicosis. This approach should be used judiciously, however, and with the best possible understanding of the pathophysiology of the individual patient. It cannot be overemphasized that β-adrenergic blockade represents a palliative aspect in the preparation for surgery and to treat or ameliorate the manifestations of thyroid storm. Therefore, it must be used in conjunction with other measures that reduce TH secretion (large doses of iodine) and T4 to T3 conversion (propylthiouracil, iopanoic acid, and glucocorticoids) and that antagonize some end effects of T3 (glucocorticoids).

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