ABSTRACT

Thyroid hormone is indispensable for normal development and metabolism of most cells and tissues. Thyroid hormones are metabolized by different pathways: glucuronidation, sulfation, and deiodination, the latter being the most important. Three enzymes catalyzing deiodination have been identified, called type 1 (D1), type 2 (D2) and type 3 (D3) iodothyronine deiodinases. D1 and D2 have outer ring deiodinase activity, converting the prohormone T4 to its bioactive form T3 and degrading rT3 to 3,3’-T2. D3 has inner ring deiodinase activity and degrades T4 to rT3 and T3 to 3,3’-T2.

D1 is largely expressed in liver and kidney. Its main role is clearance of rT3 from the circulation and it also contributes to production of plasma T3. D2 is importantly expressed in the central nervous system, pituitary, brown adipose tissue and muscle and, generally, its expression reciprocally responds to changes in thyroid state. D2 serves to adapt cellular thyroid state to changing physiological needs. D3 is importantly expressed in fetal tissues and in adult brain tissue. In addition, D3 can be re-expressed under certain pathological conditions such as critical illness or in specific cancers.

In recent years, the paradigm has evolved that D2 and D3 can locally modify thyroid hormone bioactivity independent of serum thyroid hormone concentrations. Its physiological relevance has been shown in various developmental and regenerative conditions. Future studies may reveal if modifying (local) deiodinase activity can be of use under certain circumstances. For complete coverage of all related areas of Endocrinology, please see our online FREE web-book, www.endotext.org. and WWW.THYROIDMANAGER.ORG.

 

 

CLINICAL SUMMARY

 

In healthy humans the thyroid gland produces predominantly the prohormone T4 together with a small amount of the bioactive hormone T3. Most T3 is produced by enzymatic outer ring deiodination (ORD) of T4 in peripheral tissues. Alternative, inner ring deiodination (IRD) of T4 yields the metabolite rT3, the thyroidal secretion of which is negligible. Normally, about one-third of T4 is converted to T3 and about one-third to rT3. The remainder of T4 is metabolized by different pathways, in particular glucuronidation and sulfation. T3 is further metabolized largely by IRD and rT3 largely by ORD, yielding in both cases the metabolite 3,3’T2. Thus, ORD is regarded as an activating pathway and IRD as an inactivating pathway.

Three enzymes catalyzing these deiodinations have been identified, called type 1 (D1), type 2 (D2) and type 3 (D3) iodothyronine deiodinases. All three deiodinases have been cloned and characterized in a variety of species. Together, they form a family of homologous selenoproteins which consist of »250-280 amino acids, including an essential selenocysteine residue in the active center. It is remarkable, therefore, that production and metabolism of thyroid hormone are dependent on two trace elements, namely iodine and selenium.

D1 is expressed mainly in the liver, the kidneys and the thyroid. In particular the hepatic enzyme is thought to contribute importantly to peripheral T3 production and to be the main site for the clearance of plasma rT3. These processes are mediated by the ORD activity of D1. However, D1 also has IRD activity, especially towards sulfated T4 and T3. Therefore, in addition to the bioactivation of T4 to T3, D1 also catalyzes the degradation of thyroid hormone. An important property distinguishing D1 from the other deiodinases is its sensitivity to inhibition by the anti-thyroid drug propylthiouracil (PTU). The important role of D1 in the peripheral production of plasma T3 has been demonstrated by the marked decrease in plasma T3 levels in T4-substituted athyreotic subjects treated with PTU.

D2 has been studied extensively in the central nervous system, the pituitary, brown adipose tissue and skeletal muscle of experimental animals. D2 has only ORD activity and its expression shows adaptive changes in response to alterations in thyroid state, which serves to maintain tissue T3 levels in the face of varying plasma T4 and T3 levels. Cell-specific modulation of D2 enables to adapt to physiological needs.

D3 mediates the degradation of thyroid hormone since it has only IRD activity. The brain is the predominant D3-expressing tissue in adult animals, and may thus be the main site for the clearance of plasma T3 and for the production of plasma rT3. However, high D3 activities have been demonstrated in the placenta and the pregnant uterus as well as in different fetal tissues. The high D3 activities at these sites appear to prevent exposure of fetal tissues to high T3 levels, allowing the growth of these tissues. T3 is only required at the differentiation stage of tissue development.

Whereas intitial studies focused on the role of the deiodinases in maintaining normal serum T3 concentrations, the paradigm has evolved that these enzymes can locally modify TH bioactivity independent of serum TH concentrations. An example is the critical role of D2 and D3 in cochlear development, since Dio2-/- as well as Dio3-/- mice have severe hearing loss. These enzymes prevent too little or too much hormonal stimulation at inappropriate stages in development. At immature stages, D3 limits stimulation by T3. Postnatally, a double switch occurs with a decline in D3 and an increase D2, resulting in a local T3 surge which is independent of serum T3 levels and triggers the onset of auditory function.

Clinically, the importance of the deiodinases in the regulation of thyroid hormone bioactivity is apparent when their activity is affected by patho-physiological conditions. Examples of such conditions are iodine insufficiency, thyroidal and non-thyroidal illness and malnutrition.

Expression of D1 and D3 is under positive control and that of D2 is under negative control of thyroid hormone. Therefore, the relative contribution of D1 and D2 to peripheral T3 production varies with thyroid state, with D1 prevailing in the hyperthyroid and D2 in the hypothyroid state. The proportions of T3 being produced via D1 or D2 in euthyroid subjects remain to be established.

In iodine deficiency, D1-mediated peripheral T3 production decreases but this is in part compensated by an increased thyroidal T3 production, which is mediated by an increased TSH secretion as well as by increased efficiency of D2-mediated T3 production. Simultaneously, neuronal D3 expression decreases thereby prolonging the local half-life of T3.

In non-thyroidal illness (NTI) plasma T3 is often decreased and plasma rT3 increased; plasma FT4 is still in the normal range depending on the severity of disease. The changes in plasma T3 and rT3 are explained by a diminished conversion of T4 to T3 and of rT3 to 3,3-T2 by D1 in the liver. Although this may be caused to some extent by decreased D1 expression or cofactor levels, a diminished activity of transporter(s) mediating hepatic uptake of T4 and rT3 appears to be another important mechanism. This also holds for the generation of the low T3 syndrome in malnutrition.

In addition to a decreased peripheral T3 production, the low T3 syndrome of NTI may also be caused by stimulated thyroid hormone degradation due to induction of D3 in different tissues. Pathological expression of D3 may be so high that this results in a state of consumptive hypothyroidism with low serum (F)T4 and T3 and very high rT3 levels. This has been shown in different patients with hemangiomas which express very high D3 activities.

Finally, peripheral production of T3 can be inhibited by a variety of drugs, including PTU, dexamethasone, propranolol, and iodinated compounds such as the radiographic agents iopanoic acid and ipodate and the anti-arrhythmic drug amiodarone. PTU is a specific uncompetitive inhibitor of D1, while iopanoic acid and ipodate are competitive inhibitors not only of D1 but also of D2. In addition, the radiographic agents inhibit hepatic uptake of thyroid hormone. Amiodarone and its metabolite desethylamidarone may also interfere with peripheral thyroid hormone levels by inhibition of deiodinase activities and tissue thyroid hormone transport. Little is known about the mechanisms by which propranolol and dexamethasone inhibit peripheral T3 production. Combinations of these drugs (e.g. PTU, ipodate, dexamethasone and/or propranolol) may be used to acutely decrease plasma T3 levels in patients with severe hyperthyroidism (toxic storm).

Thyroid hormone metabolism in humans

In healthy human subjects with an adequate iodine intake, the thyroid gland produces predominantly the prohormone T4 and a small amount of the bioactive thyroid hormone T3. Roughly 80% of T3 is produced by outer ring deiodination (ORD) of T4 in peripheral tissues. The relative contribution of T3 secretion increases in iodine deficiency and other conditions where the thyroid gland is stimulated by TSH or TSH receptor antibodies, since this is associated with increased de novo T3 synthesis and thyroidal expression of both D1 and D2, and thus increased intra-thyroidal T4 to T3 conversion (see below). Nevertheless, there is good agreement that about 1/3 of T4 daily produced (~130 nmol) in normal humans is converted to T3, which corresponds to about 40 nmol and thus 80% of the estimated total daily T3 production of 50 nmol. For recent comprehensive reviews of thyroid hormone metabolism and the role of the iodothyronine deiodinases therein, the reader is referred to (1-5)

 

That most plasma T3 is derived from peripheral conversion of T4 is supported by the fact that normal plasma T3 levels are obtained in athyreotic patients treated with sufficient T4 to achieve high-normal plasma (F)T4 levels. Administration of T4 to hypothyroid rats to achieve normal plasma T4 levels results in subnormal plasma T3 levels not only because of the lack of T3 secretion but also because of a decreased T3 production by D1 in peripheral tissues, since this enzyme is under positive control of T3 itself (6). Other studies in hypothyroid rats suggest that optimal restoration of serum and tissue thyroid hormone levels is achieved by the combined administration of specific amounts of T4 and T3 (7).

Also initial studies in humans suggested that replacement with a combination of T4 and T3 is better than replacement with T4 alone (8). However, this has not been confirmed in a large number of subsequent studies (reviewed in (9, 10)). A common drawback of these trials testing the possible beneficial effects of adding T3 to the T4 replacement therapy is that regular T3 tablets were used. Due to its short half-life, this results in substantial fluctuations of serum T3 levels. It remains to be investigated if administration of T3 in a slow-release formula which better mimics the continuous thyroidal T3 secretion (11) may improve the outcome of combined T4 and T3 replacement. Furthermore, psychological well-being and preference for L-T4 + L-T3 combination therapy may be influenced by polymorphisms in thyroid hormone pathway genes, specifically in thyroid hormone transporters and deiodinases (12-14).

Besides ORD to T3, T4 is converted by inner ring deiodination (IRD) to the metabolite rT3 (Fig. 1), which accounts for about 40% of T4 turnover, while thyroidal secretion of rT3 is negligible. T3 and rT3 undergo further deiodination, predominantly to the common metabolite 3,3'-diiodothyronine (3,3'T2), which is generated by IRD of T3 and by ORD of rT3 (1-5). Thus, ORD is an activating pathway by which the prohormone T4 is converted to active T3, whereas IRD is an inactivating pathway by which T4 and T3 are converted to the metabolites rT3 and 3,3'T2, respectively.

Figure 1. Pathways of Thyroid Hormone Metabolism

 

In addition to deiodination, iodothyronines are metabolized by conjugation of the phenolic hydroxyl group with sulfate or glucuronic acid (Fig. 1) (15, 16). Sulfation and glucuronidation are so-called phase II detoxification reactions, the general purpose of which is to increase the water-solubility of the substrates and, thus, to facilitate their biliary and/or urinary clearance. However, iodothyronine sulfate levels are normally very low in plasma, bile and urine, because these conjugates are rapidly degraded by D1, suggesting that sulfate conjugation is a primary step leading to the irreversible inactivation of thyroid hormone (17, 18). Plasma levels and, if investigated, biliary excretion of iodothyronine sulfates are increased by inhibition of D1 activity with PTU or iopanoic acid (IOP), and during fetal development, NTI and fasting (16, 18). Under these conditions, T3 sulfate (T3S) may function as a reservoir of inactive hormone from which active T3 may be recovered by action of tissue sulfatases and bacterial sulfatases in the intestine (15-17).

In contrast to the sulfates, iodothyronine glucuronides are rapidly excreted in the bile. However, this is not an irreversible pathway of hormone disposal. After hydrolysis of the glucuronides by bacterial ß-glucuronidases in the intestines, part of the liberated iodothyronines is reabsorbed, resulting in an enterohepatic cycle of iodothyronines (15, 16). Nevertheless, about 20% of daily T4 production appears in the feces, probably through biliary excretion of glucuronide conjugates.

Thyronamines (TAMs) are a novel class of iodothyronine-like endogenous signaling compounds (19). Their structure differs from T4 and T3 only with regard to the absence of the carboxylate group of the alanine side chain. THs and TAMs are designated Tx and TxAM, respectively, with “x” indicating the number of iodine atoms per molecule, thus following the same rules for nomenclature (see (20) for an excellent review). So far, only 3-iodothyronamine (3-T1AM) and thyronamine (T0AM) have been detected in vivo using liquid chromatography-tandem mass spectrometry (LC-MS/MS) (19, 21). 3T1AM and T0AM have been shown to exert acute and dramatic effects on heart rate, body temperature and physical activity, inducing a torpor-like state (19), but also more subtle effects on neurocognitive function (22). The physiological receptor(s) of TAMs has not been identified unambiguously, but despite their structural similarities, iodothyronines and TAMs appear to signal via different receptors. Initial studies suggested that the TAMs mediated their effects via the G-protein coupled trace amine receptor, TAR1 (19). However, the impressive hypothermic response to 3-T1AM administration is maintained in TAAR-1 knockout (23). Whether other members of the TAAR family or other plasma membrane receptors mediate the TAM response remains to be studied.

Studies in athyreotic patients provide evidence for extrathyroidal formation of 3-T1AM (24), but the pathways of TAM biosynthesis are still unknown (41). However, it has been shown that iodothyronamines are deiodinated by the different deiodinases (25), which may suggest a role in biosynthesis.

Interesting effects of other natural thyroid hormone derivatives have been described as well (26). Triac has significant thyromimetic activity and its affinity for the T3 receptor TRα1 is equal to that of T3 and for the TRβ receptor it is even higher than that of T3 (26). As a consequence, administration of Triac has successfully been used to suppress TSH secretion in patients with resistance to thyroid hormone due to mutations in TRβ (27). Interestingly, it was recently shown that the marine invertebrate Amphioxus expresses a TH receptor which is activated by Triac but not by T3 (28), as well as a non-selenoprotein that deiodinates Triac but not T3 (29). This may suggest that Triac is the primordial TH (29). A different natural TH derivative, 3,5-diiodo-L-thyronine (T2), has been shown to prevent adiposity and body weight gain when administered to rats receiving a high-fat diet (HFD) without the unfavorable side effects that are usually caused by T3 (30, 31).

However, the exact biological functions of these iodothyronine, iodothyronamine and iodothyroacetic acid metabolites remain to be established in future studies.

Cleavage of the ether bond connecting the inner and outer ring of iodothyronines represents a relatively minor pathway of thyroid hormone disposal (16) and will not be discussed here. In the following sections especially the biochemical aspects of the deiodination and conjugation pathways will be reviewed.

 

DEIODINATION

 

Three iodothyronine deiodinases have been identified, with distinct tissue distributions, catalytic specificities, physiological functions, and regulations (Fig. 2) (1-5). Whereas initial studies focused on the role of the deiodinases in maintaining normal serum T3 concentrations, the paradigm has evolved and it has now clearly been shown in different developmental and clinical conditions that these enzymes can locally modify TH bioactivity independent of serum TH concentrations. This is especially the case for D2 and D3 (see below).

 

 

D1, D2 and D3 have been cloned in different species, including mammals, frog, chicken and fish. The deduced amino acid sequences of human D1, D2 and D3 are presented in Fig. 3. The deiodinases appear to be homologous proteins, consisting of 249-278 amino acids. A particular lipophilic sequence is present in the N terminal domain of all three deiodinases, which probably represents a membrane-spanning region.

 

The most remarkable feature of all three iodothyronine deiodinase is that they are selenoproteins, i.e. they contain a selenocysteine (Sec) residue in the center of the amino acid sequence (32). In all selenoproteins, Sec is encoded by a UGA triplet which is an opal stop codon because it usually signals termination of translation. However, if the 3' untranslated region (3'UTR) of the mRNA contains a particular stem loop structure, termed selenocysteine-insertion sequence (SECIS) element, the UGA codon specifies the insertion of Sec (33, 34). Interestingly, it was recently shown that the marine invertebrate Amphioxus expresses a non-selenoprotein that deiodinates Triac but not T3 (29).

 

 

Figure 3. Alignment of the amino acid sequences of human D1, D2 and D3                 U=selenocysteine (Sec)

 

Type I iodothyronine deiodinase (D1)

Biochemistry

D1 is expressed predominantly by liver parenchymal cells, kidney proximal tubular cells, and thyroid follicular cells. Most evidence points to the localization of D1 in the plasma membrane (35). D1 catalyzes the ORD and/or IRD of a variety of iodothyronine derivatives, although it is most effective in catalyzing the ORD of rT3, while the IRD of both T4 and T3 is strongly facilitated by sulfation of these iodothyronines (17). Therefore, although D1 is thought to be a major source of circulating T3, the enzyme shows particularly high activity towards TR-inactive metabolites such as rT3 and the different sulfo-conjugates. This suggests that D1 plays an important role in the recovery of iodide from inactive compounds for reutilization in thyroidal hormone synthesis (36). In the presence of dithiothreitol (DTT) as the cofactor, D1 displays high Km and Vmax values.

 

Studies of the topography of rat D1 have suggested that the major part of the protein is exposed on the cytoplasmic surface of the membrane (37). Older studies using detergent extracts of rat liver and kidney membranes have suggested that the native enzyme largely exists as a homodimer. This has been confirmed in a number of recent studies utilizing cells transfected with different D1 constructs (2, 38-40). These studies have also demonstrated that amino acids 148-163 constitute the dimerization domain of the D1 protein (DFLVIYIEEAHASDGW in human D1).

 

The D1 gene is located on human chromosome 1p32-33. It consists of four exons, with exon 1 coding for the 5’UTR and amino acids 1-112, exon 2 for amino acids 113-160, exon 3 for amino acids 161-227, and exon 4 for amino acids 228-249 and the 3’UTR, including the SECIS element. The Sec residue in D1 is essential for deiodinase activity since replacement of Sec by Cys results in a 100-fold decrease in catalytic activity, while substitution of Sec by Leu produces an enzymatically inactive protein (42). In addition, D1 is extremely sensitive to inactivation by iodoacetate due to carboxymethylation of a highly reactive residue, probably Sec, in the enzyme active center which is prevented in the presence of substrate (2, 15). Moreover, D1 activity is inhibited by very low concentrations (»10^-8 M) of goldthioglucose (GTG), which is known to form very stable complexes with Sec residues, and this inhibition is also competitive with substrate (43). Therefore, Sec is probably the catalytic center of D1.

 

Two other observations have provided important clues about the possible catalytic mechanism of D1. Firstly, D1 shows ping-pong type reaction kinetics in catalyzing the deiodination of iodothyronines by DTT (2, 15), suggesting that reaction of iodothyronine substrate with D1 produces an enzyme intermediate, from which native enzyme is regenerated by reaction with thiol cofactor (DTT). Secondly, D1 is potently inhibited by PTU, and this inhibition is uncompetitive with substrate and competitive with cofactor, suggesting that PTU and cofactor react with the same enzyme intermediate. Thiouracil derivatives are particularly reactive towards protein sulfenyl iodide (SI) groups, and presumably even more reactive towards selenenyl iodide (SeI) groups, suggesting that such an intermediate is generated in the catalytic cycle of D1. Therefore, the selenolate (Se^-) group of the native enzyme is thought to act as an acceptor of the iodonium (I⁺) ion which is substituted in the substrate by a proton, and the SeI intermediate thus generated is reduced back to native enzyme by thiols such as DTT or converted into a dead-end complex by PTU (Fig. 4).

 

Figure 4. Putative catalytic mechanism of D1 and inhibition by PTU, IAc and GTG.

 

 

Unlike the mammalian enzyme, D1 from tilapia was found to be insensitive to PTU inhibition (44). Like all other characterized deiodinases, tilapia D1 also contains a Sec residue in the corresponding position (44). However, two positions downstream from this Sec residue, tilapia D1 features a Pro residue, which is also the case in other fish species and in frog D1. In contrast, all known PTU-sensitive D1 enzymes have a Ser residue at this position. Remarkably, a Pro residue is also present at this position in all known D2 and D3 sequences, which are also PTU-insensitive. Substitution of Pro by Ser in tilapia D1 did not restore PTU sensitivity (44). However, substitution of Pro by Ser in frog D1 (4) as well as in human D2 and D3 not only made these enzymes susceptible to inhibition by PTU but also changed the kinetic mechanism of these enzymes (45). Therefore, in addition to the Sec residue the amino acid two positions downstream plays an important role in the catalytic mechanism of the deiodinases. The lack of PTU inhibition of the tilapia D1Pro>Ser mutant suggests that additional elements of the protein are important for effect of PTU.

Pathophysiology

D1 activity in liver and kidney is stimulated in hyperthyroidism and decreased in hypothyroidism, representing the regulation of D1 activity by T3 at the transcriptional level  (46). T3 response elements (TREs) have been identified in the upstream region of the D1 gene (47, 48). Studies in TR knockout mice have indicated that D1 expression in liver is primarily controlled by the TRb isoform (49). This agrees well with the colocalization of TRb and D1 in the pericentral zone of rat liver (50). In the thyroid, D1 expression is stimulated by T3, TSH and TSH receptor antibodies, where the effects of the latter are mediated by cAMP  (51, 52).

There is controversy about the contribution of D1 to peripheral T3 production. Different animal models have been studied which may provide a clue about this function of D1. Firstly, rats have been raised on a severely selenium-deficient diet, resulting in a dramatic reduction in liver and kidney D1 activity (53). These rats showed a significant decrease in serum T3 and increase in serum T4, compatible with an important role of D1 in peripheral T4 to T3 conversion. Other studies in rats have demonstrated that D2 and D3 activities in other tissues such as brain are much less affected directly by selenium deficiency (54).It should be noted that in mice lacking the plasma Se carrier selenoprotein P (SePP), thyroid hormone metabolism is preferentially maintained indicating that selenoenzymes have a priority in the organism with respect to selenium supply (55).

Findings in mice do not support an important function of liver and kidney D1 in peripheral T3 production as suggested by selenium deficiency in rats. C3H mice show a strongly reduced hepatic and renal D1 expression compared with other mouse strains (56-58). Yet, their serum T3 levels are comparable, although the C3H mice show some increase in serum T4 suggesting that an increased T4 production may compensate for the decreased T4 to T3 conversion. Serum rT3 levels are mildly elevated as well in C3H mice. In another mouse model, hepatic synthesis of selenoproteins, including D1, is disabled by inactivation of the Sec-specific tRNA  (59). This does not result in any change in circulating thyroid hormone concentrations. Finally, D1 knockout (D1KO) mice have been generated which do not express D1 in any tissue, including thyroid and kidneys (36). These D1KO mice also show normal serum T3 and TSH levels, but like the C3H mice they have elevated serum T4 and rT3 levels as well.

However, we should be careful to draw conclusions about the contribution of D1 to serum T3 homeostasis based on these knock-out mouse models, since even mice without any ORD (D1KO/D2KO mice) are able to maintain normal levels of serum T3 (60), pointing towards a major role played by the thyroid gland as well. Although these data in D1KO/D2KO mice suggest that D1 and D2 may not be essential for the maintenance of the serum T3 level, both enzymes do serve important roles in thyroid hormone homeostasis. Fecal excretion of endogenous iodothyronines was greatly increased in D1KO mice, pointing towards an important role in iodide conservation by serving as a scavenger enzyme in peripheral tissues and the thyroid (36). Similarly, despite normal serum T3 levels in D2KO mice, brain T3 levels as well as the expression of certain T3 responsive genes in the brain was reduced.

Many studies have addressed the question about the contribution of a diminished expression of hepatic D1 to the decrease in serum T3 in rats exposed to fasting or NTI. The results of these studies are confounded by the fact that D1 not only produces T3 from T4 but its expression is also stimulated by T3. In fact, D1 expression is a very sensitive indicator of the thyroid state of the liver (61).

So far, no patients with mutations in D1 have yet been identified. However, several candidate gene association studies have reported on significant associations of single nucleotide polymorphisms (SNPs) in D1 with reciprocal changes in serum T3 versus T4 and rT3 levels (62-64). Recently, a large genome wide association meta-analysis was conducted for serum FT4 levels, and a single nucleotide polymorphism in DIO1 was one of the five genome wide significant hits (65) strongly suggesting an important role for D1 in peripheral thyroid hormone metabolism in humans as well.

 

Type II iodothyronine deiodinase (D2)

 

Biochemistry

D2 is expressed primarily in the brain, the anterior pituitary gland and (rodent) brown adipose tissue (BAT) (1-5). D2 activity has also been shown in human thyroid (66-68) and skeletal muscle (69), while D2 mRNA is also expressed in human heart (70). Localization of D2 mRNA in rat brain by in situ hybridization has indicated that the enzyme is expressed in astrocytes, in particular in tanycytes lining the third ventricles (71). D2 activity is induced in cultured astrocytes by a variety of factors (73-74). Like the other deiodinases, D2 also forms functional homodimers (38, 39, 75). Regarding cellular localization, D2 is largely present in the endoplasmic reticulum (35).

D2 has only ORD activity, exhibiting low Km and Vmax values, and a slight preference for T4 over rT3 as the substrate. In contrast to D1, it does not catalyze the deiodination of sulfated iodothyronines. The amount of T3 in D2-expressing tissues is derived to a large extent from local conversion of T4 by this enzyme and to a minor extent from plasma T3. In general, D2 activity is increased in hypothyroidism and decreased in hyperthyroidism. Part of this negative control is explained by substrate-induced inactivation of the enzyme by T4 and rT3 (1-5). Reaction of these substrates with D2 induces the ubiquitination of the enzyme, which facilitates its degradation in the proteasomes. However, active D2 may also be recovered by de-ubiquitination of the modified enzyme. Thus, ubiquitination/de-ubiquitination is an important, dynamic mechanism in the regulation of D2 activity in many tissues, except hypothalamic D2 which is less ubiquitinated (72). For a more detailed discussion of this pathway, the reader is referred to excellent studies and reviews published in this area (38, 76-80). Furthermore, Dio2 is a cAMP-responsive gene and as a consequence the adrenergic/cAMP signaling pathway mediates the transcriptional control of D2 (81).In addition, D2 expression is also importantly regulated by ER stress reducing D2 activity by inhibition of  de novo synthesis of the D2 protein (82). Finally, presumably receptor-mediated inhibition of D2 activity by T3 has been demonstrated in pituitary tumor cells (83), and D2 mRNA levels in brain, pituitary and BAT are up-regulated in hypothyroid rats and down-regulated in hyperthyroid animals (84, 85).

The central Sec residue plays an important role in the catalysis and turnover of D2. Replacement of this Sec with Cys results in a 1000-fold increase in the Km value of the substrates T4 and rT3, and a 10-fold decrease in turnover number (86, 87). Substitution of Sec by Ala completely inactivates the enzyme. Also the mechanism of substrate-induced D2 degradation is strongly or completely impaired by replacement of Sec by Cys or Ala, respectively (88), suggesting that modification of this Sec residue during catalysis may be an essential step in the inactivation of the enzyme. Interestingly, mammalian and avian D2 also have a second Sec residue near the C-terminus which, however, is not important for catalytic activity (89).

The D2 gene is located on human chromosome 14q24.2-q24.3. It consists of 2 exons of 0.7 kb and 6.6 kb, seperated by a 7.4 kb intron (2). The SECIS element in the 3’UTR is separated by ~5 kb from the UGA triplet coding for the catalytic Sec residue, resulting in a poor translation efficiency of the D2 mRNA (90). This is even further hampered by the presence of multiple short open reading frames in the 5’UTR of human D2 mRNA (90).

 

Pathophysiology

D2 is expressed in human thyroid but not in rat thyroid. Both D2 mRNA and D2 activity in human thyroid are greatly stimulated by TSH and TSH receptor antibodies circulating in patients with Graves’ disease (66, 67). The expression of D2 in human thyroid has been associated with functional TTF-1 binding sites in the 5’ flanking region of the human D2 gene which are lacking in the 5’ flanking region of the rat D2 gene (91). The stimulatory effects of TSH and TSH receptor antibodies on D2 expression in human thyroid are mediated by cAMP, which has been associated with the presence of a cAMP response element (CRE) in the 5’ flanking region of the D2 gene (81, 92). Interestingly, follicular thyroid carcinoma may express high levels of D2, and in case of a large (metastatic) tumor mass this may results in strongly elevated serum T3 levels (93-95).

D2 knockout (D2KO) mice have been generated, showing modest phenotypic changes (96). The homozygous D2KO mice have increased serum T4 and increased TSH levels, but normal levels of T3. The combination of increased serum TSH and T4 is in agreement with an important role of D2 in the negative feedback of T4 at the hypothalamus and pituitary level. However, the normal serum T3 suggests that D2 is not essential for maintaining normal serum T3 levels. However, as mentioned above, even D1KO/D2KO mice are able to maintain normal levels of serum T3 (60), pointing towards a major role for the thyroid gland in serum T3 production as well. In skeletal muscle, D2 levels are higher in slow-twitch than fast-twitch mouse skeletal muscle and are increased in hypothyroidism (97). Specific deletion of D2 in skeletal muscle does not have large effects on thyroid hormone signaling or functional outcomes (98,99).

In contrast to the marked decrease in hepatic and renal (but not thyroidal) D1 activities, the unexpectedly small effects of Se deficiency on tissue D2 and D3 activities in rats, despite that they all appear to be Sec-containing proteins, may be explained by findings that the selenium state of different tissues varies greatly in Se-deficient animals. In addition, the efficiency of the SECIS element to complex with protein factors, such as SBP2, necessary for the read-through of the UGA codon may vary between different seleno­proteins. This could result in the preferred incorporation of Sec into some seleno­proteins, e.g. deiodinases, over others, e.g. glutathione peroxidase  (33).

 

Despite normal serum T3 levels in D2KO mice, brain T3 levels as well as the expression of certain T3 responsive genes in the brain is reduced, again pointing towards the crucial role of D2 in maintaining local T3 concentrations (96, 105). Several other studies point towards a crucial role for D2 (and D3, see below) in regulating local T3 concentrations, and as a consequence it is know well accepted that these deiodinases can regulate thyroid hormone action at the cellular level during development and tissue stress relatively independent of serum T4 and T3 concentrations (3).

One of the clearest examples of the role of D2 in development is its role in the inner ear. A sharp increase in D2 activity occurs in mouse cochlea at postnatal days 6-8, which is required for normal cochlear development (100). As a consequence, D2KO mice are deaf underlining the importance of D2 in producing local T3 in the cochlea during a critical period of its development (101). Another example of the important role of D2 in development is the observation that D2KO mice have an impaired embryonic BAT development, and as a consequence a permanent thermogenic defect (102, 103). D2KO mice exhibit an impaired thermogenesis in BAT, leading to hypothermia during cold exposure and a greater susceptibility to diet-induced obesity at thermoneutrality (104).

D2 is also essential for maintaining normal local concentrations of T3 in different physiological and pathophysiological situations. D2 has an important role in pituitary and hypothalamic feedback (96). It also plays an essential role for normal myogenesis (106) and in the optimization of bone strength and mineralization (107). Adult D2KO mice have a 50% reduction in bone formation and a generalized increase in skeletal mineralization resulting from a local deficiency of T3 in osteoblasts (101).

D2 is also required for the regeneration of skeletal muscle after injury (106), since regeneration after injury is markedly delayed in D2KO mice. The increase in muscle D2 is mediated via FoxO3, thereby locally increasing intracellular T3 concentrations. Muscle D2 expression during critical illness is differentially regulated, probably related to differences in the inflammatory response and type of pathology (108). In humans, skeletal muscle D2 mRNA expression is modulated by fasting and insulin, but not by hypothyroidism (109). Also in lung tissue, D2 activity increases upon injury. In a mouse model of ventilator-induced lung injury (VILI), lung D2 activity increased (110). D2KO mice had a greater susceptibility to VILI than WT mice, demonstrated by poorer alveoli integrity and quantified by lung chemokine and cytokine induction. Evidence accumulates that D2 is induced during inflammation (e.g. in macrophages) (198, 199).  The neonatal D2 peak in the liver appears relevant for susceptibility to diet-induced steatosis and obesity as shown in hepatocyte-specific D2KO (196).

No patients have been identified with mutations in D2. However, patients with homozygous or compound heterozygous mutations in the SECIS-binding protein SBP2, which is crucial for the synthesis of selenoproteins (111) have abnormal serum thyroid hormone levels: high (F)T4 and rT3, low T3, and somewhat elevated TSH levels. This resembles the changes in thyroid parameters in D2KO mice, although in patients with SBP2 mutations also the expression of functional D1 and D3 is probably affected. As SBP2 deficiency affects many selenoproteins, these patients have a multisystem disorder including growth delay in childhood, hearing loss, enhanced skin sensitivity and infertility (111,112).

Whether polymorphisms in D2 are associated with significant changes in serum thyroid hormone levels or other outcomes such as insulin resistance or osteoarthritis are controversial (62, 113-117, 200). Also uncommon D2 variants are not related to serum thyroid hormone levels (201).  The Thr92Ala polymorphism has been linked with local changes in a specific transcriptional fingerprint, although the relevance needs to be further studied (202).

Type III iodothyronine deiodinase (D3)

Biochemistry

D3 activity has been detected in a variety of tissues, i.e. brain, skin, liver, intestine, placenta, and the pregnant rat uterus (1-5, 118-120). D3 expression is usually much higher in fetal than in adult tissues. D3 activity is also highly expressed in certain tumors, including hepatocarcinomas, hemangiomas and basal cell carcinomas (121-124, 203) Because of its expression in fetal tissues and tumors, D3 has been named an oncofetal protein. The enzyme appears to be located in the plasma membrane in the form of a homodimer (38, 125, 126). D3 has only IRD activity, catalyzing the inactivation of T4 and T3 with intermediate Km and Vmax values (Fig. 2).

 

The expression of D3 in placenta, pregnant uterus, embryonic and fetal tissues may protect developing organs against undue exposure to active thyroid hormone. Also in adult subjects, D3 appears to be an important site for clearance of plasma T3 and production of plasma rT3. In brain and skin, but not in placenta, D3 activity is increased in hyperthyroidism and decreased in hypothyroidism, which in brain is associated with parallel changes in D3 mRNA levels (127).

 

The D3 gene is located on human chromosome 14q32 and consists of a single exon. In all species, D3 is a selenoprotein homologous with the amino acid sequences of D1 and D3, including the essential Sec residue positioned in a strongly conserved region (Fig. 2). It has been shown that D3 expression is predominantly regulated by TRα1 (128), and studies in TRα1-/- mice have demonstrated a reduced clearance rate of TH due to an impaired regulation of D3 (129).

 

The presence of Sec in a strongly conserved region of the proteins strongly suggests the same mechanism of deiodination for the different deiodinases. This seems to be contradicted by the widely different susceptibilities of D1 versus D2 and D3 to the different mechanism-based inhibitors PTU, IAc and GTG (Fig. 2). It also seems to be in conflict with previous findings that, in contrast to the ping-pong kinetics of D1, the other two enzymes appear to follow sequential-type kinetics, suggesting the formation of a ternary enzyme-substrate-cofactor complex during catalysis. The differences in enzyme kinetics and PTU inhibition between the deiodinases are determined by the presence of Ser (D1) or Pro (D2,D3) two positions downstream of  Sec, which may somehow influence the reactivity of the catalytic Sec residue (see above). The crystal structure of the catalytic part of D3 suggests a close similarity to 2-Cys peroxiredoxin(s) (Prx) with an  important resolving role for Cys239 by forming a selenenyl-sulfide with Sec170 (204).

 

Pathophysiology

D3 plays a very important role in the regulation of local and systemic thyroid hormone bioactivity (1, 123). It has been shown that region-specific expression of D3 in fetal and adult human brain is negatively associated with local tissue T3 levels (130, 131). High expression of D3 in vascular tumors may result in subclinical or even severe hypothyroidism in patients with such tumors, which condition has been termed consumptive hypothyroidism (122, 123, 132). Induction of D3 expression has also been demonstrated in liver and skeletal muscle biopsies from patients who died after severe illness, and D3 activities were correleated to both local and serum rT3 concentrations in these severely sick patients (133-135). Therefore, tissue and circulating iodothyronine levels are regulated not only by changes in the T3-producing deiodinases D1 and D2 but also importantly by reciprocal changes in the T3-degrading deiodinase D3.

 

D3 knockout (D3KO) mice have been generated, showing remarkable neonatal mortality and growth retardation, althought the severity of the phenotype depends on the genetic background (136-138). In addition, they show largely abnormal thyroid hormone levels, dependent on the age of the animals. Compared with wild-type mice, serum T4 is very low in D3KO mice at all ages, T3 is higher in neonatal mice but much lower in older D3KO mice, while TSH varies between very low in younger to low in older knockout mice. This picture represents a state of central hypothyroidism, suggesting that the setpoint of the hypothalamus-pituitary-thyroid axis is strongly affected by inactivation of D3, which could be due to overexposure of tissues (e.g. the developing hypothalamus) to T3. This is reminiscent of the reports of congenital central hypothyroidism in newborns from mothers who were hyperthyroid during pregnancy (139).

 

Heterozygous D3KO mice show either almost normal or strongly decreased D3 expression, depending on whether the defective allele is inherited from the mother or the father, respectively, indicating paternal imprinting of the DIO3 gene (136, 205). However, D3 expressed from the maternal D3 allele is important in pancreatic islets to maintain normal glucose homeostasis (206). The DIO3 gene is located in an imprinted region on human chromosome 14 or mouse chromosome 12 which is about 1 Mb in size and comprises the paternally expressed genes DLK1 (delta-like 1) and DIO3, and a large number of in particular maternally expressed non-coding genes. Both Dlk1 and Dio3 expression are elevated in cultured brown pre-adipocytes and down-regulated during differentiation, suggesting that imprinting might control the dosage of these genes to regulate thermogenesis (140). Interestingly, transgenic animals with partial loss of imprinting of this locus show significant lethality in the third postnatal week, associated with developmental delay and failure to maintain UCP1 expression in BAT (141). This defect is the combined result of prolonged elevated expression of Dlk1, leading to a failure in BAT differentiation and subsequent reduced expression of β-adrenergic receptors, and hypothyroidism due to dysregulation of D3.

 

 

The important role of hepatic D3 in the regulation of circulating thyroid hormone during development has been investigated in detail in the embryonic chicken (142, 143). These studies have demonstrated that during the last (third) week of incubation there is a gradual increase in plasma T4 levels paralleled by a steady increase in hepatic D1 activity although hepatic D1 mRNA levels do not change much. D3 mRNA and D3 activity show a parallel increase to maximum levels at day 17 of embryonic development, followed by a steep decrease in both parameters in particular immediately before hatching. This is associated with an equally steep increase in plasma T3, strongly suggesting that the latter is importantly and negatively regulated by hepatic D3 activity (142, 143).

A study of the ontogeny of hepatic D1 and D3 during human development has indicated similar profiles of deiodinase expression, with substantial and relatively constant D1 activities from mid-gestation onwards, and high D3 activities at mid-gestation declining to very low levels around term (144). Since in rat liver D1 is not expressed until the last days of gestation, while hepatic D3 expression is low at all stages of rat development (118), these results indicate that the embryonic chicken is a better model than the fetal rat for the regulation of hepatic deiodinases during human development. Injection of the chicken embryo with growth hormone or glucocorticoids induces an acute down-regulation of hepatic D3 mRNA levels and D3 activities, suggesting that the D3 mRNA in the embryonic chicken has a very short half-life, and that transcription of the D3 gene is acutely blocked by these treatments (142). If D3 expression in the fetal human liver is also rapidly down-regulated by GH and glucocorticoids remains to be determined. It is likely that the high D3 activities expressed in the fetal liver, in addition to the high D3 activities in the placenta (145, 146) and perhaps the uterus (119), plays an important role in the regulation of fetal circulating T3 levels and protect the fetus against early T3 exposure.

 

In recent years, several studies have addressed the role of D3 in regulating local T3 concentrations. It is now well accepted that D3 plays a crucial role in regulating thyroid hormone action at the cellular level during development, relatively independent of serum T4 and T3 concentrations. During development, D3 is expressed in the immature cochlea before D2 (147). Like D2KO mice, D3KO mice display auditory deficits as well. However, in contrast to the retarded cochlear development in D2KO mice, D3KO mice display an accelerated cochlear differentiation due to premature stimulation of TRb. The additional deletion of TRb converts the accelerated cochlear phenotype in D3KO mice to one of delayed differentiation (147), indicating a protective role for D3 in hearing development. This clearly illustrates how different tissues can auto-regulate their developmental response to thyroid hormone through both D2 and D2. D3 also plays a crucial role in cerebellar development, since D3KO mice display abnormally accelerated cerebellar differentiation and locomotor behavioral defects, suggesting that D3 protects cerebellar tissues from inappropriate, premature stimulation by thyroid hormone (148, 207). This cerebellar phenotype results specifically from inappropriate stimulation of the TRa1 receptor isoform, since the additional deletion of TRa1 reversed the cerebellar phenotype. Also, additional deletion of MCT8 in the D3KO mice ameliorates the phenotype indicating the relevance of MCT8 for intracellular T3 levels (208). Similarly, D3 protects cones to unlimited T3 exposure in the immature mouse retina. As a consequence, approximately 80% of cones are lost through neonatal cell death in D3KO mice (149). Similar results were obtained in zebrafish (209). D3 appears also a critical factor in testis development via influencing local thyroid hormone bioavailability (210).  Furthermore, protection against untimed T3 exposure by D3 in pancreatic β-cells during development is essential for normal islet function and glucose homeostasis (150). As a consequence, D3KO mice have impaired insulin secretion in response to glucose stimulation. In contrast to most tissues, D3 expression remains throughout adulthood in human and mouse β-cells. However, whether dysregulation of Dio3 might play a role in different states of impaired insulin secretion remains to be explored in future studies (150). In addition, less fat tissue is seen in D3KO mice, which is mediated through in the leptin-melanocortin system (211).

In addition to its crucial role during development, D3 activity is also important in regulating thyroid hormone action at the cellular level in different pathophysiological conditions. Induction of D3 expression has been documented in the hypertrophic or failing heart resulting from pressure overload or myocardial infarction (151-153). Hypoxia-inducible factor 1a (HIF-1a) induces local thyroid hormone inactivation by inducing D3 during hypoxia (152), suggesting a mechanism of down-regulating metabolism during ischemia. In neuronal hypoxia, translocation of D3 to the nucleus is mediated by Hsp-40, thereby facilitating local inactivation of thyroid hormone and reducing ischemia-induced hypoxic brain damage (154). Heterozygous D3KO mice constitute a model of cardiac D3 inactivation in an otherwise systemically euthyroid animal (155). These mice have normal hearts but later develop restrictive cardiomyopathy due to cardiac-specific increase in thyroid hormone signaling. In addition, heterozygous D3KO mice are more vulnerable to isoproterenol, further worsening the restrictive cardiomyopathy and leading to congestive heart failure and increased mortality (155). D3 activity is also induced in liver and muscle of critically ill patients (133-135). See (156) for an excellent overview of the changes in local thyroid hormone metabolism during illness and inflammation. Interestingly, in a mouse model of turpentine-induced tissue inflammation, high D3 expression in invading granulocytes has also been reported (157, 158). Recent studies also documented D3 in human neutrophils (212). Furthermore, D1 decreases and D3 increases are seen in livers of premature and normal aging mice, hinting that changes in deiodinases are mediated via DNA damage and might contribute to the beneficial survival response (213).

Several recent studies have demonstrated that local regulation of thyroid hormone action also plays a crucial role in repair mechanisms, for example D3 in liver (159) and brain (160), and D2 and D3 in muscle (106, 214). The reciprocal changes in D2 and D3 are shown in elegant studies demonstrating that D2 is induced to allow proper differentiation after muscle injury, while D3 induction in proliferating muscle cells protects against excessive local thyroid hormone concentrations, preventing apoptosis (106, 214). Furthermore, D2 and D3 activities are regulated by a variety of growth factors and morphogens, which are important mediators of tissue injury repair (161).  After a large hepatectomy, ‘stem-like’ cells switch from a quiescent state to a proliferative state. During these processes, many fetal genes are reactivated (162). Among them, D3 activity was increased 10-fold and D3 mRNA expression was increased 3-fold 20 h after partial hepatectomy in rats. No significant effects on D1 and D2 activities or mRNA expression were found after partial hepatectomy in mice (159). This leads to the concept that a coordinated regulation of thyroid hormone action is essential in the control of the tight balance between proliferation and differentiation in the regeneration processes. Induction of D3 expression in the early phases of regeneration may therefore very well correlate with a requirement of increased cellular proliferation in these circumstances (3, 161).

 

The balance between proliferation and differentiation is disturbed in cancer, and D3 is turned on in several malignant cell lines and human cancers (3, 163). D3 activity in these cancers can be very high and may even lead to so-called consumptive hypothyroidism (123, 132, 203) . In basal cell carcinomas, as well as in primary proliferating keratinocytes, Sonic hedgehog  (Shh) increases the expression of D3, acting via a conserved Gli2 binding site on the human Dio3 promoter (121, 215). This suggests that Shh may induce local down-regulation of thyroid hormone activity. Interestingly, knockdown of D3 caused a 5-fold reduction in the growth of basal cell carcinoma xenografts in nude mice (121), suggesting that D3 up-regulation provides an advantage for proliferating tumor cells. This appears to be mediated by miR21 that reduces the tumor suppressor gene GRHL3 which in turn increases D3 expression (216). Interestingly, a recent study in papillary thyroid carcinoma demonstrated an  association between increased levels of D3 activity and advanced disease (164). However, since only a few tumors over-express D3, D3 expression seems not be a necessary step in tumorigenesis.

Sulfation

Iodothyronine sulfotransferases

Sulfotransferases represent a family of enzymes with a monomer molecular weight of »34 kDa, located in the cytoplasmic fraction of different tissues, in particular liver, kidney, intestine and brain (165). They catalyze the transfer of sulfate from 3'-phosphoadenosine-5'-phosphosulfate (PAPS) to usually a hydroxyl group of the substrate (165). On the basis of substrate specificity and amino acid sequence homology, mainly two sulfotransferase families have been recognized in human tissues, i.e. the phenol sulfo-transferases (SULT1 family), including estrogen sulfotransferase, and the hydroxysteroid sulfotransferases (SULT2 family) (165). Different phenol sulfotransferases have been identified with significant activity towards iodothyronines. These include human SULT1A1, 1A2, 1A3, 1B1 and 1C2 (Table 1) (166-174). These studies have indicated a large substrate preference of the recombinant enzymes as well as the native enzymes in human liver and kidney for 3,3'T2, the sulfation of which is catalyzed orders of magnitude faster than that of T3 or rT3, while sulfation of T4 is hardly detectable (168).

 

Surprisingly, it has also been demonstrated that human estrogen sulfo-transferase (SULT1E1) is an important isoenzyme for sulfation of thyroid hormone. Although human SULT1E1 shows much higher affinities for estrogens (Km »nM) than for iodothyronines (Km »μM), it is about as efficient as other isoenzymes in sulfating 3,3'T2 and T3, and much more efficient in sulfating rT3 and T4 (169). Human tissues known to express SULT1E1 include liver, uterus, and mammary gland (175). In particular the enzyme expressed in the endometrium may be a significant source for the high levels of iodothyronine sulfates in human fetal plasma (see below). Recently, different human SULTs have also been shown to catalyze the sulfation of iodothyronamines (Table 1) (172).

 

Deiodination of iodothyronine sulfates

Although D1 is capable of converting T4 with similar efficiency by ORD to T3 and by IRD to rT3, this is changed dramatically after sulfate conjugation, i.e. IRD of T4S by rat D1 is accelerated »200-fold, whereas ORD of T4S becomes undetectable (Fig. 5) (17). IRD of T3 by rat and human D1 is also markedly stimulated (»40-fold) by sulfation (Fig. 5)(17). As mentioned before, rT3 is by far the preferred D1 substrate; its ORD is not influenced by sulfation, suggesting that the catalytic efficiency of D1 is already optimal with nonsulfated rT3 (17). While sulfation inhibits ORD of T4 and is without effect on ORD of rT3, it markedly stimulates ORD of 3,3’-T2 (Fig. 5). Thus, sulfation facilitates the IRD of T4 and T3, while it either inhibits (T4), does not affect (rT3) or markedly stimulates (3,3’T2) the ORD of other substrates (17).

 

Figure 5. Efficiency of deiodination of iodothyronines and their sulfates by rat liver D1.    *) Vmax (pmol/min/mg protein)/Km (µM) ratio.

 

 

The mechanism by which sulfation stimulates especially the IRD of different substrates remains unclear. In some cases sulfation primarily effects an increase in Vmax, while in others there is a predominant decrease in apparent Km value. The facilitated deiodination of sulfated iodothyronines by rat liver D1 may be due to interaction of the negatively charged sulfate group with protonated residues in the active center of this basic protein. The effect of sulfation on deiodination of iodothyronines is both conjugation type and deiodinase type-specific since D1 does not catalyze the deiodination of T3 glucuronide, while D2 and D3 do not accept T4S and/or T3S as substrates.

 

Importance of thyroid hormone sulfation

Serum concentrations of T4S, T3S, rT3S and 3,3’T2S are low in normal human subjects but they are high in fetal and cord blood, in patients with NTI, and in patients treated with the D1 inhibitor (16, 176). The serum T3S/T3 ratio is also increased in hypothyroid patients (177, 178). High iodothyronine sulfate levels have also been detected in human fetal and neonatal serum and amniotic fluid (16). The high serum iodothyronine sulfate levels during NTI, hypothyroidism and fetal development have been ascribed to a low peripheral D1 activity in these conditions (17, 18). These results are in accordance with studies in rats, showing marked increases in the serum concentration and biliary excretion of iodothyronine sulfates when hepatic and renal D1 activities are decreased by D1 inhibitors or selenium deficiency (17). These changes are not caused by an increased sulfation of iodothyronines but by a decreased clearance of the sulfated iodothyronines by D1.

Thus, sulfation is a primary step leading to the irreversible degradation of T4 and T3 by D1. However, if D1 activity is low, inactivation of thyroid hormone by sulfation is reversible due to expression of sulfatases in different tissues and by intestinal bacteria (179). It has been speculated that especially in the fetus T3S has an important function as a reservoir from which active T3 may be released in a tissue-specific and time-dependent manner(17, 180).

Wu and coworkers have demonstrated the presence of a 3,3’T2S cross-reacting substance, termed compound W, in the serum and urine of pregnant women  (16, 181). Interestingly, compound W is derived from the fetus and its concentration in maternal serum may reflect fetal thyroid state (16, 181). The structure of compound W remains to be identified.

 

Glucuronidation

Like sulfation, glucuronidation is a phase II metabolic reaction that increases the water-solubility of endogenous and exogenous compounds to increase their biliary or urinary excretion. Glucuronidation is catalyzed by UDP-glucuronyltransferases (UGTs) that utilize UDP-glucuronic acid (UDPGA) as cofactor. UGTs are localized in the endoplasmic reticulum of predominantly liver, kidney and intestine. Most UGTs are members of the UGT1A and UGT2B families (182).

Iodothyronines are also metabolized by glucuronidation, although this appears more important in rodents than in humans (183). Especially in rodents, metabolism of thyroid hormone is accelerated through induction of T4-glucuronidating UGTs by different classes of compounds, including barbiturates, fibrates and PCBs (184-186). This may result in a hypothyroid state as the thyroid gland is not capable of compensating for the increased hormone loss. In humans, thyroid function may be affected by induction of T4 glucuronidation by anti-epileptics, but development of overt hypothyroidism is rare (187).

Glucuronidation of T4 and T3 is catalyzed by different members of the UGT1A family (Table 2) (188-191). Usually, this involves the glucuronidation of the hydroxyl group, but human UGT1A3 also catalyzes the glucuronidation of the side-chain carboxyl group, with formation of so-called acyl glucuronides (189). Interestingly, Tetrac and Triac are much more rapidly glucuronidated in human liver than T4 and T3, and this occurs predominantly by acyl glucuronidation (192). Acyl glucuronides are reactive compounds that may form covalent complexes with proteins. It is unknown if this is a significant route for the formation of covalent iodothyronine-protein complexes.

Integrated physiological role of thyroid hormone metabolism

Since most actions of thyroid hormone are initiated by binding of T3 to its nuclear receptors, it is important to consider the role of the processes discussed above in the regulation of nuclear T3. There are two sources of intracellular T3, i.e. T3 derived from plasma T3, and T3 produced locally from T4, and the degree to which they contribute to the occupied receptors varies among the different tissues in different physiological and pathophysiological states (1, 3, 5, 76, 98). The liver and kidneys are typical of most tissues in the body in which most of the T3 specifically bound to the T3 receptor is derived directly from plasma. In cerebral cortex, BAT, and anterior pituitary there is a substantial contribution to nuclear T3 from locally produced T3. Local T3 production may be an autocrine process, where T3 is produced in the same cells where it acts, or a paracrine mechanism, where T3 production and action take place in neighboring cells. The latter appears very important for T3 action in the brain, where neurons are the primary target cells for T3 produced by D2 expressed in nearby astrocytes (193-195).

 

D3 plays an additional important role in maintaining intracellular T3 concentrations in these tissues by catalyzing the degradation of T3 in case of excess or by diverting the metabolism of T4 to rT3. Indeed, the adaptations of deiodinase activities in response to changes in thyroid state are thought to serve the purpose of keeping intracellular T3 in the brain constant. Thus, when T4 supply is decreased in hypothyroidism, both D1 and D3 activities are down-regulated, so that relatively more T4 is available for conversion to T3 by D2 in the brain, the activity of which is up-regulated. Opposite changes occur in hyperthyroidism. These adaptations are not only important for the optimal function of the brain in adult life, they are also essential for the development of the brain which is critically dependent on thyroid hormone. Although the adaptations in deiodinase activities during hypo- or hyper­thyroidism go a long way in securing T3 availability in the brain, in severe iodine deficiency they may not fully compensate for the extreme decrease in T4 supply. This may result in severe impairment of neurological development in the child even when plasma T3 levels in the mother are sufficient to maintain a euthyroid state.

 

The critical role of deiodination in regulating local thyroid hormone action is clearly illustrated by the developing cochlea, where D3 is expressed before the onset of D2 activity (101, 147), preventing too much or too little hormonal stimulation at inappropriate stages in development. At immature stages, D3 limits stimulation by T3. Postnatally, a double switch occurs with a decline in D3 and an increase D2, resulting in a local T3 surge which is independent of serum T3 levels and triggers the onset of auditory function. A similar double switch, preventing premature T3 stimulation, occurs in the developing cerebellum (148), and D3 expression has also been shown to be crucial for normal retinal (149) and pancreatic b-cell development (150). Similarly, local thyroid hormone activation by D2 has been shown to be essential for normal BAT development (102) and myogenesis (106) as well.

Deiodinases are not only essential in controlling local thyroid hormone action during development, but also for normal function of adult tissues such as hypothalamus, pituitary, bone, and brown adipose tissue (96, 102, 107). Finally, deiodination is also important in regulating thyroid hormone bioactivity in different pathophysiological conditions, such as hypoxia, myocardial infarction, neuronal ischemia, critical illness, tissue injury, regeneration, and cancer (106, 121, 134, 152-154, 156, 157, 159). D2KO mice are more vulnerable to ventilator induced lung injury (110), whereas heterozygous D3KO mice are more vulnerable to a chemically induced worsening of restrictive cardiomyopathy, leading to congestive heart failure and increased mortality (155). The high expression of D3 in regenerating liver tissue and certain tumors and the crucial role of D2 and D3 in muscle regeneration (3, 106, 123, 159, 197, 214) suggest that coordinated regulation of thyroid hormone action is essential in the control of the tight balance between proliferation and differentiation in the regeneration processes, and that high expression of D3 may also be an advantage in proliferating tumor cells (98, 101, 147). The joint coordination between the different deiodinases is seen in mice lacking all deiodinases (D1/D2/D3 KO) versus individual deiodinase KO mice. D1/D2/D3 KO mice are viable and some features resulting from deficiency of either of the deiodinases is mitigated by the simultaneous lack of all deiodinases (217).

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 ABSTRACT

Diagnosis of the classic form of Graves’ disease is easy and depends on the recognition of the cardinal features of the disease and confirmation by tests such as TSH and FTI. The differential diagnosis includes other types of thyrotoxicosis, such as that occurring in a nodular gland, accompanying certain tumors of the thyroid, or thyrotoxicosis factitia, and nontoxic goiter. Types of hypermetabolism that imitate symptoms of thyrotoxicosis must also enter the differential diagnosis. Examples are certain cases of pheochromocytoma, polycythemia, lymphoma, and the leukemias. Pulmonary disease, infection, parkinsonism, pregnancy, or nephritis may stimulate certain features of thyrotoxicosis.
Treatment of Graves’ disease cannot yet be aimed at the cause because it is still unknown. One seeks to control thyrotoxicosis when that seems to be the major indication, or the ophthalmopathy when that aspect of the disease appears to be more urgent. The available forms of treatment, including surgery, drugs, and ^131-I therapy, are reviewed. There is a difference of opinion as to which of these modalities is best, but to a large degree guidelines governing choice of therapy can be drawn. Antithyroid drugs are widely used for treatment on a long- term basis. About one-third of the patients undergoing long-term antithyroid therapy achieve permanent euthyroidism. Drugs are the preferred initial therapy in children and young adults. Subtotal thyroidectomy is a satisfactory form of therapy, if an excellent surgeon is available, but is less used in 2016. The combined use of antithyroid drugs and iodine makes it possible to prepare patients adequately before surgery, and operative mortality is approaching the vanishing point. Many young adults, are treated by surgery if antithyroid drug treatment fails.
Currently, most endocrinologists consider RAI to be the best treatment for adults, and consider the associated hypothyroidism to be a minor problem. Evidence to date after well over five decades of experience indicates that the risk of late thyroid  carcinoma must be near zero. The authors advise this therapy in most patients over age 40, and believe that it is not contraindicated above the age of about 15. Dosage is calculated on the basis of ^131-I uptake and gland size. Most patients are cured by one treatment. Hypothyroidism.occurs with a fairly constant frequency for many years after therapy and may be  unavoidable  if cure of the disease is to be achieved by 131-I.. Many therapists accept this as an anticipated outcome of treatment.
Thyrotoxicosis in children is best handled initially by antithyroid drug therapy. If this therapy does not result in a cure, surgery may be performed. Treatment with ^131-I is accepted as an alternative form of treatment by some physicians, especially as age increase toward  15 years. Neonatal thyrotoxicosis is a rarity. Antithyroid drugs, propranolol and iodide may be required for several weeks until maternally-derived antibodies have been metabolized.
The physician applying any of these forms of therapy to the control of thyrotoxicosis should also pay heed to the patient’s emotional needs, as well as to his or her requirements for rest, nutrition, and specific antithyroid medication. Consult our FREE web-book WWW.ENDOTEXT.ORG  for complete coverage on this and related topics.

We note that there  are currently available 2 very extensive Guidelines on Diagnosis and Treatment of Graves’ Disease—The 2016 ATA guideline  --- http://online.liebertpub.com/doi/pdfplus/10.1089/thy.2016.0229 (270 pages), and the AACE 2011 version on Hyperthyroidism and other Causes of Thyrotoxicosis (65 pages)--https://www.aace.com/files/hyperguidelinesapril2013.pdf.
Both are well worth reviewing.

CLINICAL DIAGNOSIS

The diagnosis of Graves’ disease is usually easily made. The combination of eye signs, goiter, and any of the characteristic symptoms and signs of hyperthyroidism forms a picture that can hardly escape recognition (Fig -1). It is only in the atypical cases, or with coexisting disease, or in mild or early disease, that the diagnosis may be in doubt. The symptoms and signs have been described in detail in the section on manifestations of Graves’ disease. For convenience, the classic findings from the history and physical examination are grouped together in Table 1a and 1b.These occur with sufficient regularity that clinical diagnosis can be reasonably accurate. Scoring the presence or absence and severity of particular symptoms and signs can provide a clinical diagnostic index almost as reliable a diagnostic measure as laboratory tests(1).

Occasionally diagnosis is not at all obvious.In patients severely ill with other disease, in elderly patients with "apathetic hyperthyroidism", or when the presenting symptom is unusual, such as muscle weakness, or psychosis, the diagnosis depends on clinical alertness and laboratory tests.

The diagnosis of Graves’ Disease does not only depend on thyrotoxicosis. Ophthalmopathy, or pretibial myxedema may occasionally occur without goiter and thyrotoxicosis, or even with spontaneous hypothyroidism. While proper classification can be debated, these patients seem to represent one end of the spectrum of Graves’ Disease. Thus we are usually making two coincident diagnoses:1)- Is the patient hyperthyroid? and 2)- Is the cause of the problem Graves’ disease ?.

Table 1a---Symptoms of Graves’ disease

Preference for cool temperature Weight loss with increased appetite Prominence of eyes, puffiness of lids Pain or irritation of eyes Blurred or double vision, decreasing acuity, decreased motility Goiter Dyspnea Palpitations or pounding of the heart Ankle edema (without cardiac disease) Less frequently, orthopnea, paroxysmal tachycardia, anginal pain, and CHF Increased frequency of stools Polyuria Decrease in menstrual flow; menstrual irregularity or amenorrhea Decreased fertility Fatigue Weakness, Tremor Occasional bursitis Rarely periodic paralysis Nervousness, irritability Emotional lability Insomnia or decreased sleep requirement Thinning of hair, Loss of curl in hair Increased perspiration Change in texture of skin and nails Vitiligo Swelling over out surface of shin Family history of any thyroid  disease, especially Graves’ disease

 

TABLE 1B       PHYSICAL SIGNS

 

Weight loss Hyperkinetic behavior, thought, and speech Restlessness Lymphadenopathy and occasional splenomegaly Eyes Prominence of eyes, lid lag, globe lag Exophthalmos, lid edema, chemosis, extraocular muscle weakness Decreased visual acuity, scotomata, papilledema, retinal hemorrhage, and edema Goiter Sometimes enlarged cervical nodes Thyroid thrill and bruit Tachypnea on exertion Tachycardia, overactive heart, widened pulse pressure, and bounding pulse Occasional cardiomegaly, signs of congestive heart failure, and paroxysmal tachycardia or atrial fibrillation Tremor Objective muscle wasting and weakness Quickened and hypermetric reflexes Emotional lability Fine, warm, moist skin Fine and often straight hair Oncholysis (Plummer’s nails) Pretibial myxedema, Acropachy Hyperpigmentation or vitiligo

LABORATORY DIAGNOSIS OF GRAVE’S DISEASE

Serum Hormone Measurements

TSH and FT4 assay-Once the question of thyrotoxicosis has been raised, laboratory data are required to verify the diagnosis, help estimate the severity of the condition, and assist in planning therapy. A single test such as the TSH or estimate of FT4 (free T4) may be enough, but in view of the sources of error in all determinations, most clinicians prefer to assess two more or less independent measures of thyroid function. For this purpose, an assessment of FT4 and sensitive TSH are suitable.
As an initial single test, a sensitive TSH assay may be most cost-effective and specific. TSH should be 0 - .1 µU/ml in significant thyrotoxicosis, although values of .1 - .3 are seen in patients with mild illness, especially with smoldering toxic multinodular goiter in older patients(1.1). TSH can be low in some elderly patients without evidence of thyroid disease. TSH can be normal -- or elevated -- only if there are spurious test results from heterophile antibodies or other cause, or the thyrotoxicosis is TSH-driven, as in a pituitary TSH-secreting adenoma or pituitary resistance to thyroid hormone.
Measurement of FT4 or FTI (Free thyroxine index)is also usually diagnostic.The degree of elevation of the FT4 above normal provides an estimate of the severity of the disease. During replacement therapy with thyroxine the range of both FTI and fT4 values tend to be about 20% above the normal range, possibly because only T4, rather than T4 and T3 from the thyroid, is providing the initial supply of hormone. Thus many patients will have an fT4 or FTI above normal when appropriately replaced and while TSH is in the normal range. Except for this, elevations of fT4 not due to thyrotoxicosis are unusual, and causes are given in Table 3.

Of course the Total T4 level may normally be as high as 16 or 20 µg/dl in pregnancy, and can be elevated without thyrotoxicosis in patients with familial hyperthyroxinemia due to abnormal albumin, the presence of hereditary excess TBG, the presence of antibodies binding T4 , the thyroid hormone resistance syndrome, and other conditions listed in Table 3. The T4 level may be normal in thyrotoxic patients who have depressed serum levels of T4 -binding protein or because of severe illness, even though they are toxic. Thus, thyrotoxicosis may exist when the total T4 level is in the normal range. However measurement of FT4, FT3 (Free T3), or FTI (Free Thyroxine Index) usually obviates this source of error and is the best test. In the presence of typical symptoms, one measurement of suppressed TSH or elevated fT4 is sufficient to make a definite diagnosis, although it does not identify a cause. If the fT4 is normal, repetition is in order to rule out error, along with a second test such as serum FT3. And it should be noted that in much of Europe FT3 is the  preferred test, rather than FT4, and serves very well.

A variety of methods for FT4 determination have become available, including commercial kits. Although these methods are usually reliable, assays using different kits do not always agree among themselves or with the determination of FT4 by dialysis. Usually T4 and T3 levels are both elevated in thyrotoxicosis, as is the FTI (Free Thyroxin Index), or an index constructed using the serum T3 and rT3U levels, and the newer measures of FT3.

Table 3. Conditions Associated with Transient Elevations of the FT4 or FTI

Condition	Explanation
Estrogen withdrawal	Rapid decrease in TBG level
Amphetamine abuse	Possibly induced TSH secretion(2)
Acute psychosis	Unknown
Hyperemesis gravidarum	Associated high hCG can cause thyrotoxicosis
Iodide administration	Thyroid autonomy
Beginning of T4 administration	Delayed T4 metabolism(3)
Severe illness (rarely)	Decreased T4 to T3 conversion (4)
Amiodarone treatment	Decreased T4 to T3 conversion, iodine load
Gallbladder contrast agents	Decreased T4 to T3 conversion, iodine load
Propranolol (large doses)	Inhibition of T4 to T3 conversion
Prednisone (rarely)	Inhibition of T4 to T3 conversion
High altitude exposure	Possibly hypothalamic activation
Selenium deficiency	Decreased T4 to T3 conversion

T3 and FT3 ASSAY-The serumT3 level determined by RIA is almost always elevated in thyrotoxicosis and is a useful but not commonly needed secondary test. Usually the serum T3 test is interpreted directly without use of a correction for protein binding, since alterations of TBG affect T3 to a lesser extent than T4. Any confusion caused by alterations in binding proteins can be avoided by use of a FT3 assay or T3 index calculated as for the FTI. Generally the FT3 assay is as diagnostically effective as the FT4. In patients with severe illness and thyrotoxicosis, especially those with liver disease or malnutrition or who are taking steroids or propranolol, the serum T3 level may not be elevated, since peripheral deiodination of T4 to T3 is suppressed ("T4 toxicosis"). A normal T3 level has also been observed in thyrotoxicosis combined with diabetic ketoacidosis. Whether or not these patients actually have tissue hypermetabolism at the time their serum T3 is normal is not entirely certain. In these patients the rT3 level may be elevated. If the complicating illness subsides, the normal pattern of elevated T4 , FTI, and T3 levels may return(5,6). Elevated T4 levels with normal serum T3 levels are also found in patients with thyrotoxicosis produced by iodine ingestion(7).

T3 Toxicosis Since 1957, when the first patient with T3 thyrotoxicosis was identified, a number of patients have been detected who had clinical thyrotoxicosis, normal serum levels of T4 and TBG, and elevated concentrations of T3 and FT3[8]. Hollander et al [9] found that approximately 4% of patients with thyrotoxicosis in the New York area fit this category. These patients often have mild disease but otherwise have been indistinguishable clinically from others with thyrotoxicosis. Some have had the diffuse thyroid hyperplasia of Graves’ disease, others toxic nodular goiter, and still others thyrotoxicosis with hyperfunctioning adenomas. Interestingly, in Chile, a country with generalized iodine deficiency, 12.5% of thyrotoxic subjects fulfilled the criteria for T3 thyrotoxicosis [10]. Asymptomatic hypertriiodothyronemia is an occasional finding several months before the development of thyrotoxicosis with elevated T4 levels [11]. Since T4 is normally metabolized to T3, and the latter hormone is predominantly the hormone bound to nuclear receptors, it makes sense that elevation of T3 alone is already indicative of thyrotoxicosis.

Thyroid Isotope uptake-In patients with thyrotoxicosis the RAIU (Radioactive Iodine Uptake) at 24 hours is characteristically above normal. In the United States, which has had an increasing iodine supply in recent years, the upper limit of normal is now about 25% of the administered dose. This value is higher in areas of iodine deficiency and endemic goiter. The uptake value at a shorter time interval, for example 6 hours, is as valid a test and may be more useful in the infrequent cases having such a rapid isotope turnover that "uptake" has fallen to normal by 24 hours. If there is reason to suspect that thyroid isotope turnover is rapid, it is wise to do both a 6- and a 24-hour RAIU determination during the initial laboratory study. As noted below, rapid turnover of 131-I can seriously reduce the effectiveness of 131-I therapy. Similar studies can be done with 123-I and also technetium. Because of convenience, and since serum assays of thyroid hormones and TSH are reliable and readily available, the RAIU is now infrequently determined unless 131-I therapy is planned.. It is however useful in patients who are mildly thyrotoxic for factitia thyrotoxicosis, subacute thyroiditis and painless thyroiditis in whom RAIU is low, thus confirming thyrotoxicosis in the absence of  elevated RAIU. This may include patients with brief symptom duration, small goiter, or lacking eye signs, absent family history, or negative antibody test result. Obviously other causes of a low RAIU test need to be considered and excluded. Tests measuring suppressibility of RAIU are of historical interest(13-15)

Thyroid IsotopeScanning-Isotope scanning of the thyroid has a limited role in the diagnosis of thyrotoxicosis. It is useful in patients in whom the thyroid is difficult to feel or in whom nodules (single or multiple) are present that require evaluation, or rarely to prove the function of ectopic thyroid tissue. Nodules may be incidental, or may be the source of thyrotoxicosis (toxic adenoma), or may contribute to the thyrotoxicosis that also arises from the rest of the gland. Scanning should usually be done with 123-I in this situation, in order to combine it with an RAIU measurement.

Thyroid  Ultrasound- US exam of the thyroid is sometimes of value in diagnosis. For example, if a possible nodule is detected on physical exam. It also may confirm hypoechogenicity or intense vascularity of Graves’ disease if a color Doppler flow exam is done.

Antithyroid Antibodies Determination of antibody titers provides supporting evidence for Graves’ disease. More than 95% of patients have positive assays for TPO (thyroperoxidase or microsomal antigen), and about 50% have positive anti-thyroglobulin antibody assays. In thyroiditis the prevalence of positive TG antibody assays is higher. Positive assays prove that autoimmunity is present, and  patients with causes of thyrotoxicosis other than Graves’ disease usually have negative assays. During therapy with antithyroid drugs the titers characteristically go down, and this change persists during remission. Titers tend to become more elevated after RAI treatment.

Antibodies to TSH-Receptor-Thyrotrophin receptor antibody (TRAb) assays have become readily available, and a positive result strongly supports the diagnosis of Graves’ disease(15.1). Determination of TRAb is not required for the diagnosis, but the implied specificity of a positive test provides security in diagnosis, and for this reason the assay is now widely used. The assay is valuable as another supporting fact in establishing the cause of exophthalmos, in the absence of thyrotoxicosis. High maternal levels suggest possible fetal or neonatal thyrotoxicosis. TRAb assays measure any antibody that binds to the TSH-R. Assays for Thyroid Stimulating Antibodies (TSAb,TSI) are less available, but are more specific for the diagnosis. Using current tests, both are positive in about 90% of patients with Graves disease who are thyrotoxic. "Second generation" assays becoming available use monoclonal anti-TSH-R antibodies and biosynthetic TSH-R in coated tube assays, are reported to reach 99% specificity and sensitivity(15.2,15.3,3). Although rarely required, serial assays are of interest in following a patient’s course during antithyroid drug therapy, and a decrease predicts probable remission(15.4).

Other Assays Rarely Used-General availability of assays that can reliably measure suppressed TSH has made this the gold standard to which other tests must be compared, and has effectively eliminated the need for most previously used ancillary tests. There are only rare causes of confusion in the TSH assay. Severe illness, dopamine and steroids, and hypopituitarism, can cause low TSH, but suppression below 0.1 µ/ml is uncommon and below 0.05 µ/ml is exceptional, except in thyrotoxicosis. Thyrotoxicosis is associated with normal or high TSH in patients with TSH producing pituitary tumors and selective pituitary resistance to thyroid hormone.
If TSH, FT4, TRAb, and other tests noted above do not establish the diagnosis, it may be wise to do nothing further except to observe the course of events. In patients with significant thyroid hyperfunction, the symptoms and signs will become clearer, and the laboratory measurements will fall into line. Measurement of BMR, T3 suppression of RAIU, TRH testing, and clinical response to KI are of historical interest.

DIFFERENTIAL DIAGNOSIS of THYROTOXICOSIS

Graves’ disease must be differentiated from other conditions causing thyrotoxicosis. (Table -4).

Thyrotoxicosis factitia-Thyrotoxicosis may be caused by taking T4 or its analogs, most commonly due to administration of excessive replacement hormone by the patient’s physician. Hormone may be taken surreptitiously by the patient for weight loss or psychologic reasons. The typical findings are a normal or small thyroid gland, a low131-I uptake, a low serum TG, and, of course, a striking lack of response to antithyroid drug therapy. The problem can easily be confused with "painless thyroiditis", but in thyrotoxicosis factitia, the gland is typically small.

Toxic nodular goiter is usually distinguished by careful physical examination and a history of goiter for many years before symptoms of hyperthyroidism developed. The thyrotoxicosis comes on insidiously, and often, in the older people usually afflicted, symptoms may be mild, or suggest another problem such as heart disease. The thyroid scan may be diagnostic, showing areas of increased and decreased isotope uptake. The results of assays for antithyroid antibodies, including TRAb, are usually negative. TMNG is typically produced by activating somatic mutations in TSH-R in one or more nodules, allowing them to enlarge and become functional even in the absence of TSH stimulation. (Interestingly, cats are well known to develop hyperthyroidism, with thyroid autonomy, often due to TSH-R gene mutations as seen in humans.(16))

Hyperfunctioning solitary adenoma is suggested on the physical finding of a palpable nodule in a otherwise normal gland, and is proved by a scintiscan demonstrating preferential radioisotope accumulation in the nodule. This type of adenoma must be differentiated from congenital absence of one of the lobes of the thyroid. Toxic nodules typically present in adults with gradually developing hyperthyroidism and a nodule > 3 cm in size. These nodules are usually caused by activating somatic mutations in the TSH-R, which endows them with mildly increased function, compared to normal tissue, even in the absence of TSH. These nodules are usually, but not always, monoclonal(17). In adults toxic nodules are very rarely malignant. Rarely, functioning thyroid carcinomas produce thyrotoxicosis. The diagnosis is made by the history, absence of the normal thyroid, and usually widespread functioning metastasis in lung or bones. Invasion of the gland by lymphoma has produced thyrotoxicosis, presumably due to thyroid destruction (18).

Thyrotoxicosis associated with subacute thyroiditis is usually mild and transient, and the patient lacks the physical findings of long-standing thyrotoxicosis. If thyrotoxicosis is found in conjunction with a painful goiter and low or absent 131-I uptake, this diagnosis is likely. Usually the erythrocyte sedimentation rate (ESR) and CRP are greatly elevated, and the leukocyte count may also be increased. Occasionally the goiter is non-tender. Antibody titers are low or negative. Many patients have the HLA-B35 antigen, indicating a genetic predisposition to the disease. The rare TSH secreting pituitary adenoma will be missed unless one measures the plasma TSH level, or until the enlargement is sufficient to produce deficiencies in other hormones, pressure symptoms, or expansion of the sella turcica(19). These patients have thyrotoxicosis with inappropriately elevated TSH levels and may/or may not secrete more TSH after TRH stimulation. The characteristic finding is a normal or elevated TSH, and an elevated TSH alpha subunit level in blood, measured by special RIA. TRAbs are not present. Exophthalmos, and antibodies of Graves’ disease are absent. Family history is sometimes positive for a similar condition. Demonstration of a suppressed TSH level excludes these rare cases.

The category of patients with thyrotoxicosis and inappropriately elevated TSH levels also includes the rare persons with pituitary "T3 resistance" as a part of the Resistance to Thyroid Hormone syndrome caused by TH Receptor mutations. The syndrome of Pituitary Thyroid Hormone Resistance is usually marked by mild thyrotoxicosis, mildly elevated TSH levels, absence of pituitary tumor, a generous response to TRH, no excess TSH alpha subunit secretion [19,20, 21],and by TSH suppression if large doses of T3 are administered. Final diagnosis depends on laboratory demonstration of a mutation in the TR gene, if possible. Hyperthyroidism caused by excess TRH secretion is a theoretical but unproven possibiity.

Administration of large amounts of iodide in medicines, for roentgenographic examinations, or in foods can occasionally precipitate thyrotoxicosis in patients with multinodular goiter or functioning adenomas. This history is important to consider since the illness may be self-limiting. Induction of thyrotoxicosis has also been observed in apparently normal individuals following prolonged exposure to organic iodide containing compounds such as antiseptic soaps and amiodarone. Amiodarone is of special importance since the clinical problem often is the presentation of thyrotoxicosis in a patient with serious cardiac disease including dysrythmia. Amodarone can induce thyrotoxicosis in patients without known prior thyroid disease, or with multinodular goiter. The illness appears to come in two forms. In one the RAIU may be low or normal. In the second variety , which appears to be more of a thyroiditis-like syndrome, the RAIU is very suppressed, and IL-6 may be elevated. In either case TSH is suppressed, FTI may be normal or elevated, but T3 is elevated if the patient is toxic. Antibodies are usually negative.

An increasingly recognized form of thyrotoxicosis is the syndrome described variously as painless thyroiditis, transient thyrotoxicosis, or "hyperthyroiditis". Its hallmarks are self-limited thyrotoxicosis, small painless goiter, and low or zero RAIU(22,23). The patients usually have no eye signs, a negative family history, and often positive antibody titers. This condition is due to autoimmune thyroid disease, and is considered a variant of Hashimoto’s Thyroiditis. It occurs sporadically, usually in young adults. It frequently occurs 3 - 12 weeks after delivery, sometimes representing the effects of immunologic rebound from the immunosuppressive effects of pregnancy in patients with Hashimoto’s thyroiditis or prior Graves’ Disease, and is called Post Partum Thyroiditis(22-25). The course typically includes development of a painless goiter, mild to moderate thyrotoxicosis, no eye signs, remission of symptoms in 3 -20 weeks, and often a period of hypothyroidism before return to euthyroid function. The cycle may be repeated several times. Histologic examination shows chronic thyroiditis, but it is not typical of Hashimoto’s disease or subacute thyroiditis and may revert to normal after the attack(26). In most patients, the thyrotoxic episode occurs in the absence of circulating TSAb. This finding suggests that the pathogenesis is quite distinct from that in Graves’ disease. The thyrotoxicosis is caused by an inflammation-induced discharge of preformed hormone due to the thyroiditis. The T4/T3 ratio is higher than in typical Graves’ disease,and thyroid iodine stores are depleted. Since the thyrotoxicosis is due to an inflammatory process, therapy with antithyroid drugs or potassium iodide is usually to no avail, and RAI treatment of course cannot be given when RAIU  is suppressed. Propranolol is usually helpful for symptoms. Glucocorticoids may be of help if the process -- often transient and mild -- requires some form of therapy. Propylthiouracil and/or ipodate can be used to decrease T4 to T3 conversion and will ameliorate the illness. Repeated episodes may be handled by surgery or by RAI therapy during a remission. Occasionally painless post-partum thyroiditis is followed by typical Graves’ Disease(27-29.1).

Hyperemisis gravidarum is frequently associated with elevated serum T4 , FTI, and variably elevated T3, and suppressed TSH. The abnormalities in thyroid function are caused by high levels of hCG. This molecule, or a closely related form, share enough homology with TSH so that it has about 1/1000 the thyroid stimulating activity of TSH, and can produce thyroid stimulation or thyrotoxicosis(29.12-29.14). It is typically self limited without specific treatment, disappears with termination of pregnancy, but may occasionally require anti-thyroid treatment temporarily or throughout pregnancy(29.3). Patients with minimal signs and symptoms, small or no goiter, and elevation of FTI up to 50 % above normal probably do not require treatment. Rarely those with goiter, moderate or severe clinical evidence of thyrotoxicosis, highly elevated T4 and T3 and suppressed TSH are best treated with antithyroid drugs. If antibodies are positive or eye signs are present, the picture is usually interpreted as a form of Graves’ disease. Familial severe hyperemesis gravidarum with fetal loss has been reported with an activating germline mutation in the TSH-R, which made it specifically more sensitive to activation by hCG(.29.2,29.3).  Hyperthyroidism can be induced by “hyperplacentosis”, which is characterized by increased placental weight and circulating hCG levels higher than those in normal pregnancy(29.4). After hysterotomy, hCG levels declined in the one case reported and hyperthyroidism was corrected.

Congenital hyperthyroidism caused by a germ-line activating mutation in the TSH-R has recently been recognized . The mutations are usually single aminoacid transitions in the extracellular loops or transmembrane segments of the receptor trans-membrane domain. The diagnosis may be difficult to recognize in the absence of a family history. However the patients lack eye signs, and have negative assays for antibodies(29.2, 29.3)

Hydatidiform moles, choriocarcinomas, and rarely seminomas secrete vast amounts of hCG. hCG, with an alpha subunit identical to TSH , and beta subunit related to TSH , that binds to and activates the thyroid TSH receptor with about 1/1,000th the efficiency of TSH itself (Fig.-3)(30-33). Current evidence indicates that very elevated levels of native hCG or perhaps desialated hCG, cause the thyroid stimulation. Many patients have goiter or elevated thyroid hormone levels or both, but little evidence of thyrotoxicosis, whereas others are clearly thyrotoxic. Diagnosis rests on recognizing the tumor (typically during or after pregnancy) and measurement of hCG. Therapy is directed at the tumor.

Hyperthyroidism also is seen as one manifestation of autoimmune thyroid disease induced by interferon-alpha treatment of chronic hepatitis C. It can be self limiting, or severe enough to require cessation of IFN, or in some cases continue on after INF is stopped(33.1).

Hyperthyroidism also occurs during immune reconstitution seen after effective anti-viral therapy of patients with HIV(33.2), has occurred during recovery of low lymphocyte levels induced by therapy with CAMPATH in patients with Multiple sclerosis, has occurred after cessation of immune-suppressive treatment in patients with T1DM.

Table 4. Causes of Thyrotoxicosis

Disease	Course of disease	Physical finding	Diagnostic finding	Treatment/Comment
Graves’ disease	Familial, prolonged	Goiter	+ Ab, + RAIU, eye signs	Antithyroids, RAI, Surgery
Transient thyrotoxicosis	Brief	Small goiter	Low Ab, no eye signs, RAIU=0	Time, beta blocker, steroids
Subacute thyroiditis	Brief	Tender goiter	RAIU=0, elevated ESR, recent URI	Nothing, NSAID, steroids
Toxic multinodular goiter	Prolonged, mild	Nodular goiter	Typical scan	Antithyroids, RAI, surgery
Iodide induced	Recent, mild	Nodular goiter, occ.normal	Low RAIU, abnormal scan	Antithyroids, KClO4, time, stop I source
Toxic adenoma	Prolonged, mild	One nodule	"Hot" nodule on scan	Surgery, RAI
Thyroid carcinoma	Recent	Variable, metastases	Functioning metastases	Surgery + RAI
Exogenous hormone	Variable	Small thyroid	RAIU and TG low, psychiatric illness	Withdrawal, counseling
Hydatiform mole	Recent, mild	Goiter	Pregnancy, bleeding,HCG	Surgery, chemotherapy
Choriocarcinoma	Recent, mild	Goiter	Increased HCG	Surgery, chemotherapy
TSH-oma	Prolonged	Goiter	Excess alpha, TSH, adenoma	Op, somatostatin, thyroid ablation
Pituitary T3 resistance	Prolonged	Goiter	Elevated or normal TSH, no tumor, mod. thyrotox, no excess alpha	Triac, somatostatin, thyroid ablation, beta blocker
Struma ovarii	Variable	+ / - goiter	Positive scan or US	Surgery
Thyroid destruction	Variable	Variable	Variable	Steroids
Hamburger toxicosis	Recent, self-limited	Small gland, no eye signs	Suppressed TSH and TG and RAIU	Avoid neck meat trimmings
Hyperemesis	Onset first trimester	Pregnancy, variably toxic	UP FTI, Low TSH, High HCG	ATD if severe, pregnancy termination
TSH-R mutation	Congenital	Typical thyrotoxicosis	+ FH, germline mutation	Thyroid ablation
Familial gestational hyperthyroidism	Onset first trimester	Severe hyperthyroidism	+ FH, TSH-R mutation sensitizing to hCG	ATD, Surgery
Amiodarone	Prolonged	Thyroid usually enlarged. Often heart disease.	Suppressed RAIU, nl or increased FTI, elevated T3	ATD + KClO4,Prednisone, Surgery,iopanoic acid
Interferon-alpha induced	Induced by INF treatment of hepatitis C	Clinically significant		Often remits if IFN stopped.
Treatment of HIV	During T cell recovery	Clinically significant	With or without prior thyroid autoimmunity	May need treatment
Administration of CAMPATH	During recovery of T cells	Clinically significant	With or without prior thyroid autoimmunity	May need treatment
Sunitinib therapy	During tyrosine kinase therapy for cancer	Clinically significant	Usually induces hypothyroidism, rarely hyper	May need treatment

 

Subclinical hyperthyroidism

 It should be remembered that thyrotoxicosis is today not only a clinical but also a laboratory diagnosis. Consistent elevation of the fT4 , and the T3 level, and suppressed TSH, or only suppression of TSH, can indicate that thyrotoxicosis is present even in the absence of clear-cut signs or symptoms These elevations themselves are a sufficient indication for therapy, especially in elderly patients with coincident cardiac disease(33a,b). Antithyroid drug treatment of patients with subclinical hyperthyroidism was found to result in a decrease in heart rate, decrease in number of atrial and ventricular premature beats, a reduction of the left ventricular mass index, and left ventricular posterior wall thickness, as well as a reduction in diastolic peak flow velocity. These changes are considered an argument for early treatment of subclinical hyperthyroidism. Subclinical hyperthyroidism may disappear or evolve into Graves hyperthyroidism, or when caused by MNG, persist for long periods unchanged.
Individuals of any age with consistent suppression of TSH should be fully evaluated to determine if evidence of hyperthyroidism is present, or there is coincident disease that might be aggrevated by hyperthyroidism. SCH with TSH of 0.2-0.3.5 may not need treatment. Individuals with TSH at or below 0.1uU/ml most likely will require treatment by one of the methods described below.

Apathetic hyperthyroidism designates a thyrotoxic condition characterized by fatigue, apathy, listlessness, dull eyes, extreme weakness, often congestive heart failure, and low-grade fever.[ 34, 35] Often such patients have small goiters, modest tachycardia, occasionally cool and even dry skin, and few eye signs. The syndrome may, in some patients, represent an extreme degree of fatigue induced by long-standing thyrotoxicosis. Once the diagnosis is considered, standard laboratory tests should confirm or deny the presence of thyrotoxicosis even in the absence of classical symptoms and signs.

Other diagnostic problems  Two common diagnostic problems involve (1) the question of hyperthyroidism in patients with goiter of another cause, and (2) mild neuroses such as anxiety, fatigue states, and neurasthenia. Most patients with goiter receive a battery of examinations to survey their thyroid function at some time. Usually these tests are done more for routine assessment than because there is serious concern over the possibility of thyrotoxicosis. In the absence of significant symptoms or signs of hyperthyroidism and ophthalmologic problems, a normal FTI or TSH determination is sufficiently reassuring to the physician and the patient. Of course, the most satisfactory conclusion of such a study is the identification of an alternate cause for enlargement of the thyroid.
Some patients complain of fatigue and palpitations, weight loss, nervousness, irritability, and insomnia. These patients may demonstrate brisk reflex activity, tachycardia (especially during examinations), perspiration, and tremulousness. In the abscence of thyrotoxicosis, the hands are more often cool and damp rather than warm and erythematous. Serum TSH assay should be diagnostic.

Mild and temporary elevation of the FTI may occur if there is a transient depression of TBG production -- for example, when estrogen administration is omitted. This problem is occasionally seen in hospital practice, usually involving a middle-aged woman receiving estrogen medication that is discontinued when the patient is hospitalized. Estrogen withdrawal leads to decreased TBG levels and a transiently elevated FTI. After two to three weeks, both the T4 level and the FTI return to normal ( Table -3).
In the differential diagnosis of heart disease, the possibility of thyrotoxicosis must always be considered. Some cases of thyrotoxicosis are missed because the symptoms are so conspicuously cardiac that the thyroid background is not perceived. This is especially true in patients with atrial fibrillation.
Many disorders may on occasion show some of the features of hyperthyroidism or Graves’ disease. In malignant disease, especially lymphoma, weight loss, low grade fever, and weakness are often present. Parkinsonism in its milder forms may initially suggest thyroid disease. So also do the flushed countenance, bounding pulse, thyroid hypertrophy, and dyspnea of pregnancy. Patients with chronic pulmonary disease may have prominent eyes, tremor, tachycardia, weakness, and even goiter from therapeutic use of iodine. One should remember the weakness, fatigue, and jaundice of hepatitis and the puffy eyes of trichinosis and nephritis. Cirrhotic patients frequently have prominent eyes and lid lag, and the alcoholic patient with tremor, prominent eyes, and flushed face may be initially suspected of having thyrotoxicosis. Distinguishing between Graves’ disease with extreme myopathy and myopathies of other origin can be clinically difficult. The term chronic thyrotoxic myopathy is used to designate a condition characterized by weakness, fatigability, muscular atrophy, and weight loss usually associated with severe thyrotoxicosis. Occasionally fasciculations are seen. The electromyogram result may be abnormal. If the condition is truly of hyperthyroid origin, the thyroid function tests are abnormal and the muscular disorder is reversed when the thyrotoxicosis is relieved. Usually a consideration of the total clinical picture and assessment of TSH and FTI are sufficient to distinguish thyrotoxicosis from polymyositis, myasthenia gravis, or progressive muscular atrophy. True myasthenia gravis may coexist with Graves’ disease, in which case the myasthenia responds to neostigmine therapy. (The muscle weakness of hyperthyroidism may be slightly improved by neostigmine, but never relieved.) Occasionally electromyograms, muscle biopsy, neostigmine tests, and ACH-receptor antibody assays must be used to settle the problem.

TREATMENT OF THYROTOXICOSIS–
SELECTION OF PRIMARY THERAPY

No treatment is ideal and thus indicated in all patients ( 35.1).Three forms of primary therapy for Graves’ disease are in common use today: (1) destruction of the thyroid by 131-I; (2) blocking of hormone synthesis by antithyroid drugs; and (3) partial or total surgical ablation of the thyroid. Iodine alone as a form of treatment was widely used in the past, but is not used today because its benefits may be transient or incomplete and because more dependable methods became available. Iodine is primarily used now in conjunction with antithyroid drugs to prepare patients for surgical thyroidectomy when that plan of therapy has been chosen. There is, however, some revival of interest in use of iodine treatment as described subsequently. Roentgen irradiation was also used in the past, but is not currently [36]. Suppression of the autoimmune response is being attempted, and currently new treatments blocking the action of Thyroid Stimulating Immunoglobulins are being investigated.

Selection of therapy depends on a multiplicity of considerations [36.1]. Availability of a competent surgeon, for example, undue emotional concern about the hazards of 131-I irradiation, or the probability of adherence to a strict medical regimen might govern one’s decision regarding one program of treatment as opposed to another. More than 90% of patients are satistactorly treated cumulating the effects of these treatment.(36.2) Fig. 2

Antithyroid drug therapy offers the opportunity to avoid induced damage to the thyroid (and parathyroids or recurrent nerves), as well as exposure to radiation and operation. In recent studies patients with thyroids under 40 gm weight, with low TRAb levels, and age over 40, were most likely to enter remission (in up to 80%) (36.3, 36.31). The difficulties are the requirement of adhering to a medical schedule for many months or years, frequent visits to the physician, occasional adverse reactions, and, most importantly, a disappointingly low permanent remission rate. Therapy with antithyroid drugs is used as the initial modality in most patients under age 18, in many adults through age 40, and in most pregnant women(36.31). Remission is most likely in young patients, with small thyroids, and mild disease. ATDs may be preferred in  elderly patients, those with serious co-morbidities and who have been previously operated upon.

Iodine-131 therapy is quick, easy, moderatly expensive, avoids surgery, and is without significant risk in adults and probably teenagers. The larger doses required to give prompt and certain control generally induce hypothyroidism, and low doses are associated with a frequent requirement for retreatment or ancillary medical management over one to two years. 131-I is used as the primary therapy in most persons over age 40 and in most adults above age 21 if antithyroid drugs fail to control the disease. Treatment of children with 131-I is less common, as discussed later. It can be used in the elderly and those with co-morbidities with precautions.

Surgery, which was the main therapy until 1950, has been to a large extent replaced by 131-I treatment. As the high frequency of 131-I induced hypothyroidism became apparent, some revival of interest in thyroidectomy occurred. The major advantage of surgery is that definitive management is often obtained over an 8- to 12-week period, including preoperative medical control, and many patients are euthyroid after operation. Its well-known disadvantages include expense, surgery itself, and the risks of recurrent nerve and parathyroid damage, hypothyroidism, and recurrence. Nevertheless, if a skillful surgeon is available, surgical management may be used as the primary or secondary therapy in many young adults, as the secondary therapy in children poorly controlled on antithyroid drugs, in pregnant women requiring excessive doses of antithyroid drugs, in patients with significant exophthalmos, and in patients with coincident suspicious thyroid nodules. Early total thyroidectomy has been recommended for treating older, chronically ill patients with thyrotoxic storm if high-dose thionamide treatment, iopanoic acid, and glucocorticoids fail to improve the patient’s condition within 12 – 24 hours (36.4).

Two recent surveys reporting trends in therapeutic choices made by thyroidologists have been published [37]. In Europe, most physicians tended to treat children and adults first with antithyroid drugs, and adults secondarily with 131-I or less frequently surgery. Surgery was selected as primary therapy for patients with large goiters. 131-I was selected as the primary treatment in older patients. Most therapists attempted to restore euthyroidism by use of 131-I or surgery. In the United States, 131-I  is the initial modality of therapy selected by members of the American Thyroid Association for management of uncomplicated Graves’ disease in an adult woman [38]. Two-thirds of these clinicians attempt to give 131-I in a dosage calculated to produce euthyroidism, and one-third plan for thyroid ablation.

131-I THERAPY FOR THYROTOXICOSIS OF GRAVES’ DISEASE

Introduction-In many thyroid clinics 131-I therapy is now used for most patients with Graves’ disease who are beyond the adolescent years. It is used in most patients who have had prior thyroid surgery, because the incidence of complications, such as hypoparathyroidism and recurrent nerve palsy, is especially high in this group if a second thyroidectomy is performed. Likewise, it is the therapy of choice for any patient who is a poor risk for surgery because of complicating disease. Surgery may be preferred in patients with significant ophthalmopathy, often combined with prednisone prophylaxis.

Treatment of children-The question of an age limit below which RAI should not be used frequently arises. With lengthening experience these limits have been lowered. Several studies with average follow-up periods of 12 - 15 years attest to the safety of 131-I therapy in adults [ 39- 41]. In two excellent studies treated persons showed no tendency to develop thyroid cancer, leukemia, or reproductive abnormalities, and their children had no increase in congenital defects or evidence of thyroid damage [ 42- 44]. Franklyn and co workers recently reported on a population based study of 7417 patients treated with 131-I for thyrotoxicosis in England [44.1]. They found an overall decrease in incidence of cancer mortality, but a specific increase in mortality from cancer of the small bowel (7 fold) and of the thyroid (3.25) fold. The absolute risk remains very low, and it is not possible to determine whether the association is related to the basic disease, or to radioiodine treatment. Although there is much less data on long term results in children, there is a increased use of this treatment in teenagers age 15-18, as discussed below. The epidemic of thyroid cancer apparently induced by radioactive iodine isotopes in infants and children living around Chernobyl suggests caution in use of 131-I in younger children.
Since the possibility of a general induction of cancer by 131-I is of central concern, it is interesting to calculate the risk in children using the data presented by Rivkees et al (44.2) who are proponents of use of RAI for therapy in young children..The risk of death from any cancer due specifically to radiation exposure is noted by these authors to be 0.16%/rem for children, and the whole body radiation exposure from RAI treatment at age 10 to be 1.45 rem/mCi administered. Rivkees et al advise treatment with doses of RAI greater then 160 uCi/gram thyroid, to achieve a thyroidal radiation dose of at least 150Gy (about 15000 rads). Assuming a reasonable RAIU of 50% and gland size of 40 gm, the administered dose would thus be 40(gm) x 160uCi/gm x 2 (to account for 50% uptake) =12.8 mCi. Thus the long term cancer death risk would be 12.8 (mCi) x 1.45 rem (per mCi) x 0.16% (per rem) = 3%. For a dose of 15mCi the theoretical incremental risk of a later radiation-induced cancer mortality would be 4% at age 5, 2% at age 10, and 1% at age 15.
Whether or not accepting a specific  2-4% risk of death from any cancer because of  this treatment is of course a matter of judgment by the physician and family. However, this would seem to many persons to constitute a significant risk that might be avoided. We note that this is a thoretical risk, based on known effects of ioniing radiation to induce malignancies, but not so far proven in this setting.

Low 131-I uptake-Certain other findings may dictate the choice of therapy. Occasionally, the 131-I uptake is significantly blocked by prior iodine administration. The effect of iodide dissipates in a few days after stopping exposure, but it may take 3-12 weeks for the effect of amiodarone or IV contrast dyes to be lost. One may either wait for a few days to weeks until another 131-I tracer indicates that the uptake is in a treatable  range or use an alternative therapeutic approach such as antithyroid drugs.

Coincident nodule(s)-Sometimes a patient with thyrotoxicosis harbors a thyroid gland with a configuration suggesting the presence of a malignant neoplasm. These patients probably should have surgical exploration. While FNA may exclude malignancy, the safety of leaving a highly irradiated nodule in place for many years is not established. Currently few patients who will have RAI therapy are subjected to ultrasonagraphy or scintiscaning. However Stocker et al. found that 12% of Graves’ patients had cold defects on scan, and among these half were referred for surgery. Six of 22, representing 2% of all Graves’ patients, 15% of patients with cold nodules, 25% of patients with palpable nodules, and 27% of those going to surgery, had papillary cancer in the location corresponding to the cold defect. Of these patients, one had metastasis to bone and two required multiple treatments with radioiodine. They argue for evaluating patients with a thyroid scintigram and further diagnostic evaluation of cold defects(44.3). Certainly any patient with GD in whom a thyroid nodule is detected, deserves consideration for surgical treatment

Ophthalmopathy-131-I therapy causes an increase in titers of TSH-R Abs, and anti-TG or TPO antibodies, which reflects an activation of autoimmunity. It probably is due to release of thyroid antigens by cell damage, and possibly destruction of intrathyroidal T cells. Many thyroidologists are convinced that 131-I therapy can lead to exacerbation of infiltrative ophthalmopathy, perhaps because of this immunologic response. Tallstedt and associates published data indicating that 131-I therapy causes exacerbation of ophthalmopathy in nearly 25% of patients, while surgery is followed by this response in about half as many.The same group conducted a second randomized trial (44.3) with a follow-up of 4 yr. Patients with a recent diagnosis of Graves’ hyperthyroidism were randomized to treatment with iodine-131 (163 patients) or 18 months of medical treatment (150 patients). Early substitution with L-T4 was given in both groups.: Worsening or development of eye problems was significantly more common in the iodine-131 treatment group (63 patients; 38.7%) compared with the medical treatment group (32 patients; 21.3%) (P < 0.001). This adverse effect of RAI therapy has since been confirmed in multiple meta-analyses of randomized studies (44.4-44.7) Thus, as described below, patients with significant ophthalmopathy may receive corticosteroids along with131-I, or may be selected for surgical management. The indications and contraindications for 131-I  therapy are given in Table 5.

Table 5-Indications and Contraindication for RAI Therapy

Indications

Any patients above a preselected age limit (possibly 15-18 yrs) Patients who fail to respond to antithyroid drugs Prior thyroid or other neck surgery Contraindications to surgery, such as severe heart, lung,or renal disease Women  intending to become pregnant (more than 6 months later)

General Contraindications

Pregnancy or lactation Insufficient 131-I uptake due to prior medication or disease Question of malignant thyroid tumor Age below a preselected age limit, such as (possibly) age 15-18 Patient concerns regarding radiation exposure

Other Possible Contraindications

Unusually large glands Active exophthalmos

SELECTION OF 131-I Dosage

There are two basically different goals in 131-I dose selection. The traditional approach has been to attempt to give the thyroid 1) sufficient radiation to return the patient to euthyroidism, but not induce hypothyroidism. An alternative approach is to intend to
2) induce hypothyroidism, or euthyroidism and avoid any possible return of hyperthyroidism.

Background-The dosage initially was worked out by a trial-and-error method and by successive approximations. By 1950, the standard dose was 160 uCi 131-I per gram of estimated thyroid weight. Of course, estimating the weight of the thyroid gland by examination of the neck is an inexact procedure, but can now be made more accurate by use of ultrasound. Also, marked variation in radiation sensitivity no doubt exists and cannot be estimated at all. It was gratifying that in practice this dosage scheme worked well enough. In the early 1960s, it was recognized that a complication of RAI therapy was a high incidence of hypothyroidism. This reached 20 - 40% in the first year after therapy and increased about 2.5% per year, so that by 10 years 50 - 80% of patients had low function [45,46]. In an effort to reduce the incidence of late hypothyroidism, Hagen and colleagues reduced the quantity of 131-I to 0.08 mCi per gram of estimated gland weight [48]. No increase was reported in the number of patients requiring retreatment, and there was a substantial reduction in the incidence of hypothyroidism. Most of these patients were maintained on potassium iodide for several months after therapy, in order to ameliorate the thyrotoxicosis while the radioiodine had its effect [ 49, 50]. Patients previously treated with 131-I are sensitive to and generally easily controlled by KI. However KI often precipitates hypothyroidism in these patients, which may revert to hyperthyroidism when the KI is discontinued.

Over the years some effort was made to refine the calculation. Account was taken of uptake, half-life of the radioisotope in the thyroid, concentration per gram, and so on, but it is evident that the result in a given instance depends on factors that cannot be estimated precisely [47,]. One factor must be the tendency of the thyroid to return to normal if a dose of radiation is given that is large enough to make the gland approach, for a time, a normal functional state. In many patients, "cure" is associated with partial or total thyroid ablation. Although we, and many endocrinologists, attempt to scale the dose to the particular patient, some therapists believe it is futile, advocate giving up this attempt, and provide a standard dose giving up to 10000 rads to the thyroid(47.1). Leslie et al reported a comparison of fixed dose treatment and treatment adjusted for 24 hour RAIU, using low or high doses, and found no difference in outcome in either rate of control or induction of hypothyroidism on comparison of the methods. They favor the use of a fixed dose treatment with a single high or low dose (47.2).

Many attempts have been made to improve the therapeutic program by giving the RAI in smaller doses. Reinwein et al [51]. studied 334 patients several years after they had been treated with serial doses of less than 50 uCi 131-I per gram of estimated thyroid weight. One-third of these patients had increased levels of TSH, although they were clinically euthyroid. Only 3% were reported to be clinically hypothyroid.

Dosage adjustmentsmade to induce euthyroidism usually include a factor inc reassing with gland size, a standard dose in microCuries per gram, and a correction to account for 131-I uptake [52]. A"Low Dose Protocol" was designed to compensate for the apparent radiosensitivity of small glands and resistance of larger glands [53]. Using this approach, after one year, 10% of patients were hypothyroid, 60% are euthyroid, and 30% remained intrinsically toxic [53], although euthyroid by virtue of antithyroid drug treatment. At ten year follow-up, 40% were euthyroid and 60% hypothyroid. A problem with low-dose therapy is that about 25% of patients require a second treatment and 5% require a third. Although this approach reduces early hypothyroidism, it does so at a cost in time, money and patient convenience (Fig. 2). To answer these problems, patients can be re-treated, if need be, within six months, and propranolol and antithyroid drugs can be given between 131-I doses if needed. Unfortunately, experience shows that even low-dose ^131-Itherapy is followed by a progressive development of hypothyroidism in up to 40 - 50% of patients ten years after therapy[ 54- 57].

Table 6. LOW Dosage Schedule for 131-I Therapy

Thyroid wt. in gms.	uCi retained/gm thyroid at 24h	Thyroid rads, avg.
10-20	40	3310
21-30	45	3720
31-40	50	4135
41-50	60	4960
51-60	70	5790
61-70	75	6200
71-80	80	6620
81-90	85	7030
91-100	90	7440
100 +	100	8270

Impressed by the need to retreat nearly a third of patients, a "Moderate Dose Protocol" was developed Table -6). This is a fairly conventional program with a mean dose of about 9 mCi. The ^131-I dosage is related to gland weight and RAIU, and is increased as gland weight increases. The calculation used is as follows:

uCi given = (estimated thyroid weight in grams) X (uCi/g for appropriate weight from Table 6) / (fractional RAIU at 24 hours) (For readers who may find difficult the conversion of older units in Curies, rads, and rems to newer units of measurement, see Table -7.)

Table 6. MODERATE Dosage Schedule for 131-I Therapy

Thyroid wt. in gms.	Planned uCi retained/gm thyroid at 24h	Thyroid rads, avg.
10-20	80	6620
21-30	90	7440
31-40	100	8270
41-50	120	9920
51-60	140	11580
61-70	150	12400
71-80	160	13240
81-90	170	14060
91-100	180	14880
100 +	200	16540

 

Table 7. Conversion of International Units of Measurement

 

International Units	Conversion Factors
Becquerel (Bq)	2.7 x 10 -11Curies (1mCi=37MBq, 100mCi= 3.7GBq)
Gray (Gy)	100 rads ( 1 rad= 0.01Gy)
Sievert (Sv)	100 rems (1 rem = 0.01 Sv)

Probably it is wise to do uptakes and treatment using either capsules or liquid isotope for both events. Rini et al have reported that RAIU done with isotope in a capsule appears to give significantly lower values (25 – 30% lower) than when the isotope is administered in liquid form, and this can significantly influence the determination of the dosage given for therapy(57.1). Berg et al report using a relatively similar protocol (absorbed doses of 100-120 Gy) and that 93% of their patients required replacement therapy after 1-5 years [57.2]. Many studies have presented methods for more accurately delivering a specific radiation dose to the thyroid, and report curing up to 90% of patients, with low incidence of recurrence or hypothyroidism(57.3, 57.4). Franklyn and co-workers analyzed their data on treatment of 813 hyperthyroid patients with radioactive iodide and corroborate many of the previously recognized factors involved in response. Lower dose (in this case 5 mCi), male gender, goiters of medium or large size and severe hyperthyroidism were factors that were associated with failure to cure after one treatment. They suggest using higher fixed initial doses of radioiodine for treating such patients (58.2), as do Leslie et al(58.4). Santos et al (58.4) compared fixed doses of 10 and 15mCi and found no difference in outcome at 12 months post treatment.  These authors suggest a standard 10mCi dose, with the larger dose reserved for larger glands.

Planned thyroid partial or complete ablation-All attempts to induce euthyroidism by a calculated moderate dose protocol end up with some patients hypothyroid, and others with persistent hyperthyroidism requiring further treatment. At this time many physicians giving 131-I therapy make no attempt to achieve euthyroidism, and instead use  a dose sufficient to largely destroy the thyroid, followed by L- T4 replacement therapy [58]. For example, a dose is given that will result in 7-20 mCi retained at 24 hrs, which is intended to induce hypothyroidism, accepting that in some (or many) patients this will ablate the thyroid completely. A dose of 30 Mci was found to  offer a slightly higher cure rate, not surprisingly, at one year than 15 Mci (95 vs 74% (58.1), They argue that this is realistic and preferable since it offers 1) near certainty of prompt control, 2) avoids any chance of persistent or recurrent disease, 3)there is no benefit in having residual thyroid  tissue, and 4) hypothyroidism is inevitable in most patients given RAI. Probably many patients given this treatment do in fact have some residual thyroid tissue that is either heavily damaged or reduced in amount so that it can not produce normal amounts of hormone. So far there is no evidence, in adults, that this residual radiated tissue will develop malignant change. There is no certainty at this time that one approach is better than the other. It may be worth remembering that over 50% of patients given calculated moderate dose therapy remain euthyroid after ten years and can easily be surveyed at yearly intervals for hypothyroidism.
When giving large doses of 131-I it is prudent to calculate the rads delivered to the gland (as above), which can reach 40-50,000rads. Such large doses of radiation can cause clinically significant radiation thyroiditis, and occasionally damage surrounding structures.
And lastly, a speculation. Practitioners comment that the incidence of serious ophthalmopathy seems to be less that in former decades. Prompt diagnosis and therapy might contribute to such a change. Another factor could be the  more common ablation of the thyroid during therapy for Graves disease, since this should over time reduce exposure  of patient’s immune system to thyroid antigens.

Lithium with RAI therapy- Although rarely used, RAI combined with lithium is safe and more effective than RAI alone in the cure of hyperthyroidism due to Graves’ disease, probably because it it causes greater retention of RAI within the thyroid gland.. Bogazzi et al (58.5)reported a study combining lithium with RAI therapy. MMI treatment was withdrawn 5 days prior to treatment, Two hundred ninety-eight patients were treated with RAI plus lithium (900 mg/d for 12 d starting 5 days prior to 131-I treatment) and 353 with RAI alone. RAI dosage was 260mCi/g estimated thyroid weight, corrected for RAIU (done on lithium).. All patients receive prednisone 0.5mg/kg/day, beginning on day 7 after RAI, tapering over 2 months. Patients treated with RAI plus lithium had a higher cure rate (91.0%) than those treated with RAI alone (85.0%, P = 0.030). In addition, patients treated with RAI plus lithium were cured more rapidly (median 60 d) than those treated with RAI alone (median 90 d, P = 0.000). Treatment with lithium inhibited the serum FT4 increase seen after methimazole withdrawal and RAI therapy.

Pretreatment with antithyroid drugs--Patients are often treated directly after diagnosis, without prior therapy with antithyroid drugs. This is safe and common in patients with mild hyperthyroidsm and especially those without eye problems. However often physicians give antithyroid drugs before 131-I treatment in order to deplete the gland of stored hormone and to restore the FTI to normal before ^131-I therapy. This offers several benefits. The possibility of 131-I induced exacerbation of thyrotoxicosis is reduced, the patient recovers toward normal health, and there is time to reflect on the desired therapy and review any concerns about the use of radioisotope for therapy. If the patient has been on antithyroid drug, it is discontinued two days before RAIU and therapy. Patients can be treated while on antithyroid drug, but this reduces the dose retained, reduces the post-therapy increment in hormone levels, and reduces the cure rate, so seems illogical(58.6) . When antithyroid drugs are discontinued the patient’s disease may exacerbate, and this must be carefully followed. Beta blockers can be given in this interim, but there is no reason for a prolonged interval between stopping antithyroid drug, and 131-I therapy, unless there is uncertainty about the need for the treatment. Pretreatment with antithyroid drug does not appear in most studies to reduce the efficacy of 131-I treatment. [59] but the debate about the effect of antithyroid drug pretreatment on the efficacy of radioactive iodine therapy continues. In recent studies in which patients were on or off antithyroid therapy, which was discontinued four days, or 1-2 days before treatment, there was no effect on the efficacy of treatment at a one year endpoint (59.1,59.2, 59,3). In another study Bonnema et al found that PTU pretreatment , stopped 4 days prior to 131-I, reduced the efficacy of 131-I(59.6).

Pretreatment is usually optional but is logical in patients with large glands and severe hyperthyroidism. Antithyroid drug therapy does reduce the pretreatment levels of hormone and reduces the rise in thyroid hormone level that may occur after radioactive iodide treatment. This certainly could have a protective effect in individuals who have coincident serious illness such as coronary artery disease, or perhaps individuals who have very large thyroid glands (59.3). It is indicated in two circumstances. In patients with severe heart disease, an 131-I- induced exacerbation of thyrotoxicosis could be serious or fatal. Pretreatment may reduce exacerbation of eye disease (see below), and it does reduce the post-RAI increase in antibody titers(59.1,59.31). The treatment dose of 131-I is best given as soon as possible after the diagnostic RAIU in order to reduce the period in which thyrotoxicosis may exacerbate without treatment, and since any intake of iodine (from diet or medicines or tests) would alter uptake of the treatment dose (59.4), and 2 days seems sufficient.

Post 131-I treatment management--Many patients remain on beta-blockers but require no other treatment after 131-I therapy. Antithyroid drugs can be reinstituted after 5 ( or preferably 7 ) days, with minimal effect on retention of the treatment dose of 131-I.

Alternatively, one may prescribe antithyroid drug (typically 10 mg methimazole q8h) beginning one day after administration of 131-I and add KI (2 drops q8h) after the second dose of methimazole. KI is continued for two weeks, and antithyroid drug as needed. This promotes a rapid return to euthyroidism, but by preventing recirculation of 131-I it can lower the effectiveness of the treatment. This method has been employed in a large number of patients, and is especially useful in patients requiring rapid control- for example, with CHF. A typical response is shown in Fig -3. It also has provided the largest proportion of patients remaining euthyroid at 10 years after therapy, in comparison to other treatment protocols. Glinoer and Verelst also report successful use of this strategy [59.1]. As noted, antithyroid drugs may be given starting 7-10 days after RAI without significantly lowering the radiation dose delivered to the gland.

Treatment using 125-I was tried as an alternative to 131-I, because it might offer certain advantages [60]. 125-I is primarily a gamma ray emitter, but secondary low-energy electrons are produced that penetrate only a few microns, in contrast to the high-energy beta rays of 131-I. Thus, it might theoretically be possible to treat the cytoplasm of the thyroid cell with relatively little damage to the nucleus. Appropriate calculations indicated that the radiation dose to the nucleus could be perhaps one-third that to the cytoplasm, whereas this difference would not exist for 131-I. Extensive therapeutic trials have nonetheless failed to disclose any advantage thus far for ¹²⁵I. Larger doses -- 10-20 mCi -- are required, increasing whole body radiation considerably [ 61, 62].

SAFETY PRECAUTIONS AFTER 131-I THERAPY

Doses of 131-I up to 33 mCi can be given to an outpatient basis, and this level is rarely exceeded in treatment of Graves’ disease. However patients must be given advice (written if possible) on precautions to be followed to prevent unneccessary or excessive exposure of other individuals by radiaactivity administered to the patient. For maximum safety, patients who have received 20 mCi should avoid extended time in public places for 1 day, maximize distance (6 feet) from children and pregnant women for 2 days, may return to work after 1 day, sleep in a separate (6-feet separation) bed from adults for 8 days, sleep in a separate bed from pregnant partners, infant, or child for 20 days, and avoid contact with body fluids (saliva, urine) for at least one week. Lower therapeutic doses require proportionally more moderate precautions. The basic NRC rule is that patients may be released from hospital when (1) the ¹³¹I measured dose rate is ≤7 mrem/hr at 1 m, or (2) when the expected total dose another person would receive is unlikely to exceed 500 mrem (5 mSv). Written precaution instructions are required If 100 mrem (1 mSv) may be exceeded in any person. This topic is well covered in articles by Sisson et al
(http://www.ncbi.nlm.nih.gov/pubmed/21417738) andLiu et al (62.1).

 

Course After Treatment-

If adequate treatment has been given, the T4 level falls progressively, beginning in one to three weeks.. Labeled thyroid hormones, iodotyrosines, and iodoproteins appear in the circulation [63,63.1]. TG is released, starting immediately after therapy. Another iodoprotein, which seems to be an iodinated albumin, is also found in plasma. This compound is similar or identical to a quantitatively insignificant secretion product of the normal gland. It comprises up to 15% or more of the circulating serum 131-I in thyrotoxic patients [64]. It is heavily labeled after 131-I therapy, and its proportional secretion is probably increased by the radiation. Iodotyrosine present in the serum may represent leakage from the thyroid gland, or may be derived from peripheral metabolism of TG or iodoalbumin released from the thyroid.

The return to the euthyroid state usually requires at least two months, and often the declining function of the gland proceeds gradually over six months to a year. For this reason, it is logical to avoid retreating a patient before six months have elapsed unless there is no evidence of control of the disease. While awaiting the response to131-I  the symptoms may be controlled by propranolol, antithyroid drugs, or iodide. Hypothyroidism develops transiently in 10 - 20% of patients, but thyroid function returns to normal in most of these patients in a period ranging from three to six months. These patients rarely become toxic again. Others develop permanent hypothyroidism and require replacement therapy. It is advantageous to give the thyroid adequate time to recover function spontaneously before starting permanent replacement therapy. This can be difficult for the patient unless partial T4 replacement is given. Unfortunately, one of the common side effects of treating hyperthyroidism is weight gain, averaging about 20 lbs through four years after treatment (64.1).

Patients may develop transient increases in FTI and T3 at 2-4 months after treatment [63.1], sometimes associated with enlargement of the thyroid. This may represent an inflammatory or immune response to the irradiationinduced thyroid damage, and the course may change rapidly with a dramatic drop to hypothyroidism in the 4-5th month.

Hypothyroidism may ultimately be inescapable after any amount of radiation that is sufficient to reduce the function of the hyperplastic thyroid to normal [65]. Many apparently euthyroid patients (as many as half) have elevated serum levels of TSH long after ^131-I therapy, with "normal" plasma hormone levels [66]. An elevated TSH level with a low normal T4level is an indicator of changes progressing toward hypothyroidism [67]. The hypothyroidism is doubtless also related to the continued autoimmune attack on thyroid cells. Hypofunction is a common end stage of Graves’ disease independent of ^131-I use; it occurs spontaneously as first noted in 1895(!) [68] and in patients treated only with antithyroid drugs [69]. Just as after surgery, the development of hypothyroidism is correlated positively with the presence of antithyroid antibodies.

During the rapid development of postradiation hypothyroidism, the typical symptoms of depressed metabolism are evident, but two rather unusual features also occur. The patients may have marked aching and stiffness of joints and muscles. They may also develop severe centrally located and persistent headache. The headache responds rapidly to thyroid hormone therapy. Hair loss can also be dramatic at this time.

In patients developing hypothyroidism rapidly, the plasma T4 level and FTI accurately reflect the metabolic state. However, it should be noted that the TSH response may be suppressed for weeks or months by prior thyrotoxicosis; thus, the TSH level may not accurately reflect hypothyroidism in these persons and should not be used in preference to the FTI or FT4.

If permanent hypothyroidism develops, the patient is given replacement hormone therapy and is impressed with the necessity of taking the medication for the remainder of his or her life. Thyroid hormone replacement is not obligatory for those who develop only temporary hypothyroidism, although it is possible that patients in this group should receive replacement hormone, for their glands have been severely damaged and they are likely to develop hypothyroidism at a later date. Perhaps these thyroids, under prolonged TSH stimulation, may tend to develop adenomatous or malignant changes, but this has not been observed. Many middle-aged women gain weight excessively after radioactive iodide treatment of hyperthyroidism. Usually such patients are on what is presumed to be appropriate T4 replacement therapy. Tigas et al note that such weight gain is less common after ablative therapy for thyroid cancer, in which case larger doses of thyroxine are generally prescribed. Thus they question whether the excessive weight gain after radioactive iodide treatment of Graves’ disease is due to the fact that insufficient thyroid hormone is being provided, even though TSH is within the “normal” range. They suggest that restoration of serum TSH to the reference range by T4 alone may not constitute adequate hormone replacement [ 69a}. We noted above that the correct reference range for TT4 and FT4, when the patient is on replacement T4, should  be 20% higher than normal.

Permanent replacement therapy (regardless of the degree of thyroid destruction) for children who receive 131-I has a better theoretical basis. In these cases, it is advisable to prevent TSH stimulation of the thyroid and so mitigate any possible tendency toward carcinoma formation.

Exacerbation of thyrotoxicosis-During the period immediately after therapy, there may be a transient elevation of the T4 or T3 level [70], but usually the T4 level falls progressively toward normal. Among  treated hyperthyroid patients with Graves’ disease, only rare exacerbations of the disease are seen. These patients may have cardiac problems such as worsening angina pectoris, congestive heart failure, or disturbances of rhythm such as atrial fibrillation or even ventricular tachycardia. Radiation-induced thyroid storm and even death have unfortunately been reported [71- 73]. These untoward events argue for pretreatment of selected patients who have other serious illness, especially cardiac disease, with antithyroid drugs prior to 131-I therapy.

 

Other Problems Associate With 131-I Therapy

The immediate side effects of ^131-I therapy are typically minimal. As noted above, transient exacerbation of thyrotoxicosis can occur, and apparent thyroid storm has been induced within a day (or days) after 131-I therapy. A few patients develop mild pain and tenderness over the thyroid and, rarely, dysphagia. Some patients develop temporary hair loss, but this condition occurs two to three months after therapy rather than at two to three weeks, as occurs after ordinary radiation epilation. Hair loss also occurs after surgical therapy, so that it is a metabolic rather than a radiation effect. If the loss of hair is due to the change in metabolic status, it generally recovers in a few weeks or months. However hair thinning, patchy alopecia, and total alopecia, are all associated with Graves’ Disease, probably as another auto-immune processes. In this situation the prognosis for recovery is less certain, and occasionally some other therapy for the hair loss (such as steroids) is indicated. Permanent hypoparathyroidism has been reported very rarely as a complication of RAI therapy for heart disease and thyrotoxicosis[ 74- 76]. Patients treated for hyperthyroidism with 131-I received approximately 39 microGy/MBq administered (about 0.144rad/mCi) of combined beta and gamma radiation to the testes. This is reported to cause no significant changes in FSH. Nevertheless, testosterone declines transiently for several months, but there is no variation in sperm motility or % abnormal forms (76.1). Long term studies of patients after RAI treatment by Franklyn et al (76.2) show a slight increase in mortality which appears to be related to cardiovascular disease, possibly related to periods of hypothyroidism.

 

Worsening of ophthalmopathy after RAI---In contrast to the experience with antithyroid drugs or surgery, antithyroid antibodies including TSAb levels increase after RAI [ 77, 78]. (Fig. 11-4, above). Coincident with this condition, exophthalmos may be worsened [79].(Fig. 11-5, below). This change is most likely an immunologic reaction to discharged thyroid antigens.The relationship of radiation therapy to exacerbation of exophthalmos has beem questioned], but much recent data indicates that there is a definite correlation[ 79, 80, 80.1, 80.2, 80.3]. Many therapists consider "bad eyes" to be a relative contraindication to RAI. Induction of hypothyroidism, with elevation of TSH, may contribute to worsening of ophthalmopathy. This offers support for early induction of T4 replacement (80.3).
Pretreatment with antithyroid drugs has been used empirically in an attempt to prevent this complication. Its benefit, if any, may be related to an immunosuppressive effect of PTU, described below. Treatment with methimazole before and for three months after I-131 therapy has been shown to help prevent the treatment-induced rise in TSH-R antibodies which is otherwise seen[81].

Prophylaxis with prednisone after 131-I helps prevent exacerbation of exophthalmos, and this approach is now the standard approach in patients who have significant exophthalmos at the time of treatment [ 82, 82.1]. (Fig. 6, below) The recommended dose is 30 mg/day for one month, tapering then over 2-3 months. Of course prednisone or other measures can be instituted at the time of any worsening of ophthalmopathy. In this instance doses of 30-60 mg/day are employed, and usually are required over several months. While treatment with prednisone helps prevent eye problems, it does not appear to reduce the effectiveness of RAI in controlling the hyperthyroidism(82.2).

Thyroidectomy, with total removal of the gland, should be considered for patients with serious active eye disease. Operative removal of the thyroid is followed by gradual diminution is TSH-R antibodies.(82.3 ), and as shown by Tallstedt is associated with a lower incidence of worsening eye problems than is initial RAI treatment. Several studies document better outcomes of ophthalmopathy in patients with GD who have total thyroidectomy vs those treated by other means(82.4, 82.5, 82.6).

 

 

Failure of 131-I to cure thyrotoxicosis occurs occasionally even after 2 or 3 treatments, and rarely 4 or 5 therapies are given. The reason for this failure is usually not clear. The radiation effect may occur slowly. A large store of hormone in a large gland may be one cause of a slow response. Occasional glands having an extremely rapid turnover of 131-I  requiring such high doses of the isotope that surgery is preferable to continued 131-I therapy and its attendant whole body radiation. If a patient fails to respond to one or two doses of 131-I, it is important to consider that rapid turnover may reduce the effective radiation dose. Turnover can easily be estimated by measuring RAIU at 4, 12, 24, and 48 hours, or longer. The usual combined physical and biological half-time of 131-I retention is about 6 days. This may be reduced to 1 or 2 days in some cases, especially in patients who have had prior  therapy or subtotal thyroidectomy. If this rapid release of 131-I is found, and 131-I therapy is desired, the total dose given must be increased to compensate for rapid release. A rough guide to this increment is as follows:

Increased dose = usual dose X ( (usual half time of 6 days) / (observed half time of "X" days) )

Most successfully treated glands return to a normal or cosmetically satisfactory size. Some large glands remain large, and in that sense may constitute a treatment failure. In such a situation secondary thyroidectomy could be done, but it is rarely required in practice.

Long term care- Patients who have been treated with RAI should continue under the care of a physician who is interested in their thyroid problem for the remainder of their lives. The first follow-up visit should be made six to eight weeks after therapy. By this time, it will often be found that the patient has already experienced considerable improvement and has begun to gain weight. The frequency of subsequent visits will depend on the progress of the patient. Symptoms of hypothyroidism, if they develop, are usually not encountered until after two to four months, but one of the unfortunate facts of RAI therapy is that hypothyroidism may occur almost any time after the initial response.

 

HAZARDS OF 131-I TREATMENT

In the early days of RAI treatment for Graves’ disease, only patients over 45 years of age were selected for treatment because of the fear of ill effects of radiation. This age limit was gradually lowered, and some clinics, after experience extending over nearly 40 years, have now abandoned most age limitation. The major fear has been concern for induction of neoplasia, as well as the possibility that 131-I might induce undesirable mutations in the germ cells that would appear in later generations.

Table 8. Gonadal Radiation Dose (in Rads) From Diagnostic Procedures and 131-I Therapy

 

Proceedure	Males- median	Females- median
Barium meal	0.03	0.34
IV pyelogram	0.43	0.59
Retrograde pyelogram	0.58	0.52
Barium enema	0.3	0.87
Femur xray	0.92	0.24
131-I-therapy, 5mCi	usually <1.6	usually <1.6
Adapted from Robertson and Gorman [95]

 

Carcinogenesis

Radiation is known to induce tumor formation in many kinds of tissues and to potentiate the carcinogenic properties of many chemical substances. Radiation therapy to the thymus or nasopharyngeal structures plays an etiologic role in thyroid carcinoma both in children and in adults[ 83- 85]. 131-I radiation to the animal thyroid can produce tumors, especially if followed by PTU therapy [86]. Cancer of the thyroid has appeared more frequently in survivors of the atomic explosions at Hiroshima and Nagasaki than in control populations [87]. Thyroid nodules, some malignant, have appeared in the natives of Rongelap Island as the result of fallout after a nuclear test explosion in which the radiation cloud unexpectedly passed over the island [88].

 

Thyroid cancer following 131-I treatment?

The experience at 26 medical centers with thyroid carcinoma after 131-I therapy was collected in a comprehensive study of the problem. A total of 34,684 patients treated in various ways were included. Beginning more than one year after 131-I therapy, 19 malignant neoplasms were found; this result did not differ significantly from the frequency after subtotal thyroidectomy. Thyroid adenomas occurred with increased frequency in the 131-I treated group, and the frequency was greatest when the patients were treated in the first two decades of life [39]. Holm et al [41] have thoroughly examined the history of a large cohort of 131-I-treated patients in Sweden and similarly found no evidence for an increased incidence of thyroid carcinoma or other tumors. For reasons that are not clear, the injury caused by 131-I therapy for Graves’ disease seems to induce malignant changes infrequently.. This may be because the treatment has largely been given to adults with glands less sensitive to radiation, because damage from 131-Itherapy is so severe that the irradiated cells are unable to undergo malignant transformations, or because all cells are destroyed, or possibly because of the slow rate at which the dose is delivered [89]. In up to one-half of patients followed for 5-10 years, there may be no viable thyroid cells remaining. We note that two studies reported above extend through an average follow-up period of 15 years. As described above [44.1], a recent report by Franklyn and coworkers indicated that there is an increased (3.25 fold) risk of mortality from cancer of the thyroid (and also bowel) after RAI, detected in along term follow up of a very large patient cohort. However it remains uncertain that this is related to hyperthyroidism per se, or radioiodine therapy.

While these data are reassuring in regard to 131-I use in adults, Chernoby made it clear that its use in children can not be considered safe. Children in the area surrounding Chernobyl have developed a hugely increased incidence of thyroid carcinoma predominately due to ingestion of iodine-131 [89.]. The latency has been about 5 years, and younger children are most affected. Risk is probably linearly related to dose. It is apparent that low doses, possibly down to 20 rads, produce malignant change in children(89.2).Risk of carcinogenesis decreases with increasing age at exposure, and is much less common after age 12. However some data indicates that an increased incidence of thyroid carcinoma is seen even among adults exposed at Chernobyl.

 

Leukemia

The incidence of leukemia among patients treated with RAI for Graves’ disease has not exceeded that calculated from a control group [90]. This problem was also studied by the consortium of 26 hospitals [91]. The incidence of leukemia in this group was slightly lower than in a control group treated surgically, but slightly higher in the latter surgical group than in the general population.

 

Genetic Damage

In the group of RAI-treated patients, there has been no evidence of genetic damage, although, as will shortly be seen, this problem cannot be disregarded. In the United States, about 100 x 10⁶ children will be born to a population of over 200 x 10⁶ persons. Approximately 4% of these children will have some recognizable defect at birth. Of these, about one-half will be genetically determined or ultimately mutational, and represent the effects of the baseline mutation rate in the human species. These mutations are attributed in part to naturally occurring radiation.

All penetrating radiation, from whatever sources, produces mutations. The effects may vary with rate of application, age of the subject, and no doubt many other factors, and are partially cumulative. Nearly all of these mutations behave as recessive genetic factors; perhaps 1% are dominant. Almost all are minor changes, and those produced by experimental radiation are the same as those produced by natural radiation.

Whether or not mutations are bad is in essence a philosophic question. Most of us would agree that the cumulative effect of mutations over past eras brought the human race to its present stage of development. However, most mutations, at least those that are observable, are detrimental to individual human adaptation to the present environment. In terms of the human population as a whole, detrimental mutant genes must be eliminated by the death of the carrier. We can agree that an increase in mutation rate is not desirable. It is hardly worth considering the pros and cons of the already considerable spontaneous mutation rate.

In mice, the occurrence of visible genetic mutations in any population group is probably doubled by acute exposure of each member of the group over many generations to about 30 - 40 rads, or by chronic exposure to 100 - 200 rads [92]. This radiation dosage is referred to as the doubling dose. Ten percent of this increase in mutations might be expressed in the first-generation offspring of radiated parents, the remainder gradually appearing over succeeding generations. The change in mutation rate in Drosophila is in proportion to the dosage in the range above 5 rads. Data from studies of mice indicate that at low exposures (from 0.8 down to 0.0007 rads/min), the dose causing a doubling in the spontaneous rate of identifiable mutations is 110 rads [92,93]. Linearity, although surmised, has not been demonstrated at lower doses.

At present, residents of the United States receive about 300 mrad/year, or 9 rad before age 30, the median parental age. Roughly half of this dose is from natural sources and half from medical and, to a lesser extent, industrial exposure. The National Research Council has recommended a maximum exposure rate for the general population of less than 10 rad above background before age 30. (The present level may therefore approach this limit.)

The radiation received by the thyroid and gonads during ^131-I therapy of thyrotoxicosis can be estimated from the following formula:

Total beta radiation dose = 73.8 x concentration of 131-I in the tissue (µCi/g) x average beta ray energy (0.19 meV) x effective isotope half-life

For illustration, we can assume a gland weight of 50 g, an uptake of 50% at 24 hours, a peak level of circulating protein-bound iodide (PB ^131-I) of 1% dose/liter, an administered dose of 10 mCi, a thyroidal iodide biologic half-life of 6 days, and a gamma dose of about 10% of that from beta rays. On this basis, the thyroid receives almost 8200 rads, or roughly 1,600 rads/mCi retained. The gonadal dose, being about one-half the body dose, would approximate 4 rads, or roughly 0.4 rads/mCi administered.

If the radiation data derived from Drosophila and lower vertebrates are applied to human radiation exposure (a tenuous but not illogical assumption), the increased risk of visible mutational defects in the progeny can be calculated. On the basis of administration to the entire population of sufficient ^131-I to deliver to the gonads 2 rads or 2% of the doubling dose (assumed to be the same as in the mouse), the increase in the rate of mutational defects would ultimately be about 0.04%, although only one-tenth would be seen in the first generation. Obviously only a minute fraction of the population will ever receive therapeutic 131-I. The incidence of thyrotoxicosis is perhaps 0.03% per year, or 1.4% for the normal life span. At least one-half of these persons will have their disease after the childbearing age has passed. Although most of them will be women, this fact does not affect the calculations after a lapse of a few generations. Assuming that the entire exposed population receives 131-I therapy in an average amount of 5 mCi, the increase in congenital genetic damage would be on the order of 0.02 (present congenital defect rate) x 0.04 ( 131-I radiation to the gonads as a fraction of the doubling dose) x 0.014 (the fraction of the population ever at risk) x 0.5 (the fraction of patients of childbearing age) = 0.0000056.

This crude estimate, developed from several sources, also implies that, if all patients with thyrotoxicosis were treated with ^131-I, the number of birth defects might ultimately increase from 4 to 4.0006%. This increase may seem startlingly small or large, depending on one’s point of view, but it is a change that would be essentially impossible to confirm from clinical experience.

Unfortunately, it is more difficult to provide a reliable estimate of the increased risk of genetic damage in the offspring of any given treated patient. Calculations such as the above simply state the problem for the whole population. Since most of the mutations are recessive, they appear in the children only when paired with another recessive gene derived from the normal complement carried by all persons. Assuming that only one parent received radiation from ^131-I therapy amounting to 2% of the doubling dose, the risk of apparent birth defects in the patient’s children might increase from the present 4.0% to 4.008%.

0.02 (present genetic defect rate) x 0.04 (fraction of the doubling dose) x 0.1 (fraction of defects appearing in the first generation) = 0.00008, or an increase from 4.0% to 4.008%.

Similar estimates can be derived by considering the number of visible mutations derived from experimental radiation in lower species.[ 92, 93]

6 x 10-8 (mutations produced per genetic locus per rad of exposure) x 10⁴ (an estimate of the number of genetic loci in humans) x 2 (gonadal radiation in rads as estimated above) x 0.1 (fraction of mutations appearing in the first generation) = 0.00012 or 0.012%

On this basis, the increase in the birth defect rate would be from 4.0% to 4.012%. One important observation stemming from these calculations is that large numbers of children born to irradiated parents must be surveyed if evidence of genetic damage is ever to be found. Reports of "no problems" among 30 to 100 such children are essentially irrelevant when one is seeking an increase in the defect rate of about 4.0% to about 4.008%.

These statistics are presented in an attempt to give some quantitation to the genetic risk involved in 131-I therapy, and should not be interpreted as in any sense exact or final. The point we wish to stress is that radiation delivered to future parents probably will result in an increased incidence of genetic damage, but an increase so slight that it is difficult to measure. Nonetheless, the use of 131-I for large numbers of women who subsequently become pregnant will inevitably introduce change in the gene pool.

In considering the significance of these risks, one must remember that the radiation exposure to the gonads from the usual therapeutic dose of 131-I may be only one or two times that produced during a procedure such as a barium enema [ 94, 95] and similar to the 10 rads received from a CAT scan. These examinations are ordered by most physicians without fear of radiation effect ( Table 11-8).

When assessing the risks of 131-I therapy, one must, of course, consider the risks of any alternative choice of procedure. Surgery carries a small but finite mortality, as well as a risk of permanent hypoparathyroidism, hypothyroidism, and vocal cord paralysis. Some of these risks are especially high in children, the group in which radiation damage is most feared. Some physicians have held that 131-I therapy should not be given to patients who intend subsequently to have children. In fact, there is at present no evidence to support this contention, as discussed above. Chapman [44] studied 110 women treated with 131-I who subsequently became pregnant and were delivered of 150 children. There was no evidence of any increase in congenital defects or of accidents of pregnancy. Sarkar et al [96] also found no evidence of excess abnormalities among children who received 131-I therapy for cancer. Other studies have confirmed the apparent lack of risk[ 42, 43]. It should be noted that no increase in congenital abnormalities has been detected among the offspring of persons who received much larger radiation doses during atomic bomb explosions [97].

Often the patient wishes to know about the possibility of carcinogenesis or genetic damage. These questions must be fully but delicately handled. It is not logical to treat a patient of childbearing age with 131-I and have the patient subsequently live in great fear of bearing children. These problems and considerations must be faced each time a patient is considered for RAI therapy.

Pregnancy and 131-I Pregnancy is an absolute contraindication to ^131-I therapy. The fetus is exposed to considerable radiation from transplacental migration of ^131-I, as well as from the isotope in the maternal circulatory and excretory systems. In addition, the fetal thyroid collects ^131-I after the 12th week of gestation and may be destroyed. The increased sensitivity of fetal structures to radiation damage has already been described. Physicians treating women of childbearing age with ^131-I should be certain that the patients are not pregnant when given the isotope. Therapy during or immediately after a normal menstrual period or performance of a pregnancy test are appropriate precautions if pregnancy is possible. Women should be advised to avoid pregnancy for at least six months after treatment with RAI, since it usually takes this long to be certain that retreatment will not be needed.

TREATMENT OF THYROTOXICOSIS WITH DRUGS

Drug therapy for thyrotoxicosis was introduced by Plummer when he observed that the administration of iodide ameliorated the symptoms of this disease [98]. (Fig 7) Administration of iodide has since been used occasionally as the complete therapeutic program for thyrotoxicosis, and widely as an adjunct in preparing patients for subtotal thyroidectomy. In 1941 the pioneering observations of MacKenzie and MacKenzie [99] and Astwood [100] led to the development of the thiocarbamide drugs, which reliably block the formation of thyroid hormones. It soon became apparent that, in a certain proportion of patients with Graves’ disease, use of these drugs could induce a prolonged or permanent remission of the disease even after the medication was discontinued. It is not yet understood why a temporary reduction in the formation of thyroid hormone should result in reduction of TSHR antibodies, and permanent amelioration of the disease.

The antithyroid drug initially introduced for treatment of Graves’ disease was thiourea, but this drug proved to have a large number of undesirable toxic effects. Subsequently a number of derivatives and related compounds were introduced that have potent antithyroid activity without the same degree of toxicity. Among these substances are propyl- and methylthiouracil, methimazole, and carbimazole. In addition to this class of compounds, potassium perchlorate has been used in the treatment of thyrotoxicosis, but is infrequently employed for this purpose because of occasional bone marrow depression. This drug prevents the concentration of iodide by the thyroid. Beta adrenergic blockers such as propranolol have a place in the treatment of thyrotoxicosis. These drugs alleviate some of the signs and symptoms of the disease but have little or no direct effect on the metabolic abnormality itself. They do not uniformly induce a remission of the disease and can be regarded as adjuncts, not as a substitute for more definitive therapy.

Mechanism of Action- Antithyroid drugs inhibit thyroid peroxidase, and PTU (not methimazole) has the further beneficial action of inhibiting T4 to T3 conversion in peripheral tissues. Antithyroid therapy is associated with a reduction in circulating antithyroid antibody titers [101], and anti-receptor antibodies [77, 78, 102]. Studies by MacGregor and colleagues [103] indicate that antibody reduction also occurs during antithyroid therapy in patients with thyroiditis maintained in a euthyroid state, thus indicating that the effect is not due only to lowering of the FT4 in Graves’ disease. These authors also found a direct inhibitory effect of PTU and carbimazole on antithyroid antibody synthesis in vitro and postulate that this is the mechanism for diminished antibody levels [104]. Other data argue against this hypothesis [105, 105.1].

Antithyroid drug therapy is also associated with a prompt reduction in the abnormally high levels of activated T lymphocytes in the circulation [106], although Totterman and co-workers found that this therapy caused a prompt and transient elevation of activated T suppressor lymphocytes in blood [107]. During antithyroid drug treatment the reduced numbers of T suppressor cells reported to be present in thyrotoxic patients return to normal [106, 108]. Antithyroid drugs do not directly inhibit T cell function [109]. All of these data argue that antithyroid drugs exert a powerful beneficial immunosuppressive effect on patients with Graves’ disease. While much has been learned about this process, the exact mechanism remains uncertain. Evidence that antithyroid drugs exert their immunosuppressive effect by a direct inhibition of thyroid cell production of hormones has been reviewed by Volpe [109].

Long-Term Antithyroid Drug Therapy with Thiocarbamides

Propylthiouracil warning-Propylthiouracil and methimazole have for years been considered effectively interchangeable, and liver damage was considered a very rare problem. Recently a commission appointed by the FDA reevaluated this problem, and concluded that the rare but severe complications of liver failure needing transplantation, and death, were sufficient to contraindicate the use of PTU as the normal first-line drug (109.1). The Endocrine  Society and other advisory groups have suggested that methimazole be used for treatment except in circumstances of inavailability of the drug, patient allergy, or pregnancy. Because of the association of scalp defects and probably a severe choanal syndrome with administration of methimazole during the first 12 weeks of pregnancy, current advice is to avoid use of methimazole during the first trimester, for instance giving PTU during the first trimester, and then switching to methimazole.

Selection of patients-Many patients with Graves’ disease under age 40 - 45 are given a trial of therapy with one of the thiocarbamide drugs. Younger patients, and those with recent onset of disease, small goiters [110], and mild disease, are especially favorable candidates, since they tend to enter remission most frequently (110.1). It is generally found that one-fourth to one-third of these patients who satisfactorily complete a one year course have a long term or permanent remission. The remainder need repeated courses of drug therapy, must be maintained on the drug for years or indefinitely [111, 112], or must be given some other treatment. It appears that the percentage of patients responding has progressively fallen over the past years from about 50% to at present 25 - 30%[113, 114]. This change was thought to reflect an alteration in iodide in our diet [115], which increased from about 150 µg/day in 1955 to 300 - 600 µg/day. However other factors including greater precision in diagnosis and more complete data probably play major roles in establishing the response rate recognized at present. Some physicians do not consider antithyroid drug therapy to be the most efficacious means of treating thyrotoxic patients because of the high recurrence rate.

Therapeutic program-Patients are initially given 100 - 150 mg PTU (if used) every 8 hours or 10 - 15 mg methimazole (Tapazole) every 12 hours. The initial dosage is varied depending on the severity of the disease, size of the gland, and medical urgency. Antithyroid drugs must usually be given frequently and taken with regularity since the half-time in blood is brief -- 1.65 hours or less for PTU [116]. Frequent dosage is especially needed when instituting therapy in a severely ill patient. Methimazole has the advantage of a longer therapeutic half-life, and appears to produce fewer reactions when given in low dosage. Propylthiouracil is preferred in patients with very severe hyperthyroidism since it inhibits T4>T3 conversion, and in early pregnancy[117, 118]

In most thyrotoxic patients, the euthyroid state, as assessed by clinical parameters, and FT4, can be reached within 4 - 6 weeks. If the patient fails to respond, the dosage may be increased. Iodine-131 studies may be performed to determine whether a sufficiently large dose of medication is being employed [119], but these studies are rarely needed. In general, it is assumed that iodide uptake should be nearly completely blocked, but the 24-hour 131-I thyroid uptake in the patient under therapy may range from O% to 40%. This iodide is partly unbound and is usually released rapidly from the gland by administration of 1 g potassium thiocyanate or 400 mg potassium 131-I perchlorate. If perchlorate or thiocyanate does not discharge the iodide, it is obvious that iodide organification is occurring despite the thiocarbamide therapy. The quantity of drug administered may then be increased. In experimental animals, the thiocarbamides block synthesis of iodothyronines more readily than they block formation of MIT and DIT. This observation suggests that a complete block in organification of iodide may not be necessary to produce euthyroidism. The patient’s thyroid might accumulate and organify iodide and form iodotyrosines, but be unable to synthesize the iodothyronines. Clinical observations to prove this point are not available.

An RIA for PTU has been developed but has not proven useful in monitoring therapy [120]. Doses of 300 mg PTU produced serum levels of about 7.1 µg/ml, and serum levels of PTU correlated directly with decreases in serum T ₃ levels.

It is theoretically possible to give therapeutic doses of methimazole by rectal administration in a saline enema or by suppository if the oral route is unavailable [121]. Propylthiouracil has also been administered in suppositories or in enemas and found to be effective in treating hyperthyroidism. In a recent study PTU tablets were mixed in mineral oil, and then with cocoa butter, and frozen, to produce 1 gm suppositories each containing 400mg PTU. Suppositories given 4 times daily maintained a therapeutic blood level(121.1). Jongjaroenprasert et al compared the effectiveness of a 400 mg dose of PTU in 90 ml of water vs. 400 mg of PTU given in polyethylene glycol suppositories. Both methods were effective treatments, but the enema appeared to provide greater bioavailability (121.2).

Long Term Therapeutic Program After the initial period of high-dose therapy, the amount of drug administered daily is gradually reduced to a level that maintains the patient in a euthyroid condition, as assessed by clinical evaluation and serial observations of serum T4 , FT4, or T3 . These tests should appropriately reflect the metabolic status of the patient. Measurement of TSH level is useful when the FT4 falls, to make sure that the patient has not been overtreated, but, as noted previously, TSH may remain suppressed for many weeks after thyrotoxicosis is alleviated. Serum T3 levels can also be monitored and are occasionally still elevated when the T4 level is in the normal range. During the course of treatment, the thyroid gland usually remains the same in size or becomes smaller. If the gland enlarges, the patient has probably become hypothyroid with TSH elevation; this condition should be ascertained by careful clinical and laboratory evaluation. If the patient does become hypothyroid, the dose of antithyroid drug should be reduced. Decrease in size of the thyroid under therapy is a favorable prognostic sign, and more often than not means that the patient will remain euthyroid after the antithyroid drugs have been discontinued. The dose is gradually reduced as the patient reaches euthyroidism, and often one-half or one-third of the initial dose is sufficient to maintain control. The interval between doses -- typically 8-12 hours initially -- can be extended, and patients can often be maintained on twice- or once-a-day therapy with methimazole [122]. Alternatively, antithyroid drugs can be maintained at a higher dose, and thyroxine can be added to produce euthyroidism. Occasionally ingestion of large amounts of iodide interferes with antithyroid drug therapy.

Duration of Treatment- The appropriate duration of antithyroid drug therapy is uncertain, but usually it is maintained for one year. Treatment for six months has been effective in some clinics but is not general practice [123]. Longer treatment -- such as one to three years -- does gradually increase the percentage of responders [124], but this increase must be balanced against the added inconvenience to the patient [125, 126]. Azizi and coworkers have reported treatment of a group of 26 patients for ten years, during which time no serious problems occurred, and the cost approximated that of RAI therapy(126.1). At least one study suggests that treatment with large doses of antithyroid drugs may increase the remission rate, perhaps because of an immunosuppressive action [125]. Body mass, muscle mass, and bone mineral content gradually recover, although bone mass remains below normal [126.2]. Risedronate treatment has been demonstrated to help restore bone mass in osteopenia/osteoporosis associated with Graves’ disease (126.3).

After the patient has taken the antithyroid drugs for a year, the medication is gradually withdrawn over one to two months, and the patient is observed at intervals thereafter. Elevated TRAbs at the time ATDs are to be withdrawn strongly (but imperfectly) suggest relapse will occur (110.1). Most of those who will ultimately have an exacerbation of the disease do so within three to six months; others may not develop recurrent hyperthyroidism for several years [127]. Some patients may have a recurrence after discontinuing the drug that lasts for a short time, and then a remission without further therapy [128]. Addition  of iodide therapy is also a useful possibility, as noted below. A report that administration of iodide increases the relapse rate after drug therapy is withdrawn has not been confirmed [129].

Hashizume and co-workers reported that administration of T4 to suppress TSH for a year after stopping antithyroid drugs produced a very high remission rate [130]. Similar results were found when T4 treatment was given after a course of antithyroid drugs during pregnancy. [131]. These studies engendered much interest because of the uniquely high remission rate obtained by the continuation of thyroxine treatment to suppress TSH for a year or more after the usual course of antithyroid drug therapy. Possibly such treatment is beneficial since it inhibits the release of thyroid antigens. However subsequent studies have not found a beneficial effect of added T4 therapy [131.1,131.2]. It appears that the results are, for some reason, peculiar to this study group.

The probability of prolonged remission correlates with reduction in gland size, disappearance of thyroid-stimulating antibodies from serum[132, 133], (Fig.11-8) return of T3 suppressibility, decrease in serum TG, and a haplotype other than HLA-DR3 [130 -136]. However, none of these markers predict recovery or continued disease with an accuracy rate above 60-70% [136.1]. Long after apparent clinical remission, many patients show continued abnormal thyroid function, including partial failure of T3 suppression, or absent or excessive TRH responses [127-140]. These findings probably indicate the tenuous balance controlling immune responses in these patients.

Breast feeding- Lactating women taking PTU have PTU levels of up to 7.7 µg/ml in blood, but in milk the level is much lower, about 0.7 µg/ml [141]. Only 1-2 mg PTU could be transferred to the baby daily through nursing; this amount is inconsequential except for the possibility of reactions to the drug. Azizi et al. studied intellectual development of children whose mothers took methimazole during lactation, and found that there was no evident effect on physical and intellectual development, at least in children whose mothers took up to 20 mg of MMI daily [141a].

Hypothyroidism- It has long been known that some patients with Graves’ disease eventually develop spontaneous hypothyroidism [68]. Reports have shown that most patients who become euthyroid after antithyroid drug therapy, if followed long enough, also develop evidence of diminished thyroid function [69]. In a prospective study, Lamberg et al [139]found that the annual incidence in these patients of subclinical hypothyroidism was 2.5%, and of overt hypothyroidism 0.6%.

 

TOXIC REACTIONS TO ANTITHYROID DRUGS

The use of antithyroid drugs may be accompanied by toxic reactions, depending on the drug and dose, in 3 - 12% of patients[ 117, 118, 142- 146]. Most of these reactions probably represent drug allergies[ 147- 148]. Chevalley et al., in a study of 180 patients given methimazole[ 143], found an incidence of toxicity of 4.3%, broken down as follows: Total reactions 4.3%; Pruritus 2.2%; Granulocytopenia 1.6%; Urticaria 0.5%.Methimazole may be the drug least likely to cause a toxic reaction, but there is little difference between it and PTU. When the antithyroid drugs are prescribed, the patient should be apprised of the possibility of reactions, and should be told to report phenomena such as a sore throat, fever, or rash to the physician and to discontinue the drug until the cause of the symptoms has been evaluated. These symptoms may herald a serious reaction.

Allergic rash-If a patient taking a thiocarbamide develops a mild rash, it is permissible to provide an antihistamine and continue using the drug to see whether the reaction subsides spontaneously, as it commonly does. If the reaction is more severe or if neutropenia occurs, another drug should be tried or the medication withdrawn altogether. Usually a switch is made to another thiocarbamide, because cross-reactions do not necessarily occur between members of this drug family. Alternatively, the program of therapy may be changed to the use of RAI, which may be given after the patient has stopped taking the antithyroid drug for 48 hours, or the patient may be prepared for surgery by the administration of iodides and propranolol.

The incidence of agranulocytosis in a large series of patients was 0.4% [149]. It occurs most frequently in older patients and those given large amounts of the drug (20-30 mg methimazole every eight hours) [117].Reactions tend to be most frequent in the first few months of therapy but can occur at any time, with small doses of drug, and in patients of all ages [117]. The most common reactions are fever and a morbilliform or erythematous rash with pruritus. Reactions similar to those of serum sickness, with migratory arthralgias, jaundice, lymphadenopathy, polyserositis, and episodes resembling systemic lupus erythematosus have also been observed [147]. Pyoderma gangrenosum can occur (147.1). Neutropenia and agranulocytosis are the most serious complications. These reactions appear to be due to sensitization to the drugs, as determined by lymphocyte reactivity in vitro to the drugs [148]. Occasionally agranulocytosis can develop even though the total WBC remains within normal ranges- a hazard to be remembered and differential counts should be  done. Fortunately, even these problems almost always subside when the drug is withdrawn. Aplastic anemia with marrow hypoplasia has been reported (perhaps 10 cases), again with spontaneous recovery in 2-5 weeks in 70%, but fatal outcome in 3 patients [149]. Thrombocytopenia and/or anemia may accompany the neutropenia. Vasculitis is a fortunately rare complication during treatment with antithyroid drugs.
Neutropenia-It is probably wise to see patients receiving the thiocarbamides at least monthly during the initiation of therapy and every two to three months during the entire program. Neutropenia can develop gradually but often comes on so suddenly that a routine white cell count offers only partial protection. A white cell count must be taken whenever there is any suggestion of a reaction, and especially if the patient reports malaise or a sore throat. A white cell count taken at each visit will detect the gradually developing neutropenia that may occur. While many physicians do not routinely monitor these levels, the value of monitoring is suggested by the study of Tajiri et al [144]. Fifty-five of 15398 patients treated with antithyroid drugs developed agranulocytosis, and 4/5 of these were detected by routine WBC at office visits. Low total leukocyte counts are common in Graves’ disease because of relative neutropenia, and for this reason a baseline WBC and differential should be performed before starting anti-thyroid drugs. However, total polymorphonuclear counts below 2,000 cells/mm3 should be carefully monitored; below 1,200 cells/mm3 it is unsafe to continue using the drugs.

In the event of severe neutropenia or agranulocytosis, the patient should be monitored closely, given antibiotics if infection develops, and possibly adrenal steroids. There is no consensus on the use of glucocorticoids, since they have not been shown to definitely shorten the period to recovery. Administration of recombinant human granulocyte colony stimulating factor (75 µg/day given IM) appears to hasten neutrophile recovery in most patients who start with neutrophile counts > 0.1 X 10⁹/L [150-151]. Antithymocyte globulin and cyclosporin have also been used [151]. Care must be taken to ensure against exposure to infectious agents, and some physicians prefer not to hospitalize their patients for this reason. If the patient is hospitalized, he or she should be placed in a special-care room with full bacteriologic precautions.

ANCA antibodies- Patients may develop antineutrophil cytoplasmic antibodies, either pericytoplasmic or cytoplasmic, during treatment, with or without vasculitis. Most cases appear to be associated with the use of propylthiouracil, and therapy includes cessation of the drug, sometimes treatment with steroids or cyclophosphamide for renal involvement, and rarely plasmapheresis. The commonest cutaneous lesion associated is leukocytoclastic vasculitis associated with purpuric lesions. Symptoms may include fever, myalgia, arthralgia, and lesions in the kidneys and lungs. Prognosis is usually good if the medication is discontinued, although death has occurred. ANCA positivity (pericytoplasmic, cytoplasmic, directed to myeloperoxidase, proteinase3, or human leukocyte elastase) can occur in patients on antithyroid drugs associated with vasculitis. It is also found without clinical evidence of vasculitis, and the significance of this finding is unclear [151.1]. Guma et al recently reported that, in a series of patients with Graves’ disease, 67% were found to be ANCA positive before medical treatment, and that 19% remained positive after one year of antithyroid treatment. This data suggests that ANCA antibodies reflect in some way the autoimmunity associated with Graves’ hyperthyroidism, rather than simply being a manifestation due to the treatment with antithyroid drugs (151.2). In addition to suppression of hematopoiesis and agranulocytosis, methimazole has been associated in one patient with massive plasmocytosis, in which 98% of the cells in the bone marrow were plasma cells. After discontinuation of the drug, and treatment with dexamethasone and G-CSF, the patient’s marrow recovered to normal (151.3).

Liver damage-Thiocarbamides can also cause liver damage ranging from elevation of enzymes, through jaundice, to fatal hepatic necrosis. Toxic hepatitis (primarily with propylthiouracil) and cholestatic jaundice (primarily with methimazole) are fortunately uncommon [150].Toxic hepatitis can be severe or fatal, but the incidence of serious liver complications is so low that routine monitoring of function tests has not been advised[ 1514, 152]. Liver transplantation has been used with success in several patients [152.1]. As noted above, any sign of liver damage must be carefully monitored, and progress of abnormalities in liver function tests demand cessation of the drug[147, 152].

Diffuse interstitial pneumonitis has also been produced by propylthiouracil [153].

Pregnancy-(Please also see chapter on Thyroid Regulation and Dysfunction in the Pregnant Patient). Methimazole should be avoided in early pregnancy as disc ussed above. Very rare cases of esophageal atresia, omphalocele, and choanal atresia occurred in Sweden almost only in infants whose mothers took methimazole during early pregnancy.This is thought to be a true, although fortunately very infrequent, complication of methimazole use. Their observations obviously suggest that methimazole should best not be given during early months of pregnancy (153.1). As noted elsewhere in this web-book, various options are available, including 1) arranging definitive treatment before pregnancy, 2) switching to propylthiouracil as soon as possible and use of that drug during the first trimester, and leaving mild hyperthyroidism untreated (wich associated risks).  iodide treatment can be tried instead of ATD, and is reported to be  significantly more safe, although experience with this approach is inadequate for recommendation (154)

 

Potassium Perchlorate, Lithium,and Cholestyramine

Potassium perchlorate was introduced into clinical use after it was demonstrated that several monovalent anions, including nitrates, have an antithyroid action. Perchlorate was the only member of the group that appeared to have sufficient potency to be useful. This drug, in doses of 200 - 400 mg every six hours, competitively blocks iodide transport by the thyroid. Accordingly, therapeutic doses of potassium iodide will overcome its effect. Institution and control of therapy with perchlorate are similar to those discussed for the thiocarbamides. Toxic reactions to this agent occur in about 4% of cases [155] and usually consist of gastric distress, skin rash, fever, lymphadenopathy, or neutropenia; they usually disappear when the drug is discontinued. The reaction rate is higher when doses of more than 1 g/day are given [155]. Nonfatal cases of neutropenia or agranulocytosis have been reported, and four cases of fatal aplastic anemia have been associated with the use of this drug [156]. Because of toxic reactions, perchlorate is not used at present for routine therapy. It has found a role in therapy of thyrotoxicosis induced by amiodarone [157]. Apparently blocking of iodide uptake is an effective antithyroid therapy in the presence of large body stores of iodide, while in this situation, methimazole and propylthiouracil are not effective alone.

Lithium ion inhibits release of T4 and T3 from the thyroid and has been used in the treatment of thyrotoxicosis, but is most effective when used with a thiocarbamide drug. It does not have a well-established place in the treatment of Graves’ disease[ 157, 158]. It has possible value in augmenting the retention of ^131-I [159] and in preparing patients allergic to the usual antithyroid drugs or iodide for surgery, although propranolol is generally used for the latter problem.

Cholestyramine (4gm, q8h) for a month has been shown to hasten return of T4 to normal [159.1] by binding hormone in the gut. It can be used as an adjunct to help speed return of hormone levels to normal, and may be especially beneficial in thyroid storm.

Iodine treatment- Plummer originally observed that the administration of iodide to thyrotoxic patients resulted in an amelioration of their symptoms. This reaction is associated with a decreased rate of release of thyroid hormone from the gland and with a gradual increase in the quantity of stored hormone. The effect of iodide on thyroid hormone release and concentration in blood is apparent in Figure 7. The mechanism of action may be by inhibition of generation of cAMP, and involves inhibition of TG proteolysis, but is not fully understood. Therapeutic quantities of iodide also have an effect on hormone synthesis through inhibition of organification of iodide. Iodide has similar but less intense effects on the normal thyroid gland, apparently because of adaptive mechanisms.

Administration of large amounts of iodide to laboratory animals or humans blocks the synthesis of thyroid hormone and results in an accumulation of trapped inorganic iodide in the thyroid gland (the Wolff-Chaikoff effect, see Ch 2). The thyrotoxic gland is especially sensitive to this action of iodide. Raising the plasma iodide concentration to a level above 5 µg/dl results in a complete temporary inhibition of iodide organification by the thyrotoxic gland. In normal persons elevation of the inorganic 127-I level results, up to a point, in a progressive increase of accumulation of iodide in the gland. When the plasma concentration is above 20 µg/dl, organification is also inhibited in the normal gland [160]. The sensitivity of the thyrotoxic gland, in comparison with that of the euthyroid gland, may be due to an increased ability to concentrate iodide in the thyroid, and its failure to "adapt" by decreasing the iodide concentrating mechanism.

When iodine is to be used therapeutically in Graves’ disease, one usually prescribes a saturated solution of potassium iodide (which contains about 50 mg iodide per drop) or Lugol’s solution (which contains about 8.3 mg iodide per drop). Thompson and co- workers [161] found that 6 mg of I- or KI produces a maximum response. This fact was reemphasized by Friend, who pointed out that the habit of prescribing the 5 drops of Lugol’s or SSKI three times daily is unnecessary [162]. Two drops of Lugol’s solution or 1 drop of a saturated solution of potassium iodide two times daily is more than sufficient.

The therapeutic response to iodide begins within two to seven days and is faster than can be obtained by any other methods of medical treatment. Only 3% of patients so treated fail to respond. Men, older persons, and those with nodular goiter are in the group less likely to have a response to iodide. Although almost all patients initially respond to iodide, about one-third respond partially and remain toxic, and another one-third initially respond but relapse after about six weeks [163].

Because of the partial responses and relapse rate, use of iodide as definitive therapy for thyrotoxicosis has been replaced by the modalities described  above. Currently Iodides are given sometimes after 131-I therapy to control hyperthyroidism, and are usually given as part of treatment before thyroidectomy. However some recent reports suggest iodide might have a larger role to play. Addition  of iodine (38 mg/day) to methimazole (15mg/d) accelerated response over methimazole alone (154), and long term iodine treatment induced remission in 38% of patients who were given this treatment because of adverse reactions to ATD (164). In a study of 30 drug-naïve patients with “mild” GD, all but 3 were controlled on iodine alone (165.). Use of iodides instead of methimazole during the first trimester of pregnancy reduced major anomalies from 4.1% to 1.5% in one study (165.1). Iodine treatment is not currentty considered standard, but this may change soon.

 

Adjunctive Therapy for Graves’ Disease
Propranolol, metopranol, atenolol

Beta-adrenergic blocking agents have won a prominent position in the treatment of thyrotoxicosis. Although they alleviate many of the signs and symptoms, they have little effect on the fundamental disease process[ 166, 167]. Palpitations, excessive sweating, and nervousness improve, and tremor and tachycardia are controlled. Many patients feel much improved, but others are psychologically depressed by the drug and prefer not to take it. Improvement in myocardial efficiency and reduction in the exaggerated myocardial oxygen consumption have been demonstrated [168]. Propranolol lowers oxygen consumption [169, 170] and reverses the nitrogen wasting of thyrotoxicosis, although it does not inhibit excess urinary calcium and hydroxyproline loss. Propranolol is useful in symptomatic treatment while physician and patient are awaiting the improvement from antithyroid drug or 131-I therapy [171]. Some patients appear to enter remission after using this drug alone for six months or so of therapy[ 169, 172]. It has been useful in neonatal thyrotoxicosis [173] and in thyroid storm [174]. The drug must be used cautiously when there is evidence of severe thyrotoxicosis, or heart failure, but often control of tachycardia permits improved circulation. Beta blockade can induce cardiovascular collapse in patients with or without heart failure, and asystolic arrest (174.1,174.2). Administration of beta blocker was shown by Ikram to reduce CO by 13% in patients with uncontrolled CHF, and apparently this reduction in CO can be near fatal in rare patients.
Some surgical groups routinely prepare patients for thyroidectomy with propranolol for 20 - 40 days and add potassium iodide during the last week [175]. The BMR and thyroid hormone level remain elevated at the time of operation, but the patient experiences no problems. We prefer conventional preoperative preparation with thiocarbamides, with or without iodide, and would use propranolol as an adjunct, or if the patient is allergic to the usual drugs.

Propranolol is usually given orally as 20 - 40 mg every four to six hours, but up to 200 mg every six hours may be needed. In emergency management of thyroid storm (see also Chapter 12) or tachycardia, it may be given intravenously (1 - 3 mg, rarely up to 6 mg) over 3 - 10 minutes and repeated every four to six hours under electrocardiographic control. Atropine (0.5 - 1.0 mg) is the appropriate antidote if severe brachycardia is seen.

Reserpine and Guanethidine Drugs such as reserpine [177] and guanethidine [178] that deplete tissue catecholamines were used extensively in the past as adjuncts in the therapy for thyrotoxicosis, but fell into disuse as the value of beta -sympathetic blockade with propranolol became recognized.

Glucocorticoids, Ipodate, and Other Treatments As described elsewhere, potassium iodide acts promptly to inhibit thyroid hormone secretion from the Graves’ disease thyroid gland. PTU, propranolol, glucocorticoids [181], amiodarone, and sodium ipodate (Oragrafin Sodium) inhibit peripheral T4 to T3 conversion, and glucocorticoids may have a more prolonged suppressive effect on thyrotoxicosis [182]. Orally administered resins bind T4 in the intestine and prevent recirculation [183]. All of these agents have been used for control of thyrotoxicosis [ 184, 185]. Combined dexamethasone, potassium iodide, and PTU can lower the serum T3 level to normal in 24 hours, which is useful in severe thyrotoxicosis. Prednisone has been reported to induce remission of Graves’ disease, but at the expense of causing Cushing’s syndrome [187]. Ipodate (0.5 - 1 g orally per day) acts to inhibit hormone release because of its iodine content, in addition to its action to inhibit T4 to T3 conversion. This dose of ipodate given to patients with Graves’ disease reduced the serum T3 level by 58% and the T4 level by 20% within 24 hours, and the effect persisted for three weeks[188, 189]. This dose of ipodate was more effective than 600 mg of PTU, which decreased the T3 level by only 23% during the first 24 hours, whereas the T4 level did not drop. Ipodate may prove to be a useful adjunct in the early therapy of hyperthyroidism, but will increase total body and thyroidal iodine. However, when the drug is stopped, the RAIU in Graves’ patients usually returns to pre- treatment levels within a week [189]. Because it is the most effective agent available in preventing conversion of T4 to T3, it has a useful role in managing thyroid storm.

Immunosuppressive Therapy- Development of new targeted and relatively safe immune suppressive treatments has allowed their extension to Graves’ disease. Rituximab, an anti CD20  B cell lymphocyte depleting monoclonal antibody, was initially found to induce remission in Graves’ ophthalmopathy. It also mediates decreases in anti thyroid antibodies, and is currently employed in a Phase II trial for therapy of mild, relapsing Graves’ disease (189.1, 189.2). Significant adverse events during therapy with rituximab (“serum sickness”, mild colitis, iridocyclitis, polyarthritis) have been reported, and will probably limit its usefulness (189.3) Use of agents of this type, that work by increasing function of regulatory T cells, will probably become common in the next few years. Another approach has been pioneered by Gershengorn and colleagues, who devised a small molecule that is an “allosteric inverse agonist” of TSHR, and inhibits stimulation of TSH receptor activation by TSAbs (189.4 ). Such agents are used in current clinical trials, and should offer entirely new treatment stategies in the future.

 

SURGICAL THERAPY

Subtotal thyroidectomy is an established and effective form of therapy for Graves’ disease, providing the patient has been suitably prepared for surgery. In competent hands, the risk of hypoparathyroidism or recurrent nerve damage is under 1%, and the discomfort and transient disability attendant upon surgery may be a reasonable price to pay for the rapid relief from this unpleasant disease. In some clinics it is the therapy of choice for most young male adults, especially if a trial of antithyroid drugs has failed. Total thyroidectomy may be preferred in patients with serious eye disease or high TRAb levels, in order to help the eye disease and to keep down the incidence of recurrence [190-194].
As with other effective methods available, it is necessary for the physician and the patient to decide on the form of therapy most suitable for the case at hand. Because of the potential but unproved risks of 131-I therapy, it is not always possible to make an entirely rational choice; the fears and prejudices of the physician and the patient will often enter into the decision. Surgery is clearly indicated in certain patients. Among these are (1) patients who have not responded to prolonged antithyroid drug therapy, or who develop toxic reactions to the drug and for whatever reason are unsuitable for 131-I therapy; (2) patients with huge glands, which frequently do not regress adequately after 131-I therapy; and (3) patients with thyroid nodules that raise a suspicion of carcinoma. Stocker et al have reviewed the problem of nodules in Graves’ glands (195). They found that 12% of Graves’ patients had cold defects on scan, and among these half were referred for surgery. Six of 22, representing 2% of all Graves’ patients, 15% of patients with cold nodules, 25% of patients with palpable nodules, and 27% of those going to surgery, had papillary cancer in the location corresponding to the cold defect. Of these patients, one had metastasis to bone and two required multiple treatments with radioiodine. These authors argue for evaluating patients with a thyroid scintigram and further diagnostic evaluation of cold defects. Subtotal or near total thyroidectomy is often the treatment of choice for patients with amiodarone induced thyrotoxicosis, since response to ATDs is typically poor, and RAIU can not be given (196). Surgery may also have a place in therapy of older patients with thyroid storm and/or cardio-respiratory failure, who do not respond rapidly to intensive medical therapy(197).

 

Surgery in patients with ophthalmopathy

Contemporary data indicate that exophthalmos may be exacerbated by RAI therapy [80],although in some studies appearance of progressive ophthalmopathy was about the same after treatment with 131-I as with surgery [79]. Thus, in the presence of serious eye signs, treatment with antithyroid drugs followed by surgery is an important alternative to consider, and total thyroidectomy is preferred [ 80-82]. The preferential use of surgery rather than radioactive iodide in the management of patients with severe Graves’ ophthalmopathy, and the greater, more frequent exacerbation of eye disease after RAI therapy, has been supported in a number of studies including those by Torring et al [36.2], Moleti et al [44.4], and De Bellis et al [44.5] and others documented above. Marcocci et al, in contrast, report that near-total thyroidectomy had no efffect on the course of ophthalmopathy in a group of patients who had absent or non-severe preexisting ophthalmopathy. The relevance of this to patients with more severe ocular disease is uncertain, since it is logical to expect that in these patients there would be no effect of removing antigens, if the patients  lacked any tendency to develop ophthalmopathy [44.6]. Moleti et al recently reported on 55 patients with Graves’ disease and mild to moderate Graves’ ophthalmopathy, who underwent near-total thyroidectomy, and of whom 16 had standard ablative doses of radioactive iodide. They found that the course of ophthalmopathy, both short and long term after treatment, was significantly better in the group of patients who underwent thyroidectomy and ^131-I ablation, and suggest that this is a more effective means of inducing and maintaining ophthalmopathic inactivity (44.7). In a randomized, prospective study, total thyroidectomy, rather than partial thyroidectomy, was followed by a better outcome of GO in patients given iv glucocorticoids. Radioiodine uptake test and thyroglobulin assay showed complete ablation in the majority of total, but not of partial thyroidectomy patients(44.6) .

The rate of patient rehabilitation is probably quickest with surgery. Although the source of hormone is directly and immediately removed by surgery, the patient usually must undergo one to three months of preparation before operation. The total time from diagnosis through operative convalescence is thus three to four months. Antithyroid drugs, in contrast, provide at best only 30 - 40% permanent control after one year of therapy. Iodine-131 can assuredly induce prompt remission, but low dose protocols, as noted, are plagued by a need for medical management and retreatment over one to three years before all patients are euthyroid. Treatment with higher doses provides more certain remission at the expense of more certain hypothyroidism.

There are several strong contraindications to surgery, including previous thyroid surgery, severe coincident heart or lung disease, the lack of a well-qualified surgeon, and pregnancy in the third trimester, since anesthesia and surgery may induce premature labor.

More enthusiastic surgeons have in the past recommended surgery for all children as the initial approach, claiming that there is less interference with normal growth and development than with prolonged antithyroid drug treatment [191]. Therapy for childhood thyrotoxicosis is discussed further below.

Preparation for Surgery

Antithyroid drugs of the thiocarbamide group are employed to induce a euthyroid state before subtotal thyroidectomy when surgery is the desired form of treatment. Two approaches are used. Mmethimazole (or PTU if used) may be administered until the patient becomes euthyroid. After this state has been reached, and while the patient is maintained on full doses of thiocarbamides, Lugol’s solution or a saturated solution of potassium iodide is administered for 7 - 10 days. This therapy induces an involution of the gland and decreases its vascularity, a factor surgeons find helpful in the subsequent thyroidectomy. In one study Lugol solution treatment resulted in a 9.3-fold decreased rate of intraoperative blood loss. Preoperative Lugol solution treatment decreased the rate of blood flow, thyroid vascularity measured by histomorphometry , and intraoperative blood loss during thyroidectomy(198).

The iodide should be given only while the patient is under the effect of full doses of the antithyroid drug; otherwise, the iodide may permit an exacerbation of the thyrotoxicosis. Alternatively patients may be prepared by combined treatment with antithyroid drugs and thyroxine. It is not obvious that one method is superior to the other. Severely ill patients can be prepared for surgery rapidly by combining several treatments-iopanoic acid 500mg bid, dexamethasone 1mg bid, antithyroid drugs, and beta-blockers(199).

Pre-treatment should have the patient in optimal condition for surgical thyroidectomy. By this time the patient has gained weight, the nutritional status has been improved, and the cardiovascular manifestations of the disease are under control. At the time of surgery, the anesthesia is well tolerated without the risk of hypersensitivity to sympathoadrenal discharge characteristic of the thyrotoxic subject. The surgeon finds that the gland is relatively avascular. Convalescence is customarily smooth. The stormy febrile course characteristic of the poorly prepared patient in past years is rarely seen.

Reactions to the thiocarbamide drugs occasionally occur during preparation for surgery. If the problem is a minor rash or low-grade fever, the drug is continued, or a change is made to a different thiocarbamide. More severe reactions (severe fever or rash, leukopenia, jaundice, or serum sickness) necessitate a change to another form of therapy, but no entirely satisfactory alternative is available. One course is to administer iodide and propranolol and proceed to surgery. In some patients, it is best to proceed directly to 131-I therapy if difficulties arise in the preparation with antithyroid drugs.

Propranolol has been used alone or in combination with potassium iodide [199] in preparation for surgery, and favorable results have generally been reported[200-201]. This procedure is doubtless safe in the hands of a medical team familiar and experienced with this protocol and willing to monitor the patient carefully to ensure adequate dosage. It is safe to use in young patients with mild disease, but is not advised as a standard protocol. Propranolol is used as an adjunct, or combined with potassium iodide as the sole therapy only when complications with antithyroid drugs preclude their use and surgery is strongly preferred to treatment with 131-I.

Amiodarone induced hyperthyroidism is typically difficult to manage, as described in Chapter 13. Administration of iopanoic acid, 1 gm daily for 13 days, has been shown to provide successful pre-operative therapy, reducing T3 levels to normal (196). Propranolol is the usual drug used for preparation of patients with amiodarone induced hyperthyroidism going to surgery.

Surgical Techniques and Complications

The standard operation is a one-stage subtotal thyroidectomy. General anesthesia is standard, but cervical plexus block and out-patient surgery is employed by some surgeons [202]. The amount of tissue left behind is about 4-10 grams, but this amount is variable. Taylor and Painter [203] found that the average volume of this remnant in 43 patients achieving a remission was about 8 ml, and Sugino et al recommended leaving 6 grams of tissue [204]. The toxic state recurred in only two patients in their series, and in these twice the amount of tissue mentioned above was left. Ozaki also noted the importance of the amount of thyroid remaining as the principal predictor of eu- or hypo-thyroidism [205].There seems however to be no relation between the original size of the thyroid and the size of the remnant necessary to maintain normal metabolism.

Motivated in part by economic considerations, there has been in recent years a reevaluation of thyroidectomy done under local anesthesia as a day-surgery proceedure. Pros and cons have recently been discussed. In proper hands local anesthesia and prompt discharge seem acceptable, but most surgeons opt for the standard in hospital approach since it offers a more controlled operative setting and an element of safety the night after surgery. Some clinicians argue for total-thyroidectomy in an effort to reduce recurrence rates (206, 207), and point out that this operation seems to reduce anti-thyroid autoimmunity and reduces the chance of exacerbation of ophthalmopathy. Permanent cure of the hyperthyroidism is produced in 90 - 98% of patients treated this way.

 

Complications of Surgery

Although surgery of the thyroid has reached a high degree of perfection, it is not without problems even in excellent hands. The complication rates at present are low [208]. Among 254 patients operated on at three Nashville hospitals in the decade before 1970, there was no mortality, only minor wound problems, a 1.9% incidence of permanent hypoparathyroidism, and a 4.2% recurrence rate [209]. Hypo-parathyroidism is the major undesirable chronic complication. Surgical therapy at the Mayo Clinic has [210] been associated with a 75% rate of hypothyroidism but only a 1% recurrence rate, as an effort was made to remove more tissue and prevent recurrences. There is typically an inverse relationship between these two results of surgery. In the recent experience of the University of Chicago Clinics, the euthyroid state has been achieved by surgery in 82%; 6% became hypothyroid, and the recurrence rate was 12% [200]. Palit et al. published a meta analysis of collected series of patients treated for Graves’ disease, either by total thyroidectomy or subtotal thyroidectomy. Overall, the surgery controlled hyperthyroidism in 92% of patients. There was no difference in complication rates between the two kinds of operations, with permanent laryngeal nerve injury occurring in 0.7 - 0.9% of patients, and permanent hypoparathyroidism in 1 – 1.6% of patients. Since many surgeons have become more familiar with and capable of total thyroidectomy, and this avoids the possible recurrence of disease, although possibly slightly increasing the risk of nerve or parathyroid damage, total thyroidectomy has become a common or even preferred alternative to subtotal thyroidectomy for managing hyperthyroidism. Recurrence rates are higher in patients with progressive exophthalmos or strongly positive assays for TRAb, suggesting that total thyroidectomy may be preferred in these cases [207]. Geographic differences in iodine ingestion have been related to the outcome.

Death rates are now approaching the vanishing point [206-210] Of the nonfatal complications, permanent hypoparathyroidism is the most serious, and requires lifelong medical supervision and treatment. Experienced surgeons have an incidence under 1%. Unfortunately, the general experience is near 3%. More patients, perhaps 10%, develop transient post-operative hypocalcemia but soon recover apparently normal function. Perhaps these patients have borderline function that may fail in later years.

Unilateral vocal cord paralysis rarely causes more than some hoarseness and a weakened voice, but bilateral injury leads to permanent voice damage even after corrective surgery. Bilateral recurrent nerve injury may be associated with severe respiratory impairment when an acute inflammatory process supervenes and may be life-threatening. Fortunately, it is now extremely rare after subtotal thyroidectomy. Damage to the superior external laryngeal nerve during surgery may alter the quality of the voice and the ability to shout without causing hoarseness. One may speculate whether declining skills in the techniques of subtotal thyroidectomy, attendant upon a dramatic fall in the use of this procedure, may lead to an increase in the hazards of the procedure.

Hypothyroidism, whether occurring after surgery or 131-I therapy, can be readily controlled. Transient hypothyroidism is common, with recovery in one to six months. The presence of autoimmunity to thyroid antigens predisposes to the development of hypothyroidism after subtotal thyroidectomy for thyrotoxicosis. A positive test for antibodies to the microsomal/TPO antigen was found years ago by Buchanan et al [211] to correlate with an increased incidence of postoperative hypothyroidism. The incidence of hypothyroidism is certainly of importance in weighing the virtues of 131-I and surgical therapy. The ability of surgical therapy to produce a euthyroid state in many patients over long-term follow-up gives it one advantage over RAI therapy, but this must be weighed against the risk of hypoparathyroidism and recurrent nerve damage.

Course After Surgery --

In the immediate postoperative period, patients should be followed closely. They should ideally have a special duty nurse or family member providing watch during the first 24 hours, and a tracheotomy set and calcium chloride or gluconate for infusion should be at the bedside. During this period, undetected hemorrhage can lead to asphyxiation. Current use of drains with constant suction helps protect against this problem.
Transient hypocalcemia is common, resulting from trauma to the parathyroid glands and their blood supply and also possibly to rapid uptake of calcium by the bones, which have been depleted of calcium by the thyrotoxicosis [212,213]. Oral or intra- venous calcium supplementation suffices in most instances to control the symptoms. The calcium may be given slowly intravenously as calcium gluconate or calcium chloride in a dose ranging from 0.5 to 1.0 g every 4-8 hours, as indicated by clinical observation and determination of Ca2+.

 

Replacement thyroid hormone-

If sub-total throidectomy has been performed, thyroid hormeone replacement may not be needed. In 50-70% of patients, the residual gland is able to form enough hormone to prevent even transient clinical hypothyroidism. Serum hormone levels should be determined every two to four months until it is clear that the patient does not need replacement. Some surgeons give their patients thyroxine for an indefinite period after the operation in an attempt to avoid transient hypothyroidism and to remove any stimulus to regeneration of the gland.
If total thyroidectomy has been performed, as is increasingly the case, full replacement doses of thyroxine (1.7 ug/kg BW, or about 1ug/pound of lean body mass) should be instituted immediately, and T4 levels checked in about 2 weeks for adjustment. Patients should be informed that they will need this treatment for life, and that they should re regularly checked, and consistent in their daily dosage.

 

Long Term Follow-Up

Probably the thyroid remnant is not normal. It has a rapid ^131-I turnover rate and a small pool of stored organic iodine. Suppressibility by T3 administration returns within a few months of operation in some patients. TSAb tend to disappear from the blood in the ensuing 3 - 12 months [214-2156]. After subtotal thyroidectomy, thyrotoxicosis recurs in 5 - 10% of patients, often many years after the original episode. The long term outcome of thyroid surgery for hyperthyroidism was reviewed by the Department of Surgery at Karolinska Institute. Of 380 patients observed and treated by surgery for thyrotoxicosis, primarily by subtotal thyroidectomy, 1% developed permanent hypoparathyroidism. Recurrent disease occurred in 2%. The operators intended to leave less than two grams of thyroid tissue, which presumably accounts for the low recurrence rate (216).

Finally, adequate follow-up must be carried out after any kind of treatment of Graves’ disease. Recurrence is always possible, either early or late, and there is always the threat that the ophthalmopathic problems may worsen when all else in the progress of the patient seems favorable. A surprisingly large proportion of patients who have had subtotal thyroidectomy for Graves’ disease and who are clinically euthyroid can be shown to have an abnormal TRH response (excessive or depressed), and up to a third have elevated serum TSH levels [217, 218]. Some of them are undoubtedly mildly hypothyroid, whereas others are close to euthyroid but require the stimulation of TSH to maintain this state. These patients should have replacement T ₄ therapy if the elevated TSH persists. Over subsequent years the residual thyroid fails in more patients, due either to reduced blood supply, fibrosis from trauma, or continuing autoimmune thyroiditis. After 10 years, and depending on the extent of the original surgery, 20 - 40% are hypothyroid. This continuing thyroid failure is also seen after antithyroid drug therapy with ^131-I and represents the natural evolution of Graves’ disease.

SPECIAL CONSIDERATIONS IN THE TREATMENT OF THYROTOXICOSIS IN CHILDREN

Thyrotoxicosis may occur in any age group but is unusual in the first five years of life. The same remarkable preponderance of the disease in females over males is observed in children as in the adult population, and the signs and symptoms of the disease are similar in most respects. Behavioral symptoms frequently predominate in children and produce difficulty in school or problems in relationships within the family. Thyrotoxic children are tall for their age, probably as an effect of the disease. These children are restored to a normal height/age ratio after successful therapy for the thyrotoxicosis. Permanent brain damage and craniosynostosis are reported as complications of early childhood thyrotoxicosis ( 219). Bone age is also often advanced [220].

No more is known about the cause of the disease in children than in adults. Diagnosis rests upon eliciting a typical history and signs and upon the standard laboratory test results. Normal values for children are not the same as for adults during the first weeks of life, and these differencesshould be taken into account.

 

Therapy of Childhood Graves’ Disease

131-I Treatment- In some clinics, RAI is used in the treatment of thyrotoxicosis in children. In an early report, 73 children and adolescents were so treated. Hypothyroidism developed in 43. Subsequent growth and development were normal [221]. In another group of 23 treated with 131-I, there were 4 recurrences, at least 5 became hypothyroid, and one was found to have a papillary thyroid cancer 20 months after the second dose [222]. Safa et al. [40] reviewed 87 children treated over 24 years and found no adverse effects except the well-known occurrence of hypothyroidism. Hamburger has examined therapy in 262 children ages 3 - 18 and concluded ^131-I therapy to be the best initial treatment [42]. Read et al (223) reviewed  experience with 131-I over a 36 year period, including six children under age 6, and 11 between 6 and 11 years. No adverse effects on the patients or their offsprings were found, and they advocate 131-I as a safe and effective treatment.
Nevertheless, most physicians remain concerned about the risks of carcinogenesis, and the experience of Chernobyl has accentuated this concern. This problem was more fully discussed earlier in this chapter. Others believe that the risks of surgery and problems with antithyroid drug administration outweigh the potential risk of ^131-I therapy. This problem was critically reviewed by Rivkees et al [224]. They point out the significant risks of reaction to antithyroid drugs, and of surgery. Surgery may have a mortality rate in hospital in children of about one per thousand operations, although this may have decreased in recent years. Among problems with radioactive iodide therapy, they note the whole body radiation, possibly worsening of eye disease, and the apparent lack of significant thyroid cancer risk so far reported among children treated with I-131 for Graves’ disease. They assumed that risk would be lower in children after age five, and especially after age ten, and if all thyroid cells were destroyed. They advise using higher doses of radioiodine to minimize residual thyroid tissue, and avoiding treatment of children under age five, but they believe that RAI is a convenient, effective, and useful therapy in children with Graves’ disease. However, as noted above in the section on risks related to use od 131-i, Rivkees own data indicate that treatnment of children with conventional doses of RAI may induce a lifetime risk of any fatal cancer of over 2%, a very serious consideration (44.2) .Concern about the potential long term induction of cancer by RAI given to children is discussed above. Many physicians remain reluctant to use 131-I in children under age 15-18 as a first line therapy.

Surgery in children- Although ^131-I therapy may gain acceptance, the most common choice for therapy is between antithyroid drugs and subtotal thyroidectomy [225-227]. Proponents of antithyroid drug therapy believe that there is a greater tendency for remission of thyrotoxicosis in children compared to adults and that antithyroid drug therapy avoids the psychic and physical problems caused by surgery in this age group. With drugs the need for surgery (or 131-I) can be delayed almost indefinitely until conditions become favorable.

As arguments against surgery, one must consider the morbidity and possible, although rare, mortality. Surgery means a permanent scar, and the recurrence rate is much higher (up to 15%) than that observed in adults. If the recurrence rate is kept acceptably low by performing near-total thyroidectomies, there is always an attendant rise in the incidence of permanent hypothyroidism, and greater potential for damage to the recurrent laryngeal nerves and parathyroid glands. Damage to the parathyroids necessitates a complicated medical program that may be permanent, and is one of the major reasons for opposing routine surgical therapy in this disease. However Rudberg et al [228] reported that, in a series of 24 children treated surgically, only one had permanent hypoparathyroidism, and two recurred within 12 years. Soreide et al [229] operated on 82 children and had no post-op nerve palsy, no tetany, nor mortality, and point out that surgery can provide a prompt, safe, and effective treatment. Childhood Graves’ disease was managed by near-total thyroidectomy in 78 patients of average age 13.8 years as reported by Sherman et al. Transient hypoparathyroidism and RCN damage were seen. Only three patients required subsequent 131-I treatment. Eighty-five % of those with ophthalmopathy were improved after surgery. The authors conclude that the treatment is safe and effective when performed by experienced surgeons (230).Others have pointed out the high relapse rate with all forms of therapy in the pediatric age group.

The main argument favoring surgery is that it may correct the thyrotoxicosis with surety and speed, and result in less disruption of normal life and development than is associated with long-term administration of antithyroid drugs and the attendant constant medical supervision. Often children are unable to maintain the careful dosage schedule needed for control of the disease.

If surgery is elected, the patient should be prepared with an antithyroid drug such as methimazole in a dosage and duration sufficient to produce a euthyroid state, and then should be given iodide for seven days before surgery. Lugol’s solution, or a saturated solution of potassium iodide, 1 or 2 drops twice daily, is sufficient to induce involution of the gland.

Anti-thyroid drug therapy in  children-  Antithyroid drug therapy is the usual preferable initial therapy in children. Favorable indications for its use are mild thyrotoxicosis, a small goiter, recent onset of disease, and especially the presence of some obvious emotional problem that seems to be related to precipitation of the disease. Antithyroid drug administration necessitates much supervision by the physician and the parents, the permanent remission rate will be 50% or less, and there is always the possibility of a reaction to the medication.

There is no consensus on secondary treatment if antithyroid drugs fail.. Some physicians favor surgery if the patient and parents seem incapable of following a regimen requiring frequent administration of medicine for a prolonged period or drug reactions occur. A factor that must be remembered in selecting the appropriate course of therapy is the experience of the available surgeon. Lack of experience contributes to a high rate of recurrence, permanent hypothyroidism, or permanent hypoparathyroidism. Other physicians believe the possible but unproven risks of 131-I are more than outweighed by the known risks of operation, and 131-I treatment is increasingly accepted for patients over age 15.

If antithyroid drugs are chosen as primary therapy, the patient is initially given a course of treatment for one or two years, according to the dosage schedule shown in Table 11-9. The dosage of PTU (if used) needed is usually 120 - 175 mg/m² body surface area daily divided into three equal doses every eight hours. Methimazole can be used in place of PTU; approximately one-tenth as much, in milligrams, is required. Methimazole is now the preferred drug. During therapy the dosage can usually be gradually reduced. Many patients will be satisfactorily controlled by once-a-day treatment. Although the plasma half-life of methimazole in children is only 3-6 hours, the drug is concentrated in the thyroid and maintains higher levels there for up to 24 hours after a dose [231].

The program is similar to that employed in adult thyrotoxicosis. It is sensible to see the child once each month, and at that time to make sure that the program is being followed and progress made. Any evidence of depression of the bone marrow should prompt a change to an alternative drug or a different form of treatment, as discussed below.

At the end of one or two years the medication is withdrawn. If thyrotoxicosis recurs, a second course of treatment lasting for one year or more may be given. A decrease in the size of the goiter during therapy is good evidence that a remission has been achieved. Progressive enlargement of the gland during therapy implies that hypothyroidism has been produced. This enlargement can be controlled by reduction in the dose of antithyroid drug or by administration of replacement thyroid hormone. There is no adequate rule for deciding when medical therapy has failed. After courses of antithyroid drug therapy totaling two to six years and attainment of age 15, if the patient still has not entered a permanent remission it is probably best to proceed with surgical or ^131-I treatment. Barrio et al (225) reported on truly long term antithyroid drug therapy, which achieved 40% remissions in pediatric patients, with average time to remission of 5.4 years. Non-remitters were cured by RAI or surgery. Leger reported a similar program with 50% of children appearing to enter a permanent remission (232). In an other study 72% of children treated for 2 years relapsed. Occasionally a drug reaction develops while the condition is being controlled with an antithyroid drug. A change to another thiocarbamide may be satisfactory, but patients should be followed carefully. If a reaction is seen again, or if severe neutropenia occurs, it is usually best to stop antithyroid drug therapy and (1) give potassium iodide and an agent such as propranolol and to proceed with surgery, or (2) to give ^131-I.  RAI therapy will be necessary if surgery is contraindicated by uncontrollable thyrotoxicosis,for whatever reason, or with prior thyroidectomy.

Table 9
Surface area-M2	Weight (lbs)	Approximate daily dose of MMI (mg)
0.1	5	2-3
0.2	10	2-5
0.5	30	5-10
0.75	60	10
1.0	90	10-15
1.25	110	15-20
1.5	140	20
2.0	200	20-25

INTRAUTERINE AND NEONATAL THYROTOXICOSIS

Thyrotoxicosis in utero is a rare but recognized syndrome occurring in pregnant women with very high TSH-R stimulating Ab in serum, due to transplacental passage of antibodies. It can also develop in the neonate. It is possible to screen for this risk by assaying TSAb in serum of pregnant women with known current or prior Graves’ Disease. Intra-uterine thyrotoxicosis causes fetal tachycardia, failure to grow, acceleration of bone age, premature closure of sutures, and occasionally fetal death. Multiple sequential pregnancies with this problem have been recorded. Clinical diagnosis is obviously inexact. Antithyroid drugs can be given, but control of the dosage is uncertain [233]. Propylthiouracil is considered to be the safest drug to use in the first trimester, because of fetal anomalies attributed to methimazole exposure in early pregnancy( 234), with switching to MMI in the second and third trimesters..

Luton et al (233) provided their extensive experience in managing these difficult cases. Measurement of TSAb is important. Mothers with negative TSAb assay, and not on ATD, rarely have any fetal problem. Mothers with positive TSAb or on ATD must be monitored by following maternal hormone and TSH levels, fetal growth, heart rate, and by ultrasound for evidence of goiter or other signs of fetal hyper- or hypothyroidism. If maternal hormone levels are low and TSH elevated, with fetal goiter and evidence of hypothyroidism, ATD therapy is reduced and intra-amniotic T4 may be given. If maternal T4 levels are high and TSH low, with fetal goiter and signs of fetal hyperthyroidism, increased doses of ATD are suggested. If the probable metabolic status of the fetus is not clear, fetal blood sampling is feasible although carrying significant risk to the fetus. Plasmapheresis to reduce maternal TRAb has been recommended, but few facts are available.

Thyrotoxicosis is rare in the newborn infant and is usually associated with past or present maternal hyperthyroidism [235,236]. Neonatal hypermetabolism usually arises from transplacental passage of TSAb. Frequently the infant is not recognized as thyrotoxic at birth, but develops symptoms of restlessness, tachycardia, poor feeding, occasionally excessive hunger, excessive weight loss, and possibly fever and diarrhea a few days after birth. The fetus converts T4 to T3 poorly in utero, but switches to normal T4 to T3 deiodination at birth. This phenomenon may normally provide a measure of protection in utero that is lost at birth, allowing the development of thyrotoxicosis in a few days. The syndrome may persist for two to five weeks, until the effects of the maternal antibodies have disappeared. The patient may be treated with propranolol, antithyroid drugs given according to the schedule above, and iodide. The antithyroid drug can be given parenterally if necessary in saline solution after sterilization by filtration through a Millipore filter. Newborn infants with thyrotoxicosis are frequently extremely ill, and ancillary therapy, including sedation, cooling, fluids in large amounts, electrolyte replacement, and oxygen, are probably as important in management as specific therapy for the thyrotoxicosis. Propranolol is used to control the tachycardia (236). Because of the increased metabolism of such infants, attention to fluid balance and adequacy of nutrition are important.

The patient usually survives the thyrotoxicosis, and the disease is typically self-limiting, with the euthyroid state being established in one or two months. Antithyroid medication can be gradually withdrawn at this time.

Graves’ disease can also occur in the newborn because the same disturbance that is causing the disorder in the mother is also occurring independently in the child. Hollingsworth et al [2379] described their experience in such patients. The mothers did not necessarily have active disease during pregnancy. Graves’ disease persisted in these patients from birth far beyond the time during which TSAb of maternal origin could persist. Advanced bone age was one feature of the disorder. Behavioral disturbances were later found in some of these children at a time when they were euthyroid.

General Therapeutic Relationship of the Patient and Physician

The foregoing discussion explains several methods for specifically decreasing thyroid hormone formation. They are, in a sense, both unphysiologic and traumatic to the patient. As a good physician realizes in any problem, but especially in Graves’ disease, attention to the whole patient is mandatory.

During the initial and subsequent interviews, the physician caring for a patient with Graves’ disease should recognize any  psychological and physical stresses. Frequently major emotional problems come to light after the patient recognizes the sincere interest of the physician. Typically the problem involves interpersonal relationships and often is one of matrimonial friction. The upset may be deep-seated and may involve very difficult adjustments by the patient, but characteristically it is related to identifiable factors in the environment. To put it another way, the problem is not an endogenous emotional reaction but a difficult adjustment to real external problems. On the other hand, one must be aware that the emotional lability of the thyrotoxic patient may be a trial for those with whom he or she must live, as well as for the patient. Thus thyrotoxicosis itself may create interpersonal problems. From whatever cause they arise, these problems are dealt with insofar as possible by the wise physician.

We have been unimpressed by the benefits of formal psychiatric care for the average thyrotoxic patient, but are certain that sympathetic discussion by the physician, possibly together with assistance in environmental manipulation, is an important part of the general attack on Graves’ disease. In other cases, personal problems may play a less important etiologic role but may still strongly affect therapy by interfering with rest or by causing economic hardship.

In addition to providing assistance in solving personal problems, two other general therapeutic measures are important. The first is rest. The patient with Graves’ disease should have time away from normal duties to help in reestablishing his or her psychic and physiologic equilibria. Patients can and do recover with appropriate therapy while continuing to work, but more rapid and certain progress is made if a period away from the usual occupation can be provided. Often a mild sedative or tranquilizer is helpful.

Another important general measure is attention to nutrition. Patients with Graves’ disease are nutritionally depleted in proportion to the duration and severity of their illness. Until metabolism is restored to normal, and for some time afterward, the caloric and protein requirements of the patient may be well above normal. Specific vitamin deficiences may exist, and multivitamin supplementation is indicated. The intake of calcium should be above normal.

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47.2  Leslie, WD; Ward, L; Salamon, EA; Ludwig, S; Rowe, RC; Cowden, EA.  A randomized comparison of radioiodine doses in Graves’ hyperthyroidism.           J Clin Endocrinol Metab           88            978-983   2003

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57.1.  Rini JN, Vallabhajosula S, Zanzonico P, Hurley JR, Becker DV, Goldsmith SJ. Thyroid uptake of liquid versus capsule 131-I tracers in hyperthyroid patients treated with liquid 131-I. Thyroid 9:347, 1999

57.2. Berg G, Michanek A, Holmberg E, Nystrom E. Clinical outcome of radioiodine treatment of hyperthyroidism: a follow-up study. J Intern Med 239:165-171, 1996.

57.3-Schiavo M, Bagnara MC, Calamia I, Bossert I, Ceresola E, Massaro F, Giusti M, Pilot A, Pesce G, Caputo M, Bagnasco M.A study of the efficacy of radioiodine therapy with individualized dosimetry in Graves' disease: need to retarget the radiation committed dose to the thyroid. J Endocrinol Invest. 2011 Mar;34(3):201-5. Epub 2010 Dec 15

57.4 Chen DY, Schneider PF, Zhang XS, He ZM, Jing J, Chen TH Striving for euthyroidism in radioiodine therapy of Graves' disease: a 12-year prospective, randomized, open-label blinded end point study. Thyroid. 2011 Jun;21(6):647-54. doi: 10.1089/thy.2010.0348. Epub 2011 May 12

58. Wise PH, Burnet RB, Ahmad A, Harding PE: Intentional radioiodine ablation in Graves' disease. Lancet 2:1231, 1975.

58.1 Sapienza MT¹, Coura-Filho GB, Willegaignon J, Watanabe T, Duarte PS, Buchpiguel CA. Clinical and Dosimetric Variables Related to Outcome After Treatment of Graves' Disease With 550 and 1110 MBq of 131I: Results of a Prospective Randomized Trial. Clin Nucl Med. 2015 Sep;40(9):715-9. doi: 10.1097

58.2.  Allahabadia A, Daykin J, Sheppard MC, Gough SCL, Franklyn JA.  Radioiodine treatment of hyperthyroidism—prognostic factors for outcome.  J Clin Endocrinol Metab 86:3611-3617, 2001.

58.3:  Leslie WD, Ward L, Salamon EA, Ludwig S, Rowe RC, Cowden EA.  A randomized comparison of radioiodine doses in Graves' hyperthyroidism.J Clin Endocrinol Metab. 2003 Mar;88(3):978-83.

58.4 Santos RB, Romaldini JH, Ward LS A randomized controlled trial to evaluate the effectiveness of 2 regimens of fixed iodine (¹³¹I) doses for Graves disease treatment.Clin Nucl Med. 2012 Mar;37(3):241-4.

58.5 Bogazzi F, Giovannetti C, Fessehatsion R, Tanda ML, Campomori A, Compri E, Rossi G, Ceccarelli C, Vitti P, Pinchera A, Bartalena L, Martino E. J Clin Endocrinol Metab. 2010 Jan;95(1):201-8 Impact of lithium on efficacy of radioactive iodine therapy for Graves' disease: a cohort study on cure rate, time to cure, and frequency of increased serum thyroxine after antithyroid drug withdrawal.

58.6 Bonnema SJ, Bennedbaek FN, Veje A, Marving J, Hegedus L.Continuous methimazole therapy and its effect on the cure rate of hyperthyroidism using radioactive iodine: an evaluation by a randomized trial. J Clin Endocrinol Metab. 2006 Aug;91(8):2946-51.

59. Marcocci C, Gianchecchi D, Masini I, Golia F, Ceccarelli C, Bracci E, Fenzi GF, Pinchera A: A reappraisal of the role of methimazole and other factors on the efficacy and outcome of radioiodine therapy of Graves' hyperthyroidism. J Endocrinol Invest 13:513-520, 1990.

59.1. Glinoer D, Verelst J. Use of 131-Iodine for the treatment of hyperthyroidism in adults. Annales d Endocrinologie 57:177-185, 1996.

59.2 Nakazato N, Yoshida K, Mori K, Kiso Y, Sayama N, Tani J-I, et al. 1999 Antithyroid drugs inhibit radioiodine-induced increases in thyroid autoantibodies in hyperthyroid Graves' disease. Thyroid 9:775.

59.3.   Andrade VA, Gross JL, Maia AL.  The effect of methimazole pretreatment on the efficacy of radioactive iodine therapy in Graves’ hyperthyroidism:  one-year follow-up of a prospective, randomized study.  J Clin Endocrinol Metab 86:3488-3493, 2001.

59.31. Burch HB, Solomon BL, Cooper DS, Ferguson P, Walpert N, Howard R.  The effect of antithyroid drug pretreatment on acute changes in thyroid hormone levels after 131-I ablation for Graves’ disease.  J Clin Endocrinol Metab 86:3016-3021, 2001.

59.4 Zakavi SR¹, Khazaei G, Sadeghi R, Ayati N, Davachi B, Bonakdaran S, Jabbari Nooghabi M, Moosavi Z. Methimazole discontinuation before radioiodine therapy in patients with Graves' disease. Nucl Med Commun. 2015 Dec;36(12):1202-7. doi: 10.1097.

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62.1. Liu B¹, Tian R¹, Peng W¹, He Y¹, Huang R¹, Kuang A¹.Radiation Safety Precautions in (131)I Therapy of Graves' Disease Based on Actual Biokinetic Measurements. J Clin Endocrinol Metab. 2015 Aug;100(8):2934-41. doi: 10.1210/jc.2015-1682

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63.1. Stensvold AD, Jorde R, Sundsfjord J. Late and transient increases in free T4 after radioiodine treatment for Graves’ disease. J Endocrinol Invest 20:580-584, 1997.

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64.1.  Dale J, Daykin J, Holder R, Sheppard MC, Franklyn JA.  Weight gain following treatment of hyperthyroidism.  Clin Endocrinol 55:233-239, 2001.

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69a. Tigas S, Idiculla J, Beckett G, Toft A. Is excessive weight gain after ablative treatment of hyperthyroidism due to inadequate thyroid hormone therapy? Thyroid 10:1107, 2000.

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76.1 Ceccarelli C, Canale D, Battisti P, Caglieresi C, Moschini C, Fiore E, Grasso L, Pinchera A, Vitti P.Testicular function after 131-I therapy for hyperthyroidism.Clin Endocrinol (Oxf). 2006 Oct;65(4):446-52.

76.2. Franklyn JA, Sheppard MC, Maisonneuve P. Thyroid function and mortality in patients treated for hyperthyroidism. JAMA. 2005 Jul 6;294(1):71-80.

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80.1. Fernandez Sanchez JR, Rosell Pradas J, Carazo Martinez O, Torres Vela E, Escobar Jimenez F, Garbin Fuentes I, Vara Thorbeck R. Graves’ ophthalmopathy after subtotal thyroidectomy and radioiodine therapy. Brit J Surg 80:1134-1136, 1993.

80.2 Vannucchi G, Campi I, Covelli D, Dazzi D, Currò N, Simonetta S, Ratiglia R, Beck-Peccoz P, Salvi M.

J Clin Endocrinol Metab. 2009 Sep;94(9):3381-6 Graves' orbitopathy activation after radioactive iodine therapy with and without steroid prophylaxis.

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80.3.Taïeb D¹, Bournaud C², Eberle MC², Catargi B², Schvartz C², Cavarec MB², Faugeron I², Toubert ME², Benisvy D², Archange C², Mundler O², Caron P², Abdullah AE², Baumstarck K². Eur J Endocrinol. 2016 Apr;174(4):491-502. doi: 10.1530/EJE-15-1099. Quality of life, clinical outcomes and safety of early prophylactic levothyroxine administration in patients with Graves' hyperthyroidism undergoing radioiodine therapy: a randomized controlled study.

 

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82.1. Bartalena L, Marcocci C, Bogazzi F, Manetti L, Tanda ML, Dell’Unto E, Bruno-Bossio G, Nardi M, Bartolomei MP, Lepri A, Rossi G, Martino E, Pinchera A. Relation between therapy for hyperthyroidism and the course of Graves’ ophthalmopathy. N Engl J Med 338:73-78, 1998.

82.2 Jensen BE, Bonnema SJ, Hegedus L.Glucocorticoids do not influence the effect of radioiodine therapy in Graves' disease.Eur J Endocrinol. 2005 Jul;153(1):15-21.

82.3 Takamura Y, Nakano K, Uruno T, Ito Y, Miya A, Kobayashi K, Yokozawa T,Matsuzuka F, Kuma K, Miyauchi A.  Changes in serum TSH receptor antibody (TRAb) values in patients with Graves' disease after total or subtotal thyroidectomy. Endocr J. 2003 Oct;50(5):595-601.

82.4 De Bellis A, Conzo G, Cennamo G, Pane E, Bellastella G, Colella C, Iacovo AD, Paglionico VA, Sinisi AA, Wall JR, Bizzarro A, Bellastella ATime course of Graves' ophthalmopathy after total thyroidectomy alone or followed by radioiodine therapy: a 2-year longitudinal study.Endocrine. 2012 Apr;41(2):320-6. Epub 2011 Nov 16.

82.5 Leo M, Marcocci C, Pinchera A, Nardi M, Megna L, Rocchi R, Latrofa F, Altea MA, Mazzi B, Sisti E, Profilo MA, Marinò M. Outcome of Graves' orbitopathy after total thyroid ablation and glucocorticoid treatment: follow-up of a randomized clinical trial.J Clin Endocrinol Metab. 2012 Jan;97(1):E44-8. Epub 2011 Oct 26.

82.6 Bojic T¹, Paunovic I^2,3, Diklic A^4,5, Zivaljevic V^6,7, Zoric G⁸, Kalezic N^9,10, Sabljak V^11,12, Slijepcevic N¹³, Tausanovic K¹⁴, Djordjevic N^15,16, Budjevac D¹⁷, Djordjevic L¹⁸, Karanikolic A^19,20. Total thyroidectomy as a method of choice in the treatment of Graves' disease - analysis of 1432 patients. BMC Surg. 2015 Apr 9;15:39. doi: 10.1186/s12893-015-0023-3.

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89.2-Cardis E, Kesminiene A, Ivanov V, Malakhova I, Shibata Y, Khrouch V, Drozdovitch V, Maceika E, Zvonova I, Vlassov O, Bouville A, Goulko G, Hoshi M, Abrosimov A, Anoshko J, Astakhova L, Chekin S, Demidchik E, Galanti R, Ito M, Korobova E, Lushnikov E, Maksioutov M, Masyakin V, Nerovnia A, Parshin V, Parshkov E, Piliptsevich N, Pinchera A, Polyakov S, Shabeka N, Suonio E, Tenet V, Tsyb A, Yamashita S, Williams D. Risk of thyroid cancer after exposure to 131I in childhood.J Natl Cancer Inst. 2005 May 18;97(10):724-32.

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105.1. Weetman AP. The immunomodulatory effects of antithyroid drugs. Thyroid 4:145-146, 1994.

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110.1. Laurberg P¹, Krejbjerg A, Andersen SL. Relapse following antithyroid drug therapy for Graves' hyperthyroidism. Curr Opin Endocrinol Diabetes Obes. 2014 Oct;21(5):415-21. doi: 10.1097

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121.1. Zweig SB, Schlosser JR, Thomas SA, Levy CJ, Fleckman AM .Rectal administration of propylthiouracil in suppository form in patients with thyrotoxicosis and critical illness: case report and review of literature. Endocr Pract. 2006 Jan-Feb;12(1):43-47.

121.2Jongjaroenprasert W, Akarawut W, Chantasart D, Chailurkit L, Rajatanavin R.  Rectal administration of propylthiouracil in hyperthyroid patients:  comparison of suspension enema and suppository form.  Thyroid 12:627-631, 2002

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126.1 Azizi F, Ataie L, Hedayati M, Mehrabi Y, Sheikholeslami F.Effect of long-term continuous methimazole treatment of hyperthyroidism: comparison with radioiodine.Eur J Endocrinol. 2005 May;152(5):695-701

126.2. Jodar E, Munoz-Torres M, Escobar-Jimenez F, Quesada M, Luna JD, Olea N. Antiresorptive therapy in hyperthyroid patients: Longitudinal changes in bone and mineral metabolism. J Clin Endocrinol Metab 82:1989-1994, 1997.

126.3 Majima T, Komatsu Y, Doi K, Takagi C, Shigemoto M, Fukao A, Morimoto T, Corners J, Nakao K.Clinical significance of risedronate for osteoporosis in the initial treatment of male patients with Graves' disease.J Bone Miner Metab. 2006;24(2):105-13.

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131.1. Rittmaster RS, Zwicker H, Abbott EC, Douglas R, Givner ML, Gupta MK, Lehmann L, Reddy S, Salisbury SR, Shlossberg AH, Tan MH, York SE. Effect of methimazole with or without exogenous L-thyroxine on serum concentrations of thyrotropin receptor antibodies in patients with Graves’ disease. J Clin Endocrinol Metab 81:3283-3288, 1996.

131.2. Lucas A, Salinas I, Rius F, Pizarro E, Granada ML, Foz M, Sanmarti A. Medical therapy of Graves’ disease: does thyroxine prevent recurrence of hyperthyroidism? J Clin Endocrinol Metab 82:2410-2413, 1997.

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ABSTRACT

The sensitive and tightly regulated feedback control system, thyroid gland autoregulation, and the large intrathyroidal and extrathyroidal storage pools of thyroid hormone serve to provide a constant supply of thyroid hormone to peripheral tissues in the face of perturbations imposed by the external environment, chemicals and drugs, and a variety of diseases processes. The thyroid is subject to a great number of exogenous and endogenous perturbations. The same agent may produce alterations in various aspects of thyroid hormone economy. For this reason, it is difficult to precisely classify all external and internal influences according to their mode of action. This chapter reviews effects on the thyroid produced by changes in the external environment, chemicals and drugs. The effects of non-thyroidal illness are reviewed in Chapter 5b. The effects of the more important factors and chemical agents and drugs are discussed individually.

 

RESPONSES TO ALTERATIONS IN THE EXTERNAL ENVIRONMENT

Environmental Temperature

Changes in environmental temperature may cause alterations in TSH secretion and in the serum concentration of thyroid hormones and their metabolism. The changes are probably mediated through the hypothalamus and the pituitary and by peripheral effects on the pathways and rates of thyroid hormone degradation and fecal losses and alterations in thyroid hormone action. The in vitro effects of temperature on the firmness of binding of T4 to its transport serum proteins conceivably also play a role in vivo.¹  The overall effects of environmental temperature have been more obvious and easier to demonstrate in animals than in humans but differences in thermal regulation ^1a may mean that findings in animal models may not apply to humans. Additionally, studies of individuals with prolonged residence in Arctic and Antarctic regions may be confounded by other alterations in daylight, activity levels, living conditions and sleep deprivation. ^1b,1c

Effects of Cold

Dramatic, although transient, increases in serum TSH levels have been observed in infants and young children during surgical hypothermia.²  Also, a prompt and important secretion of TSH occurs in the newborn, in the first few hours after birth, accompanied by an increase in thyroid hormone secretion and clearance.^3,4  Since this TSH surge is partially prevented by maintaining infants in a warm environment, postnatal cooling appears to be responsible in part for the rise in TSH secretion. In most studies, exposure of adults to cold or even intensive hypothermia has produced no changes,^5,6 or at best minimal increases⁷ in serum TSH. More prolonged exposure to cold generally results in maintenance of the total T4 (TT4) and free T4 (fT4) levels with maintenance of a normal or decreased total T3 (TT3) and free T3 (fT3) levels. ^7a,7b , however, others have shown prolonged arctic residence leads the increase in TSH to be associates with an increase in, thyroglobulin and T3..^7c These alterations may be partly the consequence of a direct effect of temperature on the rate and pathways of thyroid hormone metabolism with more rapid production and clearance of T3. Altered kinetics have been demonstrated in humans ^7d, but have been more thoroughly studied in animals.^8,9,9a,9b    It has been more difficult to show a clear seasonal variation in serum hormone concentration. However, the variation demonstrated in several studies^10,11 has been that T4 and T3 values are higher during the colder months.

Cold exposure in animals leads to thyroid gland hyperplasia, enhanced hormonal secretion, degradation, and excretion, accompanied by an increased demand for dietary iodine. All of these effects are presumably due to an increased need for thyroid hormone by peripheral tissues. The prompt activation of pituitary TSH secretion after cold exposure of the rats^12,13 is possibly due in part to a direct effect on the hypothalamus.¹⁴  Exposure to cold has also resulted in augmented TRH production, and serum levels,¹⁶ and blunted responses of TSH to exogenous TRH.¹⁷  These effects have not been reproduced by other laboratories^13,18 although an increase in thyroid hormone secretion has been clearly demonstrated.^6,19,20  In the rat, it is associated with augmented rates of T4 and T3 deiodination, increased conversion of T4 to T3, and enhanced hepatic binding and biliary and fecal clearance of the iodothyronines.^8,9,9a,21,22  Finally, thyroid hormone effects may be enhanced by alterations in co-activators which enhance the activity of thyroid hormone receptors on gene activation. ^22a

Effects of Heat

In general, an increase in ambient temperature has produced effects opposite to those observed during cold exposure, although the effects of heat have not been extensively investigated. As indicated above, thyroid hormone levels in serum tend to be lower during the summer months. A decrease in the serum T3 concentration, with reciprocal changes in the levels of rT3, have been observed in normal subjects acutely exposed to heat and during febrile illnesses.^23,24  In the latter condition, the contribution of the rise in body temperature relative to other effects of systemic illness cannot be dissociated. A decrease in the elevated serum TSH level associated with primary hypothyroidism has been induced by increases in body temperature.²⁵

High Altitude and Anoxia

Acute elevations in serum T4 and T3 concentrations occur in humans during the early period of exposure to high altitude.²⁶  Increases in the rate of T4 degradation and thyroidal RAIU have also been reported.^27,28 At very high elevations (5400-6300 m), elevations in T4, fT4, T3, and TSH with a normal fT3 have been reported.^28a When compared to those residing at sea level, individuals adapted to altitude were noted to have a lower T4 with higher fT4 and fT3 levels and a normal TSH response to TRH.^28b Moderate, transient increases in oxygen consumption, not a result of sympathetic activation, were found in one study.²⁸

The responses of rats exposed to high altitude or anoxia seem to be quite different. Thyroidal iodinative activity and T4 formation are diminished.^29-31  The partial reversal of these changes by the administration of TSH led the authors of these studies to conclude that the primary effect is probably diminished TSH secretion.

Alterations in Light

Pinealectomy induces a moderate increase in thyroid weight,³² and continuous light exposure³³ increases the T4 secretion rate of rats by about 20%. In squirrels, continuous darkness produces a decrease in thyroid weight and T4 levels^33a, but this effect is blocked by pinealectomy.^33a These studies suggest that melatonin has an inhibitory effect on thyroid gland function.^33a,34 A nocturnal increase in Type II deiodinase activity Is blocked by exposure to continuous light.^34a   Although the retinas of rat pups reared in total darkness are totally devoid of TRH, the content of TRH in the hypothalamus remains unaltered.³⁵  The diurnal variation in hypothalamic TRH content, reflecting both rhythmic synthesis and secretion, is, however, blunted in the absence of cyclical light changes. Little is known about the effect of light on the thyroid in humans. The normal TSH rhythm can be reset by a pulse of light.^35a

Nutrition

Since thyroid hormone plays a central role in the regulation of total body metabolism, it is not surprising that nutritional factors may profoundly alter the regulation, supply, and disposal of this thermogenic hormone. Although many dietary changes can affect the thyroid economy, the most striking and important effects are related to alterations in total caloric intake and the supply of iodine. The changes associated with caloric deprivation appear homeostatic in nature producing alterations in thyroid hormones which would conserve energy through a reduction in catabolic expenditure. The changes observed with a deficiency or excess of iodine supply generally serve to maintain an adequate synthesis and supply of thyroid hormone, principally through modifications in thyroidal iodide accumulation and binding.

 

Starvation and Fasting

Multiple alterations in thyroid hormone regulation and metabolism have been noted during caloric restriction. The most dramatic effect is a decrease in the serum TT3 within 24-48 hours of the initiation of fasting.^36-40b  Because changes in the free T3 fraction are usually small, the absolute concentration of FT3 is also reduced, clearly into the hypothyroid range The marked reduction in serum T3 is caused by a reduction in its generation from T4 rather than by an acceleration in its metabolic clearance rate.^41,42 The decline in T3 concentration is accompanied by a concomitant and reciprocal change in the concentration of total and free rT3. The increase in the serum rT3 concentration tends to begin later and to return to normal at the time serum T3 is being maintained at a low level with continuous calorie deprivation.^38,39 Little change occurs in the concentrations of TT4 and FT4 and the production and metabolic clearance rates of T4.^38,39,41,42  When small changes have been observed, they were generally in the direction of an increase in the FT4 concentration. They are attributed to decreased concentration of the carrier proteins in serum, as well as to their diminished association with the hormone caused by the inhibitory effect of free fatty acids (FFA) the level of which increases during fasting.^40,43

Decreased outer ring monodeiodination (5'-deiodinase activity) would explain both the decreased generation of T3 from T4 and the excess accumulation of rT3. This hypothesis seems to be fully supported by in vitro studies using liver tissue from fasted fats.⁴⁴  It is further supported by the finding of increased generation and serum concentration of 3',5'-T₂ and 3'-T₁ and decreased 3,5-T₂ and 3,3'-T2.^44-47  However, a less important increase in the monodeiodination of the inner ring of T4 (5-deiodination)⁴² explains the temporal dissociation of changes in serum T3 and rT3 concentration. A decrease in plasma T3 after fasting with an increase in hepatic type III deiodinase activity and mRNA has also been noted in chickens. ^47a An increase in the nondeiodinative pathway of T4 degradation with the formation of Tetrac has been also reported.⁴⁸

Considerable controversy remains regarding the mechanisms responsible for the observed changes in the rates of the deiodinative pathways of iodothyronines. Decreased generation of nonprotein sulfhydryls (NP-SH) as a cause of the reduction in 5'-deiodinase activity was suggested on the basis of the observed enhancement in enzyme activity by the in vitro addition of dithiothreitol. Reduced glutathione and NADPH had a similar effect.⁴⁹  Although Chopra's⁵⁰ direct measurements of NP-SH in tissue during fasting seemed to confirm this hypothesis, the precise mechanism is likely more complex. Decreased tissue NP-SH content does not always correlate with the inhibition of T3 generation, which may be restored by glucose refeeding independently of changes in NP-SH content.^50,51

Composition of the diet rather than reduction in the total calorie intake seems to determine the occurrence of decreased T3 generation in peripheral tissues during food deprivation. The dietary content of carbohydrate appears to be the key ingredient since as little as 50 g glucose reverses toward normal the fast-induced changes in T3 and rT3.⁵²  Replacement of dietary carbohydrate with fat results in changes typical of starvation.^39,53  Refeeding of protein may partially improve the rate of T3 generation, but the protein may be acting as a source of glucose through gluconeogenesis.⁵⁴  Yet, dietary glucose is not the sole agent responsible for all changes in iodothyronine metabolism associated with starvation. For example, the increase in serum rT3 concentration may not be solely dependent on carbohydrate deprivation since a pure protein diet partially restores the level of rT3 but not that of T3³⁹ (Fig. 5-1). The composition of the antecedent diet also has an effect on the magnitude of the serum T3 fall during fasting.^39,52  It is possible that the cytoplasmic redox state, measured in terms of the lactate/pyruvate ratio rather than glucose itself, regulates the rate of deiodinative pathways of iodothyronines.⁵⁵

The basal serum TSH level during calorie deprivation is either normal or low, the response to TRH is blunted^37-39 and the normal nocturnal rise in TSH is blunted.^40a These changes are quite surprising given the consistent and profound decrease in serum FT3 levels. Several hypothesis have been proposed to explain this paradox. Because the pituitary is able to continue to respond appropriately during fasting to both suppressive and stimulatory signals,⁵⁶ it has been suggested that starvation only "resets" the set point of feedback regulation. A more plausible hypothesis, supported by experimental data,^57,58 proposes that the pituitary is regulated by the intracellular concentration of T3, which may remain unaltered through factors ensuring its continuous local generation during starvation, whereas a decrease is typically found in other tissues.   Further support for this hypothesis comes from a recent study demonstrating that fasting produces a marked increase in hypothalamic Type II Deiodinase mRNA^58a which would enhance local T3 production.   This hypothesis gives credence to the preservation of a closer inverse relationship between serum FT4 and TSH than between FT3 and TSH. Hypothalamic TRH content in starved rats has been reported to be normal,⁵⁹ low⁶⁰  or even elevated.^60a The elevation of TRH was accompanied by normal levels of proTRH mRNA and decreased pituitary TSH; it was suggested that this represented decreased TRH release. ^60a In a different study of starved rats, the hypothalamic proTRH mRNA and the TRH content were both decreased,^60b but these effects were reversed by adrenalectomy suggesting that they were secondary to increased glucocorticoid levels.^60b Neonatal starvation in rats leads to diminished TRH and TSH production, with resultant hypothyroidism and growth retardation.⁶¹

Starvation produces a greater than 50% decrease in the maximal binding capacity of T3 to rat liver nuclear receptors within 48 hours.⁶²  Although accompanied by a diminution of almost equal magnitude in the nuclear T3 content, it is unlikely that the observed change represents an alteration of the receptor content by the hormone as the more profound diminution of nuclear T3 content associated with hypothyroidism does not produce changes in the maximal binding capacity of T3 in rat liver nuclei. The reduction in maximal binding capacity has been demonstrated to coincide with a reduction in the level of the thyroid hormone receptors.^62a The affinity of the rat liver T3 receptor is not affected by starvation.^62,63  Studies in humans have used circulating mononuclear cells and, probably due to the limited choice of tissue, results have been either equivocal or negative.⁶⁴

Other hormonal and metabolic changes during fasting may account for the observed alterations in the regulation and metabolism of thyroid hormones. Among them are the increase in plasma cortisol and suppression of adrenergic stimuli.⁶⁵  Both changes are known to induce independently a decrease in the serum T3 concentration by inhibition of T4 to T3 conversion in peripheral tissues (see below). Accordingly, they may be partly responsible for the decrease in T3 neogenesis during starvation. There is likely a highly complex interplay between the changes in thyroid hormone and the many metabolic changes of starvation. In addition to a direct effect of glucose, changes in FFA, ketosis, and the redox state may influence thyroid hormone metabolism, while T3 itself may impact hepatic glucose production.^40b

Two major issues of theoretical and practical importance remain unresolved - do the observed changes in thyroid function produce some degree of hypothyroidism, and is this state beneficial to the energy-deprived organism? Although the suppressed serum TSH response to TRH suggests that the starving organism does not suffer from a significant deprivation in thyroid hormone, other observations indicate the contrary. The decreased pulse rate, systolic time interval, oxygen consumption, and decrease in activity of some liver enzymes are suggestive of hypothyroidism at the level of peripheral tissues.⁶⁶  Furthermore, administration of T3 to restore its serum level to normal during fasting increased the production and excretion of urea and 3-methylhistidine.^56,67  Larger doses of T3, given during fasting, had even more profound effects. These effects included dramatic increased in the excretion of urea and creatine, and increased plasma levels of ketones and FFA indicating an accelerated protein and fat breakdown.⁶⁸  Such evidence leaves little doubt that the decrease in T3 generation during calorie deprivation has an energy- and nitrogen-sparing effect. It is tempting to speculate that the result is beneficial in the adaptation to malnutrition through reduction in metabolic expenditure.

Fasting is not only a useful model for studying the effects of calorie deprivation on thyroid hormone but is also the prototype of the "low T3 syndrome".⁶⁹  The latter is produced by a number of chemical agents and drugs, and accompanies a variety of nonthyroidal illnesses. It is possible that malnutrition, concomitant in a number of acute and chronic illnesses, is in part responsible for some of the observed changes in thyroid physiology.

 

Protein-Calorie Malnutrition (PCM)

As in the case of starvation, PCM is associated with a low serum T3 concentration and increased rT3 levels, probably due to similar changes in iodothyronine monodeiodination. However, important differences exist between the abnormalities in thyroid function observed in PCM and acute calorie deprivation. Most reports indicate important decreases in TBG and TTR concentrations, and there are also indications of hormone binding abnormalities.^70,71  As a consequence, the free concentrations of both T4 and T3 are usually normal.^70,72,72a  Recovery is associated with restoration of the level of serum thyroid hormones and binding proteins. Despite an accelerated turnover time, the absolute amount of extrathyroidal T4 disposed each day is reduced. Refeeding restores the T4 kinetics to normal.⁷⁰  The thyroidal RAIU is reduced due to a defect in the iodine-concentrating mechanism.⁷³  The most striking difference between starvation and PCM is the finding the latter of an exaggerated and sustained TSH response to TRH, with basal TSH levels either elevated or normal.^{70,72,72a,72b,74}

The experimental model of protein malnutrition in the rat yielded different results from those observed in humans. Serum T4 and T3 levels were found to be both elevated.⁷⁵  However, in the lamb, as in humans, chronic malnutrition leads to a lower rate of T4 utilization.⁷⁶

 

Overfeeding and Obesity

Overfeeding produces an increase in the serum T3 concentration as a result of an increased conversion of T4 to T3. It is particularly marked when the excess calories are given in the form of carbohydrates.⁷⁷  Thus, it appears that the effect of overnutrition on iodothyronine metabolism is the opposite of that of starvation. This finding gives further credence to the speculation that changes in thyroid hormone may serve to modulate the homeostasis of energy expenditure.

Although it has been reported that serum T3 concentrations correlate with body weight,⁷⁸ it appears that this phenomenon reflects the effect of an increase in caloric intake on T3 production. Most studies find that obese subjects have normal thyroid function and hormone metabolism.⁷⁹  Furthermore, no abnormalities in the hypothalamic-pituitary-thyroid axis have been demonstrated in obese subjects.

 

Minerals

Iodine. Of the many minerals that may affect thyroid function, iodine is the most important. It is an essential substrate for thyroid hormone synthesis and also interacts with the function of the thyroid gland at several levels.

Acute administration of increasing doses of iodide enhances total hormone synthesis until a critical level of intrathyroidal iodide is reached. Beyond this level, iodide organification and hormone synthesis are blocked (the acute Wolff-Chaikoff block). Chronic or repeated administration of moderate to large doses of iodine causes a decrease in iodide transport resulting in a decrease in its intrathyroidal concentration. The latter relieves the Wolff-Chaikoff block and is known as the escape or adaptation phenomenon. Although the exact mechanisms of the block and escape remain unknown, they appear to be autoregulatory in nature since they are independent of pituitary TSH secretion. Iodoloactones may play a role in the induction of the Wolff-Chaikoff block.⁸⁰   One mechanism through which iodide acts is via desensitization of the thyroid gland to TSH. In TSH stimulated glands, iodine rapidly reduces the level of the mRNA for thyroid peroxidase (TPO) and the Na/I symporter (NIS) but not for thyroglobulin (Tg) or the TSH receptor (TSHr).^80a Iodine also antagonizes TSH stimulated thyrocyte proliferation.^80a   In FRTL-5 cells, iodine blocks the TSH stimulation of Tg synthesis but does not alter the level of the Tg mRNA.^80b   These actions occur without a change in TSH receptor number, and may, in part, be via an action on adenylyl cyclase.^80c More detailed description is provided in Chapter 2.

Another effect of large doses of iodine, apparently independent of TSH and hormone synthesis, is the prompt inhibition of hormone release. It has been exploited to achieve rapid amelioration of thyrotoxicosis in Graves' disease and toxic nodular goiters (see Chapters 11 and 13). In normal persons, the inhibitory effect of large doses of iodine on thyroid hormone release produces a transient decrease in the serum concentration of T4 and T3. It causes, in turn, a compensatory increase in serum TSH, which stimulates hormone secretion and thus counteracts the effect of iodine.^81,82  The mechanisms of thyroidal autoregulation are believed to serve the purpose of accommodating wide and rapid fluctuations in iodine supply.

The most intriguing effects of iodine are the involution of hyperplasia and the decrease in vascularity that occur when the ion is administered to patients with diffuse toxic goiter. Iodine may be able to induce apoptosis in thyroid cells. ^82a,82b Under different circumstances, iodide may intensify the hyperplasia and produce a goiter (Chapter 20).

Iodine deficiency used to be the leading cause of goiter in the world and still remains so in certain regions. When severe, it can cause hypothyroidism and cretinism, described in detail in Chapter 20 . In the United States and the rest of the developed world, untoward effects from excess iodine supplementation or the use of iodine-containing compounds are more common than problems related to iodine deficiency.

Excess iodine can be responsible for the development of goiter, hypothyroidism, and thyrotoxicosis. However, it should be emphasized that these complications usually occur in persons with underlying defects of thyroid function who are unable to utilize the normal adaptive mechanisms. Iodide-induced goiter (iodide goiter), without or with hypothyroidism (iodide myxedema), is encountered with greater frequency in patients with Hashimoto's thyroiditis or previously treated Graves' disease.^83,84  Other predisposed persons include those who have undergone partial thyroid gland resection, patients with defects of hormonogenesis, and some with cystic fibrosis.⁸⁵ Drugs such as phenazone,^86,87 lithium,⁸⁸ sulfadiazine,⁸⁹ and cycloheximide⁹⁰ may act synergistically with iodide to induce goiter and/or hypothyroidism.

More rarely, ingestion of excess iodide may cause thyrotoxicosis (iodide-induced thyrotoxicosis or Jodbasedow).^90a   This was initially observed with the introduction of iodine prophylaxis in areas of endemic iodine deficiency.^91,92  It has also been observed after the administration of iodide in excess to patients with nodular thyroid disease residing in areas of moderate iodine deficiency or even iodine sufficiency.^93,94  Although the exact mechanism of induction of thyrotoxicosis remains obscure, it may be related to the stimulation of increased thyroid hormone synthesis in areas of the gland with autonomous nodular activity.

Ingestion of excess iodide by a gravid woman may cause an iodide goiter in the fetus, and if the gland is large enough it may result in asphyxia during the postnatal period (Chapter 20). Consumption of Kombu, the iodine-rich seaweed, is responsible for the occurrence of endemic goiter in the Japanese island of Hokkaido.⁹⁵  It has also been suggested that the increase in dietary iodine content in the United States during the last three decades is responsible for the higher recurrence rate of thyrotoxicosis in patients previously treated with antithyroid drugs.⁹⁶

 

Calcium. Calcium is said to be goitrogenic when in the diet in excess. Administration of 2 g calcium per day was associated with decreased iodide clearance by the thyroid.⁹⁷  The action is unknown, but it may in some way make overt a borderline dietary iodine deficiency. Calcium also acutely and chronically reduces the absorption of thyroxine. ^{97a, 97b}

 

 

Nitrate. Nitrate in the diet (0.3 - 0.9%) can interfere with ¹³¹I uptake in the thyroid of rats and sheep.⁹⁸  This concentration is found in some types of hay and in silages.

 

Bromine. Bromine is concentrated by the thyroid and interferes with the thyroidal ¹³¹I uptake in animals^99,99a and humans, possibly by competitive inhibition of iodide transport into the gland. Bromine can also induce alterations in cellular architecture, blood supply and can lead to a reduction in T4 and T3 levels.^99b

 

Rubidium. Rubidium is goitrogenic in rats.¹⁰⁰  However, the mechanism of action is unknown.

 

Fluorine. Fluorine is not concentrated by the thyroid but has a mild antithyroid effect, possibly by inhibiting the iodide transport process.¹⁰¹  In large amounts, it is goitrogenic in animals. The amounts of fluorine consumed in areas with endemic fluorosis are not sufficient to interfere with thyroid function or to produce goiter.^102,103  However, other data suggest that dietary fluorine may exacerbate an iodine deficiency and thus modulate the distribution of goiter in areas with low iodine intake.¹⁰⁴

 

Cobalt. Cobalt inhibits iodide binding by the thyroid.¹⁰⁵  The mechanism is unknown. Cobalt deficiency is associated with a reduction in type I monodeiodinase activity and a fall in T3^105a while cobalt excess may produce goiter and decreased thyroid hormone production. ^105b It is sufficiently active to have been used in the treatment of thyrotoxicosis.¹⁰⁶

 

Cadmium.   Administration of cadmium to rats or mice decreases serum levels of T4 and T3. ^106a,106b   It also decrease the activity of hepatic Type I - 5’Deiodinase.^106a,106c

 

Lithium Ion. Lithium ion is goitrogenic when used in the treatment of manic-depressive psychosis and can induce myxedema.¹⁰⁷  Experimentally, lithium increases thyroid weight and slows thyroid iodine release.¹⁰⁸  When lithium carbonate was given to human subjects in doses of 900 mg four times daily, there was a significant decrease in the rate of release of thyroidal iodine in euthyroid and hyperthyroid subjects.¹⁰⁹  Lithium also decreases the rate of degradation of T4 in both hyperthyroid and euthyroid subjects.¹¹⁰  Inhibition of thyroid hormone release may be the dominant effect of the ion.^110a Therefore, the decrease in serum T3 concentration is greater in hyperthyroid patients, and changes in the rT3 level, if any, are minimal.^111-113

A number of mechanisms have been suggested for the effects of lithium. One well-documented phenomenon is a potentiation of an iodide-induced block of binding and hormone release,^88,114 perhaps because lithium is concentrated by the thyroid¹¹⁵ and increases the intrathyroidal iodide concentration^109,111 (Fig. 5-2). Although it has been shown that lithium inhibits the adenylate cyclase activity in the thyroid gland as well as in other tissues,¹¹⁶ it also blocks the cAMP-mediated translocation of thyroid hormone. The latter effect, which is probably responsible for the inhibition of hormone release, appears to be due to the stabilization of thyroid microtubules promoted by lithium.¹¹⁷ In rat brain, lithium administration decreased both the levels of the Type II 5’Deiodinase and the Type III 5 Deiodinase.^117a In the rat, lithium may also lead to an alteration in the distribution of thyroid hormone receptors with the alpha 1 isoform being increased in the cortex and decreased in the hypothalamus while the beta isoform was also decreaseed in the hypothalamus. ^117b  

An exaggerated response of TSH to TRH may be seen in a majority of lithium treated patients^110a but an elevated basal TSH is usually absent. An increase in the basal serum TSH concentration and its response to TRH most likely represents an early manifestation of hypothyroidism rather than a direct effect of lithium on the hypothalamic-pituitary axis.¹¹⁸  The prevalence of goiter has been reported to be as high as 60%.^110a     Based on studies in FRTL-5 cells, lithium may have direct mitogenic effects on the thyroid that are independent of TSH and cAMP. ^110b The occurrence of hypothyroidism during lithium therapy occurs in 10-40% of lithium treated patients and is far more frequent in women than men.^{110a,118a, 118b,118c}  

 

Although much less frequent, lithium therapy has been associated with the development of thyrotoxicosis.^110a Lithium is also reported to produce exophthalamos during chronic therapy; the condition regresses when treatment is stopped. The phenomenon is a protrusion of the globe but does not involve the other changes of infiltrative ophthalmopathy of Graves' disease.^118,119

 

 

Selenium. Selenium is a component of the enzymes glutathione peroxidase (GSH-Px) and superoxide dismutase, both enzymes responsible for protection against free radicals. In addition, Type I 5’Deiodinase also contains selenium.^{119a 119c} Thus, a deficiency of selenium could predispose the thyroid to oxidative injury and lead to decreased peripheral T3 production. In the elderly, reduced selenium levels have been associated with a decreased T3/T4 ratio.^119b It has been postulated that the combined deficiency of iodine and selenium in Zaire results in myxedematous rather than neurologic cretinism because the decrease in peripheral conversion to T3 results in greater delivery of T4 into the neonatal developing brain.^119c In rats, selenium deficiency led to a decrease in renal but not hepatic Type I 5’ Deiodinase activity and serum T3 levels were unaffected.^119d Selenium deficiency led to decrease GSH-Px activity in the liver, kidney and rbc’s but not the thyroid.^119d   Serum T4 was normal when both dietary iodine and selenium were both deficient, but was reduced when either was deficient alone.^119d   In other studies, brain GSH-Px and Type I deiodinase activity were normal in the presence of iodine or selenium deficiency while brain Type II Deiodinase activity was increased by iodine deficiency and unaffected by selenium deficiency.^119e In contrast in brown adipose tissue (BAT), both selenium and iodine deficiency led to decreased deiodinase activity and decreased production of the uncoupling protein.^119e

 

            Treatment of goitrous children with combined seleium and iodine deficiency leads to a reduction in serum TSH and goiter size.^119f The response, however, was correlated with the selenium level with both the goiter and TSH responses being correlated with the baseline selenium level. ^119f  In an epidemeological study in China, low selenium levels were assocated with an increased ididence of goiter, sub-clinical and overt hypothryoidism and thyroiditis. ^119g

 

Physical and Emotional Stress

Perhaps the most dramatic study of emotional stress is that reported by Kracht,¹²⁰ who found that stress provoked thyrotoxicosis in wild rabbits. Although some stress models may prompt secretion of thyroid hormone in animals,^120,121 this effect is unlikely to occur in humans, at least for a sustained period of time. The stress-induced increase in adrenocortical activity tends not only to suppress TSH release but also to inhibit T3 production. A major problem in the analysis of available date is the difficulty in separating effects produced by non-specific stress from the effects caused by the agents used to induce the stress. Many of the changes in thyroid function described in this chapter under the headings starvation, temperature, altitude and anoxia may be due, in part, to stress.

 

Surgery

Surgery has been used as a means to study the effect of stress on thyroid physiology in animals.¹²²  Studies in humans have been prompted by the suspicion that thyroid hormone may mediate the postoperative metabolic changes leading to increased oxygen consumption and protein wastage. Some discrepancies in available data stem from lack of uniformity in the groups of patients studied in terms of preoperative state or disease, type of surgery, types of anesthetic agents and other drugs used, and the postoperative course, including nutrition and the period of recovery.

The most striking change in thyroid function is a decrease in the serum TT3 and FT3 concentrations shortly after surgery; rT3 concentrations are elevated in the postoperative period.^123,124  The combined findings suggest a diversion in the normal deiodinative pathways of T4. FT4 levels may also be depressed in the postoperative period, but to a lesser degree.¹²⁴  The TTR but not the TBG level is sharply reduced.¹²⁵  This clear reduction in the concentration of the active forms of thyroid hormone during the postoperative period is preceded by a small, short-term increase in FT4 and FT3 concentrations during surgery.^123,124  The magnitude of the subsequent reduction in T3 level appears to correlate with the severity of trauma and the morbidity during the postoperative course.¹²³  The serum TSH concentration also tends to diminish,¹²⁴ except during surgery performed in children under the conditions of hypothermia.²

Because surgical trauma produces a prompt elevation in plasma cortisol levels and food intake is curtailed during the pre-, intra-, and postoperative periods, the possibility that glucocorticoids and starvation are the principal contributors to the observed changes in thyroid function has been given strong consideration. However, Brandt et al.¹²⁶ showed equally profound diminution in the serum T3 concentration when surgery was carried out with epidural anesthesia, which abolishes the plasma cortisol surge. Similarly, the almost routine use of glucose infusion should have been able to prevent the changes in serum T3 and rT3 levels if starvation played a major role in producing the changes observed during surgery.

 

Acute Mental Stress

Data on the effect of emotional stress on thyroid function in humans are principally derived from studies in patients with psychiatric disturbances. Thus, even if only patients with acute psychiatric decompensation are considered, the results are colored by the nature of the mental illness, its antecedent history, and the use of drugs. An early suggestion of enhanced hormonal secretion came from the observation of elevated protein-bound iodine (PBI) levels in the serum of psychiatric patients presumably under emotional stress and in medical students in the course of examinations.¹²⁷  In more recent studies, elevations of the FT4I have been consistently found during admission of acute psychiatric patients. The incidence ranged from 7 to 18%.^128-130  In one study, an equal number of patients (9%) had a low FT4I.¹²⁸  In most instances, values became normal with time and treatment of the psychiatric illness. The TSH response to TRH is blunted or even absent in most psychiatric patients with elevated FT4I.¹³⁰ Significant abnormalities in the serum T3 concentration are rare.

 

 

CHEMICALS AND DRUGS

Goitrogens

A number of compounds have the ability to inhibit thyroid hormone synthesis (Fig.5-3). Irrespective of their mechanism of action, they are collectively called goitrogens. As a result of a decrease in serum thyroid hormone levels, TSH secretion is enhanced, causing goiter formation. Some goitrogens occur naturally in food, and others are in drugs with goitrogenic side effects. The least toxic and those possessing the highest thyroid-inhibiting activity are used in the treatment of hyperthyroidism.

 

 

Dietary Goitrogens

The discovery of natural and synthetic substances that impair the synthesis of thyroid hormone are landmarks in the history of pharmacology.¹³¹  These substances are discussed in more detail in Chapter 20. Although iodide deficiency is, without doubt, the major cause of endemic goiter and cretinism throughout the world, dietary goitrogens may play a contributing role in some endemics, and may possibly be the dominant factor in certain areas. The dietary goitrogens fall into several categories, more than one of which may occur in the same food.

Certain foods contain cyanogenic glucosides,¹³² compounds that, upon hydrolysis by glucosidase, release free cyanide. These foods include almond seeds and such important dietary items as cassava, sorghum, maize, and millet. Cassava contains enough cyanogenic glucoside to be lethal if large quantities are consumed raw. Ordinarily, the root is extensively soaked, then dried and powdered. Most of the cyanide is lost in this process; that left in the root is liberated after ingestion and converted to SCN^-. Chronic poisoning due to cassava is responsible for a tropical neuropathy in Nigeria¹³³ and Tanzania, and is suspected of being a contributing cause of goiter in Central Africa.^134,135

Other important classes of antithyroid compounds arise from hydrolysis of the thioglucosides.^132,136,137  These compounds are metabolized in the body to goitrin or thiocyanates and isothiocyanates, and ultimately to other sulfur containing compounds, or are excreted as such. They are important in the goitrogenic activity of seeds of plants of the genus Brassica and the cruciferae, compositae, and unbelliferae. Among the plants containing these compounds are cabbage, kale, brussel sprouts, cauliflower, kohlrabi, turnip, rutabaga, mustard, and horseradish. Myxedema was reported in a woman without previous thyroid disease who consumed extremely large amounts of raw bok choy. ^137b    Cattle may ingest these goitrogens and pass them to humans through milk, as observed in Australia,¹³⁸ Finland,^139,140 and England.¹⁴¹ . The isothiocynate, cheiroline, occurs in the leaves of choumoellier and may be related to a focal area of endemic goiter in Australia. The goitrogen is thought to be transmitted from forage to cows, to milk, and finally to children. Although there is considerable circumstantial evidence relating these compounds to endemic goiter, it has been difficult to prove their role with certainty.

Thiocyanate is a well-known inhibitor of iodide trapping when in high concentration in blood. The blood levels obtained by ingestion of dietary goitrogens are rarely of this degree. Inhibition of iodide trapping, and thyroid peroxidase activity, and augmentation of urinary iodide loss, as demonstrated by Delange and Ermans and co-workers, all may play a role in the goitrogenic activity.^132,134,135  Thiocyanate may also reduce the iodine content of breast milk or animal milk and thus indirectly impact the thyroid function of young children in areas of marginal iodine sufficiency.^141a A study in Thailand found an association between thiocyanate levels and TSH in pregnant women with low iodine excretion. ^141b

Astwood et al. and Greer^142,143 found that turnips contain progoitrin, which is a mustard oil thioglycoside. It undergoes rearrangement by enzymes in human enteric bacteria, or in the turnip, to be converted to goitrin, an active goitrogenic thioglycoside, L-5-vinyl-2-thio-oxazolidone.^144,145  Goitrin inhibits oxidation of iodine and its binding to thyroid protein in the same way as do the thiocarbamides.

Several endemics of goiter have been attributed to dietary goitrogens, usually acting together with iodine deficiency. Goitrin is apparently present in cow's milk in Finland.¹⁴⁶  In the Pedgregoso region of Chile, pine nuts of the tree Araucaria americana are made into a flour and consumed in large amounts, and may be related to endemic goiter.^147,148  In the Cauca river valley of Colombia, sulfur-containing compounds found in the water supply, derived from sedimentary rocks containing a large amount of organic matter, are believed to be responsible for endemic goiter.¹⁴⁹  At least, extracts from these waters are goitrogenic in rats. Pearl millet has been reported to cause goiter development in goats. ^149a

Other mechanisms may also contribute to dietary goitrogenicity. Thus, diets high in soybean components or other materials increasing fecal bulk may cause excess fecal loss of T4 and increase the need for this hormone.^150-153  These diets are low in iodine content, and soybean has been thought but not proven to contain a goitrogen.

The goitrogens, by blocking hormone synthesis, deplete the thyroid of iodide; this reduction itself increases the sensitivity of the gland to TSH.¹⁵⁴  This sensitivity, in turn, further promotes goitrogenicity.

 

Antithyroid Drugs

According to their principal mode of action on thyroidal iodine metabolism, antithyroid drugs are divided into two categories: (1) the monovalent anions, which inhibit iodide transport into the thyroid gland, and (2) a large number of compounds that act through inhibition of thyroidal iodide binding and iodotyrosine coupling. The most important representatives of this latter category of compounds are the group of thionamides. The effect of the drugs in the first category is counteracted by exposure to excess iodine, whereas iodine has no inhibition, and at times even potentiates, the action of drugs in the second category. Other drugs inhibit thyroid hormone secretion or act through yet unknown mechanism. A list of these agents is provided in Table 5-1.

 

Monovalent Anions. Certain monovalent anions (SCN^-, Cl0₄^-, NO₃^-) inhibit transport of iodide into the thyroid gland and thereby depress iodide uptake and hormone formation.^164-166  Thiocyanate stimulates efflux of iodide from the thyroid as well,¹⁶⁷ and also inhibits iodide binding and probably coupling.^168,169  A large number of complex anions, such as monofluorosulfonate, difluorophosphate, and fluoroborate,¹⁷⁰ inhibit iodide transport. Of these, fluoroborate,¹⁷¹ and perchlorate,¹⁷² are concentrated by the thyroid gland. These ions have a molecular volume and charge similar to those of iodide, and may compete with iodide for transport.^170,171  Perchlorate is sufficiently active to be useful clinically.¹⁷³  Perchlorate and thiocyanate also displace T4 from thyroid hormone-binding serum proteins in vivo and in vitro and cause a transient elevation of free T4.¹⁷⁴  In contrast to the pharmacologic effects of perchlorate, concerns have been raised about the potential health effects of environmental perchlorate exposure, especially in municipal water supplies. Several studies have been unable to detect an increase in hypothyroidism ^{174a. 174b}, congenital hypothyroidism ^174c, or thyroid cancer ^174d in exposed populations, but a study in Thailand found an association bwteen perchlorate levels and TSH in pregnant women. ^141b

 

Thionamides. The thionamide and thiourylene drugs do not prevent transport of iodide into the thyroid gland, but rather impair covalent binding of iodide to TG.^175-177  They may be competitive substrates for thyroid iodide peroxidase, preventing the peroxidation of iodide by this enzyme. In small doses, the thiocarbamides inhibit formation of iodothyronines from iodotyrosyl precursors. When slightly larger amounts are present, iodination of MIT and tyrosine is prevented.^177,178  Minute amounts (10^-8 M) have, paradoxically, a stimulatory effect on iodination in thyroid slices.¹⁷⁹

The basic structure necessary for the antithyroid action of these drugs is

 

N

|

S

|

-N=C-X-

where X may be C, N, or O^180,181 (Fig. 5-3). The thiocarbamides are metabolized in the thyroid gland by transsulfuration.¹⁸²  The enzyme responsible may also be involved in the iodide peroxidase enzyme system.¹⁸³  Glands under TSH stimulation metabolize the antithyroid drugs at an accelerated rate, as has been shown for thiourea.¹⁸⁴

Iodide is released more rapidly from a gland blocked by PTU than from one blocked by perchlorate.^165,185  This action occurs presumably because PTU prevents the utilization of all iodide available to the gland (transported from the blood or formed in the gland by deiodination of iodotyrosines), whereas potassium perchlorate prevents uptake of iodide but does not inhibit reutilization of iodide derived from within the gland. T4 disappears from the PTU-blocked rat thyroid at a faster rate than do iodotyrosines.¹⁸⁵

In addition to the effects on the thyroid gland, PTU (and, to a much lesser extent, methimazole) partially inhibits the peripheral deiodination of T4^186-191 and its hormonal action.^188,192-194  PTU acts directly on body tissues to inhibit the normal formation of T3 from T4.^191,195  Coincidentally, fecal excretion of T4 increases.¹⁸⁶  In order to inhibit goiter induced by antithyroid drugs in rats, one must maintain the T4 concentration in blood at a higher level that is normal for the species.^188,192  Presumably, inhibition of T4 monodeiodination by the antithyroid drug leads to a buildup of T4 in blood and diminishes the availability of T3 in the tissues.¹⁹¹  Higher doses of T4 or higher blood levels may be sufficient to push the reaction toward T3 and allow formation of quantities sufficient to prevent goiter.

Metabolism of the antithyroid drugs has been observed after administration of ³⁵S-labeled drugs. Methimazole is rapidly absorbed from the gastrointestinal tract in humans. It reaches a peak plasma level about an hour after administration, and then declines gradually to near zero levels at 24 hours. These drugs are accumulated and degraded in the thyroid, since they are substrates of the peroxidase.^196,197  Carbimazole is accumulated as its metabolic product, methimazole. The concentration ratio between thyroid and plasma for unmetabolized methimazole in rats may approach 25, eight hours after administration of the drug. The metabolic products derived from the drug are excreted in the urine, largely during the first day.

 

Other Goitrogenic Compounds

A number of other drugs, including the aminoheterocyclic compounds and substituted phenols, act as goitrogens principally by impairing TG iodination (Fig. 5-3). They are in general far less potent in their goitrogenic effect than the thionamides. None are used therapeutically as antithyroid drugs; rather, goitrogenesis is an undesirable side effect of their use. Some the compounds have multiple effects and thus influence thyroid physiology at various levels. These compounds are individually discussed in greater detail. A comprehensive list is provided in Table 5-1.

Table 5-1     Agents Inhibiting Thyroid Hormone Synthesis and Secretion

 

Block iodide transport into the thyroid gland
Substance	Common Use
Monovalent anions (SCN-, Cl04-, N03-)a	Not in current use; Cl04- test agent
Complex anions (monofluorosulfonate,difluorophosphate, fluoroborate)a	-------
Minerals (bromine, fluorine)	In diet
Lithiuma	Treatment of manic-depressive psychosis
Ethionamide	Antituberculosis drug
Impair TG iodination and iodotyrosine coupling
Substance	Common Use
Thionamides and thiourylenes, (PTU,methimazole, carbimazole)a	Antithyroid drugs
Sulfonamides (acetazolamide, sulfadiazine, sulfisoxazole)a	Diuretic, bacteriostatic
Sulfonylureas (carbutamide, tolbutamide, metahexamide, ?chloropropamide)a	Hypoglycemic agents
Salicylamides (p-aminosalicylic acid, p-aminobenzoic acid)a	Antituberculosis drugs
Resorcinol	Cutaneous antiseptic
Amphenone	Anticonvulsive
Aminoglutethimide	Antiadrenal agent
Thiocyanatea	No current use; in diet
Antipyrine (phenazone)a	Antiasthmatic
Aminotriazole	"Cranberry poison”
Amphenidone	Tranquilizer
2,3-Dimercaptopropanol (BAL)	Chelating agent
Ketoconozole	Antifungal agent
Inhibitors of thyroid hormone secretion
Substance	Common Use
Amiodarone a	Antianginal and antiarrhythmic agent
Iodide (in large doses)a	Antiseptic, expectorant, and others
Lithiuma	Treatment of manic-depressive psychosis
Cause Thryoiditis
Substance	Common Use
Amiodarone a	Antianginal and antiarrhythmic agent
Interleukin II a	Cancer therapy
g-Interferon a	Antiviral and cancer therapy
Sunitinib a	Cancer therapy
Sorafenib a	Cancer therapy
Ipilmumab a	Cancer therapy
Pembrolizumab a	Cancer therapy
Nivolumab  a	Cancer therapy
Mechanism unknown
Substance	Common Use
p-bromdylamine maleate a	Antihistamine
Phenylbutazone a	Antiinflammatory agent
Minerals (calcium, rubidium, cobalt)a	-------
Thalidomide396	Cancer therapy
aReferences given in the text

 

Sulfonamides. Sulfonamides, particularly those containing an aminobenzene grouping, have antithyroid activity. Acetazoleamide (Diamox), the diuretic agent, has a strong effect on animals and humans.^198,199  Its action, prevention of intrathyroidal iodide binding, is not related to carbonic anhydrase inhibition. Sulfadiazine and sulfisoxazole have a similar action, probably through a synergistic effect on iodide.⁸⁹

 

Sulfonylureas. Sulfonylureas, derivatives of sulfonamides and used as hypoglycemic-antidiabetic agents, also inhibit the synthesis of thyroid hormone. They include carbutamide, tolbutamide, methahexamide, and possibly chlorpropamide, but not the phenylethyl biguanide (Fig. 5-3). They impair thyroidal RAIU and cause goiter in the rat.^200,201  Carbutamide is much more potent than tolbutamide. Carbutamide, 2 g/day (but not 1 g/day), may reduce the thyroidal RAIU in humans to 20% of control values, but the uptake gradually rises as treatment is continued and is normal after 20 weeks. From 1 to 2 g tolbutamide per day does not affect RAIU in humans.²⁰²  Thus, in the usual dose range, tolbutamide will not depress thyroid function.

Chlorpropamide in large doses (3-7 g) depresses the RAIU in humans; the common therapeutic doses (up to 1 g daily) usually have no effect on serum T4.²⁰³  A mild antithyroid action is often reflected in a rise in RAIU, which may be found after the agents are withdrawn.

These drugs inhibit hormone synthesis by inhibition of iodide binding. In most instances, the pituitary compensates for the effect and maintains a euthyroid state by increased synthesis of TSH. Nevertheless, hypothyroidism is said to be more common in diabetic patients on sulfonylureas than in patients treated by other means.²⁰⁴

Sulfonylureas also block binding of T4 to the carrier proteins in serum and thus depress the T4 concentrations.²⁰⁵  This effect is most pronounced after intravenous administration.

 

Polychlorinated Biphenyls   Animal studies have suggested that polchlorinated bihenyls (PCBs) may reduce thyroid hormone levels by decreasing synthesis, increasing biliary excretion of conjugated metabolites and displacing T4 from binding proteins. ^205a A review of studies in humans, did not find significant or consistent changes. ^205a

  

Effects of Miscellaneous Compounds and Drugs

 

General Mechanisms of Action

A large number of substances may affect thyroid gland function and thyroid hormone metabolism and action. The list continues to grow with the introduction of new diagnostic agents, drugs, and food additives. Drugs affect the transport, metabolism, action and excretion of T4 and its derivatives as well as regulation at all levels of the hypothalamic-pituitary-thyroid axis. Some drugs may induce hypothyroidism or thyrotoxicosis, and if autoimmune mechanisms are involved, the thyroid dysfunction may not resolve with discontinuance of the drug. Some compounds may not have any direct effect on thyroid hormone economy or regulation, but have clinical relevance by interfering in specific diagnostic assays.

Compounds are discussed and listed below based on their major mechanisms of action. Many drugs have more than one mechanism of action and the explanation for observed abnormalities is not always known. Results of experiments conducted in animals or in vitro are not always applicable to human pathophysiology. Compounds which alter thyroid hormone secretion are generally goitrogens or anti-thyroid drugs and were discussed in the preceeding section. Selected compounds with significant effects on the thyroid, wide-spread use or that are of particular interest in understanding the mechanism of drug effects are described in greater detail.

 

Alterations of Thyroid Hormone Transport

Some hormones and drugs may affect thyroid hormone transport in blood by altering the concentration of the binding proteins in serum. Thyroid hormone transport may also be affected by substances that compete with the binding of thyroid hormone to its carrier proteins (Table 5-2). TBG synthesis is increased by estrogens^220-223 and decreased by androgens and anabolic steroids.^223,224 Estrogen’s effect to increase TBG is blunted or reversed by tamoxifen and raloxifene.^224a The most extensively studied compounds that interfere competitively with thyroid hormone binding to the carrier proteins in serum are salicylates, diphenylhydantoin, and heparin.^{212,225-231,231a,b} A clinically significant effect of furosemide²¹¹ may only be seen with very high doses and with accumulation with renal failure.

Table 5-2     Compounds that Affect Thyroid Hormone Transport Proteins in Serum

 

Increase TBG concentration
Substance	Common Use
Estrogensa	Ovulatory suppressants, anticancer agents, hormone replacement
Heroin and methadone206	Opiates (in addicts)
Clofibrate207	Hypolipemic agent
5-Fluorouracil208	Anticancer agent
Perphenazine209	Tranquilizer
Decrease TBG concentration
Substance	Common Use
Androgens and anabolic steroidsa	Virilizing, anticancer, and anabolic agents
Glucocorticoidsa	Antiinflammatory, immunosuppressive, and anticancer agents; decrease intracranial pressure
L-Asparaginase210	Antileukemic agent
Nicotinic acid210a ,210b	Hypolipidemic agent
Interfere with thyroid hormone binding to TBG and/or TTR
Substance	Common Use
Salicylates, 4 amino-salicylic acid and salsalatea	Antiinflammatory, analgesic, antipyretic, antituberculosis agents
Diphenylhydantoin and analogsa	Anticonvulsive and antiarrhythmic agents
Furosemide211	Diuretic
Sulfonylureasa	Hypoglycemic agents
Heparina	Anticoagulant
Dinitrophenola	Uncouples oxidative phosphorylation
Free fatty acids212,213	--------
o,p'-DDD214	Antiadrenal agent
Phenylbutazone215	Antiinflammatory agent
Halofenate216	Hypolipemic agent
Fenclofenac217	Antirheumatic agent
Orphenadrine218	Spasmolytic agent
Monovalent anions (SCN-, C104-)a	Antithyroid agents
Thyroid hormone analogs, including dextroisomers219	Cholesterol reducing agents
aReferences given in the text

 

 

 

In general, the effect of increased hormone binding is an increase in the serum concentration of total (bound) T4 and of reduced binding is a decrease in the total (bound) T4, with T3 effected to a lesser extent. There is no significant effect on the absolute concentration of the metabolically active fractions of FT4 and FT3, or usually their free indices (FT4I and FT3I). In the steady state, the quantity of thyroid hormone reaching peripheral tissues and the pathways and amount of hormone degradation remain unaltered. However, before this steady state is reached, an acute perturbation in the equilibrium between free and bound hormone brings about transient changes in thyroid hormone secretion and degradation. The hypothalamic-pituitary-thyroid axis participates in the reestablishment of the new steady state. For example, as illustrated in Figure 5-4, an abrupt increase in the concentration of TBG shifts the equilibrium between total and bound hormone, causing a decrease in the concentration of free hormone. The consequences are fourfold. First, there is a shift in the exchangeable hormone from tissues to blood. Second, a decreased hormone content in tissues diminishes its absolute degradation rate. Third, a decline in hormone concentration in tissues activates the hypothalamic-pituitary axis, causing an increase in TSH secretion. Fourth, the latter acts on the thyroid gland to step up its hormonal secretion and reestablish an appropriate thyroid hormone/TBG ratio. Thus, a normal thyroid hormone concentration in serum and tissues and hormonal production and disposal rates are reestablished. TSH concentration returns to normal, and a new steady state is maintained at the expense of an increased intravascular pool and a decreased fractional turnover rate and total distribution space of thyroid hormone.^232,233  The reverse sequence of events accompanies an acute decrease in TBG concentration or binding (Fig. 5-4).

 

Alterations of Thyroid Hormone Metabolism

Agents that may alter the extrathyroidal metabolism of thyroid hormone are listed in Table 5-3. Several drugs with wide use in clinical practice inhibit the conversion of T4 to T3 in peripheral tissues. Glucocorticoids,^239,240 amiodarone,^241,242 and propranolol^243-245 are a few examples. As expected, their most profound effect on thyroid function is a decrease in the serum concentration of T3,^239,241,243 usually with a concomitant increase in the rT3 level.^239,241  An increase in the serum T4 concentration has also been observed on occasion.^241,245  The serum TSH concentration may also occasionally rise,²⁴¹ provided the drug does not have a direct inhibitory effect on the hypothalamic-pituitary axis.²⁴⁶  In the absence of inherent abnormalities in thyroid hormone secretion or in its regulation, TSH levels should return to normal and hypothyroidism should not ensue from the chronic administration of compounds the only effect of which is to interfere partially with T4 monodeiodination.

Other mechanisms by which some compounds affect the extrathyroidal metabolism of thyroid hormone are acceleration of the overall rates of deiodinative and nondeiodinative routes of hormone disposal. Examples of drugs acting principally through the former mechanism are diphenylhydantoin and phenobarbital,^247-249 and via the latter, colestipol²³⁷, ferrous sulfate^238a, aluminum hydroxide^238b and sucralfate^238c. Patients receiving these drugs should increase the secretion of hormone from the thyroid gland in order to compensate for the enhanced hormonal loss through degradation or fecal excretion. Thyroid hormone concentration in blood should remain unaltered. However, hypothyroid patients receiving such drugs may require higher doses of exogenous hormone to maintain a eumetabolic state (Chapter 9). In patients on thyroid hormone therapy who are also taking drugs which bind thyroid hormone in the gastrointestinal tract, the administration of the two drugs at different times will markedly reduce or eliminate the effect on thyroid hormone absorption.

Acute increases in serum T4 and FT4 concentration after the injection of insulin or during halothane anesthesia have been attributed to an enhanced release of T4 normally stored in the liver.^250,251

 

Table 5-3 Agents that Alter the Extrathyroidal Metabolism of Thyroid

 

Substance	Common Use
Inhibit conversion of T4 to T3
PTUa	Antithyroid drug
Glucocorticoids (hydrocortisone, prednisone, dexamethasone)a	Antiinflammatory and immunosuppressive; Decrease intracranial pressure
Propranolola	ß-Adernergic blocker (antiarrhythmic, antihypertensive)
Iodinated contrast agents [ipodate (orgrafin), iopanoic acid (Telepaque)]a	Radiologic contrast media
Amiodaronea	Antianginal and antiarrhythmic agent
Clomipramine234	Tricylic antidepressant
Stimulators of hormone degradation or fecal excretion
Diphenylhydantoina	Anticonvulsive and antiarrhythmic agent
Carbamazepine235	Anticonvulsant
Phenobarbitala	Hypnotic, tranquilizing, and anticonvulsive agent
Cholestyramine236  and colestipol237	Hypolipemic resins
Soybeans151 152	Diet
Rifampin238a	Antituberculosis drug
Ferrous Sulfate238	Iron therapy
Aluminum hydroxide238b	Antacid
Sucralfate            238c	Anti-ulcer therapy
Imatinib 384	Cancer therapy
Bexarotene 387	Cancer therapy
Sevelemer 393	Phosphate Binder
Colesevelam 394	Hypolipemic resin
Lanthanum Carbonate 394	Phosphate Binder
Coffee 395	Diet
aReferences given in the text

 

Alterations of Thyroid Hormone Regulation

The last two decades have seen a prodigious growth in the list of substances that can be shown to act on the hypothalamic-pituitary axis (Table 5-4). Although many of these compounds are used frequently, only a few have significant effects on thyroid function via this central mechanism. Furthermore, patients receiving these drugs rarely have any abnormality of serum TSH although the response of TSH to the administration of TRH may be altered. An effect of these drugs may be seen in patients with untreated or partially treated primary hypothyroidism. In patients with an elevated basal level of serum TSH, addition of these drugs may produce a further increase or a significant diminution.

Although the following paragraphs discuss the general mechanisms of action for these compounds, specific mechanisms are not always known. A major problem in interpretation is the variability of experimental designs. These variables include doses, routes of administration, duration and time of treatment, drug combinations, age and sex of subjects, hormonal status at the time of testing, and time of blood sampling. Furthermore, observed responses may be effected by the method of data analysis. For example, results of TSH responses to TRH have been expressed in terms of changes in the absolute value, increments or decrements from the basal level, and percent of the basal value at either the peak and nadir of the response or the integrated area over the duration of the response.

The most potent suppressors of pituitary TSH secretion are thyroid hormone and its analogs. They act on the pituitary gland by blocking TSH secretion through the mechanisms discussed in Chapter 4. Some TSH-inhibiting agents listed in Table 5-4, such as, fenclofenac and salicylates, may act solely by increasing the free thyroid hormone level through interference with its binding to serum proteins.   Other agents appear to have a direct inhibitory effect on the pituitary and possibly on the hypothalamus. The most notable is dopamine and its agonists. They have been shown to suppress the basal TSH levels in euthyroid persons^284,285 and in patients with primary hypothyroidism.^267,284-286  More uniformly, they suppress the TSH response to the administration of TRH.^{268,285,287,288}  In contrast, most dopamine antagonists increase TSH secretion.^150-155  Increases in the basal TSH and in its response to TRH have been observed in euthyroid persons,^252,255 as well as in patients with primary hypothyroidism^250-256 who have been given these drugs. A notable exception to this rule, which casts some doubt on the assumed mechanism of action of dopamine antagonists, is neuroleptic dopamine blocker, pimozide, which has been reported to reduce the elevated serum TSH level in patients with primary hypothyroidism.²⁸⁹

 

Table 5-4     Agents that May Affect TSH Secretion

 

Substance	Common Use
Increase serum TSH concentration and/or its response to TRH
Iodine (iodide and iodine-containing compounds)a	Radiologic contrast media, antiseptic expectorants, antiarrhymic and antianginal agents
Lithiuma	Treatment of bipolar psychoses
Dopamine receptor lockers    (metclopramide,252,253 domperidone253 254)	Antiemetic
Dopamine-blocking agent(sulpiride255 )	Tranquilizer
Decarboxylase inhibitor        (benserazide256)	–
Dopamine-depleting agent(monoiodotyrosine253)	–
L-Dopa inhibitors(chloropromazine,257 biperidine,258 haloperidol258)	Neuroleptic drugs
Cimetidine (histamine receptor blocker)259	Treatment of peptic ulcers
Clomifene (antiestrogen)260	Induction of ovulation
Spironolactone261	Antihypertensive agent
Amphetamines262	Anticongestants and antiappetite
Decrease serum TSH concentration and/or its response to TRH
Thyroid hormones (T4 and T3)	Replacement therapy, antigoitrogenic and anticancer agents
Thyroid hormone analogs (D-T4,263 3,3',5-Triac,264 etiroxate-HCl,265 3,5-dimethyl-3-isopropyl-L-thyronine266)	Cholesterol-lowering and weight reducing agents
Dopaminergic agents (agonists)
Dopaminea	Antihypotensive agent
L-Dopaa (dopamine precursor)	Diagnostic and anti-Parkinsonian agent
2-Brom-alpha-ergocryptinea	Antilactation and pituitary tumor suppressive agent
Fusaric acid (inhibitor of dopamine ß-hydroxylase267)	–
Pyridoxine (coenzyme of dopamine synthesis268)	Vitamin and antiheuropathic agent
Other dopaminergic agents  (perbidil,269 apomorphine,269 lisuride270 )	Treatment of cerebrovascular diseases and migraine
Dopamine antagonist (pimozide)a	Neuroleptic agent
alpha-Noradrenergic blockers     (phentolamine,271 thioridazine272)	Neuroleptic agents
Serotonin antagonists metergoline,273           cyroheptadine,274 methysergide275)	Antimigraine agents and appetite stimulators
Serotonin agonist(5-hydroxytryptophan276)	–
Glucocorticoidsa	Antiinflammatory, immunosuppressive, and anticancer agents. Reduction of intracranial pressure
Acetylsalicylic acida	Antiinflammatory, antipyrexic and analgesic agent
Growth hormone277 b	Growth-promoting agent
Somatostatin278,279	–
Octreotide 279a	Treatment of carcinoids, acromegaly and other secretory tumors
Opiates (morphine,280 leucine- eukephaline,281 heroin282)	Analgesic agents
Clofibrate283	Hypolipemic agent
Fenclofenac216	Antirheumatic agent
Bexarotene a	Cancer therapy
Metformin 392	Anti-diabetic agent
Ipilmumab a (autoimmune hypophysitis)	Cancer therapy
Pembrolizumab a (autoimmune hypophysitis)	Cancer therapy
Nivolumab a (autoimmune hypophysitis)	Cancer therapy

 

^aReferences given in the text

^bIn hyposomatotrophic dwarfs

 

Iodine and some iodide-containing organic compounds cause a rapid increase in the basal and TRH-stimulated levels of serum TSH. This effect is undoubtedly due to a decrease in the serum thyroid hormone concentration either by inhibition of hormone synthesis and secretion by the thyroid gland^81,82 or by a selective decrease in the concentration of T3.²⁹⁰  The latter effect is mediated through the inhibition of T3 generation from T4. A more selective, intrapituitary inhibition of T4 to T3 conversion appears to be responsible for the TSH-stimulating effect of the radiographic contrast agent iopanoic acid⁵⁸ and amiodarone. Iodine does not stimulate TSH secretion in patients in whom it has produced hyperthyroidism. ⁹⁴  A decrease in the free thyroid hormone concentration in serum, albeit minimal in magnitude, may also be responsible for the increase in TSH levels observed during treatment with clomifene.²⁶⁰

It has been postulated that some agents may act by modifying the effect of TSH on its target tissue. For example, theophylline may potentiate the action of TSH through its inhibitory effect on phosphodiesterase, which may lead to an increase in the intracellular concentration of cAMP.²⁹¹  In fact, the presence of the pituitary is required to demonstrate that methylxanthines augment the goitrogenic effect of a low-iodine diet in the rat.²⁹²  One of the postulated effects of diethyl ether anesthesia in the rat is inhibition of the action of TSH on the thyroid gland,²⁹³ although it has also been reported to induce a transient redistribution of T4 between serum and tissues.²⁹⁴

 

Alterations of Thyroid Hormone Action

A handful of drugs seem to act by blocking some of the peripheral tissue effects of thyroid hormone. Others appear to mimic one or several manifestations of the thyroid hormone effect on tissues. Guanethidine releases catecholamines from tissues.²⁹⁵  It has a beneficial effect in thyrotoxicosis, including a decrease in BMR, pulse rate, and tremulousness.^296,297  This agent has little effect on the thyroid gland, but depresses manifestations of thyrotoxicosis that are mediated by sympathetic pathways. The sympatholytic agents phentolamine and dibenzyline have been reported both to depress and to stimulate thyroid function in animals. Their action is not clear, and it is of minimal clinical significance.^298-300  Among several α-adrenergic blocking agents tested, only phentolamine showed an inhibitory effect on the TSH response to TRH.²⁷¹

                  Theoretically, thyroid hormone effects could be blocked by drugs which interfere with the tissue uptake of thyroid hormone or binding to its receptors. Inhibition of both cellular uptake and nuclear receptor binding has been demonstrated in vitro for amiodarone in hepatocytes and cultured pituitary cells. Inhibition of cellular thyroid hormone uptake has also been reported for calcium channel blockers and benzodiazapines. Furosemide and non-steroidal anti-inflammatory drugs reduce T3 binfding to cytosolic receptors.   There is, however, no clear evidence that any of these drugs have a clinically significant effect on thyoid hormone action.

Among the multiple effects the ß-adrenergic blocker, propranolol, has on thyroid hormone economy, it appears to reduce the peripheral tissue responses to thyroid hormone (see also Chapters 3 and 11). Dinitrophenol enhances oxygen consumption by a direct effect on tissues and thus mimics one of the actions of thyroid hormone.³⁰¹

Recent interest has been directed toward compounds which may share some but not all thyroid hormone actions by either selective tissue uptake or receptor binding. The general goal is to develop agents which promote weight loss or decrease lipids without adverse effects on the skeleton, heart (tachycardia) or pituitary (TSH suppression). ^300a-300d  Diiodothyropropanoic acid (DIPTA) in short term studies was found to decrease cholesterol and lead to weight loss. ^300a However it was also found to increase bone turnover and reduce TSH, T3 and T4. ^300a

The drug eprotirome was shown to reduce total and LDL cholesterol, triglyerides and Lp(a) lipoprotein. ^300b,300c Eprotirome was not found to have adverse effects on the heart or bone and did not changed levels of TSH or T3 although mild, reversible dops in T4 levels were noted. ^300b,300c In a controlled trial, that was terminated prior to completion when adverse cartilage effects were noted in dogs, several patients did devlop transaminase elevations. ^300c

 

Specific Agents

Estrogens and selective estrogen receptor modulators (SERMs). Hyperestrogenism, either endogenous (caused by pregnancy, hydatidiform moles, or estrogen-producing tumors) or exogenous (due to the administration of estrogens), is accompanied by an increase in TBG and a decrease in TTR concentrations in serum.^220-222  Estrogens are the most common cause of TBG elevation, and this effect can be produced even after their topical application. The magnitude of TBG increase is in part dose related and occurs in women as well as in men. While tamoxifen blocks the estrogen induced increase of TBG^224a, tamoxifen alone in post-menopausal women increases TBG and T4 and 3 levels.^301a . The selective estrogen receptor modulator (SERM) raloxifene, increases TBG, produces small increase in T4 and insignificant changes in free T4. ^301b,301c In a single case report, raloxifene appeared to also alter thyroid hormone absorption. ^301d Estrogen increases the complexity of oligosaccharide side chains and, as a consequence, the number of sialic acids in the TBG molecule which in turn prolongs its survival in serum.³⁰²  The concentrations of other serum proteins, including several that bind hormones, such as cortisol-binding globulin and sex-hormone binding globulin, are also increased.³⁰³

The consequences of increased TBG concentration in serum are higher serum levels of T4, T3 and rT3 and, to a lesser extent, other metabolites of T4 deiodination. The fractional turnover rate of T4 is depressed principally due to an increase in the intravascular T4 pool. On the other hand, the FT4 and FT3 concentrations and the absolute amount of hormone degraded each day remain normal.^232,233  Transient changes in these parameters during the early changes in TBG concentration can be anticipated as described above. Some of the effects of pregnancy on thyroid function are also mediated by an estrogen-induced increase in the serum TBG concentration. The effects on thyroidal and renal iodide clearance and BMR are mediated by different mechanisms (see Chapter 3).

The effect of estrogen, if any, on the control of TSH secretion is controversial. Contradictory results suggesting a stimulatory³⁰⁴ and an inhibitory^305,306 effect have been obtained by different investigators and both stimulation and inhibition has been shown in a single study depending on the dosage utilized.^306a In a study of the effects of Tamoxifen, TSH was elevated at 3 months but not at 6 months.^306b Although women show a greater TSH responsiveness to TRH than men,^306-308 administration of pharmacologic doses of estrogens does not appear to have a significantly enhancing effect.^309,310 During ovarian hyperstimulation for ovulation induction, an increase in TSH and fT4 has been observed and this has been attributed to the marked increase in estrogen. ^310a

The effects of estrogens in the rat are not identical to those observed in humans. Estrogens do not induce changes in the concentration of serum T4-binding proteins in the rat.²²  Thus, investigations carried out in this species are not always representative in interpreting the effects of estrogens observed in humans

 

Androgens. Androgens decrease the concentration of TBG in serum and thereby reduce the level of T4 and T3.^223,311  The TTR concentration, however, is increased.²²³  As with estrogens, the concentration of free hormone remains unaffected, and the degradation rate of T4 is normal at the expense of an accelerated turnover rate.²²³  TSH levels are normal.³⁰⁵  Anabolic steroids with weaker androgenic action have the same effect, although similar changes observed during danazol therapy have been attributed to its androgen-like properties.²²⁴

 

Salicylates. Acetylsalycilic acid has been identified as the most commonly administered medication which may cause significant alterations in measured parameters of thyroid function.^224b,224c   Salicylate and its noncalorigenic congeners (Fig. 5-3) compete for thyroid hormone-binding sites on serum TTR and TBG.^225-228  As a result, the serum concentrations of T4 and T3 decline and their free fractions increase.²²⁸  The turnover rate of T4 is accelerated, but degradation rates remain normal.^225,226  Salicylate and its noncalorigenic congeners also suppress the thyroidal RAIU but do not retard iodine release from the thyroid gland.³¹²   The impaired respone to TRH³¹³ and the hypermetabolic effect³¹⁴ of salicylates have been attributed to the increase in the FT4 and FT3 fractions. If this were correct, hormonal release from the serum-binding proteins should produce only a temporary suppression of the thyroidal RAIU and transient hypermetabolism, but both effects are observed during chronic administration of salicylates.^225,226  In addition, this mechanism of action does not explain the lack of calorigenic effect of some salicylate congeners despite their ability to also displace thyroid hormone from its serum-binding proteins.

In vitro studies have demonstrated an inhibitory effect of salicylate on the outer ring monodeiodination of both T4 and rT3,³¹⁵ but lack of typical changes in serum iodothyronine levels suggests that this action is less important in vivo.

Acetylsalicylic acid mimics some actions of thyroid hormone, but does not reverse classic manifestations of hypothyroidism.   While salicylate administration may lower serum cholesterol levels,³¹⁶ it does not provide a therapeutic effect in myxedema, or lower TSH levels.³¹⁷ Administration of 8 g aspirin daily raises the BMR to normal in myxedema, accelerates the circulation, and increases sweating, but it has no effect on the skin change, the electrocardiogram, or the mental state.³¹⁶

Because of some analogies between the effects of salicylates and nitrophenol, uncoupling of oxidative phosphorylation has been suggested as one of its possible mechanisms of action. If this were the case, direct chemical action does not appear to be involved since analogs of salicylate that do not uncouple oxidative phosphorylation in vitro are active in vivo.³¹⁸

 

p-Aminosalicylic acid and p-aminobenzoic acid are closely related chemically to salicylate. They inhibit iodide binding in the thyroid gland and are goitrogenic.^319,320  These agents also displace thyroid hormone from its serum protein-binding sites.³²¹  Abnormalities of thyroid function tests have been also reported in patients treated with salsalate.³²²

 

Heparin. Patients receiving heparin chronically may have increased FT4 and FT3.^230,231 Reciprocal changes in serum TSH have been reported.²³¹  While it had been suggested that heparin might interact with the T4-binding proteins to alter the steric configuration of the binding sites and reduce the affinity of the proteins for T4 and T3²¹⁰, it is now thought that heparin acts via the activation of lipoprotein lipase to increase free fatty acid levels which may displace T4 from binding proteins. This effect is most likely to be significant when the levels of albumin are low and triglycerides are high such as during hyperalimentation with lipid solutions. Even low doses of heparin may be sufficient to cause artifactual, in vitro, increase in T4 especially when measured by equilibrium dialysis.^231a Although initially reported with crude heparin preparations, this heparin effect has also been noted with enoxaparin. ^231b

 

Glucocorticoids. Physiologic amounts, as well as pharmacologic doses of glucocorticoids influence thyroid function. Their effects are variable and multiple, depending on the dose and on the endocrine status of the individual. The type of glucocorticoid and the route of administration may also influence the magnitude of the effect.³²³  Known effects include (1) decrease in the serum concentration of TBG and increase in that of TTR;^324,325  (2) inhibition of the outer ring deiodination of T4 and probably rT3;^239,240  (3) suppression of TSH secretion;^246,326,327  (4) a possible disease in hepatic binding of T4; and (5) increase in renal clearance of iodide.^328,329

The decrease in the serum concentration of TBG caused by the administration of pharmacologic doses of glucocorticoids results in a decrease in the serum total T4 concentration and an increase in its free fraction and the resin uptake test result. The absolute concentration of FT4 and FT4I remain normal. The more profound decrease in the concentration of serum T3 compared to T4 associated with the administration of pharmacologic doses of glucocorticoids cannot be solely ascribed to their effect on serum TBG. It is due to the decreased conversion of T4 to T3 in peripheral tissues. Thus, glucocorticoids reduce the serum T3/T4 ratio and increase that of rT3/T4 in hypothyroid patients receiving replacement doses of thyroid hormone.²³⁹  This steroid effect is rapid and may be seen within 24 hours.^239,240 In rats, dexamethasone has been shown to decrease T4 to T3 conversion in liver homogenates. ^329a

Earlier observations of cortisone-induced depression of uptake and clearance of iodide by the thyroid^328,329 now are understood to be the result of steroid suppression of TSH secretion. Pharmacologic doses of glucocorticoids suppress the basal TSH level in euthyroid subjects and in patients with primary hypothyroidism, and decrease their TSH response to TRH.^{246,326,327,329b}  The latter effect is less marked in the presence of hypothyroidism.³²⁷  Administration of as little as 34 mg. of hydrocortisone over 24 hours can be shown to reduce the pulse amplitude and mean TSH release the nocturnal rise of TSH and the T3 and TSH response to TRH.^329b  Administration of the glucocorticoid antagonist, mifepristone, produces an increase in TSH that remains within the normal range accompanied by a transient decrease in total but not free T4.^329c Normal adrenocortical secretion appears to have a suppressive influence on pituitary TSH secretion because patients with primary adrenal insufficiency have a significant elevation of TSH.³³⁰ In cultures from rat pituitary tumors, hydrocortisone increased the number of TRH receptors ³³¹ Dexamethasone has also been shown to increase the transcription, translation and processing of TRH precursors. ^331a,b   The mechanism of glucocorticoid action on the hypothalamic-pituitary axis is covered in Chapter 4.

No single change in thyroid function can be ascribed to a specific mode of action of glucocorticoids. For example, a diminished thyroidal RAIU may be due to the combined effects of TSH suppression and increased renal clearance of iodide. Similarly, a low serum TT4 level is the result of suppressed thyroidal secretion due to diminished TSH stimulation as well as the decreased serum level of TBG. One of the common problems in clinical practice is to separate the effect of glucocorticoid action on pituitary function from that of other agents and those caused by acute and chronic illness. This situation arises often since steroids are commonly used in a variety of autoimmune and allergic disorders as well as in the treatment of septic shock. The diagnosis of coexisting true hypothyroidism is difficult, if not impossible. Due to the suppressive effects of glucocorticoids on the hypothalamic-pituitary axis, the low levels of serum T4 and T3 may not be accompanied by an increase in the serum TSH concentration, which would otherwise be diagnostic of primary hypothyroidism. In such circumstances, a depressed rather than an elevated serum rT3 level may be helpful in the detection of coexistent primary thyroid failure.

Pharmacologic doses of glucocorticoids induce a prompt decline in serum T4 and T3 concentrations in thyrotoxic patients with Graves' disease.²³⁹  Amelioration of the symptoms and signs in such patients may also be accompanied by a decrease in the elevated thyroidal RAIU and a diminution of the TSH receptor antibody titer.^325,332  This effect of glucocorticoids may be due in part to its immunosuppressive action since it has been shown that administration of dexamethasone to hypothyroid patients with Hashimoto's thyroiditis causes an increase in the serum concentration of both T4 and T3.³³³

 

 

Iodinated contrast It is estimated that in the US in the past year more than 80 million CT scans were performed and more than half of those utilized iodinated contrast.  Whether low or high ionic strength, low or high osmolality, all of these agents contain large amount of iodine ranging from 320 – 370 mg/ml.   In a prospective study, 2.6% of adults receiving contrast developed hyperthyroidism although many of theses cases were transient. ^333a   In a study of hospitalized elderly patients with hyperthyroidism, 23% of them had a contrast CT performed in the preceeding months. ^333b  When Alexander et al examined a data base of 4,500,000 patients, they found that the likelihood of developing hyperthyroidism within two years of being euthyroid was doubled by having a recent contrast CT. ^333c    In a small study, pretreatment with thionamides reduced the incidence and severity of hyperthyroidism but did not always prevent it. ^333d  Since many episodes of hyperthyroidism after iodinated contrast are transient, mild and asymptomatic, this approach may only be appropriate for patients who had more severe episodes.   Other options include avoidance of iodinated contrast and definitive treatment of any underlying thyroid disorder after the patient has recovered.   In a study of newly diagnosed hypothyroidism in children, the risk was increased nearly three fold by recent administration of iodinated contrast, ^333e  while in adults, Kornelius et al found the risk was doubled. ^333f

 

Ipodate and Iopanoic acid The principal effect of these iodine-containing radiologic contrast media is inhibition of T4 to T3 conversion by inhibiting both Type I and Type II 5’-deiodinase. In fact, they may be the most potent of all agents known to interfere with this step of iodothyronine metabolism. A triiodo-and a monoamino-benzene ring with a proprionic acid chain appear to be required because iodinated contrast agents without this chemical structure have little or no effect.³³⁴  Several of these agents, namely, ipodate (Oragrafin) and iopanoic acid (Telepaque), are used for oral cholecystography.

A decrease in the rate of deiodination of the outer ring of thyronines causes a profound decrease in the serum T3 concentration and an increase in the rT3 and T4 levels.^334,335  The serum T4 concentration may reach values well within the thyrotoxic range.³³⁴  These changes are accompanied by an increase in serum TSH secretion.²⁹⁰  The latter is particularly notable, if not characteristic of these agents, probably because of their potent inhibitory effect on T3 generation in pituitary tissue.⁵⁸  These agents have been used to study the regulation of thyroid hormone action via the process of iodothyronine deiodination.^58,336  Changes persist for at least two to four weeks after their administration.³³⁴

Ipodate and iopanoic acid also decrease the hepatic uptake of T4³³⁷ and inhibit T3 binding to its nuclear receptors.³³⁸  These effects reduce both symptoms and thyroid hormone levels even when thyrotoxicosis occurs in settings where ongoing synthesis would be minimal such as thyrotoxicosis secondary to thyroid hormone ingestion^338a , or sub-clinical hypothyroidism. ^338b The antithyroidal effect of the iodine present in these agents is believed to be responsible for the falling T4 level and some of the amelioration of the symptoms and signs of thyrotoxicosis when they are administered to patients with Graves' disease^{338,338c,338d} ,

 

Amiodarone. Most changes in thyroid function observed during the administration of this drug are similar to those seen with iodine-containing contrast agents. They include a marked decrease in serum T3, an increase in rT3, and a more modest elevation in the T4 concentration.^241,339  Basal and TRH-stimulated TSH levels are increased. The principal mechanism of action is believed to be inhibition of both Type I and Type II 5’-deiodinase resulting in a marked reduction of T3 generation from T4. Amiodarone may reduce the entry of thyroid hormone into tissues^339a, may reduce the binding of thyroid hormones to the receptor^339b and may antagonize the effects of thyroid hormone at the cellular level.^339c,339d The drug is used as an antianginal and antiarrhythmic agent and the bradycardia that almost invariably occurs when the drug is used in high doses, may suggest the presence of hypothyroidism.³⁴⁰

Amiodarone contains 37% iodine by weight. The major effects on thyroid function appear to be the result of its structural resemblance to thyroid hormone rather than its iodine content. In contrast to the typical alterations of thyroid hormone function, the more uncommon occurrence of frank hypothyroidism or thyrotoxicosis are products of the excess iodine released from the drug. The overall incidence of amiodarone induced thyroid disease is higher in areas of mild iodine deficiency³⁴⁰  as is the relative incidence of the thyrotoxic as compared to the hypothyroid form. ³⁴⁰ The iodine dependence of both of these diseases is confirmed by the improvement of both with the use of perchlorate to discharge iodine from the thyroid gland. ^{340a, 340b}

Amoidarone induced thyrotoxicosis has been identified as having two main types; type 1 usually coccuring with underlying thyroid abnormalities and type 2 in normal glands with small goiters. ^{340a, 340b}   Type 1 is more common in area of iodine deficiency. Early onset of thyrotoxicosisis is more typical for Type 1 and later onset with Type 2, but either form may present after amiodarone was discontinued. ^{340c, 340d} Type 1 is associated with increased blood flow while hypervasculaity is absent in Type 2. Radioacitve iodine uptake may be low-normal or normal in Type 1 (especially in areas with iodine deficiency) and is low in Type 2. Type 1 is treated with thionamides but patients may be realtively resistant while patients with Type 2 respond to glucocorticoids. Some patient will present with a mixed form. Surgery may be used in cases refractory to medical therapy. ^340e

Measurement of serum TSH, remains the most useful test in the differential diagnosis of hypothyroidism or thyrotoxicosis in amiodarone treated patients but the mild TSH elevation seen in euthyroid patients may make the diagnosis of mild to moderate hypothyroidism more difficult. If hypothyroidism is suspected, it is appropriate to obtain a measurement of the serum rT3 concentration. The absence of an elevated serum rT3 level in a patient receiving amiodarone suggests the patient is hypothyroid.

 

Diphenylhydantoin (Dilantin). Diphenylhydantoin (DPH) (Fig. 5-3) competes with thyroid hormone binding to TBG.^228,229  This effect of DPH and diazepam, a related compound, has been exploited to study the conformational requirements for the interaction of thyroid hormone with its serum carrier protein^229,341  It appears that the angle formed between the two phenyls and the hydantoin group of DPH is nearly identical to that formed between the two phenyls linked by an ether bond in T4.²²⁹  Although the affinity of DPH for TBG is far below that of T4, when used in therapeutic doses the serum concentration achieved is high enough to cause a significant occupancy of the hormone-binding sites on TBG. This effect of DPH is only partly responsible for the decrease in the total concentration of T4 and T3 in serum.

DPH accelerates the conjugation and clearance of T4 and T3 by the liver and probably enhances the conversion of T4 to T3.^247,342  The net result is a decrease in the serum concentration of T4 and rT3 and, less consistently, that of T3^{343,344,344a,344b} because the enhanced degradation of T3 is compensated for by an increase in its generation from T4. Yet, basal TSH- and TRH-stimulated values remain within the normal range^{343,344,344a,344b} or slightly elevated.^235,345  Calculated indices of FT4 are usually reduced, but the FT4 measured by dialysis is normal.^247,343

Both DPH and diazepam are commonly used in clinical practice, the former most commonly as an anticonvulsant and the latter as an anxiolytic. Reduced serum levels of thyroid hormone in patients having therapeutic blood levels of DPH should not be viewed as indicative of thyroid dysfunction unless the TSH level is elevated. Treatment with T4 in such patients with a low T4 and normal TSH did not alter parameters of cardiac function or symptoms which might have been considered indicative of hypothyroidism.^344b    DPH therapy may increase the required dose of thyroid hormone replacement in athyreotic individuals.³⁴⁶ .

 

Phenobarbital. Chronic administration of phenobarbital to animals induces increased binding of thyroid hormone to liver microsomes and increased deiodinating activity.^{248,249,347,347a}  Phenobarbital administration reduces the biologic effectiveness of the hormone by diverting it to microsomal degradative pathways. In humans, phenobarbital augments fecal T4 clearance by nearly 100%,³⁴⁸ but serum T4 and FT4 levels remain near no rmal because of compensatory increases in T4 secretion. It is not apparent that barbiturates have an important effect on thyroid mediated metabolic action in normal humans, but it may potentate the effects of dilantin or carbamazapine. ^348a  The augmented hepatic removal of T4 induced by phenobarbital lower the absolute T3 disposal by nearly 25%, increase T4 clearance, and lower T4 and FT4I in patients with Graves' disease but does not produce a clinical response.³⁴⁸

 

Propranolol. Propranolol, a ß-adrenergic blocker, is commonly used as an adjunct in the treatment of thyrotoxicosis Propranolol is usually used in the treatment of cardiac arrhythmias, angina and hypertension. Information regarding its effects on thyroid hormone action, and application in the symptomatic treatment of thyrotoxicosis is found in Chapters 3 and 11, respectively.

Propranolol does not affect the secretion or overall turnover rate of T4, nor TSH release or its regulatory mechanisms.^349,350  A small to moderate lowering effect on serum T3 has been reported in euthyroid subjects as well as in patients with hyperthyroidism or with myxedema under L-T4 replacement therapy.^{243,245,351,352}  Reciprocal increases in serum rT3 and 3',5'-T2 levels have also been reported.³⁵²  Such data, combined with the finding by some investigators of minimal increases in serum T4²⁴⁵ levels, suggest a mild blocking effect of this drug on the 5'-deiodination of iodothyronines. This effect does not appear to be related to the ß-adrenergic-blocking action of propranolol, since other ß-blocking agents do not share the deiodinase-blocking property and yet are effective in treating symptomatic thyrotoxicosis.^353,354 The beneficial effects include the reduction of tachycardia, anxiety, and tremor ^355-357 although the metabolic effects of thyrotoxicosis remain unaffected.

 

Reserpine. Reserpine formerly had wide use as an antihypertensive agent but has been replaced by more effective agents. Reserpine alters the manifestations of thyrotoxicosis by reducing anxiety, tachycardia, and tremulousness.³⁵⁸  This effect may arise from depression of autonomic centers or possibly from depletion of catecholamines in the peripheral tissues.³⁵⁹  Reserpine may depress the formation of iodotyrosines in thyroid tissue in vitro, but this action does not seem to be important clinically. Reserpine does not alter the results of thyroid function tests other than the BMR.³⁵⁸

 

Nitrophenols. 2,4-Dinitrophenol (Fig. 5-3) elevates the BMR, lowers the serum concentration of T4, accelerates the peripheral metabolism of T4, and depresses the thyroidal RAIU and secretion.^275,360,361  The action is probably complex. The drug stimulates the metabolism by uncoupling oxidative phosphorylation in mitochondria.³⁶²  T4 in vitro also uncouples oxidative phosphorylation. Part of the effect of dinitrophenol may be to mimic the action of thyroid hormone on hypothalamic or pituitary receptor control centers; this effect would account for the diminished thyroid activity. Dinitrophenol also displaces thyroid hormone from T4-binding serum proteins.²²⁷  This action could lower the total hormone concentration in serum but should have no persistent effect on thyroid function. Dinitrophenol increases biliary and fecal excretion of T4, and this action largely accounts for the rapid removal of hormone from the circulation.³⁶³  Deiodination of T4 is also increased.³⁶⁴  Both of these effects may be related to displacement of hormone from TTR or to changes in metabolism of hormone in the liver.

2,4-Dinitrophenol does not share some of the most important properties of T4. It cannot initiate metamorphosis of tadpoles³⁶⁵ or provide a substitute for hormonal therapy in myxedema.

 

Dopaminergic Agents. It is generally accepted that endogenous brain dopamine plays a physiologic role in regulating TSH secretion via an effect on the hypothalamic-hypophyseal axis.^252,366,367  Dopamine exerts a suppressive effect on TSH secretion and can be regarded as antagonistic to the stimulatory action of TRH at the pituitary level.^284,287,367  Much of the information regarding the role of dopamine on the control of TSH secretion in humans has been derived from observations made during the administration of agents with dopamine-agonistic and -antagonistic activity (see Table 5-4 and Chapter 4).

Dopamine infusion is commonly used in the care of acutely ill hypotensive patients. It lowers the basal serum TSH level in both euthyroid and hypothyroid patients and blunts its response to the administration of TRH.^{252,284,287,368,368a}

L-dopa, the precursor of dopamine, used in the treatment of Parkinson's disease and as a test agent in the diagnosis of pituitary diseases, also suppresses the basal and the TRH-stimulated serum TSH level in euthyroid subjects as well as in patients with primary hypothyroidism^285,288,368b (Fig. 5-5). Metoclopropamide, a dopamine antagonist used as a diagnostic agent and in the treatment of motility disorders, increased TSH secretion. ^368c

A similar effect has been observed during the administration of 2-brom-ergocryptine (bromocryptine), a dopamine agonist used in the treatment of some pituitary tumors and to suppress lactation during the puerperal period. Although the agent has been shown definitely to diminish the high serum TSH levels in patients with primary hypothyroidism,²⁸⁶ a significant inhibitory effect on TRH-induced TSH secretion has not been clearly demonstrated,^369,370

The exact mechanism whereby dopaminergic drugs inhibit pituitary TSH secretion remains unknown, although a direct interaction with pituitary receptors has been suggested.³⁷¹  While some authors have cautioned that prolonged infusion of dopamine may induce secondary hypothyroidism and worsen the prognosis of severely ill patients,³⁷² there is no evidence that chronic treatment with dopaminergic drugs induces hypothyroidism in less critically ill patients.²⁸⁸ These drugs have been used with variable success in the treatment of some rare pituitary-induced thyrotoxicoses.^373,374  When measurements of the basal or stimulated serum TSH levels are used in the differential diagnosis of primary and secondary hypothyroidism, the concomitant use of drugs with dopamine-agonistic or -antagonistic activity should be taken into account in the interpretation of results.

 

Alterations of Immunity

A number of drugs including interferon and lithium affected thyroid function either in part or completely by inducing thyroid immunity.  In the past few years a number of agents have been developed to treat cancer and multiple sclerosis by altering immune regulation.  Unintended side effects or these drugs has been the development of hyperthyroidism from Graves’ disease or thyroiditis and hypothyroidism as a consequence of autoimmune hypophyisitis or chronic thyroiditis.

 

 

Interferon and Interleukin These cytokines have been associated with the development of both hypothyroidism and thyrotoxicosis. ^375-379 The overall rate of thyroid dysfunction induced by these agents is about 6%.^379a They are used in the treatment of infectious diseases such as hepatitis, as well as malignancies including melanoma and renal cell carcinoma .   Acute administration has been used as a model of illness as the effects are similar; interferon-a leads to a decrease in T3 an increase in rT3 and a fall In TSH. ³⁸⁰ In a group of euthyroid HIV infected patients, however, short term administration of interleukin-2 was observed to lead to an increase in TSH, T3, T4 and free T4. ³⁸¹

Cytokine induced thyroid disease appears to be immune mediated. The incidence is much greater in females and in patients with positive anti-peroxidase and anti-TPO antibodies prior to the initiation of therapy. ^375-377 During therapy, patients who were antibody positive may have a rise in titer, while antibody positivity may develop in previously negative patients.³⁷⁵ In patients treated for hepatitis with interferon, the incidence of thyroid disease is much higher in those with Hepatitis C than those with Hepatitis B.³⁷⁵ The thyrotoxicosis often occurs as a manifestation of a destructive thyroiditis.^376-377 In many patients, the thyroid disease resolves within several months after stopping the cytokine therapy. ^375,377

 

Anti CD 52 Antibody  Alemtuzumab This monoclonal antibody reacts against CD52, a glycoprotein that is expressed on B cells and CD4+ T cells.  It is approved by the FDA for the treatment of multiple sclerosis.  It is initially dosed daily for five days and then a second course is given for three days, one year later.

Thyroid disease has been noted to occur in a third of treated patients with some cases seen within weeks of initiating treatment and most cases seen within the first three years but cases have been seen up to seven years after starting treatment. ^{376a,376b,377a}

The most frequently observed disorder has been Graves’ disease which affects almost a quarter of all treated patients. ^{376a,376b,377a} Most affect patients develop antibodies.  Most cases are overt and some patients have experienced significant ophthalmopathy.  While as many as 35% of these patients have been reported to have spontaneous resolution, most have been treated medically. Hypothyroidism develops in 5-7% of patients.  Most of these patients develop anti-thyroid antibodies and the deficits are usually permanent.  Less than 5 % of patients will develop typical painless thyroiditis with transient hyperthyroidism sometimes followed by hypothyroidism.  ^{376a,376b,377a}

 

 

Check Point Inhibitors

 

These agents target systems that normally act to limit activation of the immune system but are utilized by cancer cells to block immune mediated destruction.  Use of these agents allows the activated immune cells to kill tumor cells. . ^{377b- 377d}   The same mechanism of action, however, leads to activation of immune mediated damage to other cells including skin, liver and thyroid cells. . ^{377b- 377d}

 

Antibody against CTLA-4 ipilimumab Co-stimulation via HLA and B7 expressed on antigen presenting cells (and tumor cells) interacting respectively with T cell receptors and CD 28 expressed on T-cells leads to T-cell activation.  Activated T-cells then express CTLA-4 that competes with CD 28 for B7 binding and thus reduces T cell activation.   The monoclonal antibody, ipilmumab, specifically binds to CTLA-4 markedly enhancing T cell activation. ^{377b- 377d} This promotes immune-mediated destruction of tumor cells.     This agent was approved by the FDA for the treatment of melanoma in 2011.  Usual dosing is every three weeks for four doses. The drug also remains under investigation for treating other tumors.

The most common associated autoimmune disorder affecting the thyroid has been the development of hypophyisitis. ^{377b- 377f}   Prior to the introduction of this agent, autoimmune hypophyisitis was typically seen in women in late pregnancy or post-partum, while hypophysitis secondary to ipilimumab has been seen almost solely in men.   Onset has been within weeks of initiating therapy until almost two years later. ^{377b- 377f}     Most patients present with systemic symptoms while some present with headaches or visual symptoms.  MRI abnormalities are common and include pituitary enlargement and stalk thickening.  Similar to post-partum hypophyisitis, the pituitary-adrenal axis is most commonly affected, but most deficits are permanent.  ^{377b- 377f}

Hypothyroidism occurs in 4-6% of treated patients from 2 months to 3 years after starting treatment.  Fatigue is the most common presenting symptom.  The hypothyroidism is usually permanent.  Some 1-3 % of treated patients will develop typical painless, thyroiditis with transient hyperthyroidism. Onset is usually two to four months after starting treatment. ^{377b- 377f}  Hyperthyroidism is sometimes followed by hypothyroidism.  The package insert advises checking thyroid function prior to starting therapy, before each dose and as “clinically indicated’” but does not recommend checking cortisol or ACTH.

 

Antibodies Against Programmed Death Receptor Ligand (PDL-1)  Pembrolizumab and Nivolumab Recognition of tumor cells via MHC/T cell receptor interaction leads to T cell activation and interferon production which stimulates tumor cell production of the PD-1 ligand.  This then binds with the PD-1 receptor on the T cell and inhibits activation.   Dendritic cells also express this ligand to inhibit T-cell activation. Pembrolizumab and Nivolumab are monoclonal antibodies directed against the PD1 ligand that act to increase T-cell activity and thus promote immune-mediated destruction of tumor cells. ^{377d, 377g}       These drugs were approved by the FDA in 2014 for the treatment of melanoma.   Pembrolizumab  is administered intravenously every 3 weeks.  Nivolumab is administered intravenously every 2 weeks.  These drugs also remains under investigation for treating other tumors.

Both agents may lead to the development of immune mediated hypothyroidism, thyroiditis and hypophysitis with hypothyroidism being the most common problem. ^377g-377i   Hypothyroidism may occur within weeks of starting therapy or may not occur until after a year.   It is usually permanent. ^377g-377i   In contrast, reported cases of hyperthyroidism from thyroiditis have occurred from 2 weeks to 5 months after initiating therapy and always resolves. ^377g-377i

For pembrolizumab the occurrence of these complications has been reported as 8% for hypothyroidism, 2-3% for thyroiditis and 0.5% for hypophyisitis.   For nivolumab the rate of occurrence of these complications have been reported as 4-8% for hypothyroidism and 1-3% for thyroiditis.  For both drugs, it is recommended to check thyroid function tests prior to starting therapy and periodically afterwards.

Tyrosine Kinase Inhibitors Sunitinib maleate an oral tyrosine kinase inhibitor used in the treatment of renal cell carcinoma and gastrointestinal stromal tumors has also been associated with the development of hypothyroidism.^381a In two studies, an elevated TSH has been seen in over 50% of patients treated with sunitinib. ^382.383  In a prospective study, this was persistent in 36% and transient in 17%. ³⁸²  The mechanism remains unknown. ^382a Antiperoxidase activity was demonstrated in vitro³⁸², but other mechanisms include induction of destructive thyroiditis, ³⁸³  reduction of vascularity ot the gland, ^383b and enhanced apoptosis. ^383c

 

The thyroid effects are seen with other TK inhibitors as well although the frequency and severity of the effect may vary. Hypothyroidism has also been seen with Sorafenib, but the rate is about 1/3 of that seen with sunitinib.^383d,383e In a few patients, transient thryotoxicosis has preceeded the hypothyroidism consistent with a destructive thyroiditis. ^383d There is also evidence for enhanced thyroid hormone metabolism attributed to increased Type 3 deiodination. ^383f   This would also explain the need for increased thyroid hormone doses in athyreotic thyroid cancer patients.

 

Imatinib mesylate is a selective tryrosine kinase inhibitor used in the treatment of chronic mylogenous leukemia (CML) and other malignancies. Thyroidectomized patients being treated with imatinib were noted to have a rise in TSH and a fall in serum T4 levels which responded to an increase in the T4 dose, suggesting enhanced metabolism of thyroid hormone ³⁸⁴ but changes have also been seen in euthyroid patients. ^384a In most, cases, these changes were transient (74%) but have persisted in others. ^384a   Even higher rates of thyroid dysfunction have been seen with the newer agents nilotinib (55%) and dasatinib (75%). ^384a   As with the other TK inhibitors some patients have had thyrotoxicosis and some have developed antithyroid antibodies. ^384a

 

Retinoids Bexarotene is a retinoid which is specific for the retinoid X- receptor and is used for the treatment of lymphomas and other malignancies. Therapy has been reported to produce central hypothyroidism ^{376a,376b,385}, and a single dose, leads to a decrease in T3, T4 and TSH. ³⁸⁶  In addition to suppression of TSH synthesis and secretion, bexarotene also increases the peripheral metabolism of thyroid hormone by a nondeiodinase mediated pathway. ³⁸⁷

 

TSH Receptor Agonists and Antagonists A number of small molecules that interact with the TSH receptor were identified and characterized to select compounds which could behave as TSH receptor agonists or antagonists. ³⁸⁷ These were then further modified to increase their activity. Of note, these molecules do not bind to the TSH ligand binding region but rather to the serpentine trans-membrane region of the receptor. These compounds have multiple potential uses including use as imaging agents for thyroid cancer and Graves’ ophthalmopathy and as therapeutic agents for patients with Graves’ or thyroid cancer.

 

A TSH receptor agonist has been developed that when added to primary cultures of human thyrocytes increased messenger RNA expression for thyroglobulin, the sodium-iodide symporter, thyroid peroxidase (TPO), and deiodinase 2 similar to TSH. ³⁸⁸ When administered orally to mice, this compound increased radioactive iodine uptake in the thyroid and serum T4. ³⁸⁸ As an oral agent, this compound could potentially be used for imaging and treatment of thyroid cancer rather than parenteral rTSH or thyroid hormone withdrawal.

 

A TSH receptor antagonist has also been developed that has activity both in cells overexpressing the human TSH receptor and in primary cultures of human thyrocytes. ³⁸⁹ The compound reduces both basal and TSH stimulated cAMP production. Recently it was demonstrated in cultured human thyrocytes to reduce basal TPO mRNA expression and to antagonize the effect of sera from Graves’ patients to induce TPO mRNA expression. ³⁸⁹ As an oral agent, this compound could potentially be used for imaging, to treat Graves’ patients or to suppress thyroid cancer without requiring use of supraphysiologic T4 doses.

 

 

Thyronamines Thyronamines are small molecules identical to thyroxine, triiodothyronine and all of the deiodinated thyroid hormone metabolites except that they lack a carboxyl moiety at the amino terminus (ethylamine rather than alanine group). ³⁹⁰ Each compound is identified similar to the corresponding thyroid hormone or metabolite as T_X(AM) where X is the number of iodine molecules and ranges from zero, T₀(AM), to four, T₄(AM).   Two of these compounds, [3-T₁(AM) and T₀(AM)], have been identified by liquid chromatography-tandem mass spectrometry as naturally present in small amounts in tissues and sera from hamsters, mice and rats. ³⁹⁰ They have been detected in both cardiac and brain tissue. ³⁹⁰    No published report has confirmed the presence of any of these compounds in humans. It has been speculated that some of these compounds could be directly produced by the decarboxylation of T4 or T3, but this has never been demonstrated. These compounds can be deiodinated, in vitro, by Deiodinases 1, 2 and 3. ³⁹⁰

 

These compounds can bind to a number of receptors and 3-T₁(AM) binds strongly to APO B 100 in serum. Despite the structural similarities to thyroid hormones, the thyronamines do not bind to nuclear thyroid hormone receptors and they do not alter T3 binding to these receptors. ³⁹⁰  Several thyronamines bind to the beta-adrenergic receptor, but any effects on cAMP signaling remain unclear. ³⁹⁰  There is conflicting evidence regarding the ability of these compounds to signal via the trace amine associated receptor 1 (TAAR-1) or via the Alpha_2A adrenergic receptor. ³⁹⁰ There is also conflicting evidence about the ability of these compounds to alter intracellular signaling via the cAMP or tyrosine phosphorylation or dephosphorylation pathways. ³⁹⁰

 

There are no known physiologic actions of any of these compounds.   In animals, several of these compounds have been found to have pharmacologic activity both in vitro and after intraperitoneal or intraventicular injection. These observations include a reduction in cardiac contractility and rate, a reduction in the metabolic rate, a reduction in fat mass and the development of hypothermia, ketonuria and hyperglycemia. ³⁹⁰ Many of these activities are noted within minutes after injection and resolve after a few hours but the development of ketonuria and the reduction of fat mass occur later and persist longer. ³⁹⁰  Potential therapeutic uses of these compounds are being evaluated in animal models. The ability of these compounds to induce hypothermia, has been shown to decrease infarct size when they were administered 2 days before or 1 hour after the induction of a stroke in an animal model. ³⁹⁰

 

Metformin Metformin is a biguanide used in the treatment of diabetes mellitus as well as insulin resistance and polycystic ovary syndrome. In four patients with hypothyroidism on stable thyroxine therapy, TSH levels became markedly reduced with either no change in serum thyroid hormone levels or despite a reduction in the T4 dose and serum thyroid hormone levels suggesting a direct suppression of TSH release. ³⁸⁸ Subsequent studies have reported mixed effects, but a meta-analysis conluded that TSH alterations are seen in both overt and sub-clinical hypothryoidism but not in euthyroid patients suggesting an effect to suppress TSH that is not seen when the thyroid gland is able to respond to any change in TSH. ^388b  

 

Biotin Biotin is a B vitamin that acts as a cofactor for carboxylase enzymes involved in gluconeogenesis and fatty acid synthesis.  It is produced by gut bacrteria and normal daily intake is 35-350 mcg daily.  It is used in the treatment of biotinidase deficiency and proprionic acidemia and as a supplement for TPN.  It is frequently used by individuals in doses of 5,000 to 10,000 mcg daily as a supplement to improve hair and nail growth and to treat hair and nail disorders

 

Many laboratory platforms for the measurement of fT4, fT3 TSH and thyroglobulin depend on the strong binding of biotin and strep avidin.  If patients ingest biotin in doses of 5,000 to 10,000 mcg prior to blood being drawn for these analytes, measurements of fT4 and fT3 will be falsely high and thyroglobulin and TSH will be falsely low as biotin interferes in the assays. . ^397,398  The combination of a high fT4 and low TSH mimics hyperthyroidism. ^397-400   These effects correspond to the blood level of biotin with a peak effect seen several hours after ingestion and potentially even lasting until the next day.  ^398,400   Variable times between ingestion and blood measurements can results in confusing variations in these measurement not corresponding to patents clinical status.  Confirmation of this effect can be made by measuring several hours after ingestion and after abstaining for 48 hours or by re-measuring in an assay not utilizing biotin. ^397-400    This effect is not limited to thyroid hormone measurements but have also been reported for PTH, DHEA-sulfate, estradiol and ferritin. ³⁹⁸

 

 

SUMMARY

This chapter considers the effects of various environmental factors, drugs and chemicals, and nonthyroidal diseases on thyroid function.

In animals, cold exposure causes a prompt increase in TSH secretion, which gives rise to thyroid hormone release and leads to thyroid gland hyperplasia. Part of this effect is due to an apparent increase in the need for thyroid hormone by peripheral tissues and to an excessive rate of hormone degradation and excretion. In humans, hypothermia causes a dramatic TSH secretion in the newborn, but this response is lost after the first few years of life. Exposure to heat has an opposite effect, although of lesser magnitude. A small seasonal variation in serum thyroid hormone levels that follow this general pattern has been reported.

Simulated altitude and anoxia depress thyroid hormone formation in rats, but in humans serum T4 and T3 concentrations, T4 degradation, and oxygen consumption are at least temporarily augmented by high altitude.

Starvation has a profound effect on thyroid function, causing a decrease in serum T3 concentration and a reciprocal increase in rT3 level. These changes are due to a selective inhibition of the 5'-monodeiodination of iodothyronines by peripheral tissues. Reduction in carbohydrate intake rather than total calorie deprivation appears to be the determinant factor. These alterations in thyroid function are believed to reduce the catabolic activity of the organism and thus to conserve energy in the face of decreased calorie intake. Chronic malnutrition is accompanied by similar changes. Overfeeding has opposite although transient effects.

Physical and emotional stresses can have variable and opposite effects. Increased thyroid hormone secretion and serum levels have been observed in stressed animals and in acute psychiatric patients on admission. The physical stress of surgery causes a prompt decrease in the serum T3 concentration, probably as a consequence of decreased T3 neogenesis. This effect of surgery cannot be fully explained on the basis of increased adrenocortical activity or calorie deprivation.

Many minerals alter the synthesis of thyroid hormone, mainly through their interference with iodide concentration and binding by the thyroid gland. The action of iodine is only briefly covered here since it is discussed in Chapters 2 and 13. Calcium, nitrate, bromine, rubidium, and fluorine are allegedly goitrogenic. Lithium carbonate, used in the usual doses for the treatment of affective disorders, can produce goiter in susceptible persons. It inhibits iodide binding and hormonal release from the thyroid gland, probably through a synergistic action with iodide.

Numerous dietary goitrogens, including cyanogenic glucosides, thioglucosides, thiocyanate, and goitrin, are present in a wide variety of foods, and are believed to contribute to the occurrence of endemic goiter in some areas of the world. Monovalent anions such as thiocyanate and perchlorate inhibit iodide transport into the thyroid and cause goiter.

Thionamide drugs such as PTU and the related compound, methimazole, inhibit thyroid peroxidase and thus prevent thyroid hormone synthesis. In addition, PTU but not methimazole inhibits the conversion of T4 to T3 in peripheral tissues. Under appropriate circumstances, sulfonamides, sulfonylureas, salicylamides, resorsinol, amphenone, aminoglutethamide, antipyrine, aminotriazole, amphenidone, 2,3-dimercaptopropanolol, and phenylbutazone have antithyroid action.

A growing list of drugs and diagnostic agents have been found to affect thyroid economy by modulating the regulation of the hypothalamic-pituitary-thyroid axis, as well as by interfering with thyroid hormone transport, metabolism, excretion, and action. Some drugs, such as salicylates, diphenylhydantoin, and glucocorticoids, act at several levels. Several compounds, most notably estrogens, diphenylhydantoin, diazepam, heparin, halophenate, fenclofenac, and some biologically inactive thyroid hormone analogs compete with binding of thyroid hormone to its carrier proteins in serum. The only consequence of drugs affecting hormone transport is a decrease or increase in the concentration of total but not free hormone in serum.

Glucocorticoids, drugs such as propranolol, and amiodarone and some iodinated contrast media inhibit the extrathyroidal generation of T3. The result is a decrease in serum T3 and an increase in rT3 concentrations, with a slight increase or no change in T4 values. Thyroid hormone disposal is accelerated by diphenylhydantoin and phenobarbital, which increase several of the pathways of hormone degradation, and by hypolipemic resins, which increase the fecal loss of hormone. Homeostasis is usually maintained by a compensatory increase in thyroid hormone secretion.

Some drugs act through inhibition or stimulation of TSH secretion. Most notable of the former effect are dopamine agonists such as L-dopa and bromocryptine, as well as some -adrenergic blockers, glucocorticoids, acetylsalicylic acid, and opiates. A variety of dopamine antagonists as well as cimetidine, clomifene, and spirolactone appear to increase TSH secretion. These compounds seem to interfere with the normal dopaminergic suppression of the hypothalamic-pituitary axis. Observed changes in TSH secretion are not associated with significant metabolic alterations. Some of the drugs have an apparent effect on TSH secretion through changes induced at the levels of the free and active forms of the thyroid hormone. A handful of drugs appear to block or antagonize the action of thyroid hormone on tissues. These drugs include guanethidine, propranolol, and dinitrophenol. Some drugs may induce autoimmune thyroid disease. Notably among these are lithium, interferon, interleukin, alemtuzumab. prembrolizumab and nivolumab.

The clinician should be thoroughly familiar with the effects of drugs, nonthyroidal illnesses, and other extraneous factors on thyroid function. These factors should all be taken into account in the differential diagnosis of primary thyroid disease.

 

 

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ABSTRACT

Multinodular goiter (MNG) is the most common of all the disorders of the thyroid gland. MNG is the result of the genetic heterogeneity of follicular cells and apparent acquisition of new cellular qualities that become inheritable. Nodular goiter is most often detected simply as a mass in the neck, but sometimes an enlarging gland produces pressure symptoms. Hyperthyroidism develops in a large proportion of MNGs after a few decades, frequently after iodine excess. Diagnosis is based on the physical examination. Thyroid function test results are normal, or indicate subclinical or overt hyperthyroidism. Imaging procedures are useful to detect details such as distortion of the trachea, and to provide an estimation of the volume before and after therapy. From 4 to 17% of MNGs fulfill the criteria of malignant change, however, the majority of these lesions are not lethal. If a clinical and biochemically euthyroid MNG is small and produces no symptoms, treatment is controversial. T4 given to shrink the gland or to prevent further growth is effective in about one third of patients. If the clinically euthyroid goiter is unsightly, shows subclinical hyperthyroidism or is causing pressure symptoms, treatment with ¹³¹I preceded by recombinant human TSH is successful but causes hypothyroidism in varying degrees. This treatment can lead to 45-65% shrinkage of the MNG, even if in an intrathoracic position, with a relatively low cost, thus it is considered a good alternative to surgery. However, surgery is an acceptable option. The efficacy of T4 treatment after surgery, to prevent regrowth, is debatable although frequently usedt. For complete coverage of all related aeas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

The normal thyroid gland is a fairly homogenous structure, but nodules often

form within its substance. These nodules may be only the growth and fusion of localized colloid-filled follicles, or more or less discrete adenomas, or cysts. Nodules larger than 1 cm may be detected clinically by palpation. Careful examination discloses their presence in at least 4% of the general population. Nodules less than 1 cm in diameter not clinically detectable unless located on the surface of the gland, are much more frequent. The terms adenomatous goiter, nontoxic nodular goiter, and colloid nodular goiter are used interchangeably as descriptive terms when a multinodular goiter is found.

INCIDENCE

The incidence of goiter, diffuse and nodular, is very much dependent on the status of iodine intake of the population. In areas of iodine deficiency, goiter prevalence may be very high and especially in goiters of longstanding, multinodularity develops frequently (Figure 17-1). The incidence of multinodular goiter in areas with sufficient iodine intake has been documented in several reports (1-10). In a comprehensive population survey of 2,749 persons in northern England, Tunbridge et al (1) found obvious goiters in 5.9% with a female/male ratio of 13:1. Single and multiple thyroid nodules were found in 0.8% of men and 5.3% of women, with an increased frequency in women over 45 years of age. Routine autopsy surveys and the use of sensitive imaging techniques produce a much higher incidence. In three reports nodularity was found in 30% to 50% of subjects in autopsy studies, and in 16% to 67% in prospective studies of randomly selected subjects on ultrasound (2). In Framingham the prevalence of multinodular goiter as found in a population study of 5234 persons over 60 years was 1% (3). Results from Singapore show a prevalence of 2.8% (4). In an evaluation in 2,829 subjects, living in southwestern Utah and Nevada (USA, between 31 and 38 years) of age, 23% had non-toxic goiter, including 18 single nodules, 3 cysts, 38 colloid goiters and 7 without a histological diagnosis. No mention was made of multinodular goiters, although some might have been present in the colloid and unidentified group (5). In general, in iodine sufficient countries the prevalence of multinodular goiter is not higher than 4% (6). In countries with previous deficiency that was corrected by universal salt iodination, elderly subjects may have an incidence of, approximately, 10% of nodular and multinodular goiter, attributed to lack of nutritional iodine in early adult life (7).

ETIOLOGY

The first comprehensive theory about the development of multinodular goiter was proposed by David Marine (8) and studied further by Selwyn Taylor (9), and can be considered one of the classics in this field. Nodular goiter may be the result of any chronic low-grade, intermittent stimulus to thyroid hyperplasia. Supporting evidence for this view is circumstantial. David Marine first developed the concept, that in response to iodide deficiency, the thyroid first goes through a period of hyperplasia as a consequence of the resulting TSH stimulation, but eventually, possibly because of iodide repletion or a decreased requirement for thyroid hormone, enters a resting phase characterized by colloid storage and the histologic picture of a colloid goiter. Marine believed that repetition of these two phases of the cycle would eventually result in the formation of nontoxic multinodular goiter (8). Studies by Taylor of thyroid glands removed at surgery led him to believe that the initial lesion is diffuse hyperplasia, but that with time discrete nodules develop (9).

By the time the goiter is well developed, serum TSH levels and TSH production rates are usually normal or even suppressed (10). For example, Dige-Petersen and Hummer evaluated basal and TRH-stimulated serum TSH levels in 15 patients with diffuse goiter and 47 patients with nodular goiter (11). They found impairment of TRH-induced TSH release in 27% of the patients with nodular goiter, suggesting thyroid autonomy, but in only 1 of the 15 with diffuse goiter. Smeulers et al (12), studied clinically euthyroid women with multinodular goiter and found that there was an inverse relationship between the increment of TSH after administration of TRH, and size of the thyroid gland (Figure 17-1). It was also found that, while being still within the normal range, the mean serum T3 concentration of the group with impaired TSH secretion was significantly higher than the normal mean, whereas the mean value of serum T4 levels was not elevated (12). These and other results (13) are consistent with the hypothesis that a diffuse goiter may precede the development of nodules. They are also consistent with the clinical observation that, with time, autonomy may occur, with suppression of TSH release, even though such goiters were originally TSH dependent.

Comprehensive reviews about insights into the evolution of multinodular goiter have been published by Studer and co-workers (14-16). An adapted summary of the major factors that are discussed is presented in Table 17-1 and will be referred to in the discussion that follows.

Table 17-1. Factors that may be involved in the evolution of multinodular goiter.

PRIMARY FACTORS

• Functional heterogeneity of normal follicular cells, most probably due to genetic and acquisition of new inheritable qualities by replicating epithelial cells. Gender (women) is an important factor.

• Subsequent functional and structural abnormalities in growing goiters.

SECONDARY FACTORS

• Elevated TSH       (induced by iodine deficiency, natural goitrogens, inborn errors of thyroid hormone synthesis)

• Smoking, stress, certain drugs

• Other thyroid-stimulating factors (IGF-1 and others)

• Endogenous factor (gender)

PRIMARY FACTORS

Genetic heterogeneity of normal follicular cells and acquisition of new inheritable qualities by replicating epithelial cells. (Figure 17-2).It has been shown cells of many organs, including, the thyroid gland, are often polyclonal, rather than monoclonal of origin. Also from a functional aspect it appears that through developmental processes the thyroid epithelial cells forming a follicle are functionally polyclonal and possess widely differing qualities regarding the different biochemical steps leading to growth and to thyroid hormone synthesis like e.g. iodine uptake (and transport), thyroglobulin production and iodination, iodotyrosine coupling, endocytosis and dehalogenation. As a consequence there is some heterogeneity of growth and function within a thyroid and even within a follicle Studer et al (14-16) demonstrated the existence of monoclonal and polyclonal nodules in the same multinodular gland. They analyzed 25 nodules from 9 multinodular goiters and found 9 to be polyclonal and 16 monoclonal. Three goiters contained only polyclonal nodules and 3 contained only monoclonal nodules. In 3 goiters poly- and monoclonal nodules coexisted in the same gland (17).

Newly generated cells may acquire qualities not previously present in mother cells. These qualities could subsequently be passed on to further generations of cells. A possible example of this process is the acquired abnormal growth pattern that is reproduced when a tissue sample is transplanted into a nude mouse (16). Other examples are acquired variable responsiveness to TSH (13). These changes may be related to mutations in oncogenes which do not produce malignancy per se, but that can alter growth and function. An example of acquisition of genetic qualities is the identification in the last few years of constitutively activating somatic mutations not only in solitary toxic adenoma, but also in hyperfunctioning nodules of toxic multinodular goiters (18). So far these mutations in MNG have only been found in the TSH-receptor (TSHR) gene, and not in the Gs-alpha gene. Different somatic mutations are found in exon 9 and 10 of the TSHR gene and the majority of mutations that are present in toxic adenomas are also found in toxic nodules in multinodular goiter (19-21).

Genes associated with multinodular goiter

In contrast to sporadic goiters, caused by spontaneous recessive genomic variation, most cases of familial goiter present an autosomal dominant pattern of inheritance, indicating predominant genetic defects. Gene-gene interactions or various polygenic mechanisms (i.e. synergistic effects of several variants or polymorphisms) could increase the complexity of the pathogenesis of nontoxic goiter and offer an explanation for its genetic heterogeneity (22-26). A strong genetic predisposition is indicated by family and twin studies (27-29). Thus, children of parents with goiter have a significantly higher risk of developing goiter compared with children of nongoitrous parents (24). The high incidence in females and the higher concordance in monozygotic than in dizygotic twins also suggested a genetic predisposition (24). Moreover, there is preliminary evidence of a positive family history for thyroid diseases in those who have postoperative relapse of goiter, which can occur from months to years after surgery.

Defects in genes that play an important role in thyroid physiology and thyroid hormone synthesis could predispose to the development of goiter, especially in case of borderline or overt iodine deficiency. Such defects could lead to dyshormonogenesis as an immediate response, thereby indirectly explaining the nodular transformation of the thyroid as late consequences of dyshormonogenesis, as a form of maladaptation (12). The genes that encode the proteins involved in thyroid hormone synthesis, such as the thyroglobulin-gene (TG-gene), the thyroid peroxidase-gene (TPO-gene), the sodium – iodide – symporter-gene (SLC5A5), the Pendred syndrome-gene (SLC26A4), the TSH receptor-gene (TSH-R-gene), the iodotyrosine deiodinase (DEHAL 1) and the thyroid oxidase 2 gene3 (DUOX2) are convincing candidate genes in familial euthyroid goiter (30). Originally, several mutations in these genes were identified in patients with congenital hypothyroidism (30). However, in cases of less severe functional impairment, with can still be compensated, a contribution of variants of these genes in the etiology of nontoxic goiter is possible. 

Linkage studies

A genome-wide linkage analysis has identified a candidate locus, MNG1 on chromosome 14q31, in a large Canadian family with 18 affected individuals (31). This locus was confirmed in a German family with recurrent euthyroid goiters (32). A dominant pattern of inheritance with high penetrance was assumed in both investigations. Moreover, a region on 14q31 between MNG1 and the TSH-R-gene was identified as a potential positional candidate region for nontoxic goiter (33). However, in an earlier study the TSH-R-gene was clearly excluded (31). Furthermore, an X-linked autosomal dominant pattern and linkage to a second locus MNG2 (Xp22) was identified in an Italian pedigree with nontoxic familial goiter (34). To identify further candidate regions, the first extended genome-wide linkage analysis was performed to detect susceptibility loci in 18 Danish, German and Slovakian euthyroid goiter families (35). Assuming genetic heterogeneity and a dominant pattern of inheritance, four novel candidate loci on chromosomes 2q, 3p, 7q and 8p (36) were identified . An individual contribution was attributable to four families for the 3p locus and to 1 family to each of the other loci, respectively. On the basis of the previously identified candidate regions and the established environmental factors, nontoxic goiter can consequently be defined as a complex disease. However, for this first time a more prevalent putative locus, present in 20% of the families investigated, was identified (35).

The candidate region on 3p (37) suggests a dominant pattern of inheritance for goiter. However, whereas linkage studies are suitable for the detection of candidate genes with a strong effect it is possible to miss weak genetic defects of first-line candidate gene-variants or of novel genes by linkage studies. Moreover, it is conceivable that the sum of several weak genetic variations in different genomic regions could lead to goiter predisposition. Therefore, the widely accepted risk factors such as iodine deficiency, smoking, old age, and female gender are likely to interact with and / or trigger the genetic susceptibility (22).

Mutagenesis leading to multinodular goiter

Most goiters become nodular with time. (Figure 17-3) From animal models of hyperplasia caused by iodine depletion (38) we have learned that besides an increase in functional activity a tremendous increase in thyroid cell number occurs. These two events likely induce a number of mutation events. It is known that thyroid hormone synthesis goes along with increased H2O2 production and free radical formation with may damage genomic DNA and cause mutations. Together with a higher spontaneous mutation rate, a higher replication rate will more often prevent mutation repair and increase the mutation load of the thyroid, thereby also randomly affecting genes essential for thyrocyte physiology. Mutations that confer a growth advantage (e.g. TSH-R mutations) very likely initiate focal growth. Hence, autonomously functioning thyroid nodules (AFTNs) are likely to develop from small cell clones that contain advantageous mutation as shown for the TSH-R in “hot” microscopic regions of euthyroid MNG (18).

Epidemiologic studies, animal models and molecular/genetic data outline a general theory of nodular transformation. Based on the identification of somatic mutations and the predominant clonal origine of AFTNs and cold thyroid nodules (CTNs) the following sequence of events could lead to thyroid nodular transformation in three steps. First, iodine deficiency, nutritional goitrogens or autoimmunity cause diffuse thyroid hyperplasia (39-41). Secondly, at this stage of thyroid hyperplasia, increased proliferation together with a possible DNA damage due to H2O2 action causes a higher mutation load, i.e. a higher number of cells bearing mutations. Some of these spontaneous mutations confer constitutive activation of the cAMP cascade (e.g. TSH-R mutations) which stimulates growth and function. Finally, in a proliferating thyroid, growth factor expression (e.g. insulin-like growth factor 1   [IGF-1], transforming growth factor ß [TGF-ß], or epidermal growth factor [EGF]) is increased (42-51). As a result of growth factor co-stimulation most cells divide and form small clones. After increased growth factor expression ceases, small clones with activating mutations will further proliferate if they can achieve self-stimulation. They could thus form small foci, which could develop into thyroid nodules. This mechanism could explain AFTNs by advantageous mutations that both initiate growth and function of the affected thyroid cells as well as CTNs by mutations that stimulate proliferation only. Moreover, nodular transformation of thyroid tissue due to TSH secreting pituitary adenomas, nodular transformation of thyroid tissue in Graves´ disease and in goiters of patients with acromegaly could follow a similar mechanism, because thyroid pathology in these patients is characterized by early thyroid hyperplasia.

As an alternative to the increase of cells mass, and as illustrated by those individuals who do not develop a goiter when exposed to iodine deficiency, the thyroid might also adapt to iodine deficiency without extended hyperplasia. Although the mechanism that allows this adaptation is poorly understood, data from a mouse model suggests an increase of mRNA expression of TSH-R, NIS and TPO in response to iodine deficiency, which might be a sign of increased iodine turnover in the thyroid cell in iodine deficiency. Moreover, expansion of the thyroid microvasculature, caused by up regulation of vascular endothelial growth factor and other proangiogenic factors, could be an additional mechanism that might help the thyroid to adapt to iodine deficiency (52).

SECONDARY FACTORS

The secondary factors discussed below stimulate thyroid cell growth and / or function and, because of differences in cellular responsiveness that are presumed to exist, aggravate the expression of heterogeneity which leads to further growth and focal autonomic function of the thyroid gland. Local necrosis, cyst formation sometimes with bleeding and fibrosis may be the anatomical end stage of such processes (Figure 17-3).

Iodine Deficiency

Stimulation of new follicle generation seems to be necessary in the formation of simple goiter. (Figure 17-3) Evidence accumulated from many studies indicates that iodine deficiency or impairment of iodine metabolism by the thyroid gland, perhaps due to congenital biochemical defects, may be an important mechanism leading to increases in TSH secretion (30,53). Since in experimental animals the level of iodine per se may modulate the response of thyroid cells to TSH, this is an additional mechanism by which relatively small increases in serum TSH level may cause substantial effects on thyroid growth in iodine-deficient areas (53). It was found that the thyroidal iodine clearance of patients with nontoxic nodular goiter was, on overage, higher than that in normal persons (Fig. 17-3). This finding was interpreted as a reflection of a suboptimal iodine intake by such patients. When data published from various major cities in Western Europe, regarding thyroid volume and iodine excretion are put together (54) and inverse relation is found between urinary iodine excretion and thyroid volume (Fig. 17-4). Physiologic stresses, such as pregnancy, may increase the need for iodine and require thyroid hypertrophy to increase iodine uptake that might otherwise satisfy minimal needs. An elevated renal clearance   of iodine   occurs during normal pregnancy (24). It has been suggested that in some patients with endemic goiter there are similar increases in renal iodine losses (53). Increased need for thyroxin during pregnancy may also lead to thyroid hypertrophy when iodine intake as limited. Iodide need in pregnancy is increased by increased iodide loss through the kidneys, but also because of significant transfer of thyroid hormone from the mother to the fetus (24). In areas of moderate iodine intake, thyroid volume increase is predominantly affected by a higher HCG serum concentration during the first trimester of pregnancy, and by a slightly elevated serum TSH level present at delivery (24). Finally mutations in the thyroglobulin gene may impair the efficiency of thyroid hormone synthesis and release, leading to a decreased rate of inhibition of TSH at pituitary level. The relatively high TSH released from the thyrotrophs will continuously stimulate the thyroid gland growth (55).

Natural occurring goitrogens

Patients occasionally have thyroid enlargement either because of goitrogenic substances in their diet or because of drugs that have been given for other conditions (53). Feeding rats with minute doses of a natural goitrogen over many months will result in the same kind of response. Similar results have been obtained using combinations of the three most prevalent goitrogens contained in cabbage. The explanation for the effect of such substances is that the goitrogen is much more effective at the level of iodothyronine synthesis than at earlier steps in hormone production such as iodide trapping. Thus, the RAIU may be high, but with a block in hormone synthesis the stage would be set for the production of a goiter. This possibility remains to be proved in humans, but one might surmise that, if true, it would operate most effectively in a situation of borderline iodine supply. The goitrogen thiocyanate potentiates the effect of severe iodine deficiency in endemic areas of Africa (53).

Several natural occurring goitrogens are listed in Table 17-2. Note that excessive

Nutritional use of seaweed (rich in iodine) may induce goiter. Moreover malnutrition (protein-caloric malnutrition) iron deficiency, selenium deficiency when associated with marginally low nutritional iodine may impair thyroid hormone synthesis and induce thyroid enlargement.

Table 17-2. Natural goitrogens associated with Multinodular Goiter

Goitrogens	Agent	Action
Millet, soy beans	Flavonoids	Impairs thyroperoxidase
Cassava, sweet potato, sorghum	Cyanogenic glucosides metabolized to thiocyanates	Inhibits iodine thyroidal uptake
Babassu coconut	Flavoniods	Inhibits thyroperoxidase
Cruciferous vegetables: Cabbage, cauliflower, Broccoli, turnips	Glucosinolates	Impairs iodine thyroidal uptake
Seaweed (kelp)	Iodine excess	Inhibits release of thyroidal Hormones
Malnutrition, Iron deficiency	Vitamin A deficiency Iron deficiency	Increases TSH stimulation Reduces heme-dependent thyroperoxidase thyroidal activity
Selenium	Selenium deficiency	Accumulates peroxidase and cause deiodinase deficiency; impairs thyroid hormone synthesis
Modified and adapted from Medeiros-Neto & Knobel, ref. 53

Inherited defects in thyroid hormone synthesis and resistance to thyroid hormone action

Inherited goiter and congenital hypothyroidism were first described by Stanbury and associated (30) in two goitrous siblings with defective thyroperoxidase action resulting in impaired iodine organification. Both siblings were mentally retarded and had enormous multinodular goiters. In the next fifty years a number of genetic defects in every step of thyroid hormone synthesis have been described in detail. If not diagnosed at birth the impaired thyroid hormone synthesis would result in an elevated TSH secretion and diffuse goiter could progressively appears. Other factors might be of importance regarding goiter formation. The level of nutritional iodine seems to be quite important in patients with the defective sodium iodine symporter (NIS), thyroglobulin gene mutations and the defective dehalogenase system (DEHAL gene). If a relatively high intake of iodine is provided goiter formation may be slowed down to a certain extent. On the contrary in marginally low nutritional iodine intake goiter will progress to a very large size and nodules will appear (multinodular goiter). It has been proposed that mutations of certain genes involved in thyroid hormone synthesis that do not entirely affect the physiological action of the translated protein may cause goiter later on life and more frequently in women (55). Thus the variable phenotype resulting from genetically documented mutations may be quite variable depending on environmental factors (iodine). Individual adaptation to the defective protein, rapid hydrolysis of defective TG, serum level of TSH and response of the thyroid epithelial cells to the growth-promoting effect of TSH are other factors to be considered.

It is conceivable that multinodular goiter could result from a defect in any step of thyroid hormone synthesis, and to resistance to thyroid hormone action. In both groups of defects in the thyroid hormone system serum TSH would be elevated and goiter would be the logical consequence of a prolonged stimulation to growth. In the context of other factor that might induce multinodular goiters the defective thyroid hormone system and resistance to thyroid hormone action are relatively rare conditions as compared to other factors.

IOD Iodine organification defect; PIOD: Partial IOD;TIOD: Total IOD; RAI: radioactive iodine. Source: modified from “Genetic causes of dyshormonogenesis. Grasberger and Refetoff, 2011.

Other Thyroid-Stimulating Factors

Other substances that could be involved in stimulating thyroid enlargement are epidermal growth factor (EGF) and insulin-like growth factors (IGF). EGF stimulates the proliferation of thyrocytes from sheep, dogs, pigs, calves, and humans (42-51). While stimulating growth, EGF reduces trapping and organification of iodide, TSH receptor binding, and release of thyroglobulin, T3 and T4. On the other hand TSH may modulate EGF binding, to thyroid cell membranes and thyroid hormone may stimulate EGF production and EGF receptor number. In a study on adenomatous tissue, obtained from patients with multinodular goiter, it was found, by immunohistochemistry, that expression of EGF was increased (43). IGF-2 interacts with trophic hormones to stimulate cell proliferation and differentiation in a variety of cell types. The interaction between TSH and IGF-2 is synergestic (44). Increased IGF-I expression may contribute to goiter formation. A similar synergistic effect may exist between IGF-I and TSH. This synergism on DNA synthesis is mediated by complex interactions including the secretion of one or more autocrine amplification factors. Non-functioning nodules in patients with multinodular goiter contain the same IGF-1 receptors that are present in the normal adjacent extra-nodular follicles but are expressed in higher concentrations. Fibroblast growth factor (FGF)-1, stimulates colloid accumulation in thyroids of rat s but only in the presence of TSH (43). Expression of FGF-1 and -2 and FGF-receptor-1 will be followed by thyroid hyperplasia and may play a role in development of multinodular goiter (49). Fancia et al (50) found that in goiters with aneuploid components growth rate was higher than when euploid components were present (51). Other factors promoting cell growth and differentiation have been identified in the past. These include cytokines, acetylcholine, norepinephrine, prostaglandins, substances of neural origin like vasoactive intestinal peptide, and substances of C-cell origin. It is however not known to what extent these compounds play a role in the genesis of multinodular goiter.

The hypothesis that the development of thyroid autonomy is due to a gradual increase in the numbers of cells having relatively autonomous thyroid hormone synthesis is supported by the 27% prevalence of impaired TSH responses to TRH in patients with nodular goiter as opposed to such responses in only 1 of 15 patients with diffuse goiter (11). Such partial autonomy may appear only with time and could possibly be prevented by TSH-suppressive therapy. The fact that it is possible to induce hyperthyroidism in some patients with multinodular goiters by administration of iodide suggests that certain of the nodules in the multinodular gland are autonomous but unable under normal iodine intake to concentrate sufficient quantities of iodide to cause hyperthyroidism (53). Presumably iodide administration provides sufficient substrate for generation of excessive amounts of hormone, although it does not readily account for the long persistence of the hyperthyroidism in some of those cases.

Thus, there may be several etiologic factors in simple and nodular goiter, and some of these factors may act synergistically. The end result is a collection of heterogeneously functioning thyroid follicles, some of which may be autonomous and produce sufficient amounts of thyroid hormone to cause hyperthyroidism.

PATHOLOGY

Although it is rare to obtain pathological examination of thyroid glands in the early phase of development of multinodular goiters, such glands should show areas of hyperplasia with considerable variation in follicle size. The more typical specimen coming to pathologists is the goiter that has developed a nodular consistency. Such goiters characteristically present a variegated appearance, with the normal homogeneous parenchymal structure deformed by the presence of nodules     (Figure 17-6). The nodules may vary considerably in size (from a few millimeters to several centimeters); in outline (from sharp encapsulation in adenomas to poorly defined margination for ordinary nodules); and in architecture (from the solid follicular adenomas to the gelatinous, colloid-rich nodules or degenerative cystic structures). The graphic term “Puddingstone goiter” has been applied. Frequently the nodules have degenerated and a cyst has formed, with evidence of old or recent hemorrhage, and the cyst wall may have become calcified. Often there is extensive fibrosis, and calcium may also be deposited in these septae. Scattered between the nodules are areas of normal thyroid tissue, and often-focal areas of lymphocytic infiltration. Radioautography shows a variegated appearance, with RAI localized sometimes in the adenomas and sometimes in the paranodular tissue. Occasionally, most of the radioactivity is confined to a few nodules that seem to dominate the metabolic activity of the gland.

If careful sections are made of numerous areas, 4-17% of these glands removed at surgery will be found to harbor microscopic papillary carcinoma (56-60). The variable incidence can most likely be attributed to the different criteria used by the pathologists and the basis of selection of the patients for operation by their physicians. These factors are discussed below.

NATURAL HISTORY OF THE DISEASE

Multinodular goiter is probably a lifelong condition that has its inception in adolescence or at puberty. Minimal diffuse enlargement of the thyroid gland is found in many teenage boys and girls, and is almost a physiologic response to the complex structural and hormonal changes occurring at this time. It usually regresses, but occasionally (much more commonly in girls) it persists and undergoes further growth during pregnancy. This course of events has not been documented as well as might be desired in sporadic nodular goiter, but it is the usual evolution in areas where mild endemic goiter is found.

Patients with multinodular goiter seek medical attention for many reasons. Perhaps most commonly they consult a physician because a lump has been discovered in the neck, or because a growth spurt has been observed in a goiter known to be present for a long time. Sometimes the increase in the size of the goiter will cause pressure symptoms, such as difficulty in swallowing, cough, respiratory distress, or the feeling of a lump in the throat. Rarely, an area of particularly asymmetrical enlargement may impinge upon or stretch the recurrent laryngeal nerve. Commonly the goiter is discovered by a physician in the course of an examination for some other condition. An important scenario is for the patient to seek medical attention because of cardiac irregularities or congestive heart failure, which proves to be the result of slowly developing thyrotoxicosis. (The issue is discussed more fully later in this chapter). Many times the goiter grows gradually for a period of a few too many years, and then becomes stable with little tendency for further growth. It is rare for any noteworthy spontaneous reduction in the size of the thyroid gland to occur, but patients often describe fluctuation in the size of the goiters and the symptoms they give. These are usually subjective occurrences, and more often than not the physician is unable to corroborate the changes that the patient describes. On the other hand, it could be that changes in blood flow through the enlarged gland account for the symptoms.

Occasionally, a sudden increase in the size of the gland is associated with sharp pain and tenderness in one area. This event suggests hemorrhage into a nodular cyst of the goiter, which can be confirmed by ultrasound. Within 3-4 days the symptoms subside, and within 2-3 weeks the gland may revert to its previous dimensions. In such a situation, acute thyrotoxicosis may develop and subside spontaneously.

Rarely, if ever, do the patients become hypothyroid and if they do, the diagnosis is more probably Hashimoto´s thyroiditis than nodular goiter. In a study in clinically euthyroid subjects with multinodular goiter, 13 out of 22 had subnormal TSH release after TRH. (12) If the goiter is present for long time, thyrotoxicosis develops in a large number of patients. In a series collected many years ago at the Mayo Clinic, 60% of patients with MNG over 60 were thyrotoxic. The average duration of the goiter before the onset of thyrotoxicosis was 17 years; the longer the goiter had been present the greater was the tendency for thyrotoxicosis to develop. This condition appears to occur because with the passage of time, autonomous function of the nodules develops. In a study of patients with euthyroid multinodular goiter, thyroid function was autonomous in 64 and normal in 26. After a mean follow-up of 5.0 years (maximum 12 years) 18 patients with autonomous thyroid function became overtly hyperthyroid and in 6 patients with primarily normal thyroid function autonomy developed (25-26). Thyroid function tests is illustrated in a patient with multinodular goiter starting from complete euthyroidism on to overt thyrotoxicosis. Occasionally a single discrete nodule in the thyroid gland becomes sufficiently active to cause thyrotoxicosis and to suppress the activity of the rest of the gland. (see Chap13). If these patients are given thyroid hormone, continued function of nodules can be demonstrated by radioiodine scanning techniques. Thus, these nodules have become independent of pituitary control. When patients with euthyroid multinodular goiter are frequently tested, it appears that in some of them occasional transient increases of serum T3 and / or T4 are seen. The possibility that the abrupt development of hyperthyroidism may follow administration of large amounts of iodine to these patients was reviewed by Stanbury and collaboration (61). In several areas of the world previously iodine deficiency the introduction of iodine supplementation lead to an increase of hyperthyroidism (non-autoimmune) possibly by excessive thyroid hormone production by “hot” thyroid nodules.

MULTINODULAR GOITER AND CANCER

If surgical specimens of multinodular goiters are examined carefully, 4-17% are found to harbor a carcinoma (56-60, 62-64). The use of ultrasound-guided fine needle aspiration (FNA) for evaluating these patients is not clearly defined. The biopsy of all the numerous nodules is impractical. Recently, a retrospective study with 134 patients showed a significant incidence (46,3%) of thyroid cancer in patients with multinodular goiter and benign FNA (65).These carcinomas vary widely in size and are typically of the papillary variety. Similar tumors are occasionally found in thyroid glands affected by Hashimoto´s thyroiditis and in otherwise normal glands. Bisi et al (59) reported that 13% of the glands resected in thyroid operations for any reason contained papillary adenocarcinoma. In Japan, routine autopsies of patients who were not suspected of having thyroid disease and who had no known irradiation experience, 17% were found to have small carcinomas when careful serial sections of the thyroid glands were done (62). If the figures of Bisi et al (59) were confirmed (63, 64) truly represent the prevalence of invasive carcinoma, one would certainly be forced to conclude that all multinodular goiters should be resected in order to prevent dissemination of malignant disease. However, it seems quite unlikely that all lesions that appear to satisfy the histological criteria for malignant neoplasia are potentially lethal. This view is strongly supported by the final report of the study on the significance of nodular goiter carried out in Framingham (see ref. 24). They followed for 15 years all 218 nontoxic thyroid nodules previously detected in a total population of approximately 5,000 persons. None of these lesions showed any clinical evidence of malignancy at the end of that time. Despite of the low-quality, the evidence suggests a lower prevalence of thyroid caner in multinodular goiter compared to single nodules, particularly in iodine-deficient areas (66, 67).

A strong case can be made for the view that there is only minimal risk from carcinoma in multinodular goiter. The prevalence of clinical nodularity of the thyroid is at least 4%, or 40,000 per 1,000,000 populations. Use of a much higher figure can be justified by the autopsy studies described above. Despite the high frequency of nodular goiter, only 36-60 thyroid tumors appear per 1,000,000 persons each year or by analysis of reported statistics on thyroid surgical specimens (57-60). A recent national cancer survey in the United States found an incidence of 40 per 1,000,000. An overview of the incidence of thyroid cancer in 409 countries, both with and free of endemic goiter was reported previously (58). The range of incidence varied between 7.5 and 56 per 1,000,000 persons each year. The prevalence of significant thyroid carcinoma at routine autopsy is less than 0.1% and persons with this type of tumor are probably examined as frequently as are those with other forms of neoplasia. The United States mortality figures for thyroid carcinoma are constant at about 6 per 10-6 population each year. Riccabona also summarized death rates from thyroid cancer in non-endemic and in endemic countries. (64) For Austria this was 16 per 10-6 per year in 1952 and 10 per 10-6 per year in 1983. For Switzerland this was in 1952, 18 per 10-6 per year and in 1979, 9 per 10-6 per year. The death rate per year for the United States in 1979 was 3 per 10-6, for Israel in 1952 1 per 10-6 per year and for the UK 7 per 10-6 in 1963. Death rates from thyroid cancer in endemic goiter areas from regions in Austria, Yugoslavia, Finland and Israel were between 10 and 16 per 10-6 per year between 1980 and 1984.

Lastly, it should be recognized that meticulous examination of autopsy specimens from persons dying of nonthyroid disease may show small (less than 0.5 cm) papillary lesions in4-24% of human thyroid glands (63,64). A report of 1020 sequential autopsies revealed the presence of microscopic papillary carcinoma in 6%. (60) Although the prevalence of this type of lesion increases with age, there is no question that such lesions may be present even in younger persons. The proportion of these lesions that even become clinically apparent is unknown, but their presence in otherwise normal thyroid glands should be kept in mind when evaluating reports of similar prevalences of thyroid carcinoma in multinodular thyroid glands.

If 4% of patients with nodular goiter actually have thyroid carcinoma, the prevalence of tumor in the general population would be 1,600 per 1,000,000. It is remarkable that only about 25 of these 1,600 hypothetical tumors would become apparent each year, or that only about 10 would prove fatal. Thus, there appears to be a gross discrepancy between the mortality form thyroid carcinoma and its reported frequency in surgical specimens of multinodular goiters. Reasonable arguments can be mustered in an effort to reconcile the information. Perhaps the most important single factor is selection. Persons with nodular goiter who come to operation are not representative of the general population but are patients with clinically significant thyroid disease who have been selected by their physicians for thyroid surgery. One of the factors controlling the selection process is the suspicion of malignant tumor. In fact, the selection process is especially good, as reflected by the high recovery of malignant thyroid tumors in patients operated on with this presumptive diagnosis. A second factor is that the histologic diagnosis of thyroid carcinoma may not correlate well with true invasiveness. It is impossible to prove this thesis, but pathologists agree that the criteria for judging malignancy are variable and that it is exceedingly difficult to predict with any degree of certainty the growth potential of a particular thyroid lesion.

Other arguments may be used to defend a conservative therapeutic position. In the first place, the tumors that are usually found in multinodular goiters are papillary tumors, and their degree of invasiveness is low. Indeed, the survival rate for intrathyroid papillary carcinoma is only slightly less than that for normal persons of the same age and sex (69-74). Furthermore, prophylactic subtotal thyroidectomy is not a guarantee of protection from cancer arising in a nodular goiter, since the process is usually diffuse, and it may be assumed that abnormal tissue is left in the neck after operation. In fact, unless replacement therapy is given, partial thyroidectomy might be expected to induce a tremendous growth stimulus in the remaining gland (75-80). A further point is that thyroidectomy, even in the best of hands, carries its own risk and its own morbidity, with dimensions comparable to those of missing a small papillary carcinoma within a multinodular goiter (81-84). Obviously this last possibility does not apply when a focus of unusual induration or rapid growth rate is detected clinically.

Diagnosis

Many of the symptoms of multinodular goiter have already been described. They are chiefly due to the presence of an enlarging mass in the neck and its impingement upon the adjacent structures. There may be dysphagia, cough, and hoarseness. Paralysis of recurrent laryngeal nerve may occur when the nerve is stretched taut across the surface of an expanding goiter, but this event is very unusual. When unilateral vocal cord paralysis is demonstrated, the presumptive diagnosis is cancer. Pressure on the superior sympathetic ganglions and nerves may produce a Horner´s syndrome.

As the gland grows it characteristically enlarges the neck, but frequently the growth occurs in a downward direction, producing a substernal goiter. A history sometimes given by an older patient that a goiter once present in the neck has disappeared may mean that it has fallen down into the upper mediastinum, where its upper limits can be felt by careful deep palpation. Hemorrhage into this goiter can produce acute tracheal obstruction. Sometime substernal goiters are attached only by a fibrous band to the goiter in the neck and extend downward to the arch of the aorta. They have even been observed as deep in the mediastinum as the diaphragm. Occasionally the skilled physician can detect a substernal goiter by percussion, particularly if there is a hint from tracheal deviation, or the presence of a nodular mass in the neck above the manubrial notch.

Symptoms suggesting constriction of the trachea are frequent, and displacement of the trachea is commonly found on physical examination. Computer Tomography examination is useful in defining the extent of tracheal deviation and compression. Compression is frequently seen but rarely is functionally significant have expected to find softened tracheal cartilage after the removal of some large goiters, but tracheomalacia has been observed only on the rarest occasion. Patients may be remarkably tolerant of nodular goiter even when the enlargement is striking. This finding is especially true in the endemic goiter areas of the world.

It is generally agreed that, thyroid isotope or ultrasound scanning are of little or no use in the diagnosis of carcinoma in a multinodular goiter. Two aspects are important in the differentiation from malignancy. First, the clinical presentation, if the goiter is of longstanding, showing little or no growth, absence of a dominant node, familial, while there is no neck irradiation in the past, especially in childhood, no hoarse voice, and no suspicious lymphnodes in the neck, there is little fear for carcinoma.

Table 17-4      Clinical symptoms and investigations in the diagnosis of MNG

Simptoms and signs Often family history of benign thyroid disease Slowly growing anterior neck mass Uni- or multinodularity on examination Enlargment during pregnancy Cosmetic complaints Asymmetry, tracheal deviation, and/or compression Rarelly upper airway obstruction, dyspnea, cough, and dysphagia Sudden transient pain or enlargement secondary to hemorrhage Gradually developing hyperthyroidism Superior vena cava obstruction syndrome (rare) Recurrent nerve palsy (rare) Horner´s syndrome (rare) Investigations TSH normal or decreased, normal free T4, and free T3, Serum Tg usually elevated Thyroid autoantibodies (TPO and Tg) usually negative Scintigraphy with solitary or multiple hot and/or cold areas Ultrasound finding of solitary or multiple nodules with varying echogenicity (nonhomogeneity) Computed tomography and MR imaging demonstrating solitary or multiple nodules with varying echogenicity Lung function testing may demonstrate impaired inspiratory capacity Fine-needle aspiration of solitary or dominant nodules – benign cytology   Modified and adapted from Hegedus et al (24)

Laboratory investigation

The choice of tests to investigate the functional status of a patient with a Simple diffuse goiter or Multinodular goiter may differ depending on the geographic areas of the world. Recent surveys conducted in the American, European and Latin American Thyroid Associations have indicated that the North American thyroidologists are quite restrictive in the choice of laboratory tests. Most of the experts, however, would perform a serum TSH and serum Free T4 test. In other settings Total T4 and Total T3 are also included because of the preferential secretion of T3 over T4 in mild iodine deficiency (53).

Antibodies against thyro-peroxidase (anti-TPO) and thyroglobulin (anti-TG) are measured, routinely, by most Europeans and Latin Americans thyroidologists. This seems to be relevant because thyroid auto antibodies are found approximately in 10% of the population and, consequently, autoimmunity may coexist with a goiter. Also diffuse or focal lymphocytic infiltration in an enlarged gland may represent chronic autoimmune thyroiditis.

Although serum TG correlates with the iodine status and the size of the enlarged thyroid gland it has little or no value in the diagnosis of goiter.

Diagnostic imaging

Neck palpation is notoriously imprecise with regard to thyroid morphology and size estimation (85). Several imaging methods are available in most settings: scintilography (with radioiodine, technetium), ultrasonography, computed tomography scans, magnetic resonance imaging and, less frequently used, positron emission tomography (PET). In Table 17-5 it is listed the characteristics, advantages and disadvantages of these imaging methods.

Ultrasonography of the thyroid

The main reasons for the widespread use of thyroid sonography are availability (several portable models are widely available at a relatively affordable price), the low cost of the procedure (if performed in the office or in the thyroid clinic), limited discomfort for the patient, and the non ionizing nature of the method. Ultrasonography may detect non palpable nodules cysts, will estimate nodule and goiter size (volume), will monitor the changes following therapy and will guide the Fine Needle Aspiration Biopsy (FNAB). After the introduction of ultrasonography it has become clear that nodules in the thyroid gland are very prevalent, ranging from 17% to 60% if older people are included in the study (85-95).

Hypoechogenicity, micro-calcifications, indistinct borders, increased nodular flow (visualized by DOPPLER) may have predictive value in distinguishing malignant from benign nodules (even in Multinodular Goiters).

The possibility of measuring thyroid volume is another highly useful feature of ultrasonographic studies particularly after therapy with L-T4 or radioiodine ablation. The volume of the goiter is usually based on the ellipsoid method (length, width depth X pi/6). This has an observer coefficient of variation of more than 10%. When compared to CT planimetry the ellipsoid method underestimate the goiter volume by 20%. Ultrasonography can not evaluate a multinodular goiter that has partially migrated to the upper mediastinum.

Ultrasound elastography can also provide information regarding malignant risk of thyroid nodules and multinodular goiter, however with questionable sensitivity (75%) and specificity (45,73%) (96).

Scintigraphy (isotope imaging)

It was used routinely in the past but at present has little place in the evaluation of a multinodular goiter (97-101). It is helpful in the determination of the functionality of the various nodules of a MNG. Thyroid scintigrams have been used through many years for measurement of the thyroid volume but compared to other methods is very inaccurate (24).

Computed tomography (CT) and Magnetic resonance (MR)

CT and MR provide high-resolution visualization of the goiter (Simple diffuse, multinodular). The major strength of CT and MR is their ability to diagnose and assess the extent of subesternal goiters (Fig. 17-7). Another advantage of the CT is the possibility for planimetric volume estimations, quite useful in irregularly enlarged multinodular goiter (102-105).

Recently the ionizing radiation delivered by a CT procedure has been source of concern for both clinicians and radiologists. Therefore the use of CT as an imaging method should be reserved for intra thoracic multinodular goiters, with tracheal compression.

Table 17-5      Characteristics of imaging procedures in relation to nodular thyroid disease
	Advantages	Disadvantages
Sonography	·  High Availability ·  High morphologic resolution ·  No ionizing irradiation ·  Dynamic picture ·  Blood flow visualization (Doppler) ·  Biopsy guidance, also of lymph nodes ·  Moderate precision in volume estimation	·  Operator dependency ·  No information of functionality ·  Not feasible in substernal goiter ·  Poor prediction of malignancy
Scintigraphy	·  Information of functionality ·  Differentiates between destructive and hyperthyroid conditions ·  Measurement of thyroid iodine uptake ·  Predictive of feasibility of ¹³¹I therapy ·  Detects ectopic thyroid tissue	·  Requires nuclear medicine ·  Ionizing irradiation ·  Poor resolution ·  Poor differentiation between solid and cystic cold nodules ·  Volume estimationinaccurate
CT Scan	·  High morphologic resolution ·  Visualization of adjacent structure ·  Ideal for substernal goiter ·  Planimetric volume estimation ·  Volume estimation probably accurate	·  Ionizing irradiation ·  No information of functionality ·  Poor prediction of malignancy
MR imaging	·  No ionizing irradiation ·  High morphologic resolution ·  Visualization of adjacent structure ·  Ideal for substernal goiter ·  Planimetric volume estimation ·  Volume estimation with high precision	·  Moderate availability ·  Long procedure time ·  Not usable with metallic objects inside patient ·  No information of functionality ·  Poor prediction of malignancy
PET	·  Information of functionality ·  Metabolic investigations ·  Good prediction of malignancy	·  Low availability and high cost ·  Requires specialized units ·  Ionizing irradiation
CT, Computed tomography. MR, magnetic resonance   Modified and adapted from Hegedus et al (24)

Treatment of multinodular goiter

In the past iodine supplementation seems to be an adequate approach because goiter development is associated with mild iodine deficiency in many countries worldwide. The effect of iodine once a multinodular goiter has developed a limited value in reducting the MNG. A major problem of iodine supplementation is the risk for inducing subclinical / clinical hyperthyroidism (Jod-Basedow). Therefore aside from a few European Countries iodine is no longer used alone or associated with L-T4 to treat thyroid enlargement (24).

This leaves in essence three modalities of therapy:

(1). L-T4 suppressive therapy

(2). Radioiodine (¹³¹I) alone or preceded by rhTSH

(3). Surgery

L-T4 suppressive therapy

L-T4 suppressive therapy is used extensively both in Europe, USA and Latin America, according to their respective surveys. A beneficial effect of L-T4 has been demonstrated in diffuse goiters in many controlled trials (106-112). A goiter reduction of 20-40% can be expected in 3-6 months of therapy, the goiter returning to the pre-treatment size after L-T4 withdrawal. The efficacy of L-T4 is shown to depend on the degree of TSH suppression. When it comes to the nontoxic MNG there are five controlled studies in which sonography was used for objective size monitoring. Berghout et al (113) in a randomized double-blind trial showed that the goiter volume was reduced by 15% (9 months of L-T4 therapy). In the placebo group the goiter continued to increase in size by more than 20% in the 9 months period. The goiter volume returned to baseline values after discontinuation of the therapy. Lima et al (109) studied 62 patients with nodular goiter. Thirty per cent of patients were regarded as responders (reduction > 50% of the initial volume). In the control group 87% showed no change or an increase in goiter size. Wesche et al (110) compared L-T4 with ¹³¹I therapy in a randomized trial. The median reduction of goiter volume in the radioiodine treated group was 38-44% whereas only 7% of the L-T4 treated patients had a significant goiter reduction.

Papini et al (111) treated 83 goitrous patients (nodular goiter) with suppressive doses of L-T4 comparing the results with a control group. The L-T4 therapy was extended for 5 years. There was a decrease in nodular size in the L-T4 treated group and a mean volume increase in the control group. After 5 years sonograms detected 28.5% new nodules in the control group but only 7.5% in the L-T4 treated group. In conclusion long term TSH suppression induced volume reduction in a subgroup of thyroid nodules but effectively prevented the appearance of new nodules.

Zelmanovitz et al (112) studied 42 women with a single colloid nodule. Twenty one patients were treated with 2.7µg/kg of L-T4 for one year. Six of the 21 treated patients had a >50% reduction of the nodule volume as evaluated by sonography as compared to only 2 (out of 24 patients) that received placebo. They concluded that L-T4 therapy is associated with 17% of reduction of a single colloid nodule and may inhibit growth in other patients. They also conducted a meta-analysis of 6 prospective controlled trials and concluded that four of seven studies favors treatment with L-T4. The treatment of single nodules or multinodular goiter with L-T4 is an open issue as the reduction of the nodule / MNG is only obtained in about one third of patients. The possible unwanted effects of L-T4 therapy have also to be considered (114, 115).

Table 17-6: Controlled studies of L-T4 therapy in multinodular goiter using a precise thyroid size determination
Authors (Country)	(n)	Duration of L-T4 therapy	Dose of L-T4	Outcome of continuous L-T4	Therapy vs. Controls
Berghout et al (The Netherlands)	55	9 months	2.5μg/kg	25% reduction among responders*	20% had Increase of nodular volume
Lima et al (Brazil)	62	12 months	200μg/dia	30% reduction**	No variation volume
Wesche et al (The Netherlands)	57	24 months	2.5μg/kg	22% reduction	44% volume with Radioidine
Papini et al (Italy)	83	5 years	2,0μg/kg 7.5% new nodules	47.6% reduction 28.5% new nodules	22% had reduction nodules
Zelmanovitz et al (Brazil)	45	12 months	2.7μg/kg	28% reduction**	8.3% had reduction
(*) Effective response to L-T4 therapy: volume was reduced by 13% of basal (**) Effective response to L-T4 therapy: volume reduction >50% of basal

Radioiodine ablation of goiter

General considerations: It has long been recognized that radioiodine administration results in shrinkage of the goitrous thyroid gland. Over 20 years ago ¹³¹I therapy reduced the MNG volume by approximately 40% in the first year, and 50-60% in the second year. In very large goiters with volume over 100 mL the reduction is less (around 35%). Patient with substernal MNG have also been treated with beneficial results. The individual response to radioiodine therapy, regarding goiter reduction and development of hypothyroidism is very difficult to predict. Goiter reduction is related to the absorbed thyroid dose. In most centers ¹³¹I doses of 3.7 MBq/g of thyroid tissue corrected for 100% 24h radioiodine uptake have been given. In other centers a fixed doses of radioiodine (100mCi, 150mCi) are administered according to the thyroid volume. The risk of permanent hypothyroidism after ¹³¹I therapy in MNG ranges from 11 to 58% after 1 to 8 years of follow-up (116-124).

 

The use of rhTSH for improving ¹³¹I therapy of nontoxic multinodular goiter

(1). Increased uptake and goiter volume reduction

In recent years, pretreatment with rhTSH has been used in patients with MNG (which typically have only a fraction of the normal RAIU) to increase ¹³¹I uptake in the goiter and allow treatment with lower doses of ¹³¹I to induce thyroid volume reduction (125-129). Accordingly, in a study of 15 patients with nontoxic MNG, pretreatment with a single low dose of rhTSH (0.01 or 0.03 mg 24 h before ¹³¹I administration) resulted in a doubling of RAIU (130). In addition, the single dose of rhTSH caused a more homogeneous distribution of ¹³¹I by stimulating more uptake in relatively cold areas than in hot areas, particularly in patients with low serum TSH levels (Figure 17- 7).

Various studies have demonstrated the effect of rhTSH on ¹³¹I therapy for MNG. Twenty-two patients with MNG were treated with ¹³¹I 24h after administration of 0.01 or 0.03 mg rhTSH (131). In this study, the dose of ¹³¹I was adjusted to the increase in uptake induced by rhTSH, aimed at 100 µCi/g thyroid tissue retained at 24h. Pretreatment with 0.01 and 0.03 mg rhTSH resulted in reductions in the ¹³¹I dose by a factor of 1.9 and 2.4, respectively. One year after treatment, there was a reduction in thyroid volume of 35% and 41% in the two groups, respectively. Despite delivering a good therapeutic response, the administration of ¹³¹I 100 µCi/g of thyroid tissue corrected for 24-h RAIU raises concerns of irradiation of the surrounding neck structures and potential risk for stomach, bladder, and breast cancer, which have been reported after ¹³¹I therapy for toxic nodular goiter (24). In another study (132), 16 patients with MNG were treated with a fixed dose of ¹³¹I (30 mCi) 72h after pretreatment with 0.3 mg rhTSH, or 24h after pretreatment with 0.9 mg rhTSH. The two regimens were equally effective, leading to a 30 to 40% reduction in thyroidal volume at 3 to 7 months. Giusti et al compared the 12-months outcome after RAI and rhTSH arbitrarily chosen (0.1mg for 24-h RAIU > 30 %; 0.2 mg for RAIU<30 %) between patients with basal non-toxic (TSH>0.3 mIU/l)) and non autimmune pre-toxic MNG (TSH<0.3 mIU/l). They confirmed the effectiveness of rhTSH adjuvant treatment in reducing thyroid volume after low RAI dose (<600 MBq) independently of the baseline TSH level. A more severe thyrotoxic phase after rhTSH was observed in patients with TSH<0.3 mIU/L, while L-T4 therapy was more frequently needed when initial TSH levels were > 0.3 mIU/l (133)

As mentioned, rhTSH was administered 24h before ¹³¹I therapy in most studies. However, results from a study published by Duick and Baskin (134, 135) suggested that the time interval may be even longer to achieve a maximum stimulation of the thyroid RAIU.

Recently in a phase II, single blinded, placebo-controlled study with 95 patients evaluating two low doses (0.01 and 0.03mg) of modified-release rhTSH, no statistical significant enhancement of thyroid volume reduction was achieved at three years follow-up (41% to 53%) . The modified-release rhTSH was developed to minimize the side effects related to thyroid hormone excess, (136).

(2). Tracheal compression and pulmonary function

Many elderly patients have significant intrathoracic extension of the MNG, which may cause tracheal compression with subsequent airflow reduction. Bonnema et al (137) evaluated upper airway obstruction by flow volume loops in 23 patients with very large goiter. In one third of the patients, there was impairment of the forced inspiratory flow at 50% of the vital capacity (FIF50%).The authors found a significant correlation between FIF50% and the smallest tracheal cross-sectional area. Reduction of the MNG volume after high dose of ¹³¹I had a remarkable effect in enlarging tracheal cross-sectional area and consequently improving inspiratory capacity in these patients.

(3). Transient hyperthyroidism after ¹³¹I ablation

Other studies using different doses of rhTSH and showing comparable RAIU increases with lower doses, demonstrated significant goiter reduction, but also transient hyperthyroidism after ¹³¹I therapy (131-144). A study in which 34 patients with large MNGs were randomized to receive ¹³¹I therapy (100 µCi/g of thyroid tissue) alone or following a single relatively high dose of rhTSH (0,45 mg) 24h before ¹³¹I administration, showed that patients who received rhTSH had transient elevations in thyroid hormone levels lasting a few weeks, a greater reduction in goiter size (60% vs. 40%), and a higher incidence of hypothyroidism (65% vs. 21%) (142). In another study, 18 patients received two 0.1 mg doses of rhTSH followed by 30 mCi of ¹³¹I. RAIU increased from 12 to 55%, free T 4 increased from 1.3 to 3.2 ng/dL, and goiter size reduced from 97 to 65 mL. However, about 30% of the patients experienced painful thyroiditis and 39% had mild hyperthyroidism (137). In a randomized trial of ¹³¹I treatment   calculated to deliver a thyroidal absorbed dose of 100 Gy (10 mrads) and administered 24h after rhTSH (0.3 mg) or placebo, patients with MNG (mean goiter volume of 55 cm³) who received rhTSH had more symptoms of hyperthyroidism and neck pain during the first week after treatment, a greater reduction in goiter size (52% vs. 46%), and a higher frequency of hypothyroidism (62% vs. 11%) (145). Using a similar study design, Bonnema et al (141) compared the effects of rhTSH (0.3 mg) or placebo, followed by a maximum dose of ¹³¹I 100 mCi on goiter volume reduction in 29 patients with very large goiters (median volume of 160 mL). After 12 months, the median goiter volume (monitored by magnetic resonance imaging) was reduced by 34% in the placebo group and by 53% in the rhTSH group. In the placebo group, the goiter reduction correlated positively with the retained thyroidal ¹³¹I dose, whereas this relationship was absent in the rhTSH group. Adverse effects, mainly related to thyroid pain and cervical compression, were more frequent in the rhTSH group. At 12 months, goiter-related complaints were significantly reduced in both groups without any between-group difference. One patient in the placebo group and three patients in the rhTSH group developed hypothyroidism.

Recently, an uncontrolled study (140) demonstrated the effect of rhTSH (0.1 mg, single dose) followed by ¹³¹I 30mCi 24h later in 17 patients with MNG (mean thyroid volume of 106 cm³). Pretreatment with rhTSH resulted in a mean RAIU increase from 18 to 50% and an increase in free T4 of 55% at 24h. Mean T3 levels increased by 86% and peaked at 48h, and median TG levels increased about 600% and peaked on the fifth day. Symptomatic tachycardia was promptly relieved with ß-blocker administration. After 12 months, mean thyroid volume measured by computed tomography had reduced by 46%. The adverse effects observed were transient hyperthyroidism (17.6%), painful thyroiditis (29.4%), and hypothyroidism (52.9%).

 

(4). Degree of goiter reduction, ¹³¹I dose, and rhTSH

Most investigators (Table 17-7) could not find any correlation of thyroid volume reduction with post-rhTSH RAIU, area under the curve of TSH, basal thyroid volume, or effective activity of ¹³¹I. Also, in the placebo-controlled study by Bonnema et al (141), no significant correlation was found, in either the placebo group of the rhTSH-treated group, between the degree of goiter reduction and the initial goiter size. However, in the placebo group, there was a correlation (r = 0.74) between the degree of goiter reduction and the retained ¹³¹I thyroid dose, an observation in agreement with previous reports (135). At variance, Albino et al (131) found a positive correlation (r = 0.68) between the degree of goiter volume reduction and the effective activity of administered post-rhTSH ¹³¹I dose. This issue, therefore, needs further clarification, but overall, these studies suggest that goiter reduction may be dependent on other factors caused by rhTSH pre-stimulation and not only on the applied ¹³¹I thyroid dose. For example, rhTSH could induce reactivation of inactive thyroid tissue or render the thyrocytes more vulnerable to ionizing radiation. Generally, the dose of ¹³¹I in these studies ranged from 75 to 400 µCi/g tissue, and most patients received doses between 100 and 200 µCi/g, similar to those used to treat hyperthyroidism.

Table 17-7. Studies on the effect of recombinant human TSH on goiter reduction

in multinodular goiter patients.

No. of subjects

Dose of rhTSH (mg)

Time interval between rhTSH and radioiodine (123I or 131I)

Therapeutic dose of 131I (mCi)

Peak increase in thyroid hormones (%)

Goiter reduction(%)

Time of follow-up

Goiter size estimation (Methods)

Remarks

Nieuwlaat et al. (128)

12

0.01

24 h

~39 (mean)

Free T4: 47       Free T3: 41

35

1 year

MRI

0.01 mg: 131I activity reduced by a factor 1.9

10

0.03

24 h

~23 (mean)

Free T4: 52       Free T3: 59

41

0.03 mg: 131I activity reduced by a factor 2.4;   Hypothyroidism: 36%

Duick & Baskin (134)

6

0.3

72 h

30

NI

NI

7 m

Palpation

0.3 mg: increase in 4 h RAIU 72 h after rhTSH: from 3.9 to 17

10

0.9

24 h

30

NI

30-40

0.9 mg: remission of compressive symptoms in 69%                                           Hypothyroidism: 56%

Silva et al.   (142)

17

none

~96 (mean)

Free T4: 34 T3: 33

40

1 year

CT

131I:                                                   Hypothyroidism: 23%

17

0.45

24 h

~90 (mean)

Free T4: 594         T3: 73

58

131I + rhTSH:                                     Hypothyroidism: 64%; hyperthyroidism: 100%

Albino et al. (131)

18

2 x 0.1

24 h

30

Free T4: 146           T3: 191

39

6 m

CT

24 h RAIU increased from 12 – 53%; Hypothyroidism: 65%; hyperthyroidism: 39%

Giusti et al. (140)

8

none

NM

NM

25

20 m

US + CT

12

2x0.2

24 h

NM

Free T4: 290*        Free T3: 340*

44

22 m

US + CT

Cohen et al. (132)

17

0.03

24 h

~30

Free T4: 46 T3: 33

34

6 m

CT

24 h RAIU increased from 26% to 43%; Hypothyroidism: 18%; hyperthyroidism: 18%

Nielsen et al. (145)

29

none

14 (median)

NM

46

1 year

US

131I: 24 h RAIU decreased from 32 to 29; Hypothyroidism: 11%; hyperthyroidism: 21%

28

0.3

24 h

~16 (median)

NM

62

131I + rhTSH: 24 h RAIU increased from 34 to 47; Hypothyroidism: 62%; hyperthyroidism: 36%

Bonnema et al. (141)

15

none

24 h

~42 (median)

NM

34

1 year

MRI

131I: hypothyroidism: 7%

14

0.3

~38 (median)

NM

53

131I + rhTSH: hypothyroidism: 21%

Paz-Filho et al. (137)

17

0.1

24 h

30

Free T4: 56 T3: 87

46

1 year

CT

24 h RAIU increased from 18 to 50%; Hypothyroidism: 53%; hyperthyroidism: 18%

Cubas et al. (147)

28

A: 0.1 B: 0.005 C: NONE

24 h

30

Free T4: 31 Free T4: 23 Free T4: 19

37.2 39.3 15.3

2 years

CT

43% had hypothyroid signs 25.9% had persistant hypothyroidism

Romão et al. (148)

Eu: 18 SCH: 18 CH: 6

0.1

24h

30

Free T4: 67 Free T4: 106 Free T4: 170

79.5 70.6 68.7

3 years

CT

Hypothyroidism: 50% 11% 16% Side effects more commonly find in SCH and CH

Fast et al

Clontrol

24h

rh TSH>

1 year

see Figure 17-7

(146)

Rh TSH

X control

Fast et al. (136)

95

Placebo 0.01 0.03

24hs

100Gy

NM

44 41 53

3 years

CT

Hypothyroidism: more frequently in 0.03 mg group

Giusti et al (133)

26

TSH>0.3mlU/l   TSH<0.3mlU/l

24hs

600 MBq

NM

67,1     61.7

55.3 ± 4.1m   57.2 ± 5.1m

Ultrasonography

Several side effects in both groups

M: months

(5). Increase in goiter size immediately after ablation

It is worth mentioning the possibility of increase in goiter size with rhTSH (142, 145). In a study of 10 patients with MNG who were given 0.3 mg of rhTSH, it was shown that 24h after rhTSH, the mean goiter volume increased by 9.8% and after 48h, by 24%, reverting to baseline at 1 week. This suggests that rhTSH may lead to significant cervical compression in patients with near obstructive goiters, when used for improving ¹³¹I therapy in patients with goiter (145). All side effects related to acute thyroid enlargement causing tenderness and dyspnea due to possible obstruction of tracheal airway were promptly resolved with corticosteroid therapy.

(6). Radioactive iodine and rhTSH in elderly with hyperthyroidism

Treatment with ¹³¹I following rhTSH stimulation is also an attractive alternative in elderly patients considered poor surgical candidates or who refuse surgery. The prevalence of MNG rises in the elderly, a population in whom comorbities prevail. Of even greater concern in iodine repleted areas is the development of subclinical or overt hyperthyroidism, since thyroid hyper-function may increase the mortality risk in these patients (148). An Italian study assessed 20 elderly patients with large goiters and compared treatment with ¹³¹I (10 to 15 mCi fixed dose) following two consecutive 0.2 mg doses of rhTSH (n = 12; 3 patients had subclinical hyperthyroidism with TSH <0.3 µU/ml) with treatment with ¹³¹I alone (n = 8; subclinical hyperthyroidism recorded in 5). Patients who received rhTSH had higher transient elevations in free T4 and Free T3 lasting 2 weeks, a greater reduction in goiter size (44% vs. 25%). Both groups had a 17% incidence of hypothyroidism ~ 2 years after ¹³¹I therapy. Symptomatic relief occurred in all but 1 patient following rhTSH with a 50% median reduction on thyroid volume after about 2 years (140). In study conducted by Silva et al (142), 17 elderly subjects with MNG treatment with ¹³¹I 24h after pretreatment with 0.45 mg rhTSH and were compared with 17 elderly controls treated with ¹³¹I alone. In patients pretreated with rhTSH, serum TSH and T3 levels rose to a peak level in 24h, returning to normal at 72h. Serum free T4 concentrations rose significantly at 48h returning to normal at 7 days. Serum TG increased and remained elevated during the following 12 months. Patients pretreated with rhTSH had a 58% reduction in goiter volume when compared with 40% in patients treated with ¹³¹I alone. Hypothyroidism was more frequent in pretreated patients (65% versus 21% in non-pretreated) after 1 year. No symptoms of hyperthyroidism were observed in these patients. Four years after ¹³¹I therapy, additional thyroid volume reduction was similar for patients treated with rhTSH prior to ¹³¹I or with ¹³¹I alone, but it was significantly more pronounced in the rhTSH group, mainly in the first year (149). Although no additional benefit of rhTSH was observed after a long follow-up, the initial difference in thyroid volume reduction was maintained, denoting the advantage of using rhTSH pretreatment to achieve higher thyroid volume reduction during the first treatment (Table 17-6).

In another report of a short-term observational study, the investigators assessed the efficacy of a low-dose (0.03 mg) rhTSH stimulation on a fixed therapeutic activity of ~ 30 mCi ¹³¹I in 17 patients with large nodular goiters (12 with overt or subclinical hyperthyroidism / TSH <0.5 µU/ml and five on treatment with thionamides) (147). RAIU increased from 26% to 43%, free T4 increased from 1.4 to 2.0 ng/dl, and goiter size decreased from 170 to 113 cm³ by 6 months. Symptomatic relief, improved well-being and / or reduction, or elimination of anti-hyperthyroid drug was seen in 76% of the patients. However, 3 (18%) patients presented transient neck pain or tenderness, 1 experienced asymptomatic thyroid enlargement, and 3 became hypothyroid by 3 months (Table 17-6). A recent paper (146) compared the results of RAI alone and RAI preceded by rhTSH (see Figure 17-8) clearly demonstrating the efficacy of pre-treatment with rh TSH.

(7). Cardiovascular events after RAI ablation

Cardiovascular parameters to detect transient elevation of serum thyroid hormones were evaluated in 27 of 42 patients (age range 42-80 years) with large MNGs who were treated with rhTSH before receiving ¹³¹I 30 mCi (150). All patients presented a transient surge in serum levels of free T4 and total T3 into the hyperthyroid range following therapy. However, post-treatment cardiovascular evaluation did not show significant changes when compared with baseline evaluation, suggesting that treatment of MNGs with RAI after rhTSH stimulation does not affect structural and functional parameters of the heart. These findings are reassuring, particularly when considering treatment for older adults with comorbidities that preclude surgery.

(8). Thyroid autoantibodies occurrence after ¹³¹I therapy

Some studies have reported the development of thyroid antibodies associated with ¹³¹I therapy (151), however a direct cause-effect linking to rhTSH has not been demonstrated. These observations have been interpreted as an immunological response caused by the release of thyroid antigens from destroyed follicular cells. In a study published by Rubio et al (152), it was found that rhTSH pretreatment had no significant effect in the development of antibodies (TSH receptor and TPO) when compared with treatment with ¹³¹I alone. As noted below, up to 5% of individuals develop auto-immune hyperthyroidism after 131-I therapy.

(9). Potential induction of malignancy

Although generally ignored, treatment with large doses of 131-I obviously raises the possibility of induction of malignancy. This has not so far been recorded in relation to therapy of MNG. Depending on functionality of the thyroid tissue, dose administered, size of the goiter, and size of the patient, whole body radiation could be up to 1 rad/mCi given, a dosage similar to that obtained during therapy of thyroid cancer. Perhaps the major use of this treatment will be in older individuals, with a shorter potential life span after treatment, which would presumably make this less of a concern.

Conclusions and comments

Given the limited experience published in the literature so far, before considering the routine use of rhTSH administration before ¹³¹I treatment of MNG, several issues must be taken into consideration (153-157).

• ¹³³I treatment alone can lead to a 15-25% transient increase in thyroid volume during the first week after treatment;
• rhTSH administration alone occasionally can lead to a significant increase, albeit transient, in thyroid volume, of up to 100% in normal subjects with 48h.
• The combination of the two modalities may lead to a substantial acute increase in thyroid volume;
• ¹³¹I treatment of MNG leads to transient hyperthyroidism during the first 2-3 weeks after therapy and the combination with rhTSH administration can enhance this effect, with potential consequences particularly for the elderly patients (148);
• The optimal dose of rhTSH for pretreatment of MNG remains to be determined. Studies have used different doses and regimens or rhTSH administration, from as low as 0.01 or 0.03 mg to as high as 0.45 mg or   0.9 mg 24h before RAI treatment;
• There is a significant occurrence of hypothyroidism after ¹³¹I treatment following rhTSH stimulation;
• Although rare, autoimmune hyperthyroidism (approximate reported incidence of 4-5%) can develop after treatment of MNG with ¹³¹I;
• Currently, rhTSH is not approved by the FDA as an adjuvant for ¹³¹I treatment of goiter.

 

Based on these results, pretreatment with rhTSH seems a promising alternative to thyroid surgery for the management of nontoxic MNG, particularly in elderly individuals. However, the optimal dose and timing of both, rhTSH and ¹³¹I as well as the criteria for patient eligibility remain to be determined.

Figure 17-8 – An elderly woman with a large and longstanding MNG that migrated to the upper mediastinal region with subsequent compression of the subclavian system. Note the subcutaneous enlarged venous circulation (a). In the next panel (b), it is presented the scintilographic studies after a tracer dose of 131I before and (c) after stimulation by 0.45 mg of recombinant human TSH. (ref. 142.).

Surgery for MNG

As indicated by Fast et al (154) it is time to consider radioiodine treatment for MNG as an alternative to surgery. As indicated previously radioiodine (¹³¹I) is a simple, cost-effective and safe procedure with an impressive goiter reduction up to 65% of the original volume. Surgery of the MNG, however, is equally effective and the choice among the two procedures depends largely on their availability, clinical features, and last but not least the personal preference of the patient (and also the physician in charge). In many centers, specially in countries with large populations previously living in iodine deficiency, the number of patients with MNG, most of them, over 50 years old, are very common in the thyroid clinic daily routine. Therefore sending all those patients to surgery will inevitably, cause a logistic problem in terms of available surgical rooms, surgeons well trained in head and neck surgery, post surgical follow-up and all the costs involved. Moreover with the widespread use of ultrasonographic studies followed by Fine Needle Aspiration Biopsy (FNAB) the number of new cases of thyroid cancer has increased dramatically in the past few years. Obviously these patients will have precedence for a surgical therapy as compared with the patient with MNG. This situation is quite common in many countries where there is a long waiting list for a given patient to be selected for thyroid surgery. Frequently surgery of the thyroid due to a nodule harboring a papillary cancer in a relatively young subject has a definite preferential status over an elderly patient with a long standing MNG.

The preferred operation for MNG is subtotal thyroidectomy. The frequency of complications due to surgical depends on several factors and well-trained and experienced surgeons will reduce the rates of such complications. Recurrence after goiter surgery is rare and the frequency of hypothyroidism is low. It is advisable to introduce L-T4 therapy after surgery in order to avoid goiter recurrence although this option is considered highly controversial.

Laser Ablation Therapy

A retrospective study that assessed clinical records of 1534 benign nodules in 1531 patients treated with image-guided laser ablation therapy (LAT) showed that LAT induced a clinical relevant nodule volume reduction that ranges from 48 to 96% (72±11%) twelve months after treatment (158). This picture was more significantly in mixed nodules (range 70-92%, 79±7%). Most of the nodules (83%) received a single LAT dose while 13% received two doses and 3% three doses, with a total energy delivery based on the initial volume. The symptoms improved from 10% to 49% of cases (p<0.001), while major (voice changes) and minor complications (hematomas, skin burn) were rare. Thus, LAT is considered clinically effective and well-tolerated as an alternative to surgery for benign thyroid lesions.

To summarize: treatment of MNG with L-T4 suppressive doses is not accepted by many thyroidologists in spite of the fact that goiter reduction is achieved in one third of the patients and new nodules appearance is lower in the L-T4 treated patients.The results so far published using radioiodine preceded by rhTSH are quite encouraging . It is an excellent alternative when surgical teams are not available for all patients. LAT treatment should be performed only by experience operators. Finally, patients preference for a non- surgical alternative should always be taken into consideration.

SUMMARY

Perhaps the most common of all the disorders of the thyroid gland is multinodular goiter. Even in non-endemic regions it is clinically detected in about 4% of all adults beyond the age of 30. Pathologically it is much more frequent, the percentage incidence being roughly the same as the age of the group examined. The disease is much more common in women than in men.

Multinodular goiter is thought to be the result of primarily two factors. The first factor is genetic heterogeneity of follicular cells with regard to function (i.e. thyroid hormone synthesis) and growth. The second factor is the acquisition of new qualities that were not present in mother cells and become inheritable during further replication. Mutations may occur in follicular cells leading to constitutively activated adenomas and to hyperthyroidism. These factors may lead to loss of anatomical and functional integrity of the follicles and of the gland as a whole. These processes ultimately lead to goiter formation and are accelerated by stimulatory factors. These stimulatory factors are basically an elevated serum TSH, brought about by events such as iodine deficiency, inborn errors of thyroid hormone synthesis, goitrogens or local tissue growth-regulating factors. These basic and secondary factors may cause the thyroid to grow and gradually evolve into an organ containing hyperplastic islands of normal glandular elements, together with nodules and cysts of varied histologic pattern.

Nodular goiter is most often detected simply as a mass in the neck, but at times an enlarging gland produces pressure symptoms on the trachea and the esophagus. Occasionally tenderness and a sudden increase in size herald hemorrhage into a cyst. Hyperthyroidism develops in a large proportion of these goiters after a few decades frequently after iodine excess. Rare complications are paralysis of the recurrent laryngeal nerve, and pressure on the superior sympathetic ganglion causes a Horner´s syndrome.

The diagnosis is based on the physical examination. Thyroid function test results are normal or disclose subclinical or overt hyperthyroidism. Thyroid autoantibodies are usually absent or low, excluding Hashimoto´s thyroidits. Imaging procedures may reveal distortion of the trachea, calcified cysts, or impingement of the goiter on the esophagus. Sonographic studies, Scintilography (¹³¹I), CT and MRI are useful to detect details of the MNG and to provide an estimation of the volume before and after therapy.

From 4 to 17% of multinodular thyroids removed at operation contain foci that on microscopic examination fulfill the criteria of malignant change. The infrequency of thyroid cancer as a cause of death clearly proves that the vast majority of these lesions are not lethal or even clinically active. One of the reasons for the high incidence of cancer in surgical specimens is that patients with multinodular goiters were often selected for surgery because of a concern for carcinoma.

If a clinical and biochemically euthyroid multinodular goiter is small and produces no symptoms, treatment is controversial. T4 given in an effort to shrink the gland or to prevent further growth is effective in about one third of the patients. This therapy is more likely to be effective if begun at an early age while the goiter is still diffuse than in older patients in whom certain nodules may have already become autonomous. If the clinically euthyroid goiter is unsightly, shows subclinical hyperthyroidism or is causing, pressure symptoms, treatment with ¹³¹I preceded by recombinant human TSH is successful in virtually all cases but causes hypothyroidism at varying degree. Surgery is an acceptable alternative. The efficacy of T4 treatment after surgery, to prevent regrowth, is frequently used albeit debatable.

Overt toxic nodular goiter is usually treated with radioiodine. A gratifying reduction in the size of the goiter and control of the hyperthyroidism may be expected. Hypothyroidism often ensues.

During the past few years the use of recombinant human TSH has been used to enhance the uptake of radioiodine and to provide a more homogenous distribution of the radionuclide. Results have been rewarding with a 45-65% shrinkage of the MNG, even with an intrathoracic position. A surge of high levels of serum Free T4, total T3 and serum TG is observed in the first weeks after therapy. Clinically hyperthyroid patients seem to have more unwanted signs and symptoms as compared to euthyroid patients. Hypothyroidism (permanent) is commonly observed at 6-12 months after rhTSH plus RAI treatment. Taking all into account, this modality of treatment of MNG has a relatively low cost and it is considered a good alternative to surgery that might not be available for all patients with MNG in many centers around the world.

The term colloid is applied to glands composed of uniformly distended follicles appearing as a diffuse enlargement of the thyroid gland. The condition is found almost exclusively in young women. With time and due to a number of primary and secondary factors it may gradually develop into a multinodular goiter which becomes increasingly prominent as the decades pass. Appropriate therapy, if required, is the timely administration of thyroid hormone that may be continued for several years.

An intrathoracic goiter is usually an acquired rather than a development abnormality. It may come about in embryonic life by a carrying downward into the thorax of the developing thyroid anlage, or in adult life by protrusion of an enlarging thyroid through the superior thoracic inlet into the yielding mediastinal spaces. These lesions may produce pressure symptoms and may also be associated with hyperthyroidism. If too large for treatment with ¹³¹I, the appropriate therapy is resection of the goiter through the neck, if possible. Attachment of the intrathoracic goiter to the gland in the neck ordinarily proves the site of origin and provides a method for its easy surgical removal. In many of these patients a safe and easily performed therapy, in an outpatient mode, is the administration of a fixed dose of radioiodine (¹³¹I) of 30 mCi preceded by rhTSH.

 

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