Christoph A. Meier
Albert C. Burger
Various drugs and other substances are known to interfere with thyroid hormone homeostasis. Although the action of some compounds on thyroid hormone secretion and metabolism are considered to be adverse effects, the inhibitory effect of certain molecules (e.g., thionamides, perchlorate, and iodinated compounds) is exploited clinically for the treatment of thyrotoxicosis. Pharmacologic agents may influence thyroid hormone homeostasis at four different levels (Fig. 11C.1 and Table 11C.1). First, they may alter the synthesis and/or secretion of thyroid hormones. Second, they may change the serum concentrations of thyroid hormones by altering either the level of binding proteins or by competing for their hormone binding sites. Third, they may modify the cellular uptake and metabolism of thyroid hormones. Lastly, they may interfere with hormone action at the target tissue level. Although most drug-induced changes in thyroid hormone homeostasis are transient, they may hinder the interpretation of thyroid function tests. However, with improvements in the quality of routine measurements of serum-free thyroid hormone and thyroid-stimulating hormone (thyrotropin; TSH) concentrations, the latter difficulties have decreased in importance.
FIGURE 11C.1. Drugs may perturb thyroid hormone homeostasis at different levels. Some drugs, such as amiodarone and phenytoin, have several mechanisms of interaction. FFA, free fatty acids; IFN, interferon; IL, interleukin; NSAID, nonsteroidal anti-inflammatory drugs; 5′-DI, 5′-monodeiodinase type 1.
TABLE 11C.1. COMPOUNDS INTERFERING WITH THYROID FUNCTION
Site of Action
Mode of Action
Competitive inhibition of iodination
Deiodinase type 1
Na/I symporter thyroid peroxidase and secretion
Steric inhibition of iodination and independent block of secretion
Transient effect (except after 131I treatment) as discussed in this chapter
Radiographic contrast agents
Na/I symporter, thyroid peroxidase and ssecretion
Steric inhibition of iodination and independent block of secretion
Na/I symporter thyroid peroxidase and secretion
Steric inhibition of iodination and independent block of secretion
Transient effect (except after 131I treatment) as discussed in this chapter
Liver, brain, thyroid
Deiodinase types 1 and 2
Na/I symporter, thyroid peroxidase and secretion
Steric inhibition of iodination and independent block of secretion
2 g first day, then 0.5 g/day
Liver, brain, thyroid
Deiodinase types 1 and 2
Na/I symporter, thyroid peroxidase and secretion
Steric inhibition of iodination and independent block of secretion
2 g first day, then 0.5 g
Liver, brain, thyroid
Deiodinase types 1 and 2
Transthyretin and monodeiodination
Binding site for T4
Cytokines (IFN-γ IL-2, GM-CSF)
Stimulation or inhibition
Serum levels used in psychiatric disease
Binding site of T4
TBG and transthyretin
Binding site of T4
Free fatty acids
TBG and transthyretin
Binding site of T4
Small intestine and liver
Liver, peripheral β-blockade
Monodeiodinase type 1
SUBSTANCES INTERFERING WITH THYROID HORMONE SYNTHESIS
In the early part of the twentieth century, the prevalence of severe to moderate iodine deficiency in developed countries was still widespread. Goiter formation was therefore ubiquitous, yet its degree varied despite similar levels of iodine deficiency. This also has been observed more recently in developing countries. Low iodine intake is a good experimental condition for discovering additional factors leading to goiter formation, and it is probable that in the presence of high iodine intake many substances interfering with thyroid hormone synthesis would not have been discovered so easily. The development of large goiters in rabbits fed cabbage led to the discovery of the precursor of the presently used thionamides. Of the ionic antithyroid compounds, precursors of thiocyanate are present in cassava, which led to severe endemic goiter in Congo; however, they can also be found in maize, bamboo shoots, and sweet potatoes. Mechanistically, the thionamides interfere with the process of hormone synthesis, whereas the ionic compounds mainly but not exclusively inhibit the active transport of iodide.
THIONAMIDES (ANTITHYROID DRUGS)
Three compounds of this class are the most widely used antithyroid drugs. In the United States, propylthiouracil (PTU) and methimazole (MMI) are the most frequently used antithyroid drugs, whereas in Europe carbimazole is the main antithyroid drug (Table 11C.1). Carbimazole differs from MMI by a carboxy side chain, which is cleaved off during the first liver passage, converting carbimazole to MMI (See Chapter 45).
All three compounds are completely absorbed, and their metabolism is little affected by liver or kidney disease (Table 11C.1) (1). The thyroid avidly concentrates these compounds. This uptake is more pronounced in very active glands, as in iodine deficiency or hyperthyroidism. The thyroid also plays an important role in the degradation of these drugs (2,3). In rat 35S-labeled metabolites of PTU can be detected up to 40 hours after injection. In vitro studies indicate that the intrathyroidal degradation of PTU and MMI is strongly influenced by the intrathyroidal iodide content (Fig. 11C.2). The serum half-life is < 6 hours for MMI and < 2 hours for PTU (Table 11C.2 Clinical studies have shown effects of MMI lasting as long as 24 to 36 hours, and a single dose of PTU was effective for more than 12 hours. This correlates well with the intrathyroidal presence of 35S-labeled metabolites of these drugs. The intrathyroidal mechanism of action of the three drugs is similar. They inhibit hormone synthesis by thyroid peroxidase (TPO). This synthesis can be separated into two steps, whereby initially a tyrosine residue of thyroglobulin (Tg) is iodinated followed by a coupling reaction, also under the control of TPO, resulting in the formation of an ether bond between two diiodotyrosines of Tg and the formation of thyroxine (T4) and, to a minor extent, of triiodothyronine (T3) (See section Thyroid Hormone Synthesis in Chapter 4). Both reactions are inhibited by thionamides. There is a marked competition between iodide and the thionamides for the active site of TPO. The mechanism of this competition is complex. There is competitive inhibition for the active site, and the residence time of PTU or MMI is inversely related to the intrathyroidal iodide concentration. In vitro the degradation of 35S-labeled PTU was extremely slow in iodine deficiency and accelerated with increasing iodide concentrations (2,3). In situations of severe iodine excess, these are the two major mechanisms leading to the loss of efficiency of these drugs. It is also likely that iodine excess reduces the capacity of the thyroid to concentrate the thionamides.
FIGURE 11C.2. Schematic presentation of the intrathyroidal metabolism of propylthiouracil (PTU). In the presence of low intrathyroidal iodine concentrations, the PTU and/or its metabolites remain in the thyroid for a much longer time than in serum. With an iodide load, PTU is more rapidly metabolized, and during chronic iodine contamination, its uptake is also decreased.
TABLE 11C.2. PHARMACOKINETICS OF ANTITHYROID DRUGS
Rapid and complete
Rapid and complete
Rapid and complete
< 2 h
High and prolonged
High and prolonged
High and short-lived
Decreased with iodine excess
Duration of action
24 h (15 mg)
< 12 h (300 mg)
Passage into breast milk
All three thionamide drugs have similar side effects. At least 5% of patients initially complain of pruritus, and more rarely of an urticarial rash and drug fever. These symptoms often appear during early treatment and with high doses. Reducing the dose is in general helpful, but an occasional patient may have to stop treatment or to switch from one drug to the other. In an occasional patient the drugs, particularly PTU, can be cause a bitter taste, which does not disappear with time. Carbimazole and MMI may cause cholestatic jaundice. PTU occasionally increases serum aminotransferases and can cause fulminant hepatic failure has been reported (4).
The major serious complication of these drugs is agranulocytosis (< 500 neutrophils/mm3). It is rare complication and probably occurs with all three drugs in < 0.25% of cases. Its onset is usually abrupt. Due to the rapid appearance of agranulocytosis, monitoring of the white blood cell count is not helpful. Patients must, however, seek medical care in case of a sore throat and fever and stop treatment until the white blood cell count is determined. Stopping antithyroid drug treatment is sufficient to permit complete recovery in almost all patients.
PTU-induced antineutrophil cytoplasmic antibody (ANCA)–related vasculitis and nephritis have also been reported, and it has been suggested that in patients treated with PTU the presence of ANCA should be monitored (5,6,7).
Special Indications and Differences between Propylthiouracil and Methimazole
PTU differs in two clinically relevant aspects from MMI and carbimazole. Probably due to its very short plasma half-life, its transplacental effects are minor, and it is also excreted less in maternal milk. Therefore, PTU is the drug of choice in pregnancy (8,9,10), although this remains somewhat controversial (see Chapter 80). In the postpartum period, MMI is also very safe, and its tolerance is even better documented than PTU (11). Only PTU has an inhibitory effect on deiodinase type 1 activity (12). In cases of severe iodine contamination, PTU probably has an advantage over MMI because of its extra thyroidal action. However, in humans this effect can only be achieved by large doses of PTU, and it results in only a 30% reduction of serum T3 levels; in practice, therefore, the therapeutic advantage is small.
In vitro, MMI and PTU have an immunosuppressive effect. The relevance of this effect on remission rates is debated, but a difference has not been detected in the cure and relapse rates of patients with Graves' hyperthyroidism (13,14).
The molecular mechanism of iodide trapping by the thyroid has been elucidated through the cloning of the thyroid sodium iodide (Na+/I-) symporter (NIS) (15,16). Two anionic compounds, perchlorate and thiocyanate, are of some clinical relevance. These are bulky anions, which sterically resemble iodide. Their mode of action is to compete with iodide for the symporter, and perchlorate is a more potent inhibitor than thiocyanate. Perchlorate is also able to discharge intrathyroidal iodide rapidly and may have additional actions, such as actions inhibiting the transport of iodide from the cell into the lumen of the follicles. Perchlorate can accumulate in the follicular cell; as for iodide, its accumulation is dependent on TSH stimulation. The trapping of iodide is closely linked to countertransport of Na+, and here, too, perchlorate could have an inhibitory action (17). The peak blood levels occur approximately 3 hours after oral intake, and its intrathyroidal concentration peaks at 4 to 6 hours. Its duration of action has not been studied in detail, but it is believed to be short, and is therefore preferably given two to four times daily.
The first reports of the clinical use of perchlorate date to the 1950s. Its use for treatment of thyrotoxicosis when irreversible aplastic bone marrow suppression was reported. Other side effects are rashes, drug fever, lymphadenopathy, and agranulocytosis, but these complications are likely to be less frequent than with thionamides. Rare cases of nephrotic syndrome also have been reported. The appearance of aplastic anemia limited the use of this drug to few specific clinical conditions. In case of congenital goiters due to genetic defects of thyroid hormone synthesis, the perchlorate discharge test is the diagnostic standard for revealing an abnormally large pool of intracellular iodide that has not been incorporated into thyroglobulin. This metabolic block can be mimicked by thionamides, which induce a functional block at the level of TPO (see Chapter 4). There are two variations of the perchlorate discharge test. The classical test uses only 1 g perchlorate, which is given 2 hours after administration of iodine-123 (123I). Uptake of 123I is measured just before administering perchlorate and 1 and 2 hours later. In normal thyroids the discharge should not exceed 15% of the accumulated thyroidal dose. A modification of this test has been introduced in order to reveal partial organification defects. In this case, 500 µg iodide administered at the same time as the 123I. This leads to a transient increase in intracellular free iodide, and perchlorate can reveal small defects that are not seen with the classical test. This modification has been applied to demonstrate mild organification defects in autoimmune thyroiditis.
Perchlorate also has been used for short-term inhibition of thyroidal radioactive iodide accumulation after administration of contrast media for angiographic studies and computed axial tomography. Perchlorate is also indicated for the treatment of severe cases of amiodarone- or iodine-induced thyrotoxicosis, which can be a life-threatening situation. The addition of 0.5 g perchlorate twice daily to high-dose PTU or MMI treatment has shortened the period of thyrotoxicosis (see Chapter 51). In contrast to perchlorate, thiocyanate is not used in clinical medicine.
ENVIRONMENTAL CONTAMINANTS WITH GOITROGENIC ACTION
Isothiocyanates and thiocyanates or their precursors are substances that can be found in various geographic regions in plants of the Cruciferae family. In Africa cassava contains large amounts of thiocyanate and is responsible for aggravating goiter formation in iodine-deficient areas (18,19,20,21). Thiocyanate is also found in high concentrations in tobacco and waste water effluents of coal conversion processes. The most potent goitrogenic substance, L-5-vinyl-2-thiooxazolidone, known as goitrin, is found in yellow turnips and Brassica seeds. This substance inhibits thyroid hormone synthesis, and its mechanism of action resembles that of the thionamides. The concentrations of these goitrogens as contaminants of food and drinking waters are nevertheless too low to induce goiter if iodine intake is sufficient.
In recent years there has been great interest in flavonoids. These compounds are present in most fruits and vegetables, and they are particularly abundant in subtropical and arid areas. They may aggravate goiter formation in areas with coexistent iodine deficiency. These substances have complex actions, and synthetic analogues have been tested (22,23,24). One of these substances, EMD 21388, decreased deiodinase type 1 activity, and it very efficiently displaced T4 from transthyretin, resulting in an increase in free T4 concentrations.
Other substances of potential goitrogenic action are phenols, ubiquitous contaminants of drinking and waste water (25). Their toxic effects are well documented experimentally at high concentrations. Such concentrations are unlikely to be obtained under present environmental conditions, but if present could impart fetal and neonatal development (26). One of them, resorcinol, was used as a dermatologic ointment and resulted in goiter formation. Polyvinylfluoride products contain phthalate esters that, in very high concentrations, are able to produce goiters in rats (27). It is unlikely that the environmental concentrations, cause goiters in rats (27). It is unlikely that the environmental concentrations of these substances are sufficient to increase goiter size in iodine-deficient areas in humans.
IODINE AND IODINATED DRUGS
Thyroid hormone secretion can be either increased or decreased in response to iodinated drugs, such as radiographic contrast media and amiodarone (Table 11C.1). Although the inhibitory effect of iodine on thyroidal hormone synthesis and secretion is usually spontaneously reversible after several days, TSH and free T4 levels may transiently change for 1 to 2 weeks following an acute iodine load. Long-standing iodine-induced thyrotoxicosis and hypothyroidism occur less frequently and are described elsewhere in this chapter.
Amiodarone in particular induces thyrotoxicosis and hypothyroidism. Although amiodarone-induced thyrotoxcisosis is particularly prevalent (10%) in iodine-deficient regions and in patients with underlying thyroid disease, such as nodular autonomy or Graves' disease, can also occur in patients with no preexisting thyroid disease (28,29,30,31). There are two forms of amiodarone-induced thyrotoxicosis: (a) type I, which is similar to classical iodine-induced excess of hormone synthesis in patients with preexisting thyroid abnormalities (32), and (b) type II, which resembles subacute destructive thyroiditis with excess hormone release in patients with no history of prior thyroid disease, possibly due to a direct cytotoxic effect of amiodarone (33,34,35,36,37). The latter form is characterized by a low 24-hour thyroidal radioactive iodine uptake and high serum interleukin-6 (IL-6) levels, the latter reflecting a thyroid-destructive process (35). However, high IL-6 concentrations have not been found by others, and C-reactive protein levels have not been found to be helpful in the differential diagnosis between type I and type II (37a). Color flow Doppler sonography may be able to distinguish between these two entities (38). The therapeutic response of both forms is similar (39). Amiodarone-induced thyroid gland dysfunction, including thyrotoxicosis and hypothyroidism, is discussed in detail elsewhere in this chapter. The inhibitory effects of amiodarone on thyroid hormone deiodination and the peripheral actions of thyroid hormone also are discussed in detail later in the chapter.
Several cytokines alter thyroid hormone secretion and metabolism (40,41). Administration of interferons, interleukins, and granulocyte-macrophage colony-stimulating factor has been associated with a high frequency of transient thyrotoxicosis and hypothyroidism (40,42,43,45,46,47,48) (Table 11C.1). Although these cytokines may elicit either the appearance of thyroid antibodies or an increase in thyroid antibody titers, these changes are not always associated with thyroid dysfunction, which also may occur in the absence of antibodies, possibly through direct effects on the thyroid gland. In addition, the pattern of antibodies after cytokine therapy appears to be different from that in patients with endogenous autoimmune thyroid disease (49).
About 5% of patients receiving treatment with interferon-α for hepatitis C develop thyroid dysfunction, mostly autoimmune thyroiditis, and more rarely Graves' disease (50,51,52). Similarly, patients with multiple sclerosis and treated with interferon-β are at risk of developing thyroid dysfunction (53). However, the appearance of thyroid antibodies without thyroid dysfunction during interferon-α therapy is much more common, and it is not influenced by the concomitant administration of ribavirin (54). The occurrence of transient thyrotoxicosis followed by a hypothyroid phase, typical for silent thyroiditis, has also been reported (55,56,57). It is notable that patients with hepatitis C have an increased risk for thyroid autoimmunity even before undergoing antiviral treatment (51,58). Moreover, positive thyroid antibodies at baseline are a clear risk factor for developing hypothyroidism during treatment (51). While it is tempting to screen for thyroid antibodies in patients with hepatitis C, its impact on patient management is unclear. Given the low incidence of hypothyroidism in these patients and the fact that most patients develop subclinical hypothyroidism, this author prefers to measure serum TSH before and after completion (usually 1 year) of treatment for hepatitis C, and to perform an additional TSH measurement 6 months late only in patients with symptoms of thyroid dysfunction. Others suggest more frequent measurements of thyroid function (58a). Thyroid dysfunction usually appears after 3 months of treatment and may persist even after its discontinuation (59). It is important to recognize that patients with a history of thyroid dysfunction during interferon-α therapy remain susceptible to developing iodine-induced thyroid disease later (60).
Interferons, interleukin-1 (IL-1), and tumor necrosis factor-α are also known to inhibit iodine organification and hormone release, as well as to modulate thyroglobulin production and thyrocyte growth (61,62,63,64). In contrast to interferon-α and interleukin-2 (IL-2), interferon-γ increases the expression of the major histocompatibility complex class II molecules on the cell surface, which is thought to be an important event in the initiation of autoimmune diseases (65,66). IL-2 is used experimentally in the immunotherapy of cancer, which results in transient thyroid dysfunction in 15% to 40% of patients (44). Thyroid function sometimes normalizes during therapy, but always after stopping the cytokine treatment.
SUBSTANCES INHIBITING THYROID HORMONE SECRETION
Lithium, used in the treatment of bipolar depression, is associated with subclinical and overt hypothyroidism in up to 34% and 15% of patients, respectively, and can appear abruptly even after many years of treatment (67). Therefore, patients should be regularly examined for symptoms and signs of thyroid dysfunction, and thyroid function tests should be performed once or twice a year (68,69). The inhibitory effect of lithium occurs mainly at the level of hormone secretion, although effects on iodine trapping, release, and coupling have been described. In contrast to lithium-induced hypothyroidism, lithium-associated thyrotoxicosis is not common and occurs mainly after the long-term use of this drug (70). Although the mechanisms are unclear, the induction of antibodies and of ophthalmopathy has been reported, and histologic features of either autoimmune or destructive thyroiditis have been reported in some cases (71,72,73). Finally, transient euthyroid hyperthyroxinemia has been reported after the discontinuation of lithium treatment (74).
The inhibitory effect of lithium on the secretion of thyroid hormone and iodine may be of some therapeutic use in the treatment of severe thyrotoxicosis (e.g., after amiodarone), as well as for enhancement of the efficacy of radioactive iodine in Graves' hyperthyroidism (75,76) or differentiated thyroid cancer (76A).
SUBSTANCES ALTERING THYROID HORMONE TRANSPORT
Alterations in Concentrations of Thyroxine Hormone–Binding Globulin
The three major serum T4- and T3-binding proteins are thyroxine-binding globulin (TBG); transthyretin, formerly called thyroxine-binding prealbumin; and albumin. In addition, the high-density lipoproteins transport 3% to 6% of the circulating T4 and T3, and high-affinity binding sites have been demonstrated on one of the apoproteins, apoprotein A-I (77,78,79).
In humans, approximately 0.02% of the circulating T4 and about 0.1% of circulating T3 are free; hence, the serum total T4 and T3 concentrations are equivalent to the concentrations of bound T4 and T3 (80). The bound hormones represent a circulating reservoir and are usually not directly accessible to the tissues. Little evidence suggests that substantial amounts of protein-bound T4 or T3 can be taken up by cells (80,81). There may be some exceptions to this rule. For example, the choroid plexus synthesizes and secretes transthyretin into the cerebrospinal fluid. This represents a transport mechanism for T4. In addition, glial cells have specific receptors for transthyretin, so there may be uptake of T4 bound to protein into these cells (82,83,84). For most tissues, however, the circulating free T4 and T3 concentrations determine delivery of T4 and T3 and are considered responsible for the cellular effects of thyroid hormones.
Further details on the physiology and abnormalities of the thyroid hormone–binding proteins and the clinical understanding of these perturbations in thyroid hormone transport are discussed in detail in Chapter 6 and Chapter 13 and elsewhere in this chapter.
DRUGS THAT COMPETE WITH THYROXINE- AND TRIIODOTHYRONINE-BINDING SITES ON SERUM THYROID HORMONE–BINDING PROTEINS
Many drugs inhibit the binding of T4 and T3 to their binding sites on serum transport proteins in vitro (85,86) (Table 11C.1). These effects require high concentrations of such drugs, and the effects do not occur in vivo. The following paragraphs describe the effects of drugs that result in in vivo alteration of serum thyroid hormone levels. When such alterations occur, serum total T4 and T3 concentrations decline, but the free hormone concentrations do not.
Nonsteroidal Anti-inflammatory Drugs
Salicylates are important drugs in this category because of their widespread use in clinical medicine. Salicylates inhibit T4 and T3 binding to both TBG and transthyretin, resulting in a fall in serum T4 and T3 concentrations (87,88). Other nonsteroidal antiinflammatory drugs also displace T4 from its binding sites, particularly fenclofenac, but this drug is no longer available in most countries (89).
Furosemide has been reported to inhibit T4 binding (90). The effect does not occur with oral doses of < 100 mg, but is found consistently with very large intravenous doses of furosemide.
These naturally occurring substances are structurally similar to thyroid hormones. A synthetic flavonoid (EMD 21388) has been designed to optimize its competitive effect for thyroid hormone binding, and in rats it has proven to be a potent inhibitor of T4 binding to transthyretin. Its effects on T3 are less marked. It does not compete for T4 binding to TBG. The flavonoid-induced alterations of free hormone levels in rats affect TSH feedback regulation and tissue transfer and elimination of thyroid hormones. EMD is also an inhibitor of deiodination. Naturally occurring flavonoids may have similar but less dramatic effects on thyroid function (24,84).
HEPARIN AND FATTY ACIDS
Although the addition of heparin to serum does not increase serum free T4 levels, it causes transient increases in free T4 levels in vivo, particularly when equilibrium dialysis was used for its measurement (91,92). These findings have been confirmed with enoxaparin (93). The authors proposed a 10-hour delay in measuring free T4 after an intravenous injection of 2,000 U enoxaparin. These recommendations may depend on the type of heparin and free T4 method, but caution in interpretation of free T4 values in these circumstances remains necessary. It is thought that large doses of heparin alter the distribution of T4between plasma and its rapidly exchangeable tissue pools so as to increase the former and decrease the latter (94,95). These changes are of diagnostic, but not clinical, consequence because heparin-treated patients do not become thyrotoxic. The underlying pathogenesis of the heparin effect is thought to be lipoprotein lipase activation both in vivo and in vitro, with hydrolysis of triglycerides to free fatty acids (FFAs). In vitro activation of the lipoprotein lipase can be minimized by rapid and careful pre-analytical handling and by avoiding repeated freezing and thawing. To be effective, serum FFA levels have to exceed 2.5 to 3 mEq/L. In vivo, such concentrations occur rarely. They may be encountered during hemodialysis and intravenous hyperalimentation, particularly if serum albumin levels are low and if the patient is treated with heparin (92). It is claimed that some newer analogue methods for measuring serum free T4 or T3 are unaffected by heparin–lipase–FFA effects.
ALTERATIONS OF THYROID HORMONE METABOLISM AND ACTION
Drugs can alter thyroid hormone availability not only by means of changes in the free serum hormone concentration, but also by modulating the cellular uptake, metabolism, and nuclear actions of the hormone.
THYROID HORMONE UPTAKE
The inhibition of thyroid hormone uptake by drugs may occur at the intestinal level, thereby leading to decreased serum hormone levels, or in target tissues, potentially resulting in cellular hypothyroidism, despite normal serum levels. However, the physiologic relevance of cellular thyroid hormone transport systems is still controversial (96,97,98).
Several drugs are known to reduce the absorption of T4 from the gut, such as cholestyramine, calcium carbonate, aluminum hydroxide, ferrous sulfate, activated charcoal, and sucralfate (99,100,101,102). Although normally 80% of a dose of T4 is absorbed within 6 hours, this value decreases when these substances are taken simultaneously, resulting in lower serum T4 and higher TSH levels. This problem can be circumvented by separating the intake of both drugs by several hours. The malabsorption of T4 in the presence of these substances may be due to either the formation of an insoluble complex or an inhibition of hormone transport by intestinal cells.
Amiodarone is the best known drug that inhibits cellular thyroid hormone uptake. A selective decrease in hepatic T4 transport was demonstrated in hepatocytes and perfused rat liver, and impaired T3 uptake was observed in an anterior pituitary cell line (103,104). In addition, amiodarone inhibits T4 and T3deiodination and binding of T3 to nuclear receptors, as described later in the chapter. Benzodiazepines also inhibit cellular T3 uptake, possibly due to their conformational similarity with this hormone (105). Hepatic and muscule T3 uptake seem to a calcium-dependent process, as inferred from the inhibition of T3uptake by various calcium channel blockers, such as nifedipine, verapamil, and diltiazem (106). Finally, furosemide and some nonsteroidal anti-inflammatory drugs compete for cytosolic T3-binding sites in cultured cells (107). However, whether the in vitro observations for these various drugs are quantitatively relevant in vivo remains to be demonstrated.
DRUGS THAT ALTER THE INTRACELLULAR METABOLISM OF IODOTHYRONINES
Drugs That Induce the Hepatic p450 Complex (Mixed-Function Oxygenases)
Many lipophilic drugs are made water soluble by oxidation and conjugation in the liver before their elimination from the body by enzymes that are part of the type II metabolic processes (108). The type I metabolic processes include enzymes responsible for the oxidative and reducing reactions and belong to the cytochrome p450 complex, which consists of more than 100 isoenzymes. Some of these enzymes (CYP3A) can be induced by the antiepileptic drug phenytoin, phenobarbital, and carbamazepine, as well as the antituberculous drug rifampicin (Table 11C.1).
It has been known for 30 years that the administration of phenytoin causes alterations in serum thyroid hormone levels (109,110,111,112). Serum thyroid hormone levels can decrease markedly during phenytoin (and rifampicin therapy); the effects on serum TSH are, however, minor. Similar but less important effects have been reported for carbamazepine. It may potentiate the effects of the other antiepileptic drugs when used in combination with them (113).
Phenytoin is of particular interest because its effects are not limited to the induction of hepatic drug metabolism. Early in vitro studies indicated that high levels of phenytoin displaced T4 and T3 from TBG. However, the in vivo serum concentrations do not reach such levels, and the free fractions of T4 and T3 that would result from a displacing drug do not occur in such patients. Nevertheless, the serum total and free T4 levels are clearly decreased in euthyroid phenytoin-treated patients, whereas in most reports the serum total and free T3 concentrations are unchanged or even slightly increased. The decreased serum T4 levels are not typical of the other drugs inducing the mixed function oxygenases, which do not change serum levels of total and free T4 and suggest more complex functions of phenytoin. For instance, it has been reported that phenytoin decreases serum TSH levels and inhibits the TSH response to thyrotropin releasing hormone (TRH) (114,115). These findings and others have led to the hypothesis that phenytoin may interfere with cellular uptake of T3and may have agonistic nuclear effects (116,117). Since serum TSH levels in euthyroid subjects are in the normal range, hypothyroidism is almost certainly not present. However, serum TSH levels increase in T4 treated hypothyroid patients. Because the metabolic clearance rate and the hepatic metabolism of T4increases in patients treated with phenytoin, it is likely that in normal subjects thyroidal secretion increases in order to compensate for the hepatic losses, whereas hypothyroid patients need increased doses of T4 (118).
Although the effects of phenytoin and the other antiepileptic drugs have received the most attention, the antituberculosis drug rifampicin is one of the most potent inducers of hepatic mixed-function oxygenases. Significant decreases in serum total and free T4 and reverse T3 (rT3) concentrations have been described in some but not other studies. Rifampicin acts like phenytoin on intracellular thyroid hormone metabolism, but it does not inhibit T4 and T3 binding to serum-binding proteins (119,120,121). T4 kinetic data show that rifampicin increases the clearance rate of T4; in normal subjects, T4 secretion increases to compensate for the increase in T4 clearance, T4 to T3 conversion does not change, and T3 production is normal. That T4 secretion increases is also suggested by the increase in thyroid volume that occurs during rifampicin treatment (122). Therefore, in hypothyroid T4-treated patients, serum TSH levels must be monitored. One T4-treated hypothyroid patient developed marked hypothyroidism during rifampicin treatment (123).
Neither phenytoin nor rifampicin has much effect on T3 metabolism. This was shown more clearly in studies in rats given the most potent inducer of mixed function oxygenases, nafenopin (124). In rats, this drug greatly increases the metabolic clearance rate of T4 and its hepatic disposal without changing the T3kinetics. This difference is best explained by the fact that glucuronidation of T4 is increased, whereas T3 is preferentially a substrate for sulfation, which is not increased by the induction of mixed-function oxygenases.
In summary, drugs that increase the activity of the hepatic p450 enzymatic system result in a decrease in serum total T4 concentrations. This is due primarily to an acceleration of the hepatic metabolism of T4 and results in a decrease in its plasma half-life or, more specifically, in an increase in its metabolic clearance rate. In euthyroid subjects there is also a slight increase in T4 production, with the consequence that serum T4 levels do not change. Basal serum TSH concentrations increase slightly but not significantly. These findings suggest that the function of the pituitary–thyroid axis can compensate in euthyroid patients, and this is in accordance with the clinical impression of euthyroidism in these subjects. However, in T4-treated patients, with hypothyroidism, the T4dose often needs to be raised.
Drugs That Inhibit the Deiodination of Thyroxine
Deiodination involves the sequential removal of iodine atoms from T4 and is the most important metabolic pathway of this iodothyronine (125, 126). This topic is discussed in detail in Chapter 7. Deiodination of the outer phenolic ring (5′-deiodination) of iodothyronines is different than that of the inner ring (5-deiodination). Outer-ring deiodination is responsible not only for the conversion of T4 to T3, but also for the degradation of rT3. At least two enzymes are known to catalyze this reaction: one present primarily in liver, kidney, heart, muscle, and thyroid, called 5′-deiodinase type 1; the other predominating in brain cortex, cerebellum, anterior pituitary, and placenta, called 5′-deiodinase type 2. 5′-deiodinase type 1 is reduced in hypothyroidism and catabolic states. It can be inhibited by several drugs (see later in the chapter), including PTU.
5′-deiodinase type 2 has a different tissue distribution, and its regulation is opposite to 5′-deiodinase type 1. For example, its activity is reduced in thyrotoxicosis and increased in hypothyroidism. It is not affected by catabolic states, and so far the only known specific inhibitors are T4 and rT. It can be inhibited by iodinated contrast agents, but these agents are not specific inhibitors because they do not directly block the catalytic site. PTU does not inhibit type 2 deiodinase, and this property is used for determining its specific activity (127).
Only one deiodinating enzyme has been demonstrated for the inner ring, 5-deiodinase type 3. It is found in the brain, skin, subcutaneous tissue, and placenta. All three enzymes are selenoproteins (128) (See Chapter 7).
Drugs inhibiting deiodination can be divided into two groups: those that are iodinated and those that are not. The iodinated drugs are more potent in vivo and inhibit 5′-deiodinase type 1 and 2 as well as 5′-deiodinase type 3 activities; the noniodinated drugs inhibit mainly 5′-deiodinase type 1 activity. Both types of compounds exert their effects predominantly on the process of 5′-deiodination, and this results in a decrease in serum T3 concentrations. Reverse T3concentrations are increased to a variable extent by the action of these agents. The increase in its serum concentration can mainly be explained by inhibition of its metabolism, which depends on 5′-deiodinase type 1. Dexamethasone is an exception; it also increases production of rT3 (129).
The most important drugs in the noniodinated class are PTU, the synthetic glucocorticoid dexamethasone, and the β-receptor antagonist propranolol.
PTU was the first drug shown to inhibit the conversion of T4 to T3 in peripheral tissues, but it is not the most potent (130). When it is administered in doses of 450 to 600 mg/day to T4-treated hypothyroid patients, serum T3 concentrations decrease by 25% to 30% within 48 hours and remain at this level as long as PTU is given (131). Basal serum TSH concentrations increase slightly, and the serum TSH response to TRH is augmented. In untreated euthyroid subjects, serum rT3 concentrations increase initially but tend to decline slowly if the drug is continued (132,133). All values return to pretreatment levels when the drug is discontinued. Therapeutically, this effect is exploited in the treatment of iodine-induced thyrotoxicosis, where antithyroid drugs are less potent inhibitors of thyroid hormone synthesis and this additional action is most welcome. A PTU analogue, anilino-thiouracil, has been demonstrated to inhibit 5′-deiodinase type 1 but does not affect thyroid hormonogenesis in rats (134).
Dexamethasone has multiple effects on thyroid physiology in humans. Large doses given acutely or moderate doses administered for a prolonged period suppress the secretion of TSH by the anterior pituitary in normal and hypothyroid individuals and therefore decrease thyroid hormone secretion (135,136). In addition, large doses of dexamethasone decrease serum T3 concentrations in normal subjects and in hypothyroid patients receiving T4 therapy (117,137). This latter effect is predominantly due to an inhibitory action on 5′-deiodination (138,139). Kinetic data on the in vivo effects of dexamethasone, however, are not identical to those of PTU; dexamethasone increases serum rT3 levels by increasing rT3 production, whereas PTU increases rT3 by decreasing its plasma clearance (129). In patients with thyrotoxicosis caused by Graves' disease, large doses of dexamethasone decrease serum concentrations of T4 (140). This is due to a decrease in T4 secretion (whether this is by a direct thyroidal effect or by decreasing thyroid-stimulating immunoglobulin production is not known). Other glucocorticoids in comparable doses have similar effects, but none have been studied as extensively as dexamethasone. Clinically, the effect of dexamethasone on thyroid hormone metabolism is helpful in rapidly decreasing serum T3 concentrations in preparation of thyrotoxic patients for surgery, and its antiinflammatory effect is useful in a subset of patients with amiodarone-induced thyrotoxicosis (see earlier in this chapter).
These above findings are supported by the observations that treatment of rats for 5 days with dexamethasone reduces the rate of T4 to T3 conversion and the rate of rT3 degradation in vitro in liver homogenates. In contrast to other potent inhibitors of the deiodination reaction, however, the addition of dexamethasone to rat liver homogenates in vitro has no effect on the rate of T4 to T3 conversion (86).
Beta-receptor antagonists are useful drugs in the symptomatic treatment of thyrotoxicosis (see Chapter 45). These drugs reduce pulse rate, tremor, anxiety, and hyperreflexia, and they are particularly useful in the treatment of thyrotoxic crisis (141,142,143,144,145,146,147) (see Chapter 43). The mechanisms by which decreased sympathetic nervous system activity alleviates these symptoms and signs are far from clear. Studies in thyrotoxic patients have shown that propranolol has no demonstrable effect on thyroid iodine release or T4 turnover (148). When given in moderate to high doses to euthyroid and/or thyrotoxic subjects, it induces a modest reduction in serum free T3 concentrations and a small increase in rT3 concentrations. This action of propranolol on T4 metabolism in vivo is not shared by the β-receptor antagonists metoprolol or atenolol, or the mixed β- and α-receptor antagonist labetalol (145,149). These drugs are nevertheless effective in the relief of the symptomatology of thyrotoxicosis.
The effects of propranolol on the extrathyroidal metabolism of T4, T3, and rT3 have been evaluated by noncompartmental kinetic methods. The results indicate that the reduction in serum T3 is mainly due to a reduction in its generation from T4. The increase in serum rT3 is largely due to reduction in its metabolic clearance rate, and its generation rate from T4 is unchanged. The disposal rate of T4 is reduced, suggesting that its bioavailability to tissues is reduced by the drug.
In vitro studies have shown that the racemic form of propranolol and other β-adrenergic antagonists (149) inhibit T4 conversion to T3 and rT3 degradation in rat liver homogenates, isolated intact liver cells, and renal tubules. The latter results suggested that the major site of action of propranolol might be at the cell membrane (150,151). Generation of T3 from T4 in isolated rat renal tubules is inhibited not only by DL-propranolol but also by the D- and L-isomers of propranolol. Because D-propranolol is devoid of β-receptor antagonist properties, DL-propranolol is thought to affect T45′-deiodination by its ability to stabilize cell membranes. This latter action is akin to that exerted by quinidine; indeed, quinidine also inhibits T43′-deiodination in this system. Alternatively, propranolol could block T4 transport into cells (96,97), although the effect of propranolol did not appear to be due to an alteration in the cellular uptake of T4by the renal tubules.
In summary, propranolol, as well as other β-receptor antagonists, alleviates the peripheral manifestations of thyrotoxicosis. This clinical benefit far exceeds the modest reduction in serum T3 concentrations caused by the drug, and other related drugs have the same clinical benefits without altering serum T3concentrations. These results indicate that the clinical benefits of β-receptor antagonists are not related to their ability to inhibit T4 to T3 conversion.
Drugs considered in this section include the iodinated radiographic contrast agents and the antiarrhythmic drug amiodarone.
All iodinated agents affect thyroid function by their large iodine content. Some of these compounds, all of which are lipid soluble, are used for cholecystography, namely iopanoic acid, sodium ipodate, and tyropanoate, also inhibit T4 deiodination (152,153). When given to normal subjects, they significantly increase serum free T4 and rT3 and decrease serum free T3 concentrations (152). However, the extent of the changes varies from one compound to another. In contrast to these lipid-soluble substances, water-soluble contrast agents such as those used for arteriography and venography do not affect deiodination. The lipid-soluble agents can be useful for the treatment of severe thyrotoxicosis (154).
In people with normal thyroid function, most changes of serum thyroid hormone levels are due to alterations in their metabolism. This can be illustrated in normal subjects receiving 0.2 mg T4 daily in whom serum TSH levels were suppressed. Iopanoic acid caused significant increases in serum total and free T4levels and decreases in serum T3 and rT3 concentrations similar to those in normal subjects not receiving T4 (Fig. 11C.3). The increase in serum T4concentrations is mainly a reflection of a decreased disposal rate. In addition, kinetic studies have shown that these drugs can acutely discharge T4 from hepatic (and possibly renal) storage sites (155). For example, in normal subjects who received an intravenous injection of 125I-T4, tyropanoate and, to a lesser extent, ipodate led to a 50% to 60% reduction in hepatic radioactivity within 4 hours. This reduction was accompanied by a 57% to 70% increase in serum radioactivity, as well as an increase in serum T4 concentrations. The plasma clearance rate of T4 decreased. In euthyroid subjects, changes in thyroid secretion also occur during the readaptation of thyroid homeostasis. There is an initial increase in serum TSH concentration, likely due to a dual effect of these inhibitors, which inhibit 5′-deiodinase type 2 as well as 5′-deiodinase type 1. Serum TSH levels subsequently return to normal.
FIGURE 11C.3. Effect of iopanoic acid on serum thyroid hormone levels in four normal subjects maintained on 0.2 mg thyroxine (T4) per day. Iopanoic acid was given on Days 0, 7, and 14. Serum total and free T4 and reverse triiodothyronine (T3) concentrations rapidly increased above the normal range (upper and lower panels), and serum T3 concentrations decreased by ~40%. The normal range for each hormone is indicated by the hatched bars. (From Burgi H, Wimpfheimer C, Burger A, et al. Changes of circulating thyroxine, triiodothyronine, and reverse triiodothyronine after radiographic contrast agents. J Clin Endocrinol Metab 1976;43:1203, with permission.)
In addition to the radiographic contrast agents, the antiarrhythmic drug amiodarone is known to interfere with thyroid function. Besides causing thyroid dysfunction, as discussed earlier in this chapter, it induces in every euthyroid subject alterations in thyroid hormone metabolism, due to the ability of the drug to inhibit T4 deiodination (156,157,158). The changes in serum T4, T3, rT3, and TSH concentrations are similar to those caused by the iodinated radiographic contrast agents, and the magnitude of these alterations is dose dependent. In normal subjects given 400 mg amiodarone (150 mg organic iodine) for 3 weeks, serum total and free T4 concentrations increased, again due to a decrease in the T4 metabolic clearance rate. The results of kinetic studies suggest decreased transfer of T4 from the plasma pool to the rapidly exchangeable tissue pools, such as the liver (159). The T3 plasma clearance rate was only slightly decreased (160). Therefore, the decreased serum T3 levels mainly reflect the decreased conversion of T4 to T3. This observation is substantiated by the observed changes in thyroid function tests after the acute intravenous administration of amiodarone. Serum TSH levels increased from the first day of therapy, followed by a decrease in T3 level after the second day, whereas free and total T4 levels did not increase until the fourth day of treatment (161).
After the first 2 weeks, the thyroid escapes from this inhibition, and under the drive of increased TSH secretion, T4 production tends to increase. This has been demonstrated to occur for iopanoic acid, which induces effects on thyroid hormone metabolism similar to those of amiodarone. However, T4 secretion does not increase sufficiently to restore serum T3 to pretreatment levels. This suggests that inhibition of intrapituitary conversion is less than in the periphery. These effects have attracted much attention, and it has been postulated that some of the antiarrhythmic effects of this drug might be due to a hypothyroid state of the heart. Experiments in rats support this hypothesis, even though in these studies only tissue T3 content and not the actual saturation of the T3 receptor with T3 was measured (162). In addition, amiodarone and/or its main metabolite desethylamiodarone is a weak antagonist of thyroid hormone action (163,164). Despite these experimental studies, most clinical studies do not support the hypothesis that the antiarrhythmic effect of amiodarone is due its action on thyroid hormone metabolism or action (165,166).
In clinical practice, amiodarone is used for long-term treatment. After several weeks of treatment with a moderate dose (200 or 100 mg/day), serum thyroid hormone levels tend to remain within the normal limits, even though serum free T4 levels are higher and serum T3, free T3, and TSH levels are lower than before treatment. In some patients, however, particularly those treated with higher doses of amiodarone, serum free T4 levels can be as high as in moderate thyrotoxicosis (158). When T4 kinetic parameters are compared in chronically treated subjects with normal TSH levels with those of thyrotoxic Graves' disease patients, striking differences are found. Thus, the T4 production rate of the amiodarone-treated group is significantly lower than that of the thyrotoxic group, and the disappearance of injected 125I-T4 is significantly delayed (Fig. 11C.4). These findings demonstrate that, despite increased serum total and free T4concentrations, T4 kinetics in amiodarone-treated patients more closely approximate those of a euthyroid subject. In addition, these patients have normal serum T3 and/or free T3 levels. These patients often have no obvious clinical stigmata of thyrotoxicosis, and the peripheral tissues may not be frankly thyrotoxic. Nevertheless, the suppressed serum TSH suggests the escape of thyroidal secretion from the normal feedback control mechanism.
FIGURE 11C.4. The disappearance of serum 125I-thyroxine (T4) in four patients with classic thyrotoxicosis (open circle) and five patients with selective increases in serum total and free T4 concentrations (dots) due to a reduced clearance rate of T4 during amiodarone treatment without evidence of hyperthyrodism. (From Lambert MJ, Burger AG, Galeazzi RL, et al. Are selective increases in serum thyroxine (T4) due to iodinated inhibitors of T4monodeiodination indicative of hyperthyroidism? J Clin Endocrinol Metab 1982;55:1058, with permission.)
Clinical Use of Iodinated Inhibitors of Deiodination
These agents have been used successfully in the treatment of severe forms of thyrotoxicosis caused by Graves' disease or toxic multinodular goiter (167,168,169). Most studies have used the more rapidly cleared ipodate, which decreases serum T3 levels to within the normal range in a short period of time (2–6 days) (170,171). Serum T4 levels decrease more slowly than with potassium iodide treatment, probably reflecting the decrease in T4 plasma clearance rate induced by ipodate. The therapeutic use of these agents is mainly restricted to preoperative treatment; during long-term treatment, escape from the iodide inhibition of thyroidal secretion often occurs (172). Another rare indication may be thyrotoxicosis factitia (173); their long half-life makes this unwise (174,175).
In summary, the lipid-soluble radiographic contrast agents and amiodarone induce alterations in thyroid hormone levels by actions on the peripheral tissues, on thyroidal secretion, and probably on the pituitary gland. These actions result in elevations in serum T4 and rT3 concentrations, transient increases in TSH concentrations, and decreases in T3 concentrations. These findings may be explained by inhibition of T4 and rT33′-deiodination in many tissues (liver, kidney, brain), and by the liberation of T4 (and rT3) from hepatic and renal storage pools. In contrast to their effects in normal subjects, in thyrotoxic patients these agents cause a decrease in serum T4 concentrations as well as a decrease in serum T3 levels. In addition, these agents, particularly amiodarone, are prone to induce thyroid dysfunction, which is particularly difficult to treat.
Effects on Thyroid Hormone Action in the Nucleus
Amiodarone decreases thyroid hormone synthesis, secretion, and deiodination. In addition, desethylamiodarone, the major metabolite of amioderone, is a noncompetitive inhibitor of T3 binding to Escherichia coli–expressed T3-receptor protein, with an IC50 of 2 × 10-5M and preferential binding to unoccupied receptors (176,177). However, at higher concentrations (>2 mM) amiodarone appears to a competitive antagonist (178). This observation might explain the decreased nuclear receptor T3-binding capacity in the myocardium of amiodarone-treated rats, as well as the antagonistic effect of amiodarone treatment on pituitary growth hormone expression and cardiac b-adrenoreceptor density (103,179,180,181,182). No data exist to support the notion of selective target tissue resistance to T3 in amiodarone-treated patients. Although an elevation of serum TSH levels during amiodarone treatment has been described in patients on a constant replacement dose of T4, this finding is most compatible with an amiodarone-induced decrease in pituitary and peripheral deiodination. However, a contribution from decreased cellular uptake and nuclear action cannot be excluded (183,184). In contrast, phenytoin, in addition to its effects on thyroid hormone metabolism, as described earlier, has been considered as a partial thyroid hormone agonist (114,115).
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