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

11C.Effects of Drugs and Other Substances on Thyroid Hormone Synthesis and Metabolism

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


 

Organ

Site of Action

Mode of Action

Dose/Day

Remarks


PTU

Thyroid

Thyroid peroxidase

Competitive inhibition of iodination

50–600 mg

 Liver, thyroid

Deiodinase type 1

Inhibition

600 mg

 Methimazole, carbimazole

Thyroid

Thyroid peroxidase

Inhibition

5–60 mg

 Thiocyanate

Thyroid

Na/I symporter

Steric inhibition

Perchlorate

Thyroid

Na/I symporter

Steric inhibition

1 g

 Iodine

Thyroid

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

Thyroid

Na/I symporter, thyroid peroxidase and ssecretion

Steric inhibition of iodination and independent block of secretion

 Amiodarone

Thyroid

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

Inhibition

 Iopanoic acid

Thyroid

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

Inhibition

 Iopodate

Thyroid

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

Inhibition

 Goitrin

Thyroid

Thyroid peroxidase

 Not used

 Flavenoids

Transthyretin and monodeiodination

Binding site for T4

Displacement

Not used

 Cytokines (IFN-γ IL-2, GM-CSF)

Immune system

Follicular cell

Stimulation or inhibition

 Lithium

Thyroid

Thyroid secretion

Inhibition

Serum levels used in psychiatric disease

Salicylates

Transthyretin

Binding site of T4

Displacement

>2 g

Furosemide

Transthyretin

  0.5–1 g

 Heparin

TBG and transthyretin

Binding site of T4

Displacement

 Free fatty acids

TBG and transthyretin

Binding site of T4

Displacement

>3.5mM

 Cholestyramine

Small intestine

Absorption

Chelation

  Phenytoin

Small intestine and liver

Liver metabolism

Conjugation

200–300 mg/day

 Propranolol

Liver, peripheral β-blockade

Monodeiodinase type 1

Inhibition

>240 mg/day

Aluminum hydroxyde

Small intestine

Absorption

Chelation

 Ferrous sulfate

Small intestine

Absorption

Chelation

Charcoal

Small intestine

Absorption

Chelation

Sucralfate

Small intestine

Absorption

Chelation

 Phenobarbital

Liver

Hepatocyte

Conjugation

100 mg/day

 Carbamazepine

Liver

Hepatocyte

Conjugation

200–800 mg/day

 Rifampine

Liver

Hepatocyte

Conjugation

400–1200 mg/day

Dexamthasone

?(liver)

Hepatocyte

Deiodination

2–12 mg/day

 


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


 

Methimazole (carbimazole)

PTU

Perchlorate


Absorption

Rapid and complete

Rapid and complete

Rapid and complete

Serum half-life

4-6 h

< 2 h

4-6 h

Excretion

 Renal

Intrathyoidal concentrations

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)

4-8 h

Transplacental passage

Minimal

Minimal

?

Passage into breast milk

Minimal

Minimal

?


Side Effects

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).

IONIC INHIBITORS

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.

CYTOKINES

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).

Diuretics

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.

Flavons

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).

Absorption

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.

Cellular Uptake

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).

Antiepileptic Drugs

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).

Rifampicin

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).

Noniodinated Drugs

The most important drugs in the noniodinated class are PTU, the synthetic glucocorticoid dexamethasone, and the β-receptor antagonist propranolol.

Propylthiouracil

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

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 Tsecretion (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).

Propranolol

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.

Iodinated Drugs

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).

REFERENCES

1. El Sheikh M, McGregor AM. Antithyroid drugs: their mechanism of action and clinical use. In: Weetman AP, Grossman A, eds. Pharmacotherapeutics of the thyroid gland. New York: Springer-Verlag New York, 1998:189–201.

2. Taurog A, Dorris ML, Guziec FS, et al. Metabolism of 35S- and 14C-labeled propylthiouracil in a model in vitro system containing thyroid peroxidase. Endocrinology 1989;124:3030–3037.

3. Engler H, Taurog A, Luthy C, et al. Reversible and irreversible inhibition of thyroid peroxidase-catalyzed iodination by thioureylene drugs. Endocrinology 1983;112:86–95.

4. Ruiz JK, Rossi GV, Vallejos HA, et al. Fulminant hepatic failure associated with propylthiouracil. Ann Pharmacother 2003; 37:224–228.

5. Casis FC, Perez JB. Leukocytoclastic vasculitis: a rare manifestation of propylthiouracil allergy. Endocr Pract 2000;6:329–332.

6. Gunton JE, Stiel J, Clifton-Bligh P, et al. Prevalence of positive anti-neutrophil cytoplasmic antibody (ANCA) in patients receiving anti-thyroid medication. Eur J Endocrinol 2000;142:587.

7. Sato H, Hattori M, Fujieda M, et al. High prevalence of antineutrophil cytoplasmic antibody positivity in childhood onset Graves' disease treated with propylthiouracil. J Clin Endocrinol Metab 2000;85:4270–4273.

8. Burrow GN, Fisher DA, Larsen PR. Maternal and fetal thyroid function. N Engl J Med 1994;331:1072–1078.

9. Becks GP, Burrow GN. Thyroid disease and pregnancy. Med Clin North Am 1991;75:121–150.

10. Wing DA, Millar LK, Koonings PP, et al. A comparison of propylthiouracil versus methimazole in the treatment of hyperthyroidism in pregnancy. Am J Obstet Gynecol 1994;170:90–95.

11. Azizi F, Khoshniat M, Bahrainian M, et al. Thyroid function and intellectual development of infants nursed by mothers taking methimazole. J Clin Endocrinol Metab 2000;85:3233–3238.

12. Leonard JL, Rosenberg IN. Thyroxine 5′-deiodinase activity of rat kidney: observations on activation by thiols and inhibition by propylthiouracil. Endocrinology 1978;103:2137–2144.

13. Reinwein D, Benker G, Lazarus JH, et al. A prospective randomized trial of antithyroid drug dose in Graves' disease therapy: European Multicenter Study Group on Antithyroid Drug Treatment. J Clin Endocrinol Metab 1993;76:1516–1521.

14. Lucas A, Salinas I, Rius F, et al. Medical therapy of Graves' disease: does thyroxine prevent recurrence of hyperthyroidism? J Clin Endocrinol Metab 1997;82:2410–2413.

15. Vieja A, Dohan O, Levy O, et al. Molecular analysis of the sodium/iodide symporter: Impact on thyroid and extrathyroid pathophysiology. Physiol Rev 2000;80:1083–1105.

16. Dohan O, De la Vieja A, Paroder V, et al. The sodium/iodide Symporter (NIS): characterization, regulation, and medical significance. Endocr Rev 2003;24:48–77.

17. Wolf J. Perchlorate and the thyroid gland. Pharmacol Rev 1998; 50:89–105.

18. Delange F. The role of goitrogenic factors distinct from iodine deficiency in the etiology of goiter [in French]. Ann Endocrinol (Paris) 1988;49:302–305.

19. Moreno-Reyes R, Boelaert M, el Badawi S, et al. Endemic juvenile hypothyroidism in a severe endemic goitre area of Sudan. Clin Endocrinol (Oxf) 1993;38:19–24.

20. Vanderpas J, Bourdoux P, Lagasse R, et al. Endemic infantile hypothyroidism in a severe endemic goitre area of central Africa. Clin Endocrinol (Oxf) 1984;20:327–340.

21. Bourdoux P, Delange F, Gerard M, et al. Evidence that cassava ingestion increases thiocyanate formation: a possible etiologic factor in endemic goiter. J Clin Endocrinol Metab 1978;46: 613–621.

22. Kohrle J, Brabant G, Hesch RD. Metabolism of the thyroid hormones. Horm Res 1987;26:58–78.

23. Schroder-van der Elst JP, van der Heide D, Kohrle J. In vivo effects of flavonoid EMD 21388 on thyroid hormone secretion and metabolism in rats. Am J Physiol 1991;261:227–232.

24. Abend SL, Fang SL, Alex S, et al. Rapid alteration in circulating free thyroxine modulates pituitary type II 5′ deiodinase and basal thyrotropin secretion in the rat. J Clin Invest 1991;88: 898–903.

25. Winneke G, Walkowiak J, Lilienthal H. PCB-induced neurodevelopmental toxicity in human infants and its potential mediation by endocrine dysfunction. Toxicology 2002;181/182: 161–165.

26. Moriyama K, Tagami T, Akamizu T, et al. Thyroid hormone action is disrupted by bisphenol A as an antagonist. J Clin Endocrinol Metab 2002;87:5185–5190.

27. Muakkassah-Kelly SF, Krinke AL, Malinowski W, et al. The effect of short term feeding of the antioxidant triethyleneglycol-bis-3(3-tert-butyl-4-hydroxy-5-methyl)propionate on serum thyrotropin and thyroid hormones in the male rat. Toxicol Appl Pharmacol 1991;107:129–140.

28. Martino E, Safran M, Aghini-Lombardi F, et al. Environmental iodine intake and thyroid dysfunction during chronic amiodarone therapy. Ann Intern Med 1984; 101:28–34.

29. Trip, MD, Wiersinga, W, and Plomp, TA. Incidence, predictability, and pathogenesis of amiodarone-induced thyrotoxicosis and hypothyroidism. Am J Med 1991; 91:507–511.

30. Vorperian VR, Havighurst TC, Miller S, et al. Adverse effects of low dose amiodarone: a meta-analysis [see comments]. J Am Coll Cardiol 1997;30:791–798.

31. Harjai KJ, Licata AA. Effects of amiodarone on thyroid function [see comments]. Ann Intern Med 1997; 126:63–73.

32. Martino E, Bartalena L, Mariotti S, et al. Radioactive iodine thyroid uptake in patients with amiodarone-iodine-induced thyroid dysfunction. Acta Endocrinol (Copenh). 1988;119:167–173.

33. Roti E, Minelli R, Gardini E, et al. Thyrotoxicosis followed by hypothyroidism in patients treated with amiodarone: a possible consequence of a destructive process in the thyroid. Arch Intern Med 1993;153:886–892.

34. Smyrk TC, Goellner JR, Brennan MD, et al. Pathology of the thyroid in amiodarone-induced thyrotoxicosis. Am J Surg Pathol. 1987;11:197–204.

35. Bartalena L, Grasso L, Brogioni S, et al. Serum interleukin-6 in amiodarone-induced thyrotoxicosis. J Clin Endocrinol Metab 1994; 78:423–427.

36. Chiovato L, Martino E, Tonacchera M, et al. Studies on the in vitro cytotoxic effect of amiodarone. Endocrinology 1994;134: 2277–2282.

37. Bartalena, L, Brogioni, S, Grasso, L et al. Treatment of amiodarone-induced thyrotoxicosis, a difficult challenge: results of a prospective study. J Clin Endocrinol Metab 1996;81:2930–2933.

37a. Pearce EN, Bogazzi F, Martino E, et al. The prevalence of elevated serum C-reactive protein levels in inflammatory and noninflammatory thyroid disease. Thyroid 2003;13:643–648.

38. Bogazzi F, Bartalena L, Brogioni S, et al. Color flow Doppler sonography rapidly differentiates type I and type II amiodarone-induced thyrotoxicosis. Thyroid 1997;7:541–545.

39. Osman F, Franklyn JA, Sheppard MC, et al. Successful treatment of amiodarone-induced thyrotoxicosis. Circulation 2002; 105:1275–11277.

40. Vial T, Descotes J. Immune-mediated side-effects of cytokines in humans. Toxicology 1995;105:31–57.

41. Ajjan RA, Watson PF, Weetman AP. Cytokines and thyroid function. Adv Neuroimmunol 1996;6:359–386.

42. Burman P, Totterman TH, Orberg K, et al. Thyroid autoimmunity in patients on long term therapy with leukocyte-derived interferon. J Clin Endocrinol Metab 1986; 63:1086–1090.

43. Reichlin S. Neuroendocrine-immune interactions. N Engl J Med 1993;329:1246–1253.

44. Atkins MB, Mier JW, Parkinson DR, et al. Hypothyroidism after treatment with interleukin-2 and lymphokine-activated killer cells. N Engl J Med 1988;318:1557–1563.

45. Hoekman K, von Blomberg-van der Flier B, Wagstaff J, et al. Reversible thyroid dysfunction during treatment with GM-CSF. Lancet 1991;338:541–542.

46. van Hoff ME, Howell A. Risk of thyroid dysfunction during treatment with G-CSF. Lancet 1992;340:1169.

47. Miossec P. Cytokine-induced autoimmune disorders. Drug Saf 1997;17:93–104.

48. Sachithanandan S, Clarke G, Crowe J, et al. Interferon-associated thyroid dysfunction in anti-D-related chronic hepatitis C. J Interferon Cytokine Res 1997;17:409–411.

49. Schuppert F, Rambusch E, Kirchner H, et al. Patients treated with interferon-alpha, interferon-beta, and interleukin-2 have a different thyroid autoantibody pattern than patients suffering from endogenous autoimmune thyroid disease. Thyroid 1997; 7:837–842.

50. Russo MW, Fried MW. Side effects of therapy for chronic hepatitis C. Gastroenterology 2003; 124:1711–1719.

51. Deutsch M, Dourakis S, Manesis EK, et al. Thyroid abnormalities in chronic viral hepatitis and their relationship to interferon alfa therapy. Hepatology 1997;26:206–210.

52. Villanueva RB, Brau N. Graves' ophthalmopathy associated with interferon-alpha treatment for hepatitis C. Thyroid 2002; 12:737–738.

53. Rotondi M, Mazziotti G, Biondi B, et al. Long-term treatment with interferon-beta therapy for multiple sclerosis and occurrence of Graves' disease. J Endocrinol Invest 2000;23: 321–324.

54. Carella C, Mazziotti G, Morisco F et al. The addition of ribavirin to interferon-alpha therapy in patients with hepatitis C virus-related chronic hepatitis does not modify the thyroid autoantibody pattern but increases the risk of developing hypothyroidism. Eur J Endocrinol 2002;146:743–749.

55. Schwartzentruber DJ, White DE, Zweig MH, et al. Thyroid dysfunction associated with immunotherapy for patients with cancer. Cancer 1991;68:2384–2390.

56. Vialettes B, Guillerand MA, Viens P, et al. Incidence rate and risk factors for thyroid dysfunction during recombinant interleukin-2 therapy in advanced malignancies. Acta Endocrinol (Copenh) 1993;129:31–38.

57. Vassilopoulou-Sellin R, Sella A, Dexeus FH, et al. Acute thyroid dysfunction (thyroiditis) after therapy with interleukin-2. Horm Metab Res 1992;24:434–438.

58. Huang MJ, Tsai SL, Huang BY, et al. Prevalence and significance of thyroid autoantibodies in patients with chronic hepatitis C virus infection: a prospective controlled study. Clin Endocrinol (Oxf) 1999;50:503–509.

58a. Pearce, En, Farwell, AP, Braverman, LE. Thyroiditis. N Engl J Med 2003;348:2646–55.

59. Carella C, Mazziotti G, Morisco F, et al. Long-term outcome of interferon-alpha-induced thyroid autoimmunity and prognostic influence of thyroid autoantibody pattern at the end of treatment. J Clin Endocrinol Metab 2001;86:1925–1929.

60. Minelli R, Braverman LE, Giuberti T, et al. Effects of excess iodine administration on thyroid function in euthyroid patients with a previous episode of thyroid dysfunction induced by interferon-alpha treatment. Clin Endocrinol (Oxf) 1997;47:357–361.

61. Sato K, Satoh T, Shizume K, et al. Inhibition of 125I organification and thyroid hormone release by interleukin-1, tumor necrosis factor-alpha, and interferon-gamma in human thyrocytes in suspension culture. J Clin Endocrinol Metab 1990;70: 1735–1743.

62. Mooradian AD, Reed RL, Osterweil D, et al. Decreased serum triiodothyronine is associated with increased concentrations of tumor necrosis factor. J Clin Endocrinol Metab 1990;71:1239–1242.

63. Chopra IJ, Sakane S, Teco GN. A study of the serum concentration of tumor necrosis factor-alpha in thyroidal and nonthyroidal illnesses. J Clin Endocrinol Metab 1991;72:1113–1116.

64. Yamazaki K, Kanaji Y, Shizume K, et al. Reversible inhibition by interferons alpha and beta of 125I incorporation and thyroid hormone release by human thyroid follicles in vitro. J Clin Endocrinol Metab 1993;77:1439–1441.

65. Kraiem Z, Sobel E, Sadeh O, et al. Effects of gamma-interferon on DR antigen expression, growth, 3,5,3′- triiodothyronine secretion, iodide uptake, and cyclic adenosine 3′,5′-monophosphate accumulation in cultured human thyroid cells. J Clin Endocrinol Metab 1990;71:817–824.

66. Kasuga Y, Matsubayashi S, Akasu F, et al. Effects of recombinant human interleukin-2 and tumor necrosis factor-alpha with or without interferon-gamma on human thyroid tissues from patients with Graves' disease and from normal subjects xenografted into nude mice. J Clin Endocrinol Metab 1991; 72:1296–1301.

67. Lazarus JH. The effects of lithium therapy on thyroid and thyrotropin-releasing hormone. Thyroid 1998;8:909–913.

68. Davies PH, Franklyn JA. The effects of drugs on tests of thyroid function. Eur J Clin Pharmacol 1991;40:439–451.

69. Kirov G. Thyroid disorders in lithium-treated patients. J Affect Disord 1998;50:33–40.

70. Barclay ML, Brownlie BE, Turner JG, et al. Lithium associated thyrotoxicosis: a report of 14 cases, with statistical analysis of incidence. Clin Endocrinol (Oxf) 1994;40:759–764.

71. Bocchetta A, Bernardi F, Pedditzi M, et al. Thyroid abnormalities during lithium treatment. Acta Psychiatr Scand 1991;83: 193–198.

72. Mizukami Y, Michigishi T, Nonomura A, et al. Histological features of the thyroid gland in a patient with lithium induced thyrotoxicosis. J Clin Pathol 1995; 48:582–584.

73. Miller KK, Daniels GH. Association between lithium use and thyrotoxicosis caused by silent thyroiditis. Clin Endocrinol (Oxf) 2001;55:501–508.

74. Stratakis CA, Chrousos GP. Transient elevation of serum thyroid hormone levels following lithium discontinuation. Eur J Pediatr 1996;155:939–941.

75. Bogazzi F, Bartalena L, Brogioni S, et al. Comparison of radioiodine with radioiodine plus lithium in the treatment of Graves' hyperthyroidism. J Clin Endocrinol Metab 1999;84: 499–503.

76. Dickstein G, Shechner C, Adawi F, et al. Lithium treatment in amiodarone-induced thyrotoxicosis. Am J Med 1997;102:454–458.

76a. Koong SS, Reynolds JC, Movius EG, et al. Lithium as a potential adjuvant to 131I therapy of metastatic well differentiated thyroid cancer. J Clin Endocrinol Metab 1999;84:912–916.

77. Benvenga S, Cahnmann HJ, Gregg RE, et al. Characterization of the binding of thyroxine to high density lipoproteins and apolipoproteins A-I. J Clin Endocrinol Metab 1989;68:1067–1072.

78. Benvenga S, Cahnmann HJ, Robbins J. Localization of the thyroxine binding sites in apolipoprotein B-100 of human low density lipoproteins. Endocrinology 1990;127:2241–2246.

79. Benvenga S, Cahnmann HJ, Robbins J. Characterization of thyroid hormone binding to apolipoprotein-E: localization of the binding site in the exon 3-coded domain. Endocrinology 1993;133:1300–1305.

80. Mendel CM. The free hormone hypothesis: a physiologically based mathematical model. Endocr Rev 1989;10:232–274.

81. Mendel CM, Cavalieri RR, Weisiger RA. Uptake of thyroxine by the perfused rat liver: implications for the free hormone hypothesis. Am J Physiol 1988;255:E110–E119.

82. Divino CM, Schussler GC. Receptor-mediated uptake and internalization of transthyretin. J Biol Chem 1990;265:1425–1429.

83. Harms PJ, Tu GF, Richardson SJ, et al. Transthyretin (prealbumin) gene expression in choroid plexus is strongly conserved during evolution of vertebrates. Comp Biochem Physiol B Biochem Mol Biol 1991;99:239–249.

84. Chanoine JP, Alex S, Fang SL, et al. Role of transthyretin in the transport of thyroxine from the blood to the choroid plexus, the cerebrospinal fluid, and the brain. Endocrinology 1992;130: 933–938.

85. Wenzel KW. Disturbances of thyroid function tests by drugs. Acta Med Austriaca 1996;23:57–60.

86. Cavalieri RR. Effects of drugs on human thyroid hormone metabolism. In: Hennemann G, ed. Thyroid hormone metabolism. New York: Marcel Dekker Inc, 1986.

87. Ratcliffe WA, Hazelton RA, Thompson JA. Effect of fenclofenac on thyroid-function tests. Lancet 1980;1:432–430.

88. Baranetsky NG, Chertow BS, Webb MD, et al. Combined phenytoin and salicylate effects on thyroid function tests. Arch Int Pharmacodyn Ther 1986;284:166–176.

89. Humphrey MJ, Capper SJ, Kurtz AB. Fenclofenac and thyroid hormone concentrations. Lancet 1980;1:487–480.

90. Lim CF, Bai Y, Topliss DJ, et al. Drug and fatty acid effects on serum thyroid hormone binding. J Clin Endocrinol Metab 1988;67:682–688.

91. Wang YS, Hershman JM, Smith V, et al. Effect of heparin on free thyroxin as measured by equilibrium dialysis and ultrafiltration. Clin Chem 1986;32:700.

92. Mendel CM, Frost PH, Kunitake ST, et al. Mechanism of the heparin-induced increase in the concentration of free thyroxine in plasma. J Clin Endocrinol Metab 1987;65:1259–1264.

93. Jain R, Uy HL. Increase in serum free thyroxine levels related to intravenous heparin treatment. Ann Intern Med 1996;124: 74–75.

94. Saeed-Uz-Zafar M, Miller JM, Breneman GM, et al. Observations on the effect of heparin on free and total thyroxine. J Clin Endocrinol Metab 1971; 32:633–630.

95. Schwartz HL, Schadlow AR, Faierman D, et al. Heparin administration appears to decrease cellular binding of thyroxine. J Clin Endocrinol Metab 1973;36:598–590.

96. Krenning EP, Docter R. Plasma membrane transport of thyroid hormone. In: Thyroid hormone metabolism. Hennemann G, ed. New York: Marcel Dekker Inc. 1986:131–186.

97. Pontecorvi A, Robbins J. The plasma membrane and thyroid hormone entry into cells. Trends Endocrinol Metab 1989;1: 90–94.

98. Dejong M, Visser TJ, Bernard BF, et al. Transport and metabolism of iodothyronines in cultured human hepatocytes. J Clin Endocrinol Metab 1993;77:139–143.

99. Northcutt RC, Stiel JN, Hollifield JW, et al. The influence of cholestyramine on thyroxine absorption. JAMA 1969;208: 1857–1861.

100. Liel Y. Levothyroxine therapy. Ann Intern Med 1994;120:619–620.

101. Shakir KM, Chute JP, Aprill BS, et al. Ferrous sulfate-induced increase in requirement for thyroxine in a patient with primary hypothyroidism. South Med J 1997;90:637–639.

102. Sherman SI, Tielens ET, Ladenson PW. Sucralfate causes malabsorption of L-thyroxine. Am J Med 1994;96:531–535.

103. Norman MF, Lavin TN. Antagonism of thyroid hormone action by amiodarone in rat pituitary tumor cells. J Clin Invest 1989;83:306–313.

104. de Jong M, Docter R, Van der Hoek H, et al. Different effects of amiodarone on transport of T4 and T3 into the perfused rat liver. Am J Physiol 1994;266:E44–E49.

105. Kragie L, Forrester ML, Cody V, et al. Computer-assisted molecular modeling of benzodiazepine and thyromimetic inhibitors of the HepG2 iodothyronine membrane transporter. Mol Endocrinol 1994;8:382–391.

106. Topliss DJ, Scholz GH, Kolliniatis E, et al. Influence of calmodulin antagonists and calcium channel blockers on triiodothyronine uptake by rat hepatoma and myoblast cell lines. Metabolism 1993;42:376–380.

107. Barlow JW, Curtis AJ, Raggatt LE, et al. Drug competition for intracellular triiodothyronine-binding sites. Eur J Endocrinol 1994;130:417–421.

108. Nebert DW, Russell DW. Clinical importance of the cytochromes P450. Lancet 2002;360:1155–11562.

109. Yeo PP, Bates D, Howe JG, et al. Anticonvulsants and thyroid function. BMJ 1978;1:1581–1583.

110. Cavalieri RR, Gavin LA, Wallace A, et al. Serum thyroxine, free T4, triiodothyronine, and reverse-T3 in diphenylhydantoin-treated patients. Metabolism 1979;28:1161–1165.

111. Kozlowski BW, Taylor ML, Baer MT, et al. Anticonvulsant medication use and circulating levels of total thyroxine, retinol binding protein, and vitamin A in children with delayed cognitive development. Am J Clin Nutr 1987;46:360–368.

112. Larkin JG, Macphee GJ, Beastall GH, et al. Thyroid hormone concentrations in epileptic patients. Eur J Clin Pharmacol 1989;36:213–216.

113. Rootwelt K, Ganes T, Johannessen SI. Effect of carbamazepine, phenytoin and phenobarbitone on serum levels of thyroid hormones and thyrotropin in humans. Scand J Clin Lab Invest 1978;38:731–736.

114. Surks MI, Ordene KW, Mann DN, et al. Diphenylhydantoin inhibits the thyrotropin response to thyrotropin-releasing hormone in man and rat. J Clin Endocrinol Metab 1983;56: 940–945.

115. Smith PJ, Surks MI. Multiple effects of 5,5′-diphenylhydantoin on the thyroid hormone system. Endocr Rev 1984;5: 514–524.

116. Zemel LR, Biezunski DR, Shapiro LE, et al. 5,5′-Diphenylhydantoin decreases the entry of 3,5,3′-triiodo-L- thyronine but not L-thyroxine in cultured GH-producing cells. Acta Endocrinol 1988;117:392–398.

117. Gingrich SA, Smith PJ, Shapiro LE, et al. 5,5′-Diphenylhydantoin (phenytoin) attenuates the action of 3,5,3′- triiodo-L-thyronine in cultured GC cells. Endocrinology 1985;116:2306–2313.

118. Surks MI. Hypothyroidism and phenytoin. Ann Intern Med 1985;102:871.

119. Ohnhaus EE, Studer H. The effect of different doses of rifampicin on thyroid hormone metabolism. Br J Clin Pharmacol 1980;9:285–286.

120. Ohnhaus EE, Burgi H, Burger A, et al. The effect of antipyrine, phenobarbitol and rifampicin on thyroid hormone metabolism in man. Eur J Clin Invest 1981;11:381–387.

121. Ohnhaus EE, Studer H. A link between liver microsomal enzyme activity and thyroid hormone metabolism in man. Br J Clin Pharmacol 1983;15:71–76.

122. Christensen HR, Simonsen K, Hegedus L, et al. Influence of rifampicin on thyroid gland volume, thyroid hormones, and antipyrine metabolism. Acta Endocrinol (Copenh) 1989;121:406–410.

123. Isley WL. Effect of rifampin therapy on thyroid function tests in a hypothyroid patient on replacement L-thyroxine. Ann Intern Med 1987;107:517–518.

124. Kaiser CA, Seydoux J, Giacobino JP, et al. Increased plasma clearance rate of thyroxine despite decreased 5′-monodeiodination: study with a peroxisome proliferator in the rat. Endocrinology 1988;122:1087–1093.

125. Engler D, Burger AG. The deiodination of the iodothyronines and of their derivatives in man. Endocr Rev 1984;5: 151–184.

126. Danforth E, Burger AG. The impact of nutrition on thyroid hormone physiology and action. Annu Rev Nutr 1989;9:201–227.

127. Visser TJ, Leonard JL, Kaplan MM, et al. Different pathways of iodothyronine 5′-deiodination in rat cerebral cortex. Biochem Biophys Res Commun 1981;101:1297–1304.

128. Bianco AC, Salvatore D, Gereben B, et al. Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocr Rev 2002;23:38–89.

129. LoPresti JS, Eigen A, Kaptein E, et al. Alterations in 3,3′5′-triiodothyronine metabolism in response to propylthiouracil, dexamethasone, and thyroxine administration in man. J Clin Invest 1989;84:1650–1656.

130. Geffner DL, Azukizawa M, Hershman JM. Propylthiouracil blocks extrathyroidal conversion of thyroxine to triiodothyronine and augments thyrotropin secretion in man. J Clin Invest 1975;55:224–220.

131. Saberi M, Sterling FH, Utiger RD. Reduction in extrathyroidal triiodothyronine production by propylthiouracil in man. J Clin Invest 1975;55:218–223.

132. Kaplan MM, Schimmel M, Utiger RD. Changes in serum 3,3′,5′-triiodothyronine (reverse T3) concentrations with altered thyroid hormone secretion and metabolism. J Clin Endocrinol Metab 1977;45:447–456.

133. Westgren U, Melander A, Wahlin E, et al. Divergent effects of 6-propylthiouracil on 3,3′,5′-triiodothyronine (RT3) serum levels and in man. Acta Endocrinol (Copenh) 1977;85:345–350.

134. Nogimori T, Braverman LE, Taurog A, et al. A new class of propylthiouracil analogs: comparison of 5′-deiodinase inhibition and antithyroid activity. Endocrinology 1986;118:1598–1605.

135. Wilber JF, Utiger RD. The effect of glucocorticoids on thyrotropin secretion. J Clin Invest 1969;48:2096–2090.

136. Nicoloff JT, Fisher DA, Appleman MDJ. The role of glucocorticoids in the regulation of thyroid function in man. J Clin Invest 1970;49:1922–1920.

137. Duick DA, Warren DW, Nicoloff JT, et al. Effect of single-dose dexamethasone on the concentration of serum triiodothyronine in man. J Clin Endocrinol Metab 1974;39:1151–1150.

138. Chopra IJ, Williams DE, Orgiazzi J, et al. Opposite effects of dexamethasone on serum concentrations of 3,3′,5′-triiodothyronine (reverse T3) and 3,3′5-triiodothyronine (T3). J Clin Endocrinol Metab 1975;41:911–920.

139. Burr WA, Ramsden DB, Griffiths RS, et al. Effect of a single dose of dexamethasone on serum concentrations of thyroid hormones. Lancet 1976;2:58–61.

140. Williams DE, Chopra IJ, Orgiazzi J, et al. Acute effects of corticosteroids on thyroid activity in Graves' disease. J Clin Endocrinol Metab 1975;41:354–361.

141. Verhoeven RP, Visser TJ, Docter R, et al. Plasma thyroxine, 3,3′,5-triiodothyronine and 3,3′,5′-triiodothyronine during beta-adrenergic blockade in hyperthyroidism. J Clin Endocrinol Metab 1977;44:1002–1005.

142. Lotti G, Delitala G, Devilla L, et al. Reduction of plasma triiodothyronine (T3) induced by propranolol. Clin Endocrinol (Oxf) 1977;6:405–410.

143. Saunders J, Hall SE, Crowther A, et al. The effect of propranolol on thyroid hormones and oxygen consumption in thyrotoxicosis. Clin Endocrinol (Oxf) 1978;9:67–72.

144. Kallner G, Ljunggren JG, Tryselius M. The effect of propranolol on serum levels of T4, T3 and reverse-T3 in hyperthyroidism. Acta Med Scand 1978;204:35–37.

145. Murchison LE, How J, Bewsher PD. Comparison of propranolol and metoprolol in the management of hyperthyroidism. Br J Clin Pharmacol 1979;8:581–587.

146. Feely J, Isles TE, Ratcliffe WA, et al. Propranolol, triiodothyronine, reverse triiodothyronine and thyroid disease. Clin Endocrinol (Oxf) 1979;10:531–538.

147. Faber J, Friis T, Kirkegaard C, et al. Serum T4, T3 and reverse T3 during treatment with propranolol in hyperthyroidism, L-T4 treated myxedema and in normal man. Horm Metab Res 1979;11:34–36.

148. Wartofsky L, Dimond RC, Noel GL, et al. Failure of propranolol to alter thyroid iodine release, thyroxine turnover, or the TSH and PRL responses to thyrotropin-releasing hormone in patients with thyrotoxicosis. J Clin Endocrinol Metab 1975;41:485–490.

149. Shulkin BL, Peele ME, Utiger RD. Beta-adrenergic antagonist inhibition of hepatic 3,5,3′-triiodothyronine production. Endocrinology 1984;115:858–861.

150. Heyma P, Larkins RG, Higginbotham L, et al. D-propanolol and DL-propanolol both decrease conversion of L-thyroxine to L-triiodothyronine. BMJ 1980;281:24–20.

151. Heyma P, Larkins RG, Campbell DG. Inhibition by propanolol of 3,5,3′-triiodothyronine formation from thyroxine in isolated rat renal tubules: an effect independent of beta-adrenergic blockade. Endocrinology 1980; 106:1437–1430.

152. 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;43:1203–1210.

153. Suzuki H, Kadena N, Takeuchi K, et al. Effects of three-day oral cholecystography on serum iodothyronines and TSH concentrations: comparison of the effects among some cholecystographic agents and the effects of iopanoic acid on the pituitary-thyroid axis. Acta Endocrinol (Copenh) 1979;92:477–488.

154. Brown RS, Cohen JH, Braverman LE. Successful treatment of massive acute thyroid hormone poisoning with iopanoic acid. J Pediatr 1998;132:903–905.

155. Felicetta JV, Green WL, Nelp WB. Inhibition of hepatic binding of thyroxine by cholecystographic agents. J Clin Invest 1980;65:1032–1040.

156. Burger A, Dinichert D, Nicod P, et al. Effect of amiodarone on serum triiodothyronine, reverse triiodothyronine, thyroxin, and thyrotropin. A drug influencing peripheral metabolism of thyroid hormones. J Clin Invest 1976;58:255–259.

157. Melmed S, Nademanee K, Reed AW, et al. Hyperthyroxinemia with bradycardia and normal thyrotropin secretion after chronic amiodarone administration. J Clin Endocrinol Metab 1981;53:997–990.

158. Lambert MJ, Burger AG, Galeazzi RL et al. Are selective increases in serum thyroxine (T4) due to iodinated inhibitors of T4 monocodination indicative of hyperthyroidism? J Clin Endocrinol Metab 1982;55:1058–1065.

159. Kaptein EM, Egodage PM, Hoopes MT, et al. Amiodarone alters thyroxine transfer and distribution in humans. Metabolism 1988;37:1107–1113.

160. Zaninovich AA, Bosco SC, Fernandez-Pol AJ. Amiodarone does not affect the distribution and fractional turnover of triiodothyronine from the plasma pool, but only its generation from thyroxine in extrathyroidal tissues. J Clin Endocrinol Metab 1990;70:1721–1724.

161. Iervasi G, Clerico A, Manfredi C et al. Acute effects of intravenous amiodarone on sulphate metabolites of thyroid hormones in arrhythmic patients. Clin Endocrinol (Oxf) 1997;47:699–705.

 

162. Schroder van der Elst JP, van der Heide D. Thyroxine, 3,5,3′-triiodothyronine, and 3,3′,5′-triiodothyronine concentrations in several tissues of the rat: effects of amiodarone and desethylamiodarone on thyroid hormone metabolism (corrected) (published erratum appears in Endocrinology 1991 Jan; 128 (1:393). Endocrinology 1990;127:1656–1664.

163. van Beeren HC, Bakker O, Wiersinga WM. Desethylamiodarone interferes with the binding of co-activator GRIP-1 to the beta 1-thyroid hormone receptor. FEBS Lett 2000;481:213–216.

164. van Beeren HC, Bakker O, Wiersinga WM. Desethylamiodarone is a competitive inhibitor of the binding of thyroid hormone to the thyroid hormone alpha 1-receptor protein. Mol Cell Endocrinol 1995;112:15–19.

165. Polikar R, Goy JJ, Schlapfer J, et al. Effect of oral triiodothyronine during amiodarone treatment for ventricular premature complexes. Am J Cardiol 1986;58:987–991.

166. Lambert M, Burger AG, De Nayer P, et al. Decreased TSH response to TRH induced by amiodarone. Acta Endocrinol (Copenh) 1988;118:449–452.

167. Wu SY, Chopra IJ, Solomon DH, et al. Changes in circulating iodothyronines in euthyroid and hyperthyroid subjects given ipodate (Oragrafin), an agent for oral cholecystography. J Clin Endocrinol Metab 1978;46:691–697.

168. Wu SY, Chopra IJ, Solomon DH, et al. The effect of repeated administration of ipodate (Oragrafin) in hyperthyroidism. J Clin Endocrinol Metab 1978;47:1358–1362.

169. Karpman BA, Rapoport B, Filetti S, et al. Treatment of neonatal hyperthyroidism due to Graves' disease with sodium ipodate. J Clin Endocrinol Metab 1987;64:119–123.

170. Roti E, Robuschi G, Gardini E, et al. Comparison of methimazole, methimazole and sodium ipodate, and methimazole and saturated solution of potassium iodide in the early treatment of hyperthyroid Graves' disease. Clin Endocrinol (Oxf) 1988;28: 305–314.

171. Berghout A, Wiersinga WM, Brummelkamp WH. Sodium ipodate in the preparation of Graves' hyperthyroid patients for thyroidectomy. Horm Res 1989;31:256–250.

172. Martino E, Balzano S, Bartalena L, et al. Therapy of Graves' disease with sodium ipodate is associated with a high recurrence rate of hyperthyroidism. J Endocrinol Invest 1991;14:847–851.

173. Cohen JH, Ingbar SH, Braverman LE. Thyrotoxicosis due to ingestion of excess thyroid hormone: update 1994. Endocr Rev 1994;10:364–375.

174. Van Reeth O, Unger J. Effects of amiodarone on serum T3 and T4 concentrations in hyperthyroid patients treated with propylthiouracil. Thyroid 1991;1:301–306.

175. Van Reeth O, Decoster C, Unger J. Effect of amiodarone on serum T4 and T3 levels in hyperthyroid patients treated with methimazole. Eur J Clin Pharmacol 1987;32:223–227.

176. Bakker O, van Beeren HC, Wiersinga WM. Desethylamiodarone is a noncompetitive inhibitor of the binding of thyroid hormone to the thyroid hormone beta 1-receptor protein. Endocrinology 1994;134:1665–1670.

177. van Beeren HC, Bakker O, Wiersinga WM. Structure-function relationship of the inhibition of the 3,5,3′-triiodothyronine binding to the alpha1- and beta1-thyroid hormone receptor by amiodarone analogues. Endocrinology 1996;137:2807–2814.

178. Drvota V, Carlsson B, Haggblad J et al. Amiodarone is a dose-dependent noncompetitive and competitive inhibitor of T3 binding to thyroid hormone receptor subtype beta 1, whereas disopyramide, lignocaine, propafenone, metoprolol, dl-sotalol, and verapamil have no inhibitory effect. J Cardiovasc Pharmacol 1995;26:222–226.

179. Gotzsche LBH, Orskov H. Cardiac triiodothyronine nuclear receptor binding capacities in amiodarone-treated, hypo- and hyperthyroid rats. Eur J Endocrinol 1994;130:281–290.

180. Paradis P, Lambert C, Rouleau J. Amiodarone antagonizes the effects of T3 at the receptor level: an additional mechanism for its in vivo hypothyroid-like effects. Can J Physiol Pharmacol 1991;69:865–870.

181. Perret G, Yin YL, Nicolas P, et al. Amiodarone decreases cardiac beta-adrenoceptors through an antagonistic effect on 3,5,3′ triiodothyronine. J Cardiovasc Pharmacol 1992;19:473–478.

182. Gotzsche LBH. Beta-adrenergic receptors, voltage-operated Ca2+ -channels, nuclear triiodothyronine receptors and triiodothyronine concentration in pig myocardium after long-term low-dose amiodarone treatment. Acta Endocrinol (Copenh)1993;129:337–347.

183. Figge HL, Figge J. The effects of amiodarone on thyroid hormone function: a review of the physiology and clinical manifestations. J Clin Pharmacol 1990;30:588–595.

184. Figge J, Dluhy RG. Amiodarone-induced elevation of thyroid stimulating hormone in patients receiving levothyroxine for primary hypothyroidism. Ann Intern Med 1990;113:553–555.