The Effects of Amiodarone on the Thyroid*

Transcription

1 X/01/$03.00/0 Endocrine Reviews 22(2): Copyright 2001 by The Endocrine Society Printed in U.S.A. The Effects of Amiodarone on the Thyroid* ENIO MARTINO, LUIGI BARTALENA, FAUSTO BOGAZZI, AND LEWIS E. BRAVERMAN Dipartimento di Endocrinologia e Metabolismo (E.M., F.B.), University of Pisa, Pisa, Italy 56124; Cattedra di Endocrinologia (L.B.), University of Insubria, Varese, Italy; Section of Endocrinology, Diabetes and Nutrition (L.E.B.), Boston Medical Center, Boston, Massachusetts ABSTRACT Amiodarone is a benzofuranic-derivative iodine-rich drug widely used for the treatment of tachyarrhythmias and, to a lesser extent, of ischemic heart disease. It often causes changes in thyroid function tests (typically an increase in serum T 4 and rt 3, and a decrease in serum T 3, concentrations), mainly related to the inhibition of 5 deiodinase activity, resulting in a decrease in the generation of T 3 from T 4 and a decrease in the clearance of rt 3. In 14 18% of amiodarone-treated patients, there is overt thyroid dysfunction, either amiodarone-induced thyrotoxicosis (AIT) or amiodarone-induced hypothyroidism (AIH). Both AIT and AIH may develop either in apparently normal thyroid glands or in glands with preexisting, clinically silent abnormalities. Preexisting Hashimoto s thyroiditis is a definite risk factor for the occurrence of AIH. The pathogenesis of iodineinduced AIH is related to a failure to escape from the acute Wolff- Chaikoff effect due to defects in thyroid hormonogenesis, and, in patients with positive thyroid autoantibody tests, to concomitant Hashimoto s thyroiditis. AIT is primarily related to excess iodineinduced thyroid hormone synthesis in an abnormal thyroid gland (type I AIT) or to amiodarone-related destructive thyroiditis (type II AIT), but mixed forms frequently exist. Treatment of AIH consists of L-T 4 replacement while continuing amiodarone therapy; alternatively, if feasible, amiodarone can be discontinued, especially in the absence of thyroid abnormalities, and the natural course toward euthyroidism can be accelerated by a short course of potassium perchlorate treatment. In type I AIT the main medical treatment consists of the simultaneous administration of thionamides and potassium perchlorate, while in type II AIT, glucocorticoids are the most useful therapeutic option. Mixed forms are best treated with a combination of thionamides, potassium perchlorate, and glucocorticoids. Radioiodine therapy is usually not feasible due to the low thyroidal radioiodine uptake, while thyroidectomy can be performed in cases resistant to medical therapy, with a slightly increased surgical risk. (Endocrine Reviews 22: , 2001) I. Introduction II. Pharmacology of Amiodarone III. Amiodarone and the Thyroid A. Pituitary-thyroid function tests during amiodarone therapy B. Thyroid cytotoxicity C. Effect on thyroid autoimmunity D. Interaction of amiodarone and its metabolites with thyroid hormone receptors E. Amiodarone-induced thyroid dysfunction IV. Recommendations for Following Patients Receiving Amiodarone Therapy V. Amiodarone and Pregnancy VI. Conclusions I. Introduction AMIODARONE is an iodine-rich drug widely used for the management of ventricular arrhythmias, paroxysmal supraventricular tachycardia, and atrial fibrillation and flutter (1). The drug is, to a lesser extent, also employed Address reprint requests to: Professor Enio Martino, Dipartimento di Endocrinologia e Metabolismo, University of Pisa, Ospedale di Cisanello, via Paradisa, 2, Pisa, Italy. e.martino@endoc. med.unipi.it; or Dr. Lewis E. Braverman, Boston Medical Center, 88 East Newton Street, Evans Building, Room 201, Boston, Massachusetts lewis.braverman@bmc.org. * This work was supported in part and by grants from the University of Pisa (Fondi d Ateneo) to Enio Martino e Luigi Bartalena, and from the Ministero della Università e della Ricerca Scientifica e Tecnologica (M.U.R.S.T.), Rome to Enio Martino. for severe congestive heart failure because of its minimal negative inotropic action (2). In addition, it may decrease cardiac-related mortality after myocardial infarction (3), although the latter effect has been questioned (4); decrease the immediate and late complications of atrial fibrillation in patients undergoing elective cardiac surgery (5); prevent recurrence of atrial fibrillation (6); and decrease cardiac arrhythmia death when given to patients upon arrival of emergency medical technicians (EMTs) (7). However, amiodarone also has effects on the thyroid and other organs that may counterbalance its beneficial effects on the heart (8, 9) (Table 1). The complex effects on the thyroid range from abnormalities of thyroid function tests to overt thyroid dysfunction, either thyrotoxicosis or hypothyroidism (10 12). The aim of this review is to analyze the pathophysiology of amiodarone-induced changes in thyroid function and to present the diagnostic and therapeutic aspects of amiodarone-induced thyroid dysfunction. II. Pharmacology of Amiodarone Amiodarone is a benzofuranic derivative whose structural formula closely resembles that of T 4 (Fig. 1). It contains approximately 37% iodine by weight. Because approximately 10% of the molecule is deiodinated daily, and the maintenance daily dose of the drug ranges from 200 to 600 mg, approximately 7 21 mg iodide are made available each day, resulting in a marked increase in urinary iodide excretion (13). If one considers that the optimal daily iodine intake is 240

2 April, 2001 AMIODARONE AND THE THYROID 241 TABLE 1. Side effects and complications of amiodarone therapy Overall incidence (%) Corneal microdeposits 100 Gastrointestinal changes (anorexia, nausea) 80 Skin photosensitivity and gray/bluish skin discoloration Neurological symptoms (ataxia, tremors, peripheral neuropathy) 48 Abnormalities of liver function tests a 25 Thyroid dysfunction Lung dysfunction, interstitial pneumonitis Epididymitis 11 Cardiac disorders (heart block, sinus bradycardia) 2 3 Gynecomastia Exceptional a Toxic hepatitis is rare. considered to be g (14), amiodarone treatment releases 50- to 100-fold excess iodine daily. Furthermore, amiodarone is distributed in several tissues, including adipose tissue, liver, lung, and, to a lesser extent, kidneys, heart, skeletal muscle, thyroid, and brain (15), from which it is slowly released. In the analysis of a variety of postmortem tissues, intrathyroidal concentrations of amiodarone and its metabolite, desethylamiodarone (DEA), were 14 mg/kg and 64 mg/kg, respectively, compared with 316 mg/kg and 76 mg/kg in the adipose tissue and 391 mg/kg and 2354 mg/kg in the liver (15). Terminal elimination half-lives averaged ( sd) days for amiodarone and days for DEA in eight patients after cessation of long-term amiodarone therapy (15). In another study the mean ( sdd) elimination half-lives were days for amiodarone and days for DEA (16). The above results explain why, after amiodarone withdrawal, the drug and its metabolites remain available for a long period. Amiodarone is metabolized through different pathways, the most important being dealkylation, which leads to formation of DEA (17) (Fig. 1). Approximately 66 75% of amiodarone is eliminated through bile and feces (13). III. Amiodarone and the Thyroid A. Pituitary-thyroid function tests during amiodarone therapy FIG. 1. Chemical formula of amiodarone, DEA, and thyroid hormones. In peripheral tissues, particularly the liver, amiodarone inhibits type I 5 -deiodinase (5 -D) activity, which removes an atom of iodine from the outer ring of T 4 to generate T 3 and from the outer ring of rt 3 to produce 3,3 -diiodothyronine (T 2 ) (18 20). This inhibition of 5 -D activity may persist for several months after amiodarone withdrawal (9 11). Apparently, amiodarone does not affect the distribution and fractional removal of T 3 from the plasma pool (21). In addition, the drug inhibits thyroid hormone entry into peripheral tissues (22). Both mechanisms contribute to the increased serum T 4 concentration and the decreased serum T 3 concentration in euthyroid subjects given long-term amiodarone therapy (9 12). Serum T 4 concentrations are often at the upper limit of the normal range, but may be increased, especially in patients receiving higher daily doses of the drug (23). The decrease in serum T 3, due to decreased production from T 4, and the concomitant increase in serum rt 3 concentrations, due to decreased clearance, are often found as early as 2 weeks after institution of amiodarone therapy (24, 25). The increase in serum rt 3 levels is usually far greater than the decrease in serum T 3 concentrations (17, 23, 26). Indeed, serum T 3 concentrations often remain within the low normal range. Amiodarone administration is also associated with doseand time-dependent changes in serum TSH concentration. With a daily dose of mg of the drug, serum TSH levels are usually normal, although an increased TSH response to intravenous TRH administration is frequently observed (10). With higher doses of the drug, an increase in serum TSH concentration may occur during the early months of treatment, but this is generally followed by a return to normal (24, 25). These changes in serum TSH concentration are believed to be related to the variations of serum thyroid hormone levels; amiodarone may also directly affect TSH synthesis and secretion at the pituitary level (27). The increased serum TSH concentration may also result from the inhibition of type II 5 -D, which converts T 4 to T 3 in the pituitary, by either amiodarone or desethylamiodarone (28). Indeed, after a loading dose of amiodarone by intravenous

3 242 MARTINO ET AL. Vol. 22, No. 2 TABLE 2. Reference values for serum thyroid hormones and TSH concentrations in euthyroid untreated subjects and in euthyroid patients receiving long-term amiodarone therapy Assay Untreated subjects Euthyroid patients on amiodarone Free T 4 (pmoles/liter) Total T 3 (nmoles/liter) Free T 3 (pmoles/liter) TSH (mu/liter) [Derived from C. M. Newman et al.: Heart 79: , 1998 (116).] infusion, TSH is the first hormone to undergo significant variations, even during the first day of therapy (29). During long-term amiodarone therapy, clinically euthyroid patients may show modest increases or decreases in serum TSH concentration, possibly reflecting episodes of subclinical hypoor hyperthyroidism, respectively. The above description of changes in thyroid function tests occurring during chronic amiodarone therapy underscore the important concept that standard thyroid function tests in euthyroid patients receiving amiodarone have a different range than those observed in euthyroid subjects not receiving amiodarone. Appropriate reference values for thyroid function tests in patients receiving amiodarone are shown in Table 2. FIG. 2. Cytotoxicity of amiodarone on freshly prepared human thyroid follicles. Cells were incubated for 24 h in the standard medium added with amiodarone in the concentrations shown. Black bars, viable cells; white bars, cell lysis. [Derived from L. Chiovato et al.: Endocrinology 134: , 1994 (30). The Endocrine Society.] B. Thyroid cytotoxicity In addition to the above effects on enzymatic activities relevant to pituitary-thyroid physiology, amiodarone and its metabolites also have cytotoxic effects on the thyroid. Chiovato et al. (30) reported that amiodarone had a cytotoxic effect on thyroid cells (Fig. 2), although this occurred at a lower molar concentration in freshly prepared human thyroid follicles, which trap and organify iodide, than in rat FRTL-5 cells, which have an active iodide pump but are unable to organify iodide. In human thyroid follicles, lysis of 50% of thyroid cells occurred at concentrations of amiodarone ( 200 mol/liter) much lower than potassium iodide (30). Methimazole, which inhibits iodide organification, partially, but significantly reduced the cytotoxic effects of amiodarone in human thyroid follicles (30). Finally, amiodarone cytotoxicity was also shown in Chinese hamster ovary cells, a nonthyroid cell line (30). These data, taken together, suggest that amiodarone-related thyroid cytotoxicity is mainly due to a direct effect of the drug on thyroid cells, although excess iodide released from amiodarone may contribute to its toxic action. DEA, the main amiodarone metabolite, is even more cytotoxic for thyroid cells than amiodarone (31), and its intrathyroidal concentration is higher than that of the parental drug (15). It has been shown recently that in thyroid cells (both primary thyroid cells and the cell line TAD-2 derived from human fetal thyroid cells infected with Simian virus 40), iodide excess induced apoptosis through a p53-independent mechanism involving oxidative stress and associated with production of reactive oxygen species and a marked increase in lipid peroxide levels (32). Whether these mechanisms contribute to amiodarone-associated thyroid histopathological abnormalities remains to be established. Finally, it is unclear TABLE 3. Amiodarone-induced ultrastructural changes in the rat thyroid Irregular, distended, or involuted follicles Marked follicular disruption Irregular and reduced microvilli Irregular nuclear shape and chromatin condensation around edge of nuclear membrane Apoptosis and necrosis Markedly increased number of lysosomes Inclusion bodies Lipofuscinogenesis Marked dilation of endoplasmic reticulum [Derived from V. Pitsiavas et al.: Eur J Endocrinol 137:89 98, 1997 (33).] whether nonthyroid amiodarone-induced abnormalities are more common in patients with amiodarone thyroid toxicity. In the rat, it was shown that amiodarone administration is associated with ultrastructural changes indicative of thyroid cytotoxicity, which were distinct from those induced by excess iodine alone (33). These included marked distortion of thyroid architecture, apoptosis, necrosis, inclusion bodies, lipofuscinogenesis, macrophage infiltration, and markedly dilated endoplasmic reticulum (33) (Table 3). The latter findings might be compatible with the disruption of protein sorting pathways leading to a drug-induced form of endoplasmic reticulum storage disease. The fact that amiodarone, being amphiphilic, strongly binds to intralysosomal phospholipids, making them indigestible by phospholipases, may contribute to these subcellular changes (34). Similar subcellular abnormalities have been observed during amiodarone treatment in other organs, such as liver, lung, heart, skin, cornea, and in peripheral nerve fibers and blood leukocytes (9). Accumulation of amiodarone in the different tissues and

4 April, 2001 AMIODARONE AND THE THYROID 243 the long terminal half-lives of amiodarone and its metabolites (15) represent important factors for the occurrence of the above changes. Amiodarone-induced tissue changes seem to be associated with prolonged drug treatment. In dogs, thyroid subcellular changes were not observed after a single, high-dose intravenous amiodarone injection, while they became apparent after multiple injections for 1 week (35). C. Effect on thyroid autoimmunity The effect of amiodarone on thyroid autoimmunity is a matter of disagreement. Iodine may induce thyroid autoimmunity in man (36) and animals (37, 38); therefore, the excess iodine released from amiodarone might be involved in the occurrence of thyroid autoimmune phenomena. In a prospective study of 37 patients randomly assigned to either placebo or amiodarone treatment after myocardial infarction, antithyroid peroxidase antibodies de novo occurred in the serum of 6 of 13 (55%) amiodarone-treated patients and in no placebo-treated patients (39). Interestingly, these autoantibodies, appearing early during amiodarone treatment, could no longer be detected 6 months after withdrawal of the drug (39). This phenomenon was attributed to early and transient toxic effects of amiodarone on the thyroid, leading to release of thyroid autoantigens and subsequent triggering of thyroid autoimmune reactions (39). These results were not, however, confirmed in several subsequent prospective or cross-sectional studies (40 44). Safran et al. (40) failed to find an increased incidence of antithyroid autoantibodies in 47 patients submitted to both short-term and long-term amiodarone treatment in geographical areas of different ambient iodine intake. Foresti et al. (43) found positive thyroid autoantibody tests at low titer in only 2 of 23 amiodaronetreated patients, a figure not different from that found in patients receiving other antiarrhythmic drugs. Thus, the majority of studies indicate that it is unlikely that thyroid autoantibodies appear in subjects who have negative tests before treatment. The finding that amiodarone treatment may be associated with an increase in certain lymphocyte subsets may indicate, however, that in susceptible individuals amiodarone may precipitate or exacerbate preexisting organspecific autoimmunity (45). This appears to be particularly important in amiodarone-induced hypothyroidism (AIH), where the majority of patients have circulating thyroid autoantibodies before amiodarone treatment (9, 10). D. Interaction of amiodarone and its metabolites with thyroid hormone receptors In addition to the inhibition of type I and type II 5 -D activities, amiodarone may induce a hypothyroid-like condition at the tissue level. This is partly related partly to a reduction in the number of catecholamine receptors (46, 47) and to a decrease in the effect of T 3 on -adrenoceptors (48). In the heart of amiodarone-treated pigs, the maximum binding capacity of -adrenoceptors and calcium channels was diminished, whereas the maximum T 3 binding capacity was unchanged, indicating that amiodarone did not induce any functional decrease in the number of T 3 receptors (49). Amiodarone has no effect on -adrenoceptor number in hypothyroid animals; however, the drug inhibits the increase in receptor density after T 3 administration (48, 50). This suggests that thyroid hormone is required for the effect of amiodarone on -adrenoceptors, and that amiodarone does not exert a direct action on -adrenoceptors. Tissue and adrenoceptor subtype differences may also exist. In the brown adipose tissue of thyroidectomized rats, amiodarone did not inhibit the positive T 3 effect on 1-adrenoceptor expression, but it antagonized the effect on 3-adrenoceptors number (51). In the liver it was shown that amiodarone causes a decreased transcription of the T 3 -responsive gene encoding for the low density lipoprotein receptor (52, 53). In pituitary cell cultures, amiodarone inhibited in a dose-dependent manner the T 3 -induced increase in GH mrna (54). The molecular mechanisms underpinning this antagonistic action of amiodarone on thyroid hormone effects are not completely understood. They might be related to a downregulation of thyroid hormone receptors (TR) caused by amiodarone. Myocardial nuclear T 3 receptor maximum binding was reduced to a similar degree in hypothyroid and amiodarone-treated rats (55). In mice treated with this drug, certain TR subtypes (TR 1 and TR 1) were effectively downregulated in a dose-dependent manner (56). However, other TR subtypes, such as TR 2 (which has the highest density in the mouse heart) and TR 2, were not affected by amiodarone treatment (56). DEA, but not amiodarone, has been reported to affect the binding of T 3 to chicken TR 1, but not to TR 1 expressed in Escherichia coli (57, 58). Inhibition of T 3 binding appeared to be competitive for TR 1 and noncompetitive for TR 1 (57, 58). Studies using TR 1 mutants would suggest that DEA does not bind to the T 3 binding pocket (59). This would be in keeping with the noncompetitive feature of the DEA inhibition on T 3 binding to TR 1. We have recently observed that in NIH3T3 cells DEA (but not amiodarone) behaves as a weak thyroid hormone agonist, using both TR and TR, and antagonizes the effect of T 3 only when present in large excess (60). Bakker et al. (61) have also reported that DEA has a thyroid hormone agonist effect. Thus, DEA, the main amiodarone metabolite, might act both as thyroid hormone agonist and antagonist, possibly depending upon TR expression in different tissues. The high tissue levels reached by the drug during chronic amiodarone treatment might explain the prevailing antagonist effect and the hypothyroid-like situation observed in tissue such as the heart and liver (9). E. Amiodarone-induced thyroid dysfunction Although the majority of patients given amiodarone remain euthyroid, some develop thyroid dysfunction, i.e., thyrotoxicosis and hypothyroidism (10). Amiodarone-induced thyrotoxicosis (AIT) appears to occur more frequently in geographical areas with low iodine intake, whereas AIH is more frequent in iodine-sufficient areas (62 64). In particular, in a study carried out simultaneously in Western Tuscany (moderately low iodine intake) and Massachusetts (normal iodine intake), it was found that the incidence of AIT was about 10% in Italy and 2% in the United States, while the

5 244 MARTINO ET AL. Vol. 22, No. 2 incidence of AIH was 5% in Italy and 22% in the United States (61) (Fig. 3). Two studies have prospectively evaluated the incidence of amiodarone-induced thyroid dysfunction. In a study of 58 consecutive euthyroid patients residing in a Dutch region with moderately sufficient iodine intake, AIT occurred in 12.1% of cases and AIH in 6.9% (44). In a prospective study carried out in a moderately iodine-deficient Italian area, AIT occurred in 2 of 13 patients (15%) and AIH in 5 of 7 patients (71%) who had evidence of Hashimoto s thyroiditis before treatment (65). A high prevalence of thyroid dysfunction was recently reported in an iodine-deficient area (Sardinia, Italy) in a young adult population with -thalassemia major who received amiodarone therapy (66). Five of 22 patients (23%) developed overt hypothyroidism, compared with 3 of 73 (4%) control -thalassemic patients not receiving amiodarone therapy, and 3 amiodarone-treated patients (14%) developed AIT (2 overt, one subclinical) (66). In the case of -thalassemia, thyroid damage related to increased intrathyroidal iron deposits probably contributed to the high rate of amiodarone-associated thyroid dysfunction, particularly hypothyroidism. In general, the various published studies reported an overall incidence of AIT ranging from 1% to 23% and of AIH ranging from 1% to 32% (11). Thus, irrespective of iodine intake, it may be estimated that the overall incidence of amiodarone-induced thyroid dysfunction be between 2% and 24% (11), most commonly in the range of 14 18% (10). It is worth mentioning that in one study the addition of phenytoin to amiodarone was associated with a 49% incidence of thyroid dysfunction after a prolonged follow-up (67). Likewise, evaluation of a large series of adults with congenital heart disease revealed a prevalence of thyroid dysfunction in 36% of patients (68): female sex, complex cyanotic heart disease, previous Fontan-type surgery, and a dose of amiodarone 200 mg/day appeared to be significant risk factors for the occurrence of amiodarone-associated thyroid dysfunction (68). 1. Amiodarone-induced thyrotoxicosis. AIT may develop, often suddenly and explosively, early or after many years of amiodarone treatment (69). Trip et al. (44) observed that the average length of amiodarone treatment before the occurrence of AIT was about 3 yr, with a probability of after 18 months and after 48 months. In the prospective study by Martino et al. (65), two patients developed AIT 12 and 29 months after institution of therapy. Mariotti et al. (66) reported the occurrence of AIT after months of amiodarone therapy. An interesting feature of AIT is that, due to tissue storage of the drug and its metabolites and to their slow release, the effect of amiodarone can persist for a long period of time. It is, therefore, not surprising that AIT may develop even many months after drug withdrawal (63). The daily or cumulative dose of amiodarone does not seem to be relevant for the occurrence of AIT. There are no parameters allowing predictability of AIT (44), although it has been suggested that the baseline lack of a TSH response to TRH may represent a risk factor for the subsequent occurrence of AIT (70). A relative predominance of AIT among men, with a M:F ratio of 3:1, has been reported (67, 71). a. Pathogenesis. The pathogenesis of AIT is complex and not completely understood. The disease may develop both in a normal thyroid gland or in a gland with preexisting abnormalities. In a study in a moderately iodine-deficient area, diffuse goiter was found in 29% of AIT, and nodular goiter occurred in 38%, but the thyroid was apparently normal in the remaining 33% of cases (63). The occurrence of AIT in apparently normal thyroid glands was also reported in studies from iodine-sufficient areas (26, 44, 69, 72). Humoral thyroid autoimmunity seems to play little, if any, role in the development of AIT in patients without underlying thyroid disorders. Circulating antithyroglobulin, antithyroid peroxidase, and TSH-receptor (TRAb) antibodies were found only in AIT patients with preexisting thyroid abnormalities (mostly diffuse goiter), but not in those with apparently normal thyroid glands (Fig. 4) (73). While most studies failed to observe the development of TRAb in AIT patients (44, 72, 73), in a study of 12 Japanese patients, 1 patient developed thyrotoxicosis associated with transient positivity for TRAb, which was, however, devoid of any thyroid hormone-releasing activity in cultured human thyroid follicles (74). A possible pathogenic hypothesis suggests that AIT is due FIG. 3. Prevalence of amiodarone-induced hyperthyroidism and hypothyroidism in an iodine-deficient area of Northern Tuscany, Italy, and in an iodine-sufficient area of Worcester, Massachusetts. [Derived from E. Martino et al.: Ann Intern Med 101:28 34, 1984 (62).] FIG. 4. TSH-receptor antibody (assessed by the increase in adenylate-cyclase activity) in 46 patients with AIT and in 35 normal controls.

6 April, 2001 AMIODARONE AND THE THYROID 245 to excessive thyroid hormone synthesis induced by the iodine load. Intrathyroidal iodine content, assessed by x-ray fluorescence, was found to be markedly increased in AIT patients, irrespective of the presence of an intrinsic thyroid abnormality (75). The perchlorate discharge test is negative, indicating that there is no relevant impairment of iodine organification (76, 77). Interestingly, a normalization of intrathyroidal iodine content has been reported after the restoration of euthyroidism in AIT patients (69). In patients with preexisting thyroid abnormalities (diffuse or nodular goiter, latent Graves disease), the 24-h thyroid radioactive iodine uptake (RAIU) values were in some cases higher than 8% (and as high as 64%) despite the iodine load (78), although in iodine-sufficient areas such as the United States, the RAIU is almost always very low. This suggests that in patients with an underlying thyroid disorder and residing in a mildly iodine-deficient area, the thyroid gland may fail to adapt normally to the excess iodine load, resulting in inappropriately elevated RAIU values despite the presence of excess plasma iodine. This subgroup of AIT patients usually have normal or slightly elevated serum interleukin-6 (IL-6) levels (79) (Fig. 5). This cytokine is a good marker of thyroiddestructive processes and, therefore, increases in the circulation after radioiodine therapy, intranodular ethanol injection, and fine needle aspiration (80). An increased IL-6 concentration is also found in subacute thyroiditis (81). The fact that serum IL-6 levels are normal or slightly increased in this subgroup of AIT patients suggests that thyroid-destructive processes do not represent an important pathogenetic mechanism in most of these cases. This form of AIT with an underlying thyroid abnormality, normal/elevated RAIU values but low values in iodine sufficient regions, and normal/slightly elevated serum IL-6 levels, has been defined as FIG. 5. Serum IL-6 in amiodarone-treated patients and in control groups. AmEu, Euthyroid amiodarone-treated patients; AIH, amiodarone-induced hypothyroidism; AIT, AIT in the absence of underlying thyroid abnormalities; AIT, AIT with underlying thyroid abnormalities; GD, Graves disease; TA, toxic adenoma; NTG, nontoxic goiter. [Reproduced with permission from L. Bartalena et al.: J Clin Endocrinol Metab 78: , 1994 (79). The Endocrine Society.] type I AIT (79) (Table 4). Further support to the concept that type I AIT is due to excess iodine-associated excessive thyroid hormone synthesis comes from the observation that these patients have color flow Doppler sonography (CFDS) patterns (pattern I-III) that indicate a hyperfunctioning gland with hypervascularity, as seen in spontaneous hyperthyroidism (82, 83) (Fig. 6). If excessive thyroid hormone synthesis can explain the occurrence of hyperthyroidism in patients with preexisting (subclinical) thyroid disorders, what is the mechanism leading to AIT in patients with apparently normal thyroid glands? These patients usually have no detectable thyroid abnormalities on physical examination or ultrasonography, although in some cases there may be a small, tender goiter, and thyroid autoantibody tests are negative. In addition they have very low (usually 2 3%) RAIU values (77, 78). Serum IL-6 concentrations are usually markedly elevated (78) (Fig. 5), and pattern 0 (indicating the absence of hypervascularity) is observed on CFDS (82, 83) (Fig. 6). Both the above features are typically encountered in thyroid-destructive processes, such as subacute thyroiditis (81, 83). Further support to the concept that this form of AIT, defined as type II (79) (Table 4), is related to a thyroid-destructive process is provided by the histopathological examination of the thyroids of a few patients. While euthyroid amiodarone-treated patients showed minimal or no evidence of thyroid follicular damage, the glands of two patients with AIT showed moderate to severe follicular damage and disruption (84). Other small surgical series showed signs of thyroid damage, with swelling of follicular cells, vacuolization of the cytoplasm, and fibrosis (85 88) (Table 5). Therefore, type II AIT appears to be a form of destructive thyroiditis with associated leakage of preformed hormones from damaged follicles. This is in keeping with the in vitro studies demonstrating the cytotoxic effect of amiodarone and its metabolites (30, 32). Further support comes from the observation that in this subgroup of AIT patients, the thyrotoxic phase is sometimes followed by mild hypothyroidism (89), as may happen after subacute thyroiditis. This progression may be accelerated by reexposure of the patient to an iodine load (90). To summarize, two main forms of AIT exist. Type I AIT usually occurs in abnormal thyroid glands and is due to iodine-induced excessive thyroid hormone synthesis and release; type II AIT is a destructive thyroiditis leading to release of preformed thyroid hormones from the damaged thyroid follicular cells. The relative prevalence of the two forms of AIT is unknown, but it may depend on the ambient iodine intake. For example, in Japan, an iodine-sufficient area with a very low incidence of toxic multinodular goiter, only destructive-type AIT was observed (91) Definitions of AIT may not be so absolute, and indeed mixed forms often exist, in which the different features of type I and type II AIT may coexist. This is suggested, for example, by the observation that some patients with type I AIT may have markedly increased serum IL-6 levels (79). Nevertheless, the effort to identify the different subgroups of AIT has important clinical implications regarding the difficult management of this challenging situation (see below).

7 246 MARTINO ET AL. Vol. 22, No. 2 TABLE 4. Classification of amiodarone-induced thyrotoxicosis Goiter/thyroid autoantibodies Often present Usually absent Thyroidal radioactive iodine uptake Low/normal/increased a Low/suppressed Serum IL-6 levels b Slightly increased Markedly increased Color flow Doppler sonography pattern I III 0 Therapeutic response to thionamides Yes No Therapeutic response to perchlorate Yes No Therapeutic response to glucocorticoids Probably no Yes Subsequent hypothyroidism No Possible [Derived from L. Bartalena et al.: J Clin Endocrinol Metab 78: , 1994 (79), with modifications.] a Almost always low in the United States and iodine-sufficient regions. b Mixed forms with underlying thyroid abnormalities and concomitant thyroid destructive phenomena (markedly elevated serum IL-6 levels) also exist. Type I Type II FIG. 6. Color flow Doppler sonography (CFDS) pattern in AIT patients, in euthyroid amiodarone-treated subjects, in Graves disease, in subacute thyroiditis, and in control subjects. Pattern 0, Absent hypervascularity; pattern I, presence of parenchymal blood flow with patchy uneven distribution); pattern II, mild increase of color flow Doppler signal with patchy distribution); pattern III, markedly increased color flow Doppler signal with diffuse homogeneous distribution). [Reproduced with permission from F. Bogazzi et al.: Thyroid 7: , 1997 (82).] b. Clinical manifestations. Classical symptoms of thyrotoxicosis may be absent, due to the antiadrenergic action of amiodarone and its impairment of conversion of T 4 to T 3 ; goiter may be present or absent, with or without pain in the thyroid region; ophthalmopathy is usually absent, unless AIT occurs in a patient with Graves disease (9 12). AIT may be heralded by a worsening of the underlying cardiac disorder, with tachyarrhythmias or angina (63). The occurrence or recurrence of tachycardia or atrial fibrillation in a patient treated with amiodarone should be considered a good reason to investigate thyroid function (92). Diagnosis of AIT may be a difficult challenge in patients with severe nonthyroidal illness, because the latter may dominate the clinical picture (84) and result in increased serum free T 4, decreased/suppressed serum TSH, and decreased serum total and free T 3 concentrations (62): under these circumstances, measurement of serum free T 3 concentration may, however, be useful in establishing the diagnosis (93). Serum thyroglobulin is often increased in AIT, but this may not represent a good marker of thyroid destruction in goitrous patients. In addition, unexplained suppression of serum thyroglobulin secretion has been reported in a few AIT patients (94). Serum sex hormone binding globulin (SHBG) concentration is increased in AIT patients but not in euthyroid amiodaronetreated subjects with hyperthyroxinemia (95); however, this assay is of limited importance in individual patients, due to the numerous factors affecting serum SHBG levels. c. Treatment. Treatment of AIT is a major challenge. The high intrathyroidal iodine content reduces the effectiveness of conventional thionamide drug therapy (63). The generally low or suppressed RAIU values makes the administration of radioiodine therapy not feasible. An increase in RAIU values has been reported after administration of exogenous TSH (96). This possibility should be reevaluated using recombinant human TSH. Thyroidectomy may represent a valid option for AIT patients resistant to medical treatment, although the underlying cardiac conditions and the thyrotoxic state may increase the surgical risk or even exclude surgery in some patients. About 30 AIT patients treated by thyroidectomy have been reported: this procedure was associated with a prompt control of thyrotoxicosis, and no death occurred (72, 87, 88, 97 99). Plasmapheresis, aimed at removing the excess thyroid hormones from the circulation, has been reported to be efficacious (100), but this is usually transient and followed by an exacerbation of AIT (101, 102). The identification of the different subtypes of AIT may provide a rational basis for the choice of the appropriate medical treatment in an effort to improve the therapeutic outcome. In type I AIT the goal of treatment should be, on one hand, to block further organification of iodine and synthesis of thyroid hormones. Since the iodine-rich thyroid is more resistant to the therapeutic efficacy of the thionamides, larger than usual daily doses of methimazole (40 60 mg) or propylthiouracil ( mg) are often necessary. On the other hand, one should also decrease the entrance of iodine into the thyroid and deplete intrathyroidal iodine stores to improve the therapeutic efficacy of thionamides and to allow subsequent radioiodine therapy. The latter effect can be achieved by potassium perchlorate, a drug that inhibits thyroid iodine uptake (103). Treatment of AIT by the simultaneous administration of potassium perchlorate and methimazole was first reported by our group (104). In this study, 23 AIT patients were treated with methimazole (40 mg daily)

8 April, 2001 AMIODARONE AND THE THYROID 247 TABLE 5. Pathology of the thyroid in amiodarone-induced thyrotoxicosis Histopathology Involuted thyroid Enlarged follicles distended by dense, deeply acidophilic colloid and lined by flattened cells Degenerative and destructive follicular lesions Segmental swelling of the lining cells, with granular, foamy, vacuolated, and balloon-like cytoplasm Lipofuscinogenesis Follicles stuffed with desquamated cells Total follicular destruction Fibrotic lesions Areas of fibrosis including degenerated and disrupted follicular structures Other changes Mild chronic inflammatory infiltration [Derived from T. C. Smyrk et al.: Am J Surg Pathol 11: , 1987 (85).] alone, with methimazole and potassium perchlorate (1 g daily), or were not treated (104). Only the combined treatment controlled thyrotoxicosis in all cases. In addition, the time required for the attainment of euthyroidism was shorter than that in patients responsive to conventional thionamide treatment (104). The combined treatment was associated with a transient rise in serum thyroid hormone levels and urinary iodine excretion (104). These results were subsequently confirmed by other studies (69, 105). The limitation of potassium perchlorate is its toxicity, particularly agranulocytosis and aplastic anemia, and renal side effects. Trotter (106) compared the toxicity of thionamides and perchlorate and reported that the total incidence of reactions to perchlorate was 2 3%. Agranulocytosis occurred in 0.3% of 1,200 perchlorate-treated patients compared with 0.94% of the 10,131 thionamide-treated patients (106). However, when the daily dose of perchlorate exceeded 1 g, the incidence of toxicity increased to 16 18% (106). More recently, Wenzel and Lente (107) treated patients with Graves disease for 2 yr with initial doses of 900 mg daily decreasing to mg, and no hematological toxicity was recorded. A complete blood count should be done every few weeks in patients receiving thionamide and perchlorate to detect the potential development of anemia and/or agranulocytosis. In addition, it seems prudent to withdraw potassium perchlorate if euthyroidism is achieved, frequently by 6 weeks, associated with removing the refractoriness to thionamides related to excess intrathyroidal iodine stores. Shorter periods of perchlorate therapy (8 days) seem to result in a high risk of recurrent thyrotoxicosis (108). The addition of lithium carbonate ( mg/day for 4 6 weeks) to propylthiouracil has been reported in a small series of AIT patients to shorten substantially the time period necessary to achieve euthyroidism (109). The latter results will require confirmation in controlled studies enrolling a larger number of patients. Thionamides with or without potassium perchlorate are not an appropriate form of therapy for type II AIT, which is a destructive thyroiditis induced by amiodarone. Steroids are a good and effective therapeutic approach in these cases because of their membrane-stabilizing and antiinflammatory effects (110). In addition, they are beneficial because of their inhibition of 5 -D activity. Steroids have been employed in AIT at different doses (15 80 mg prednisone or 3 6 mg dexamethasone daily) and different time schedules (7 12 weeks) (9 12). Results of steroid treatment, either alone or in combination with antithyroid drugs or plasmapheresis, have been favorable in most studies in patients with type II AIT (96, ), whereas the data in type I AIT are scant but seem to indicate limited effectiveness (110). It is worth mentioning the possible recurrence of thyrotoxicosis when steroid treatment is discontinued (111, 112, 115); steroid treatment must be reinstituted in these patients. For a subgroup of patients with mixed forms of AIT, a combination of methimazole, potassium perchlorate, and steroids is probably the most beneficial therapeutic regimen. A relevant problem is whether amiodarone therapy should be discontinued or not. Obviously, amiodarone is a very effective drug for the underlying cardiac problem, and quite often these patients are resistant to other antiarrhythmic drugs. This may make withdrawal of amiodarone impossible, especially in patients in whom the original indication for this pharmacological treatment was a life-threatening tachyarrhythmia, such as ventricular tachycardia or fibrillation. In addition, even discontinuation of amiodarone therapy does not prevent a continuing effect on the thyroid due to its long half-life. Furthermore, in view of the hypothyroid-like effect of amiodarone and its metabolites on the heart (9), amiodarone might, to some extent, paradoxically protect the heart from thyroid hormone excess; therefore, withdrawal of the drug might be associated with an exacerbation of heart thyrotoxicosis (116). Indeed, a worsening of thyrotoxic symptoms and cardiac conditions has occasionally been reported after amiodarone was discontinued (72, 96). There are a few reports in the literature demonstrating successful management of AIT with antithyroid drugs while amiodarone therapy was continued (105, 117, 118). Since AIT is widely accepted to be much more difficult to treat than normal hyperthyroidism, we believe that withdrawal of amiodarone, when feasible as in the case of non-life-threatening arrhythmias, should be part of the management of AIT patients, although some patients have mild disease and respond to thionamide and/or glucocorticoid therapy, depending upon the type of AIT. In these patients amiodarone may be continued since the AIT seems to be selflimited. A rational approach might be the following (Table 6): 1) Identify the subtype of AIT (type I, type II, mixed forms) if possible; 2) Treat type II with steroids for 3 months, with a starting dose of mg prednisone (or equivalent) and a gradual, slow reduction to minimize the risk of recurrences; 3) Treat type I AIT with methimazole and potassium perchlorate (1 g daily for no more than days); 4) If the two

9 248 MARTINO ET AL. Vol. 22, No. 2 TABLE 6. Therapeutic strategy in amiodarone-induced thyrotoxicosis Type I AIT Thionamides (methimazole, mg/day) in combination with potassium perchlorate (1 g/day for days). Discontinue amiodarone if possible. After restoration of euthyroidism and normalization of urinary iodine excretion, definitive treatment of the underlying thyroid abnormalities by either radioiodine or thyroidectomy. If amiodarone cannot be withdrawn and medical therapy is unsuccessful, consider total thyroidectomy. Type II AIT Glucocorticoids for 2 3 months (starting dose, prednisone 40 mg/day or equivalent). Discontinue amiodarone if possible. In mixed forms add thionamides and potassium perchlorate. After restoration of euthyroidism, follow-up for possible spontaneous progression to hypothyroidism. If amiodarone cannot be withdrawn and medical therapy is unsuccessful, consider total thyroidectomy. types cannot be distinguished (mixed forms), triple therapy with a thionamide, potassium perchlorate, and glucocorticoids is a practical solution. In cases in which withdrawal of amiodarone is not feasible and medical therapy has failed, thyroidectomy represents a useful alternative. Definitive treatment of the underlying thyroid disorder will usually be required in most type I AIT patients; this can occasionally be accomplished by radioiodine, provided the RAIU values become adequate (Table 6). Most type II patients will remain euthyroid after resolution of the thyrotoxicosis; some of them may eventually develop hypothyroidism, either spontaneously or after reexposure to iodine (89, 90). The hypothyroidism that occasionally occurs may be more prolonged than that which occurs after postpartum lymphocytic thyroiditis or painful, subacute thyroiditis since the excess iodine and amiodarone persist, even if the amiodarone is discontinued. In patients with a history of AIT in whom amiodarone becomes necessary after it has been discontinued, ablation of the thyroid with radioiodine before resuming amiodarone should be strongly considered. FIG. 7. Twenty-four-hour thyroidal RAIU in patients with spontaneous (SPONT HYPO) or amiodarone-induced (AIH) hypothyroidism, and in euthyroid subjects chronically treated with amiodarone (EUAM). 2. Amiodarone-induced hypothyroidism. AIH occurs more frequently than AIT in iodine-sufficient areas (62). In contrast to AIT, AIH is slightly more frequent in females, with a female to male ratio of 1.5:1 (25, 44, 62, 119, 120). AIH patients are older than AIT patients (119, 120). AIH usually develops earlier than AIT, both in patients with apparently normal thyroid glands and in patients with preexisting thyroid abnormalities (44, 64, ). Among 28 AIH patients, underlying thyroid abnormalities were found in 19 (68%), while the remaining 9 (32%) had no detectable abnormalities (64). Among preexisting abnormalities, the presence of circulating thyroid autoantibodies appears to be particularly relevant, since they were detected in 53% of AIH patients with underlying thyroid abnormalities (64). Indeed, female sex or the presence of circulating anti-thyroid peroxidase (TPO) antibodies represented a relative risk of 7.9 and 7.3, respectively, for the occurrence of AIH; the combination of female sex and antithyroid antibodies increased the risk to 13.5 (44). In another series, five of seven patients (71%) with baseline positive antithyroid antibody tests developed hypothyroidism during long-term amiodarone treatment (65). Thus, preexisting Hashimoto s thyroiditis is an established risk factor for the occurrence of hypothyroidism in amiodarone-treated patients (64). This is in keeping with previous observations showing that patients with Hashimoto s thyroiditis chronically treated with iodine have an enhanced susceptibility to develop myxedema (124). It is also possible that the cytotoxicity induced by amiodarone would decrease the possibility of a goiter developing while receiving amiodarone. a. Pathogenesis. The most likely pathogenic mechanism is that the thyroid gland of these patients, damaged by preexisting Hashimoto s thyroiditis, is unable to escape from the acute Wolff-Chaikoff effect after an iodine load (125) and to resume normal thyroid hormone synthesis. A subtle defect in thyroid hormonogenesis may explain the enhanced susceptibility to the inhibitory effect of iodine on thyroid hormone synthesis and the inability to escape from the acute Wolff-Chaikoff effect (64). In cell cultures, amiodarone had a more potent and persistent inhibitory effect on TSH-stimulated camp production in vitro than iodine (126). The hypothesis of a defect in the hormonogenetic process seems to be tenable in view of the observation that these patients have a positive perchlorate discharge test, indicating a defect in iodine organification (64, 123). In addition, while normally the increase in iodine intake causes a low RAIU because of dilution of the tracer by the increased stable iodide pool, in patients with AIH the thyroid iodine uptake may not be inhibited, although such findings are rare in the United States where ambient iodine intake is sufficient (76, 77) (Fig. 7). This may be due to excess TSH stimulation of the thyroid. In addition to these functional changes, AIH occurring in patients with Hashimoto s thyroiditis may also be related to the fact that iodine-induced nonspecific damage to the thyroid follicles may add to that caused by the preexisting autoim-

10 April, 2001 AMIODARONE AND THE THYROID 249 TABLE 7. Therapeutic strategy in amiodarone-induced hypothyroidism Underlying Thyroid Abnormalities (Usually Hashimoto s Thyroiditis) Amiodarone therapy can be continued. L-T 4 replacement therapy is added. Apparently Normal Thyroid Gland If amiodarone cannot be discontinued, L-T 4 replacement therapy is initiated. If amiodarone is withdrawn, strict follow-up is required for possible spontaneous restoration of euthyroidism. A short course of potassium perchloate (1 g/day for days) can be given to accelerate return to euthyroidism. mune thyroiditis, thus accelerating the natural trend of Hashimoto s thyroiditis toward hypothyroidism (64). In AIH patients without underlying thyroid abnormalities and with negative thyroid autoantibody tests, subtle defects in iodine organification and thyroid hormone synthesis are likely the best explanation for the occurrence of AIH. It has been reported that AIH may spontaneously remit (120, 123, 127, 128). In 20 patients followed prospectively, AIH was transient in 12 and persistent in 8; 7 of the latter patients had positive anti-tpo antibody tests (64). b. Clinical manifestations. Similar to spontaneous hypothyroidism, AIH patients frequently have vague symptoms and signs, such as fatigue, cold intolerance, mental sluggishness, and dry skin (123). A case of myxedema coma occurring during long-term amiodarone therapy has been reported (122). In patients already on l-t 4 replacement therapy, the dose of l-t 4 may need to be increased due to the inhibition of the generation of T 3 from T 4 induced by amiodarone (129). Laboratory findings are similar to those in spontaneous hypothyroidism, with decreased serum free T 4 and increased serum TSH concentrations (11). Serum thyroglobulin is often increased, probably because of the enhanced thyroid stimulation by TSH (64). c. Treatment. Management of AIH does not have the complexity observed with AIT (Table 7). If amiodarone is necessary for the underlying cardiac disorder, it can be continued in association with l-t 4 replacement. l-t 4 is the drug of choice, particularly in these patients with cardiac problems, because it requires only once-daily administration and is not associated with the spikes in serum thyroid hormone concentrations observed in patients given l-t 3. The serum TSH concentration is the most important parameter to monitor therapy. If discontinuance of amiodarone therapy is feasible, spontaneous remission of hypothyroidism often occurs, particularly in patients without underlying thyroid abnormalities, while this outcome is less likely to occur in patients with Hashimoto s thyroiditis (64). Thus, it is our policy to continue amiodarone and to treat with l-t 4, often requiring larger doses of l-t 4 to normalize the serum TSH in view of the inhibitory effects of amiodarone on T 4 conversion to T 3.In view of the fact that these patients often have severe underlying cardiac disease, it is advisable to maintain the serum TSH concentration in the upper half of the normal range. If amiodarone is discontinued, to shorten the period of time between discontinuing amiodarone and the attainment of hypothyroidism, a short course (10 30 days) of potassium perchlorate (1 g daily) can be given (130). This treatment was associated with a prompt restoration of euthyroidism in six of nine patients, although a second course of potassium perchlorate was required in the remaining three patients to FIG. 8. Flow chart for following patients receiving amiodarone. achieve persistent euthyroidism (130). The rationale for this treatment resides in the fact that potassium perchlorate inhibits thyroid iodide uptake, thereby blocking further entrance of iodide into the thyroid and decreasing the inhibitory effect of excess intrathyroidal iodine. IV. Recommendations for Following Patients Receiving Amiodarone Therapy It is essential to carefully evaluate patients before and during amiodarone therapy (Fig. 8). A careful thyroid gland examination, and perhaps a thyroid ultrasound on initial evaluation, is essential since the presence of a nodular or diffuse goiter increases the risk of AIT, which can occur up to years after amiodarone is begun. Baseline serum TSH, total and free T 4 or free T 4 index, total and free T 3 concentrations and thyroid peroxidase antibodies (TPOAb) are recommended so that changes in thyroid function during amiodarone administration can be carefully monitored. The presence of TPOAb markedly increases the risk of developing AIH since chronic autoimmune thyroiditis predisposes the patient for the development of iodine-induced hypothyroidism, which most often occurs during the first year of therapy. Repeat serum TSH, total and free T 4 or free T 4 index, total and free T 3 concentrations and a careful thyroid gland examination should be done every 6 months or sooner should symptoms of hyper- or hypothyroidism develop. Refractoriness to antiarrhythmic therapy may reflect the development of AIT. Although the serum TSH may occasionally be low in euthyroid amiodarone-treated patients, it remains the single best test to monitor thyroid function. If the serum TSH becomes low and the serum T 4 and T 3 do not rise above