Amiodarone and thyroid dysfunction

INTRODUCTION — Amiodarone, a class III antiarrhythmic drug, has multiple effects on myocardial depolarization and repolarization that make it an extremely effective antiarrhythmic drug. However, amiodarone is associated with a number of side effects, including thyroid dysfunction (both hypo- and hyperthyroidism), which is due to amiodarone's high iodine content and its direct toxic effect on the thyroid. This topic will review the major effects of amiodarone on thyroid function. The clinical use and other side effects of amiodarone are reviewed elsewhere. (See "Amiodarone: Clinical uses" and "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".)

PHARMACOLOGY — Amiodarone contains two iodine atoms. It is estimated that amiodarone metabolism in the liver releases approximately 3 mg of inorganic iodine into the systemic circulation per 100 mg of amiodarone ingested. The average iodine content in a typical American diet is approximately 0.3 mg/day. Thus, 6 mg of iodine associated with a 200 mg dose of amiodarone markedly increases the daily iodine load [1,2].

Amiodarone is very lipophilic and is concentrated in adipose tissue, cardiac and skeletal muscle, and the thyroid. Elimination from the body occurs with a half-life of approximately 100 days [3]. Amiodarone toxicity can therefore occur well after drug withdrawal [4].

The effects of amiodarone on thyroid function can be divided into those effects that are intrinsic properties of the drug and those effects that are due to iodine.

Intrinsic drug effects

●Amiodarone inhibits outer ring 5'-monodeiodination of thyroxine (T4), thus decreasing triiodothyronine (T3) production; reverse T3 accumulates since it is not metabolized to T2 [5].

●Amiodarone (and particularly the metabolite desethylamiodarone) blocks T3-receptor binding to nuclear receptors [6] and decreases expression of some thyroid hormone-related genes [7].

●Amiodarone may have a direct toxic effect on thyroid follicular cells, which results in a destructive thyroiditis [8]. (See 'Type II' below.)

Effects due to iodine — Iodine is a substrate for thyroid hormone synthesis. It is actively transported into thyroid follicular cells and organified onto tyrosyl residues in thyroglobulin.

The normal autoregulation of iodine prevents normal individuals from becoming hyperthyroid after exposure to an iodine load (eg, radiocontrast). When intrathyroidal iodine concentrations reach a critical high level, iodine transport and thyroid hormone synthesis are transiently inhibited until intrathyroidal iodine stores return to normal levels (the Wolff-Chaikoff effect). (See "Thyroid hormone synthesis and physiology" and "Iodine-induced thyroid dysfunction".)

Patients with underlying thyroid disease, however, have defects in autoregulation of iodine:

●Patients with autoimmune thyroid disease "fail to escape" from the Wolff-Chaikoff effect. The result is the development of goiter and hypothyroidism in Hashimoto's disease [9] and amelioration of Graves' hyperthyroidism.

●Patients with areas of autonomous function within a nodular goiter do not autoregulate iodine and the addition of more substrate may result in excessive thyroid hormone synthesis and thyrotoxicosis (Jod-Basedow) [10].

RISK OF THYROID DYSFUNCTION — Both hypo- and hyperthyroidism are complications of amiodarone therapy [1,11-14]. In a meta-analysis of four randomized trials involving 1465 euthyroid patients, the prevalence of clinical thyroid disease was higher in patients receiving amiodarone therapy (150 to 330 mg/day for a minimum of one year) when compared with placebo (3.7 versus 0.4 percent, respectively) [13]. In other reviews and reports, the risk of amiodarone-induced thyroid dysfunction ranges from 2 to 30 percent, depending upon an individual's underlying thyroid status, dietary iodine intake, and whether cases of subclinical thyroid disorders (eg, slight rise in thyroid-stimulating hormone [TSH] without symptoms) are included [1,11,12,14-17].

Underlying thyroid function — The clinical effects of amiodarone on thyroid function in any individual are dependent upon the underlying status of that individual's thyroid gland.

Normal — In normal, euthyroid individuals receiving amiodarone, acute changes in thyroid function tests include [1,18]:

●Serum T4 and free T4 concentrations rise by 20 to 40 percent during the first month of therapy.

●Serum T3 concentrations decrease by up to 30 percent within the first few weeks of therapy.

●Serum reverse T3 concentrations increase by 20 percent soon after the initiation of therapy.

●The serum TSH concentration usually rises slightly after the initiation of treatment and may exceed the upper limit of normal.

After three to six months of therapy, a steady state is reached in most patients who were euthyroid at baseline:

●Serum TSH concentration normalizes

●Serum total T4, free T4 and reverse T3 concentrations remain slightly elevated or in the upper normal range

●Serum T3 concentrations remain in the low normal range

Amiodarone may also cause a destructive thyroiditis in patients without underlying thyroid disease [8]. (See 'Type II' below.)

Abnormal

●Patients with underlying autoimmune thyroid disease are more likely to develop amiodarone-induced hypothyroidism, presumably due to failure to escape from the Wolff-Chaikoff effect. (See 'Effects due to iodine' above and 'Hypothyroidism' below.)

●In patients with underlying multinodular goiter or latent Graves' disease, hyperthyroidism (increased synthesis of T4 and T3) may occur. The excess iodine from the amiodarone provides increased substrate, resulting in enhanced thyroid hormone production [19]. (See 'Type I' below.)

Dietary iodine intake — Dietary iodine intake also affects an individual's risk of amiodarone-induced thyroid dysfunction:

●In iodine-sufficient areas, amiodarone-induced hypothyroidism appears to be more common than hyperthyroidism [15,20-22].

●In contrast, amiodarone-induced hyperthyroidism is more common than hypothyroidism in iodine-deficient regions [12].

One study illustrates the importance of both the underlying thyroid status and dietary iodine intake in relation to the risk of developing amiodarone-induced thyroid dysfunction. In Worcester, Massachusetts, an area with iodine sufficiency and a high prevalence of autoimmune thyroid disease, amiodarone was associated with a 22 percent rate of hypothyroidism and a 2 percent rate of hyperthyroidism [15]. In contrast, in Pisa, Italy, an area of borderline iodine intake and a high prevalence of nodular goiter, amiodarone was associated with a 5 percent rate of hypothyroidism and a 9.6 percent rate of hyperthyroidism.

HYPOTHYROIDISM

Epidemiology — As noted above, transient changes in thyroid function tests often occur in euthyroid individuals treated with amiodarone. However, most patients remain euthyroid during amiodarone therapy (89 percent in one study) [23]. In one trial, overt hypothyroidism (TSH >10 mU/L) developed in 5 percent of patients receiving amiodarone, but subclinical hypothyroidism (TSH 4.5 to 10 mU/L) developed in an additional 25 percent [14]. In a meta-analysis, 14 percent of patients receiving amiodarone became hypothyroid [24].

Patients with underlying Hashimoto's thyroiditis or positive antithyroid antibodies are more likely to develop persistent hypothyroidism [4,25]. This observation may explain the higher prevalence of amiodarone-induced hypothyroidism in women compared with men [12].

In iodine-sufficient areas, amiodarone-induced hypothyroidism is more common than hyperthyroidism [15,20-22] and may occur in up to 20 percent of patients treated with amiodarone [11]. In contrast, amiodarone-induced hyperthyroidism is more common than hypothyroidism in iodine-deficient regions [12]. (See 'Dietary iodine intake' above.)

Pregnancy — Transient hypothyroidism may occur in the infants of women treated with amiodarone during pregnancy. As an example, in a study of 64 pregnancies in which amiodarone was given to the mother, 11 infants (17 percent) had transient hypothyroidism; 2 of the 11 had a goiter [26]. Hypothyroidism was transient in all cases, and only five infants were treated short term with thyroid hormones.

Clinical manifestations — The clinical manifestations and diagnosis of amiodarone-associated hypothyroidism are similar to those of hypothyroidism from any cause. Hypothyroidism and hypothyroid symptoms may develop as soon as two weeks or as late as 39 months after the initiation of amiodarone therapy [27,28]. (See "Clinical manifestations of hypothyroidism".)

Diagnosis — Patients should have thyroid function assessed several weeks after starting amiodarone and every few months thereafter for the development of overt hypothyroidism, especially those with evidence for autoimmunity prior to initiating amiodarone [9,25]. Hypothyroidism should be diagnosed on the basis of a screening serum TSH value before the patient has symptoms. Since small increases in serum TSH concentrations (10 to 20 mU/L) are seen in euthyroid patients for the first three to six months after amiodarone therapy is initiated, amiodarone-induced hypothyroidism should only be diagnosed when serum T4 concentrations are low-normal or low, or mild TSH elevation persists. (See "Diagnosis of and screening for hypothyroidism in nonpregnant adults".)

Treatment — Thyroid function can be easily normalized by replacement with T4 (levothyroxine) while amiodarone is continued. The goal of therapy is to restore the serum TSH concentration to normal, keeping in mind that a larger than usual dose may be required because of the likely effects of amiodarone on intrapituitary T4 metabolism and T3 production and, possibly, thyroid hormone action [11]. The patient should be retested if amiodarone is withdrawn at a later date. (See "Treatment of primary hypothyroidism in adults".)

Amiodarone is usually not discontinued, unless it fails to control the underlying arrhythmia. However, if amiodarone is stopped, hypothyroidism in patients with no apparent preexisting thyroid disease often resolves. In contrast, hypothyroidism may persist after withdrawal of amiodarone in patients who have underlying chronic autoimmune thyroiditis with high titers of antithyroid peroxidase (TPO) antibodies and goiter, and they therefore require permanent T4 therapy [1,4,11,12,25].

HYPERTHYROIDISM

Types of hyperthyroidism — There are two types of amiodarone-induced thyrotoxicosis (AIT). In type I, there is increased synthesis of thyroid hormone, whereas in type II, there is excess release of T4 and T3 due to a destructive thyroiditis. These types differ in their pathogenesis, management, and outcome [29].

Type I — In type I AIT, there is hyperthyroidism with increased synthesis of T4 and T3. This type is typically seen in patients with preexisting multinodular goiter or latent Graves' disease; the excess iodine from amiodarone provides increased substrate, resulting in enhanced thyroid hormone production [19]. While most of these patients have underlying multinodular goiter, occasional patients have latent Graves' disease that becomes overt upon exposure to large amounts of iodine [30]. (See "Iodine-induced thyroid dysfunction".)

Type II — In type II AIT, the hyperthyroidism is a destructive thyroiditis that results in excess release of T4 and T3, without increased hormone synthesis. It typically occurs in patients without underlying thyroid disease and is caused by a direct toxic effect of amiodarone on thyroid follicular epithelial cells [31-33].

The hyperthyroid phase may last from several weeks to several months, and it is often followed by a hypothyroid phase with eventual recovery in most, but not all, patients. For unclear reasons, the toxic effects of the drug may take two to three years to become manifest. (See "Overview of thyroiditis".)

In many cases, mixed forms of AIT exist, making both diagnosis and treatment challenging (see 'Diagnosis' above and 'Treatment' above). The risk of either type increases with higher cumulative doses [34].

Prevalence — The prevalence of AIT, as well as the distribution by type (I or II), varies by geographical region. This is thought to be primarily due to differences in dietary iodine intake (see 'Dietary iodine intake' above):

●In the United States, 3 to 5 percent of patients treated with amiodarone become hyperthyroid, usually between four months and three years after the initiation of the drug [14,25]. The majority of cases are type II.

●In iodine-deficient regions, AIT is more common than in the United States, occurring in approximately 10 to 12 percent of patients with type I AIT usually predominating [11,12,15].

However, the distribution of cases by type may be changing, as illustrated in a report of 215 consecutive patients with AIT seen at a single institution in Italy over 26 years [35]. In 1980 compared with 2006, 2 of 6 (40 percent) versus 12 of 14 (86 percent) of new AIT cases were type II. Possible explanations for this observation include improved dietary iodine intake in the region and the avoidance of amiodarone in patients with known thyroid disease.

Clinical manifestations — The clinical manifestations of amiodarone-induced hyperthyroidism are often masked because its beta-blocking activity minimizes many of the adrenergic manifestations of thyroid hormone excess and possibly because amiodarone metabolites may block binding of T3 to its nuclear receptor [7].

Common presenting symptoms and signs include the development or redevelopment of atrial arrhythmias; exacerbation of ischemic heart disease or heart failure; or unexplained weight loss, restlessness, or low-grade fever [1].

Patients with amiodarone-induced hyperthyroidism have a threefold higher rate of major adverse cardiovascular events (mostly ventricular arrhythmias) compared with euthyroid controls [36]. The presence of severe left ventricular dysfunction in patients with amiodarone-induced hyperthyroidism (type I or type II) may be associated with increased mortality [37].

Differentiating the two types — The distinction between type I and type II is critical since therapy differs for the two types. However, the distinction may be difficult using clinical criteria, partly because some patients may have a mixture of both mechanisms [33]. Thyroid function tests are not helpful for differentiating type I from type II hyperthyroidism.

Type I, when seen in the setting of an underlying autonomous nodule or goiter, tends to occur early after amiodarone treatment is started (at a median 3.5 months in one study), while type II occurs much later (median 30 months) [38]. When thyrotoxicosis initially occurs after amiodarone has been discontinued (19 percent of AIT in this study), it is much more likely to be type II (95 percent in this study) [38].

In patients not taking amiodarone, the radioiodine uptake is the primary test used to distinguish between destructive subacute thyroiditis and hyperthyroidism associated with de novo synthesis of thyroid hormone; the 24-hour radioiodine uptake is <1 percent in subacute thyroiditis and elevated or normal in toxic nodular goiter or Graves' disease.

However, the daily ingestion of 6 mg or more of bioavailable iodine with amiodarone results in sufficiently high serum levels of iodine that compete with the tracer used to perform the uptake test. Therefore, the majority of patients with type I (as well as all patients with type II) has uptakes that are less than 1 percent [39]. In one European study, a significant percentage of patients with type I hyperthyroidism had measurable or even elevated uptakes [40]; however, this is an unusual finding in the United States. (See "Disorders that cause hyperthyroidism".)

The criteria used to attempt to distinguish type I from type II hyperthyroidism are:

●If the 24-hour radioiodine uptake is detectable, it suggests type I AIT [40].

●Patients with type I often have multinodular goiters or diffuse goiter, whereas those with type II usually have no goiter or a small diffuse goiter.

●In two studies, serum thyroglobulin concentrations were higher and serum interleukin-6 concentrations were lower in patients with type I hyperthyroidism [29,32]. In a third study, interleukin-6 concentrations were not useful for distinguishing type I from type II [41].

●Two studies reported that color-flow Doppler sonography (CFDS) may distinguish type I (increased vascularity) from type II (absent vascularity) hyperthyroidism [41,42]; 80 percent of patients could be classified by CFDS.

However, interpretations of CFDS in amiodarone-associated hyperthyroidism require an experienced sonographer. It is straightforward to separate patients into those with increased and low flow when a group of patients with amiodarone-associated hyperthyroidism are being scanned sequentially, but due to the lack of an accepted "gold standard," it may be difficult to interpret the CFDS of a single thyroid gland scanned during a typical day of multiorgan ultrasound examinations.

●Two reports utilized technetium-99m (99mTc)-sestamibi thyroid uptake and scintigraphy to distinguish type I (normal or increased) from type II (decreased) and found this to be more useful than CFDS [43,44].

●The presence of thyrotropin receptor antibodies (TRAb) suggests Graves' disease. However, in patients suspected of having type I AIT, TRAb measurements to diagnose Graves' disease should be measured using a thyroid-stimulating immunoglobin (TSI) assay, if available, and not a thyrotropin-binding inhibitory immunoassay (TBII) assay. TBII assays cannot distinguish between type I and II AIT.

As an example, in one study, 21 of 309 patients (7 percent) had positive TRAb when measured in a TBII [45]. Of these, 43 percent appeared to have type I AIT based on color-flow Doppler or response to methimazole, while 57 percent appeared to have type II AIT based on response to corticosteroids. TRAb, measured by a TSI assay, was positive in patients suspected of having type I AIT and negative in those suspected of having type II AIT.

Treatment

Should amiodarone be discontinued? — There are few data that directly address this question. In a retrospective study from Italy of type II AIT, the median time to normalize thyroid function was similar whether amiodarone was continued (n = 8) or discontinued (n = 32) [46]. However, five of seven patients taking amiodarone had recurrent thyrotoxicosis compared with 3 of 32 patients in whom the amiodarone was discontinued. In a study from the Netherlands of type II AIT in which 36 patients were treated with prednisone, sodium perchlorate, or both, therapy was effective in all patients receiving prednisone or perchlorate plus prednisone, despite continuation of amiodarone in all patients [47]. Recurrent thyrotoxicosis occurred in only three patients (8 percent).

When deciding whether to discontinue amiodarone, the following should be considered:

●Amiodarone may be necessary to control a life-threatening arrhythmia.

●Since the half-life of elimination from the body is approximately 100 days, there is no immediate benefit to stopping amiodarone [48].

●Amiodarone appears to ameliorate hyperthyroidism by blocking T4 to T3 conversion, beta-adrenergic receptors, and possibly T3 receptors. Stopping amiodarone might actually exacerbate hyperthyroid symptoms and signs.

In patients who develop AIT in whom the amiodarone was prescribed for life-threatening ventricular arrhythmias (and is effective), we suggest continuing the amiodarone and simultaneously treating the hyperthyroidism. If the amiodarone was not prescribed for life-threatening ventricular arrhythmias (or is ineffective), we suggest discontinuing the drug in consultation with the patient's cardiologist if alternative antiarrhythmics can be used. For type I AIT, amiodarone should not be discontinued until hyperthyroid symptoms are well controlled with thionamides, since worsening hyperthyroid symptoms due to increased T3 levels may occur when the amiodarone is discontinued.

Treatment of type I AIT

Thionamides — Patients with type I hyperthyroidism usually respond to a thionamide drug, although the response may be slow and large doses may be required, presumably because of very high intrathyroidal iodine stores [4,49]. The average initial dose is often 30 to 40 mg of methimazole daily, with careful monitoring for adverse effects such as skin rash, arthralgia, hepatotoxicity, and, rarely, bone marrow suppression. The risk of agranulocytosis in one study was higher in patients with amiodarone-induced thyrotoxicosis (8 of 593 [1.35 percent]), compared with patients with thyrotoxicosis unrelated to amiodarone (20 of 14,188 [0.14 percent]) [50]. (See "Thionamides in the treatment of Graves' disease", section on 'Initiation of therapy' and "Thionamides: Side effects and toxicities", section on 'Agranulocytosis'.)

The addition of perchlorate, which blocks further iodine uptake by the thyroid, may be of benefit [51], but chronic use has been associated (rarely) with aplastic anemia, and perchlorate is not currently available in the United States. The addition of lithium carbonate to the antithyroid drug has also been reported to speed recovery when the hyperthyroidism is severe [52].

Thionamides are usually tapered to a low maintenance dose in patients with hyperthyroidism. In amiodarone-associated type I hyperthyroidism, care must be taken not to reduce the dose of thionamide too quickly, or patients might develop recurrent and prolonged hyperthyroidism. An alternative strategy is to continue high-dose thionamides and add T4 after patients become hypothyroid.

If amiodarone is stopped (eg, if there is evidence of toxicity in other organs or if it is ineffective as an antiarrhythmic), depending upon the clinical setting one might add beta-adrenergic blocking drugs and iopanoic acid to block T4 to T3 conversion. However, neither iopanoic acid nor ipodate are available in the United States. It is unclear when, or even whether, they will ever again be marketed in the United States. (See "Iodinated radiocontrast agents in the treatment of hyperthyroidism".)

Patients with iodine-induced hyperthyroidism who are continuing amiodarone will need to continue thionamides. If amiodarone is subsequently discontinued, the thionamide should be continued until measurement of urine iodine returns to normal. This may take 6 to 18 months, after which one could cautiously attempt to taper antithyroid therapy. In one study, when amiodarone was reintroduced in patients with a history of AIT type I who were not taking a thionamide, 8 of 11 patients (73 percent) developed recurrent AIT [53].

Radioiodine — If the radioiodine uptake is high enough, one could treat the patient with radioiodine. In one series of 14 patients in whom amiodarone had been discontinued due to hyperthyroidism, subsequent radioiodine ablation of the thyroid allowed reintroduction of amiodarone (and control of recurrent tachyarrhythmias) in 12 of the 14 subjects [54]. However, radioiodine ablation is usually not an option due to low radioiodine uptake in these patients.

Surgery — Patients who are refractory to antithyroid drug therapy should be treated by thyroidectomy. This recommendation is consistent with the European Thyroid Association guidelines for the management of amiodarone-associated thyroid dysfunction [55]. When balancing the risk of a surgical procedure during careful cardiovascular monitoring with the risk of several months of unmonitored and uncontrolled thyrotoxicosis, the advantages of surgery in this setting become compelling [56-58]. In one study of 207 patients, 51 of whom had surgery and 156 of whom were treated medically, overall and cardiovascular mortality was lower in the surgery group due to reduced mortality among patients with moderate to severe reductions in left ventricular ejection fraction (under 40 percent) [59]. (See "Surgical management of hyperthyroidism".)

Treatment of type II AIT

Glucocorticoids — Patients with type II hyperthyroidism respond well to moderately large doses of corticosteroids (eg, prednisone 40 to 60 mg/day) [29,60], even if the amiodarone is continued [39,61]. We typically start with prednisone (40 to 60 mg/day) and continue therapy for one to three months before tapering (to avoid exacerbations of hyperthyroidism). Some improvement is usually seen as early as one week [29]. In one study of 66 patients, 60 percent were euthyroid within one month and 16 percent remained hyperthyroid for more than three months [62]. Prolonged hyperthyroidism was associated with higher serum free T4 levels and goiter.

Glucocorticoid therapy is more effective than iopanoic acid. In a prospective, randomized trial, both glucocorticoids and iopanoic acid were effective in type II hyperthyroidism, but thyroid function returned to normal more rapidly after steroid administration [63]. (See "Iodinated radiocontrast agents in the treatment of hyperthyroidism".)

In a randomized, clinical trial, the addition of perchlorate to prednisone added no benefit [47].

Patients with type II AIT may develop transient (or sometimes permanent) hypothyroidism when the hyperthyroidism resolves [8] and benefit from T4 replacement. (See "Overview of thyroiditis".)

Surgery — Patients who are refractory to glucocorticoids should be treated with thyroidectomy. In the study of 207 patients with AIT described above, 64 percent of patients who had surgery for amiodarone-induced thyrotoxicosis had type II AIT [59]. (See 'Surgery' above.)

Treatment if mechanism unknown — Some patients may have a "mixed" form of thyrotoxicosis or the underlying cause (type I or type II) may be uncertain. In such cases, a combination of prednisone (40 mg/day) and methimazole (40 mg/day) is prudent initial therapy. A rapid response suggests type II hyperthyroidism; the methimazole can then be tapered or stopped and, if indicated, iopanoic acid can be added (if available). A poor response initially argues for type I hyperthyroidism. If so, steroids can be tapered and, depending upon the subsequent course, perchlorate, lithium, and/or surgery may be necessary.

MONITORING — Since thyroid dysfunction is relatively common with amiodarone therapy, all patients should have thyroid function tests checked before starting therapy and at three- to four-month intervals during treatment [12]. Thyroid dysfunction may occur after amiodarone withdrawal, and therefore, thyroid function should be assessed for at least one year after the drug is discontinued, and longer in patients with high cumulative doses or a history of hypothyroidism during treatment. In a study of 71 patients followed after stopping amiodarone, five (7 percent) developed type II amiodarone-induced thyrotoxicosis (AIT) between 7 and 16 months after withdrawal [64]. Compared with patients who did not develop AIT, they had been on amiodarone longer (mean 76 versus 16 months) and had been more likely to have had hypothyroidism during amiodarone therapy.

PATIENTS ON WARFARIN — In patients taking amiodarone who are also being treated with warfarin, the consequences of amiodarone-induced thyroid dysfunction include a significant influence on warfarin response. The effect of warfarin is potentiated by thyrotoxicosis and attenuated in hypothyroidism [65]. In addition, amiodarone itself has effects on warfarin pharmacokinetics, which may be important if the amiodarone is discontinued because of thyroid dysfunction. In any patient with amiodarone-induced thyroid dysfunction who is also taking warfarin, the International Normalized Ratio (INR) should be monitored closely and appropriate adjustments in warfarin dosing made. (See "Warfarin and other VKAs: Dosing and adverse effects".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hyperthyroidism" and "Society guideline links: Hypothyroidism".)

SUMMARY AND RECOMMENDATIONS

●Thyroid dysfunction (both hypo- and hyperthyroidism) is a common complication of amiodarone therapy due to direct effects of the drug on the thyroid, as well as its high iodine content. (See 'Introduction' above.)

●Direct effects of amiodarone on the thyroid include: inhibition of outer ring 5'-monodeiodination of thyroxine (T4), thus decreasing triiodothyronine (T3) production; blocking T3-receptor binding to nuclear receptors; decreased expression of some thyroid hormone-related genes; and a direct toxic effect on the thyroid (destructive thyroiditis). (See 'Intrinsic drug effects' above.)

●Other effects on the thyroid are due to the extremely high iodine content of amiodarone. (See 'Effects due to iodine' above.)

●Transient changes in thyroid function tests often occur in euthyroid individuals treated with amiodarone. While most patients remain euthyroid during amiodarone therapy, the clinical effects of amiodarone on thyroid function in any individual are dependent upon underlying thyroid status and dietary iodine intake:

•Patients with underlying autoimmune thyroid disease are at highest risk for amiodarone-induced hypothyroidism (due to failure to escape from the Wolff-Chaikoff effect). (See 'Abnormal' above.)

•Patients with nodular goiter are at increased risk of type I amiodarone-induced thyrotoxicosis (AIT). The excess iodine from the amiodarone provides increased substrate, resulting in enhanced thyroid hormone synthesis and hyperthyroidism. (See 'Type I' above.)

•Destructive thyroiditis (type II AIT) typically occurs in patients with no underlying thyroid disease. (See 'Type II' above.)

•In iodine-sufficient areas, amiodarone-induced hypothyroidism appears to be more common than hyperthyroidism. In contrast, amiodarone-induced hyperthyroidism (usually type I AIT) is more common than hypothyroidism in iodine-deficient regions. (See 'Dietary iodine intake' above.)

●We suggest continuing amiodarone therapy in patients who develop amiodarone-induced hypothyroidism (Grade 2C). (See 'Treatment' above.)

●The diagnosis and treatment of amiodarone-induced hypothyroidism is the same as for other patients with primary hypothyroidism. Euthyroidism should be restored by replacement with thyroid hormone. Thyroid hormone, in doses larger than normal, is often required. (See 'Treatment' above.)

●Amiodarone should only be discontinued if it fails to control the underlying arrhythmia. If amiodarone is discontinued in a patient without preexisting autoimmune thyroid disease, the hypothyroidism often resolves. (See 'Treatment' above.)

●There are two types of AIT. In type I, there is increased synthesis of thyroid hormone (excess iodine provides the increased substrate), whereas in type II, there is excess release of T4 and T3 due to a destructive thyroiditis (direct toxic effect of amiodarone on the thyroid gland). For patients with type II AIT, the hyperthyroid phase may last from several weeks to several months and is often followed by a hypothyroid phase and then recovery. (See 'Types of hyperthyroidism' above.)

●It is often difficult to distinguish between the two types, and some patients may have elements of both. The 24-hour radioiodine uptake is typically not able to distinguish between types I and II AIT, because the high levels of ingested iodine with amiodarone results in 24-hour uptakes of less than 1 percent in most patients with either type I or type II AIT. Technetium-99m (99mTc)-sestamibi imaging, where available, or color-flow Doppler sonography (CFDS) may be the best ways of distinguishing between the two types of AIT. (See 'Differentiating the two types' above.)

●In patients who develop AIT in whom the amiodarone was prescribed for life-threatening ventricular arrhythmias (and is effective), we suggest continuing the amiodarone and simultaneously treating the hyperthyroidism (Grade 2C). (See 'Should amiodarone be discontinued?' above.)

●In patients who develop AIT in whom the amiodarone was not prescribed for life-threatening ventricular arrhythmias (or is ineffective), we suggest discontinuing the drug (Grade 2C). This should only be done in consultation with the patient's cardiologist if alternative antiarrhythmics can be used. For type I AIT, amiodarone should not be discontinued until hyperthyroid symptoms are well controlled with thionamides, since worsening hyperthyroid symptoms due to increased T3 levels may occur when the amiodarone is discontinued. (See 'Should amiodarone be discontinued?' above.)

●For the treatment of type I AIT, we suggest thionamides as our first choice of therapy (whether amiodarone is continued or discontinued) (Grade 2B) (see 'Thionamides' above). Although radioiodine ablation has been reported to have been used (in rare patients with high enough radioiodine uptake), this is usually not an option due to low radioiodine uptake in the majority of type I patients. (See 'Radioiodine' above.)

Higher than average initial doses of thionamides are usually needed (30 to 40 mg of methimazole or 450 to 600 mg propylthiouracil [PTU] daily). Perchlorate or lithium are sometimes added to speed recovery, however, perchlorate is not available in the United States. In addition, perchlorate has been associated, albeit rarely, with aplastic anemia. (See 'Thionamides' above.)

●For the treatment of type II AIT, we suggest glucocorticoid therapy as our first-line drug (whether amiodarone is continued or discontinued) (Grade 2B). We typically start with prednisone (40 to 60 mg/day) and continue therapy for one to two months before tapering (to avoid exacerbations of hyperthyroidism). (See 'Glucocorticoids' above.)

●Patients with type I or type II AIT who are refractory to medical therapy should be treated by thyroidectomy. When balancing the risk of a surgical procedure during careful cardiovascular monitoring with the risk of several months of unmonitored and uncontrolled thyrotoxicosis, the advantages of surgery in this setting become compelling. (See 'Surgery' above and 'Surgery' above.)

●If the mechanism of the hyperthyroidism is uncertain or the patient appears to have "mixed" type I and type II AIT, a combination of prednisone (40 mg/day) and methimazole (40 mg/day) is reasonable initial therapy. A rapid response suggests type II AIT; the methimazole can then be tapered or stopped. A poor or slow initial response argues for type I AIT. (See 'Treatment if mechanism unknown' above.)