Effects of Amiodarone on Thyroid Function

  1. Kishore J. Harjai, MD; and
  2. Angelo A. Licata, MD, PhD
  1. From Alton Ochsner Medical Foundation, New Orleans, Louisiana; and the Cleveland Clinic Foundation, Cleveland, Ohio. Requests for Reprints: Kishore J. Harjai, MD, 113 Betz Avenue, Jefferson, LA 70121. Current Author Addresses: Dr. Harjai: 113 Betz Avenue, Jefferson, LA 70121.
     
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    Abstract

    Purpose: To review the literature on the effects of amiodarone on thyroid physiology and management of amiodarone-induced thyroid disease.

    Data Sources: English-language articles identified through a MEDLINE search (for 1975 to 1995, using the terms amiodarone and thyroid) and selected cross-referenced articles.

    Study Selection: Articles on the effects of amiodarone on thyroid physiology and function tests and occurrence, recognition, and management of amiodarone-induced thyroid disease.

    Data Extraction: Data were manually extracted from selected studies and reports; emphasis was placed on information relevant to the practicing clinician.

    Data Synthesis: Amiodarone can have many effects on thyroid function test results, even in the absence of hyperthyroidism or hypothyroidism. It may cause an increase in serum levels of thyroxine, reverse triiodothyronine, and thyroid-stimulating hormone and a decrease in serum triiodothyronine levels. Thyrotoxicosis occurs in some patients and is related to several pathogenetic mechanisms. It often presents dramatically with obvious clinical manifestations and further changes in thyroid function test results. Medical options include therapy with thionamides, perchlorate, and prednisone. Radioactive iodine is of little use. Thyroidectomy is effective and is the only measure that consistently allows continued use of amiodarone. Unlike thyrotoxicosis, hypothyroidism is related to a persistent Wolff-Chaikoff effect and often has a vague presentation. The goal of treatment of amiodarone-induced hypothyroidism is to bring serum thyroxine levels to the upper end of the normal range, as often seen in euthyroid patients who are receiving amiodarone.

    Conclusions: Thyroid dysfunction commonly occurs with amiodarone therapy. It may be difficult to recognize the dysfunction because of the many changes in thyroid function test results that occur in euthyroid patients who are receiving amiodarone. Effective strategies exist for the management of hyperthyroidism and hypothyroidism; these should be tailored to the needs of the individual patient.

    Amiodarone was approved by the Food and Drug Administration in 1985 for the treatment of serious ventricular arrhythmia. It is also efficacious in the treatment of paroxysmal supraventricular tachycardia and atrial fibrillation and flutter [1]. In addition, use of amiodarone after myocardial infarction may reduce complex ventricular ectopy and cardiac-related mortality [2, 3]. Use of amiodarone may improve survival rates in patients with heart failure [4-6]. However, in view of the results of recent studies, the efficacy of amiodarone in improving survival after myocardial infarction and in patients with heart failure has been questioned ([7, 8]; Camm JA, for the European Myocardial Infarction Amiodarone Trial, paper presented at the American College of Cardiology 1996 Meeting, Orlando, Florida). Side effects of amiodarone are often related to daily or cumulative dose and duration of treatment and include corneal microdeposits, photosensitivity, cutaneous hyperpigmentation, pulmonary toxicity, hepatotoxicity, peripheral neuropathy, drug interactions, hyperthyroidism, and hypothyroidism [9-23]. Smaller doses of amiodarone, such as those used for supraventricular arrhythmias [1], may be associated with fewer side effects.

    Using a MEDLINE search of articles published from 1975 to 1995, we identified and reviewed English-language articles on the effects of amiodarone on thyroid physiology and the recognition and management of amiodarone-induced thyrotoxicosis and hypothyroidism.

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    Effects of Amiodarone on Thyroid Physiology

    Amiodarone is an iodine-rich benzofuran derivative (Figure 1). Approximately 37% of amiodarone (by weight) is organic iodine; 10% of the latter is deiodinated to yield free iodine. A maintenance dose of 200 to 600 mg/d results in a daily intake of organic iodide of 75 to 225 mg, at least 10% of which is deiodinated. Because the normal dietary requirement of iodine is only 0.2 to 0.8 mg/d [24], the increased amount of iodine intake associated with amiodarone causes a massive expansion of the iodide pool [25]. In patients treated with amiodarone, urinary and plasma levels of inorganic iodide increase 40-fold, whereas thyroid iodide uptake and clearance decrease significantly [25]. Therefore, thyroid hormone dynamics change in almost all patients receiving amiodarone [26].

    Figure 1.
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      Figure 1. Chemical structures of thyroxine, triiodothyronine, and amiodarone.

      Amiodarone has many effects on thyroid physiology. It decreases the peripheral deiodination of thyroxine to triiodothyronine by inhibiting type I iodothyronine 5′-deiodinase [27-30], resulting in an increase of serum levels of thyroxine and reverse triiodothyronine and a decrease of serum levels of triiodothyronine (by 20% to 25%), as seen in the euthyroid sick syndrome [31, 32]. Amiodarone also inhibits entry of thyroxine and triiodothyronine into peripheral tissue. Serum thyroxine levels increase by an average of 40% above pretreatment levels after 1 to 4 months of treatment with amiodarone; in 40% of all patients, the serum thyroxine levels (and free thyroxine index) may increase to levels above the normal range. This is an expected finding and in itself does not constitute evidence of hyperthyroidism [23]. In addition, an increase in thyroid-stimulating hormone levels secondary to inhibition of thyroxine-triiodothyronine deiodination in the pituitary is seen during the early phase of treatment (from 1 to 3 months) [33]. This inhibition is a crucial step in the feedback regulation of secretion of thyroid-stimulating hormone [34]. By themselves, elevated serum levels of thyroid-stimulating hormone are not an indication for thyroxine replacement therapy in these patients. With long-term administration of amiodarone (>3 months), serum levels of thyroid-stimulating hormone often return to normal, and the response of thyroid-stimulating hormone to thyrotropin-releasing hormone may be reduced [33, 35-38]. Changes in thyroid function test results, which occur in euthyroid patients receiving amiodarone, are summarized in Figure 2.

      Figure 2. The following changes in thyroid function test results occur: 1) increase in serum levels of thyroxine (T ) and reverse triiodothyronine [rT ], 2) initial increase followed by normalization of serum levels of thyroid-stimulating hormone [TSH], and 3) decrease in serum levels of triiodothyronine (T ). Asterisks indicate steps in thyroid hormone dynamics inhibited by amiodarone. Daggers indicate physiologic feedback inhibition. Bold arrow indicates that most feedback inhibition of TSH production is mediated by T rather than T .
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        Figure 2. The following changes in thyroid function test results occur: 1) increase in serum levels of thyroxine (T ) and reverse triiodothyronine [rT ], 2) initial increase followed by normalization of serum levels of thyroid-stimulating hormone [TSH], and 3) decrease in serum levels of triiodothyronine (T ). Asterisks indicate steps in thyroid hormone dynamics inhibited by amiodarone. Daggers indicate physiologic feedback inhibition. Bold arrow indicates that most feedback inhibition of TSH production is mediated by T rather than T . Changes in thyroid hormone physiology and thyroid function test results in euthyroid patients who received amiodarone.43334

        Abnormal results of thyroid function tests (without overt dysfunction of the thyroid gland) occur more often as the duration of treatment increases and doses accumulate. Serum levels of amiodarone or desethylamiodarone generally do not predict these abnormal test results [39]. One exception is the increase in reverse triiodothyronine levels in the first 2 weeks after commencement of amiodarone therapy; this shows a direct correlation with serum amiodarone levels [40]. In addition, in the absence of factors that may independently affect reverse triiodothyronine metabolism (such as hyperthyroidism, hypothyroidism, surgery, fasting, systemic illnesses, and concomitant use of corticosteroids or β-blockers), the efficacy and toxicity of amiodarone can be monitored by serial measurements of serum reverse triiodothyronine levels [41]. Serum levels of reverse triiodothyronine that are threefold to fivefold greater than baseline levels are associated with adequate antiarrhythmic response; levels that are more than five times the baseline values are associated with a greater chance for drug toxicity.

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        Effects of Amiodarone on Cardiac Tissue Receptors

        Independent of its effects on thyroid hormone physiology, amiodarone has some electrophysiologic effects on cardiac muscle cells that simulate those of hypothyroidism [42]. The effects seen with long-term administration may be mediated by amiodarone itself, its active metabolite desethylamiodarone, or both. In the hearts of pigs treated with amiodarone, the maximum binding capacity of β-receptors and calcium channels is reduced [43]. The maximum binding capacity for triiodothyronine is unchanged, suggesting that no functional reduction in the number of triiodothyronine receptors occurs. However, desethylamiodarone competitively inhibits the binding of triiodothyronine to its nuclear receptors and may be responsible for the local hypothyroid-like effects [43]. In a comparison of rats with normal thyroid function and those that had had thyroidectomy [44], amiodarone reduced cardiac β-receptor density and heart rate in the former but not the latter group. This finding implies that a minimum serum thyroid hormone level is necessary for the drug to produce some of its cardiac effects. These changes occur independently of alterations in thyroid secretion and serum triiodothyronine levels. Exogenous triiodothyronine-mediated increase in β-receptor density and heart rate is also partly inhibited by amiodarone [45]. These observations suggest that the lowering of β-receptor density by amiodarone is related to triiodothyronine antagonism at the cardiac cellular level.

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        Incidence of Clinical Thyroid Dysfunction in Patients Receiving Amiodarone

        In various studies [10, 35, 46-50], the incidence of amiodarone-induced thyrotoxicosis has been reported to be 1% to 23% and that of hypothyroidism has been reported to be 1% to 32%. As many as 49% of patients in a study in which phenytoin was used as a supplementary antiarrhythmic agent [26] developed thyroid dysfunction within 60 months of follow-up. However, the overall incidence of amiodarone-induced thyroid dysfunction is more reasonably estimated to be 2% to 24% [26].

        Amiodarone-induced thyrotoxicosis prevails in areas with low iodine intake, and hypothyroidism is prevalent in areas with high iodine intake. Thus, thyrotoxicosis is more common in Italian than American patients (10% compared with 2%), but hypothyroidism is less common (2% compared with 22%) [35]. This difference is generally similar to the difference in the incidence of iodide-induced thyrotoxicosis, which is more common in iodide-deficient areas than in iodide-replete areas [51]. However, this geographic predilection is not substantiated by all studies [52, 53].

        Although amiodarone crosses the placental barrier, its use in nine pregnant women was not associated with clinical thyroid dysfunction in their neonates [54]. Thyroid function test results were normal in all neonates except one who had clearly abnormal serum levels of thyroxine and thyroid-stimulating hormone. In another series of five neonates born to women receiving amiodarone [55], one was found to have hypothyroidism requiring treatment with triiodothyronine for a few weeks. In a review of adverse effects associated with amiodarone therapy in 34 pregnant women [56], hypothyroidism was reported in three neonates (9%) and hyperthyroidism was reported in none.

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        Amiodarone-Induced Thyrotoxicosis

        The factors leading to the development of thyrotoxicosis in some patients treated with amiodarone are not completely understood. Amiodarone-induced thyrotoxicosis occurs in patients with underlying goiter and those with no apparent thyroid disorder [57]. A predominance among men is sometimes reported [26, 58]. Lack of response of thyroid-stimulating hormone to stimulation of thyrotropin-reducing hormone may predict development of amiodarone-induced thyrotoxicosis [59], but this is not uniformly accepted [26, 60].

        Pathogenesis

        Amiodarone-induced thyrotoxicosis is often caused by excessive synthesis of thyroid hormone induced by iodine, especially in patients with underlying thyroid disease. However, various other mechanisms have been proposed.

        Disturbance of Thyroid Iodine Autoregulation

        Intrinsic autoregulatory mechanisms in the thyroid modulate the gland's iodine handling according to its iodine content [61]. Alterations in these mechanisms may cause thyroid dysfunction in the presence of excess iodine [62, 63]. A disturbance of these mechanisms is suggested by the high iodine content of the thyroid in patients with amiodarone-induced thyrotoxicosis (compared with those who have normal thyroid function) while they are receiving amiodarone [64] and by return of iodine content to normal during resolution of thyrotoxicosis [38]. The factors that affect these mechanisms are not completely understood; clearly, variation in intake and thyroid content of iodine are not the only considerations [52].

        Immunologic Factors

        The ability of amiodarone to induce thyroid antibodies may partly explain the high incidence of thyroid dysfunction [65, 66]. In one study [66], antimicrosomal antibodies formed in almost 50% of 13 patients who received short-term amiodarone therapy and in none of 24 patients who received placebo. In contrast, Safran and colleagues [67] did not find an increased incidence of antithyroid antibodies in 47 patients receiving amiodarone. It has been suggested that thyroid antibodies may not be important in the development of thyrotoxicosis in patients who do not have underlying thyroid disorders. In addition, in patients with underlying thyroid disorders who develop amiodarone-induced thyrotoxicosis, the humoral markers of thyroid autoimmunity show an incidence similar to that seen in spontaneous hyperthyroidism [57]. An increase in certain lymphocyte subsets during amiodarone therapy may be involved in the pathogenesis of thyrotoxicosis [65].

        Destruction-Inflammation Theory

        Amiodarone has a direct, dose-dependent cytotoxic effect on thyroid follicles [68]. In one series [69], thyroids that were surgically removed from four patients with amiodarone-induced thyrotoxicosis showed groups of involuted follicles with damage ranging from mild degeneration to total destruction. These changes were not seen in the glands of patients with thyrotoxicosis from other causes. The follicular changes resemble those seen in thyroiditis from other causes [70-72]. Similar cytoplasmic alterations are seen in pneumocytes and hepatocytes damaged by amiodarone; therefore, it seems likely that amiodarone caused these changes. Release of iodothyronines caused by cell damage and follicular disruption may contribute to thyrotoxicosis [69]. The increased circulating thyroglobulin levels support the theory that the thyrotoxicosis results from destruction of the thyroid by amiodarone, but the even higher levels of thyroglobulin in amiodarone-induced hypothyroidism are confounding [51]. To explain the disparity in clinical presentation between thyrotoxicosis and hypothyroidism, both of which are associated with high thyroglobulin levels, it has been suggested that patients with hypothyroidism may be unable to release iodothyronines from thyroglobulin because of poor iodination as a result of the Wolff-Chaikoff effect or underlying autoimmune thyroid disease [51].

        Serum concentrations of interleukin-6 in patients with amiodarone-induced thyrotoxicosis without underlying thyroid disease are significantly higher than concentrations in those with spontaneous hyperthyroidism [73]. In view of the known association between elevated interleukin-6 levels and subacute thyroiditis, this finding suggests an amiodarone-induced destructive process in the thyroid of patients who develop thyrotoxicosis. In addition, an increase in dyshomogeneous echo patterns and hyperechogenicity has been reported in 11 patients with a history of amiodarone-induced thyrotoxicosis; these patterns resemble those seen in patients with a history of subacute thyroiditis [38].

        Clinical Features and Diagnosis

        Amiodarone-induced thyrotoxicosis is usually suspected in patients with unexplained weight loss, muscle weakness, goiter, and tremor [38, 58]. Classic symptoms of thyrotoxicosis may not be seen in patients with the disorder, and the presenting feature may be worsening of underlying cardiac disorders (that is, angina or tachyarrhythmia) [74]. A recent occurrence of sinus tachycardia, atrial tachycardia, or atrial fibrillation in patients receiving amiodarone may herald the onset of thyrotoxicosis [75]. Onset of clinically convincing thyrotoxicosis is usually rapid and not associated with antecedent, subclinical biochemical findings; the need for frequent evaluation of thyroid function to detect thyrotoxicosis has been questioned [38]. Thyrotoxicosis can occur throughout the period during which a patient receives amiodarone; hypothyroidism, however, is rare after the first 18 months of therapy [52].

        More than 50% of patients who receive long-term amiodarone have abnormal results on thyroid function tests. However, most of these patients are euthyroid, with serum concentrations of thyroid-stimulating hormone in the normal range [10, 23, 26, 35, 74, 76-78]. By itself, even excessively increased thyroxine levels in patients receiving amiodarone should not be interpreted as being diagnostic of thyrotoxicosis [38]. A mean increase of 44% in serum thyroxine levels is seen after commencement of amiodarone therapy and before the onset of thyrotoxicosis; onset of thyrotoxicosis causes a further marked increase in serum thyroxine levels, an increase in serum triiodothyronine levels in most patients [79], and a dramatic decrease of 96% in serum thyroid-stimulating hormone levels [58]. It has been suggested that patients with elevated serum thyroxine levels and normal serum triiodothyronine levels are not hyperthyroid at the tissue level [80]; in our experience, however, elevated serum triiodothyronine levels have not been sensitive markers of thyrotoxicosis in patients treated with amiodarone. Notwithstanding serum triiodothyronine levels, which can be normal in as many as 80% of patients [58], we believe that the combination of clinical features of hyperthyroidism with elevated thyroxine levels and suppressed thyroid-stimulating hormone levels is sufficient evidence of thyrotoxicosis. The finding of elevated serum total and free triiodothyronine levels nonetheless suggests thyrotoxicosis [74]. Diagnostic changes in thyroid function test results in amiodarone-induced thyrotoxicosis are summarized in Table 1.

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        Table 1. Changes in Thyroid Function Test Results with Development of Hyperthyroidism and Hypothyroidism in Patients Treated with Amiodarone

        Treatment

        Because of the fat solubility and long half-life (22 to 55 days) of amiodarone [81], the treatment of amiodarone-induced thyrotoxicosis is difficult and more prolonged than that of other forms of iodine-induced thyrotoxicosis [24, 38, 77, 82-87]. Three questions must be addressed for the treatment of amiodarone-induced thyrotoxicosis: First, should amiodarone be discontinued? Second, is antithyroid therapy necessary? Third, what is the best form of antithyroid therapy (medical, surgical, or with radioactive iodine)?

        Discontinuation of amiodarone therapy is often difficult, especially when the drug is indicated for ventricular arrhythmias that are resistant to other antiarrhythmic therapies [88, 89]. Moreover, after amiodarone therapy is discontinued, thyrotoxicosis may take as many as 8 months to subside [85]. In addition, worsening of thyrotoxicosis and cardiac status has been reported after amiodarone treatment was temporarily stopped [79, 85]; this is probably secondary to loss of amiodarone-induced intracellular hypothyroidism in the myocardium [42, 90-92]. On the other hand, severe thyrotoxicosis is often associated with worsening tachyarrhythmias and may be incompatible with continuation of amiodarone therapy [10, 26, 74, 77] unless thyroidectomy is done [93-96].

        Some patients with biochemical findings of amiodarone-induced thyrotoxicosis do not have clinical features of thyrotoxicosis; antithyroid treatment may be withheld from such patients without clinical sequelae [38]. In patients with mild thyrotoxicosis and a normal underlying thyroid gland or a small goiter, the hyperthyroid state may spontaneously resolve after amiodarone is withdrawn. Other patients, especially those with large nodular or diffuse goiters, usually require treatment and may be resistant to antithyroid drug therapy [74].

        In our experience [58], six of eight patients with amiodarone-induced thyrotoxicosis treated with thionamides (alone in six patients and in conjunction with β-blockers or steroids in two) had a satisfactory clinical response; these six patients included two patients in whom amiodarone therapy was continued despite the occurrence of thyrotoxicosis. Success with thionamides has also been reported by others [26]. However, therapy with methimazole and propylthiouracil has proved disappointing in several studies [85, 97-99]. The inefficacy of this therapy may be secondary to high intrathyroidal iodine stores that support the thyrotoxic state [74]. To obtain a prompt discharge of intrathyroidal iodine, initial use of potassium perchlorate (800 to 1000 mg/d for 15 to 45 days) has been advocated [74] in combination with prolonged treatment with methimazole (40 mg/d) or propylthiouracil (400 to 800 mg/d) [38, 74, 83]. A rapid response has been noted with this combination treatment, with return to the euthyroid state occurring in 15 to 90 days in most patients with underlying thyroid disorders and in 6 to 55 days in all patients without underlying thyroid disorders [74]. This approach is successful even in patients in whom amiodarone therapy is continued after the development of thyrotoxicosis [83]. It should be noted, however, that use of perchlorate is associated with serious side effects, such as aplastic anemia and the nephrotic syndrome [74, 100].

        Prednisone may be beneficial in amiodarone-induced thyrotoxicosis by inhibiting 5′-deiodinase activity and perhaps by affecting the thyroid directly [99]. In a comparative study, 12 patients with severe amiodarone-induced thyrotoxicosis received thionamides either alone (n = 6) or with prednisone (0.5 to 1.25 mg/kg of body weight per day for 40 days; n = 6) after amiodarone therapy had been discontinued. In the group receiving thionamides alone, thyroxine levels did not change during the study period of 40 days, triiodothyronine levels decreased only after 30 days, and clinical status did not improve. In the group receiving thionamides with prednisone, levels of thyroxine and triiodothyronine decreased dramatically after 10 days of treatment, clinical improvement was seen in patients treated with high doses of prednisone, and elevated thyroglobulin levels decreased rapidly [101]. These effects, however, are not always sustained [82], and the need for high doses of steroids reduces the attractiveness of this option.

        Controlling amiodarone-induced thyrotoxicosis with medical treatment may take many weeks because of the large amount of preformed hormone in the gland [10, 26, 35, 74, 76, 77]. Medical therapy, even if it is useful, often requires discontinuation of amiodarone therapy and, consequently, its antiarrhythmic protection. Especially in patients who do not improve with medical therapy, those in whom discontinuation of amiodarone therapy is impractical, and those in whom thyrotoxicosis presents with ventricular arrhythmias, surgery (total or near-total thyroidectomy) may be more appropriate than medical therapy because it results in rapid control of thyrotoxicosis and is the only antithyroid treatment that consistently permits continued therapy with amiodarone [93-96]. Despite the minimally elevated risk imparted by the underlying heart disease, surgery is reasonably safe for these patients [102]. Small doses of β-blockers have been used before surgery in some patients [79], with caution that a synergistic effect with amiodarone could cause bradycardia or sinus arrest [16].

        Radioactive iodine is not a viable treatment option for amiodarone-induced thyrotoxicosis because the high iodide concentration in plasma suppresses uptake of radioactive iodine in the thyroid to low or undetectable levels [24, 86]. Increase in thyroid uptake of iodine after exogenous administration of thyroid-stimulating hormone has been reported [85] but may not be sufficient to allow treatment with (131) I [79]. Moreover, treatment of hyperthyroidism with radioactive iodine often initially exacerbates the hyperthyroid state by releasing preformed hormone that is stored in the thyroid, and the full effects of radioactive iodine are not seen for a prolonged period.

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        Amiodarone-Induced Hypothyroidism

        Pathogenesis

        The following mechanisms may play a role in the development of amiodarone-induced hypothyroidism.

        Wolff-Chaikoff Effect

        The mechanism of amiodarone-induced hypothyroidism may be mediated by iodide. The large amount of iodide released by the metabolism of amiodarone inhibits thyroid hormone biosynthesis (the Wolff-Chaikoff effect) and release. With further exposure to iodine, hormone synthesis resumes despite high iodine concentrations in plasma-a phenomenon called escape from the Wolff-Chaikoff effect [103]. This effect may be secondary to a decline in iodide in the thyroid from reduced transport of iodide across the intrathyroidal membrane, allowing thyroxine production to resume [104]. The persistence of the hypothyroid state in patients with amiodarone-induced hypothyroidism is attributed to a subtle defect in thyroid hormonogenesis that results in enhanced susceptibility to the inhibitory effect of iodine on hormone synthesis, a failure to escape from the Wolff-Chaikoff effect, or both [105].

        Preexisting Thyroid Antibodies

        Women with preexisting microsomal or thyroglobulin antibodies have a relative risk of 13.5 for developing amiodarone-induced hypothyroidism compared with men without thyroid antibodies [52]. Elevated antithyroid antibody titers are seen in as many as 40% of patients who become hypothyroid [35] after amiodarone is administered. These observations suggest that underlying autoimmune thyroiditis renders the gland more susceptible to the inhibitory effects of iodide [106] and that hypothyroidism may result from the unmasking of some preexisting subclinical thyroid abnormality caused by iodine excess [52]. This is consistent with the observation that patients with Hashimoto thyroiditis treated with long-term iodine therapy have an enhanced susceptibility to develop myxedema [107]. However, other studies [77, 108] have found no increase in the incidence of previous thyroid dysfunction (including antithyroid antibodies) in patients who developed amiodarone-induced hypothyroidism.

        Amiodarone-induced hypothyroidism may be transient or persistent. Transient hypothyroidism is seen in patients with or without underlying thyroid disorders; persistence of hypothyroidism despite amiodarone withdrawal is almost always associated with underlying disease (such as Hashimoto thyroiditis). In one series [105], 70% of patients with thyroid autoantibodies had persistent hypothyroidism and 90% of the patients without antibodies had spontaneous remission of hypothyroidism within 2 to 4 months after withdrawal of amiodarone. It is unclear why concomitant autoimmune thyroid disease predisposes patients to persistent hypothyroidism long after amiodarone therapy is discontinued. Because Hashimoto thyroiditis often results in hypothyroidism, especially in older patients, administration of amiodarone might merely precipitate clinical hypothyroidism in these patients. It is also conceivable that amiodarone use is irrelevant to the natural history of Hashimoto thyroiditis and that the occurrence of hypothyroidism after institution of amiodarone therapy is coincidental. On the other hand, chronic amiodarone use might accelerate the natural evolution of chronic lymphocytic thyroiditis by an unknown mechanism [105]. One possible explanation is that iodine enhances the autoimmune response [66, 109], thereby accelerating the underlying thyroid damage that is caused by the autoimmune process. In a recent study [110], five of seven patients who had positive thyroid autoantibody test results and ultrasound patterns compatible with Hashimoto thyroiditis developed hypothyroidism within 4 to 9 months of amiodarone treatment; however, no patients in a control group of 16 euthyroid patients with Hashimoto thyroiditis followed for 12 to 55 months developed hypothyroidism. Alternatively, excess iodine in the thyroid may induce nonspecific damage to the thyroid follicles and add to the damage caused by the underlying autoimmune disease.

        Other Factors

        Baseline levels of thyroid-stimulating hormone were significantly higher in patients who developed hypothyroidism after beginning amiodarone therapy than in those who did not. However, only 2 of 32 patients in the former category had thyroid-stimulating hormone levels that were higher than normal, and there was a considerable overlap between the levels in the two groups [26]. A positive family history of thyroid disease [23] and residence in areas with sufficient iodine intake [35] may also predispose patients to the development of amiodarone-induced hypothyroidism.

        Clinical Features and Diagnosis

        As with other forms of hypothyroidism, clinical features of amiodarone-induced hypothyroidism are often vague. Fatigue, lack of energy, intolerance of cold, mental and physical sluggishness, and dry skin are commonly reported; goiter is uncommon [111]. Laboratory diagnosis is made on the basis of low serum total thyroxine and free thyroxine levels in conjunction with elevated serum levels of thyroid-stimulating hormone [105]. Serum thyroglobulin levels may be elevated in as many as 90% of patients [105], a finding that is consistent with increased release of thyroglobulin from the thyroid due to high levels of thyroid-stimulating hormone [112]. Serum triiodothyronine and free triiodothyronine concentrations are within the normal range in many of these patients [105]. Biochemical changes diagnostic of amiodarone-induced hypothyroidism are shown in Table 1. Patients at high risk for amiodarone-induced hypothyroidism (such as women with preexisting thyroid antibodies) should be followed closely, especially during the first 2 years of treatment with amiodarone [52].

        Detectable 24-hour radioiodine uptake is seen in 80% of patients with amiodarone-induced hypothyroidism [105]. The inappropriately elevated radioiodine uptake seen in this and other studies [111, 113, 114] may be caused by excess stimulation of the thyroid by thyroid-stimulating hormone [105]. In addition, preserved radioiodine uptake may be caused by a decrease in the concentration in the thyroid of an unknown specific iodinated compound that mediates the inhibition of iodide transport [114]. This putative inhibitor may be an iodinated lipid that has been isolated from the thyroid gland and shown to inhibit iodine uptake in vitro [115].

        The perchlorate discharge test, which is used to detect defects in intrathyroidal iodide organification, has been reported to yield positive results in most patients with amiodarone-induced hypothyroidism [105, 111, 116]. After radioiodine administration, epithyroid counts are obtained at frequent intervals and again after administration of perchlorate. A decrease of 5% or more after perchlorate administration suggests an organification defect.

        Treatment

        Options for treating amiodarone-induced hypothyroidism include discontinuing amiodarone therapy or decreasing the dose, administering replacement therapy with levothyroxine, or both [117]. The goal of replacement therapy is to bring serum thyroxine levels to the upper end of the normal range or slightly above normal, as seen in euthyroid patients who receive amiodarone. Higher doses of levothyroxine are required to decrease the serum levels of thyroid-stimulating hormone to normal in these patients. In 32 patients with amiodarone-induced hypothyroidism, a mean calculated levothyroxine dose of 136 micro g/d was required to achieve serum thyroxine levels similar to those expected in euthyroid patients receiving amiodarone. In contrast, the dose required to bring thyroid-stimulating hormone levels to within the normal range was calculated (by extrapolation) to be 276 µg/d [26], which is obviously excessive. Thus, in contrast to other forms of hypothyroidism, one should not attempt to achieve normal serum levels of thyroid-stimulating hormone in amiodarone-induced hyperthyroidism, because this will most likely make the patient hyperthyroid. Also, such an attempt will be self-defeating because some of the anti-arrhythmic effect of the drug is mediated by an intracellular state of hypothyroidism in the myocardium [42, 90-92]. Therefore, prudence is generally warranted, and the levothyroxine dose should be increased cautiously. Therapy should be started with 25 to 50 µg daily and increased at intervals of 4 to 6 weeks [117]. Serum thyroxine levels will stabilize in 2 weeks, although it may take 6 weeks for serum levels of thyroid-stimulating hormone to decrease to a new steady-state level.

        The ability of perchlorate to discharge inorganic iodine and block further entry of iodide into the thyroid reduces iodine in the thyroid, thereby relieving the iodine-induced inhibition of thyroid hormone synthesis [105, 118]. In small studies [118, 119], short-term administration of perchlorate (1 g/d for 9 to 34 days) has been shown to rapidly restore normal thyroid function in patients with amiodarone-induced hypothyroidism.

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        Monitoring of Thyroid Function Tests in Patients Receiving Amiodarone

        It is probably advisable to test thyroid function once every few months in patients receiving amiodarone. A suggested scheme is presented in Figure 3. Thyroid function tests done at baseline help to exclude underlying gland dysfunction that may predispose the patient to hyper- or hypothyroidism after amiodarone therapy is started [26, 52, 57, 110]. Serum levels of thyroid-stimulating hormone, thyroxine, and triiodothyronine may be assessed 3 months after therapy with the drug is started. Values obtained at this stage (normal thyroid-stimulating hormone levels, slightly increased or normal thyroxine levels, and low normal triiodothyronine levels) [33] may be considered reference values for subsequent comparisons. After the first 3 months, periodic monitoring of serum thyroid-stimulating hormone levels alone may suffice as a screening test. Development of hyperthyroidism would decrease serum thyroid-stimulating hormone levels [58], and hypothyroidism would increase them [105]. Under these circumstances, further changes in serum levels of thyroxine, triiodothyronine, or both may be sought to confirm the diagnosis of hyper- or hypothyroidism.

        Figure 3. *Test should be done to serve as a reference for comparison with future test results. † Goal is to increase serum levels of thyroxine (T ) to high normal or slightly above normal (normalization of levels of thyroid-stimulating hormone [TSH] should not be attempted). ‡ Combination of thionamides (methimazole, 40 mg/d, or propylthiouracil, 400 to 800 mg/d) with potassium perchlorate (800 to 1000 mg/d for 15 to 45 days) or prednisone (0.5 to 1.25 mg/kg of body weight per day for 40 days) is beneficial; β-blockers may be added. AIH = amiodarone-induced hypothyroidism; AIT = amiodarone-induced thyrotoxicosis; T = triiodothyronine.
        View larger version:
          Figure 3. *Test should be done to serve as a reference for comparison with future test results. † Goal is to increase serum levels of thyroxine (T ) to high normal or slightly above normal (normalization of levels of thyroid-stimulating hormone [TSH] should not be attempted). ‡ Combination of thionamides (methimazole, 40 mg/d, or propylthiouracil, 400 to 800 mg/d) with potassium perchlorate (800 to 1000 mg/d for 15 to 45 days) or prednisone (0.5 to 1.25 mg/kg of body weight per day for 40 days) is beneficial; β-blockers may be added. AIH = amiodarone-induced hypothyroidism; AIT = amiodarone-induced thyrotoxicosis; T = triiodothyronine. Suggested algorithm for evaluation and management of thyroid dysfunction in patients treated with amiodarone.43

          Although the rationale and cost-effectiveness of routine thyroid function testing has never been systematically evaluated, we believe that such an approach could lead to earlier diagnosis of clinical thyroid dysfunction, particularly hypothyroidism (which often has a vague presentation).

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          Summary

          Treatment with amiodarone causes many effects on thyroid hormone physiology and thyroid function tests, often in the absence of hyper- or hypothyroidism. Therefore, increases in serum levels of thyroxine, thyroid-stimulating hormone, and reverse triiodothyronine and a decrease in serum triiodothyronine levels may be noted in euthyroid patients receiving amiodarone. These changes do not warrant treatment. Clinical thyroid dysfunction is also common and may occur in as many as one fourth of patients treated with amiodarone.

          Amiodarone-induced thyrotoxicosis may be related to excess iodide, disturbance of thyroid iodine autoregulation, autoimmune disturbances, and destruction or inflammation of the thyroid induced by amiodarone. Although serum levels of thyroxine and thyroid-stimulating hormone are often elevated in euthyroid patients receiving amiodarone, the onset of thyrotoxicosis is marked by a further increase in serum thyroxine levels, an increase in serum triiodothyronine levels, and a decrease in serum thyroid-stimulating hormone levels. Medical therapy with propylthiouracil or methimazole is often effective but may take weeks to control the hyperthyroid state; short courses of perchlorate or prednisone therapy in the initial phase of treatment accelerate improvement. Whether to continue amiodarone therapy in this situation is a complex decision that should be made on the basis of the severity of the condition for which the drug is being used, the severity of the hyperthyroid state, and the treatment planned (that is, medical or surgical). Total or near-total thyroidectomy rapidly alleviates the hyperthyroid state and permits continued use of amiodarone. It is therefore strongly indicated if rapid control of the hyperthyroid state is indicated or discontinuation of amiodarone therapy is impractical.

          Amiodarone-induced hypothyroidism is related to a persistent Wolff-Chaikoff effect and is more common in patients (especially women) with preexisting thyroid autoantibodies. The dose of levothyroxine in amiodarone-induced hypothyroidism should be monitored carefully to bring serum thyroxine levels to the those expected in euthyroid patients receiving amiodarone (that is, high normal or slightly above normal). Normalization of serum thyroid-stimulating hormone levels is not the goal of therapy for amiodarone-induced hypothyroidism.

          Dr. Licata: Department of Endocrinology, Cleveland Clinic Foundation, Cleveland, OH 44195.

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          1. Ann Intern Med January 1, 1997 vol. 126 no. 1 63-73
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