Amiodarone-Induced Thyrotoxicosis

Appropriate therapy for amiodarone-induced thyrotoxicosis (AIT) requires a diagnostic precision that may be difficult to achieve (1). Individual cases are rarely straight forward. On June 14, 1999, a 71-yr-old man was hospitalized with a 1-week history of exertional shortness of breath, foot swelling, and feeling poorly. In 1982, he was hospitalized with congestive heart failure and atrial fibrillation, attributed to myocarditis. In 1985, atrial fibrillation recurred and responded to chronic quinidine therapy. In early 1996, quinidine was stopped, followed by paroxysmal and then persistent atrial fibrillation with congestive heart failure (ejection fraction, 20–25%). Amiodarone (200 mg/day) and coumadin were prescribed. In May 1996, his serum TSH was 0.9 μU/mL. In September 1996, he suffered an acute myocardial infarction and underwent angioplasty of stenoses of the left anterior descending and diagonal coronary arteries. He remained in normal sinus rhythm; coumadin was discontinued. Amiodarone was discontinued in 1997 but successfully restarted in March 1998 when atrial fibrillation recurred (TSH 2.3μ U/mL). Atrial fibrillation recurred and persisted, and amiodarone was discontinued in September 1998, 9 months before admission. On admission (June 1999) he was in atrial fibrillation with a ventricular response of 180. His blood pressure was 90 systolic. He had mild proptosis (left greater than right), lid retraction, neck vein distension, and a slightly enlarged (20–25 g) thyroid. Although bilateral pleural effusions were present on the chest x-ray, interstitial edema was absent. A myocardial infarction was ruled out. His ventricular response was difficult to control despite escalating doses of β-blockers. Laboratory studies are summarized in Table 1. Laboratory data Normal range: T4, 4.5–10.9 μg/dL; free T4 index, 4.5–10.9; T3 RIA, 60–180 ng/dL; TSH, 0.5–5.0 μU/mL. Free T4, 0.7–1.5 (ng/dl); TSI, 0–129%; TBII, 0–9.9%; urine iodide, 42–350 μg/L. Laboratory data Normal range: T4, 4.5–10.9 μg/dL; free T4 index, 4.5–10.9; T3 RIA, 60–180 ng/dL; TSH, 0.5–5.0 μU/mL. Free T4, 0.7–1.5 (ng/dl); TSI, 0–129%; TBII, 0–9.9%; urine iodide, 42–350 μg/L. His 20-min 99m pertechnetate uptake was low at 0.19% (normal range, 0.5–3.75). AIT was diagnosed, possibly secondary to Graves’ disease. He was begun on methimazole (10 mg, po, tid), prednisone (40 mg, po, daily), iopanoic acid (500 mg, po, bid), metoprolol (200 mg, 4 id), and heparin, coumadin, and verapamil in doses up to 120 mg, tid. At the time of discharge his heart rate was 100–120. He was discharged on June 23, 1999, on methimazole (10 mg, po, tid), prednisone (40 mg, po, daily), iopanoic acid (500 mg, po, bid), lopressor (75 mg, 4 id), verapamil (20 mg, tid), lasix (20 mg, po, qd), and coumadin. Prednisone was discontinued after June 24. On July 2, he was in atrial fibrillation with a ventricular response of 104–108; his blood pressure was 90/60. He had lost 12 lbs since his hospital admission and noted less exertional shortness of breath. Mild proptosis, left greater than right, was noted (Hürthle exophthalmometer: left, 20 mm; right, 19 mm). TSH-binding inhibitory immunoglobulin titers (TBIIs) had been completed and were weakly positive. Graves’ disease was considered likely. On July 22, his pulse was 120 (AF). His dyspnea was unchanged, but he had a single episode of angina relieved by nitroglycerine. He noted increased fatigue and heat sensitivity. Methimazole was increased to 20 mg three times daily. Iopanoic acid was continued. On August 6, his radial pulse was 116–120. His ventricular rate on electrocardiogram was 139, increased compared with his previous electrocardiogram, and worsening ST segment depression was present. Although his dyspnea was stable, edema had increased to the mid-calf. His cardiologist considered hospital admission, but careful outpatient observation was the final recommendation. On August 17, thyroidectomy was recommended, in part, based on a serum T4 of 25.9 μg/dL, although his serum T3 had fallen to 140 ng/mL. A bilateral thyroidectomy was performed on September 10 without incident or complications. Pathological examination revealed an enlarged thyroid gland (right lobe, 5 × 2.5 × 1.5 cm; left lobe, 4.5 × 2.5 × 3 cm), but no weight was recorded. The final pathology report read: “Enlarged thyroid with fibrosis and mild chronic inflammation. There is no evidence of malignancy.” We asked to have the pathological material re-assessed. An addendum was reported: “The thyroid is diffusely affected with the lesions described as follows. Approximately half of the areas contained islands of dilated thyroid follicles that were lined by attenuated follicular epithelial cells. These islands are separated by areas of collapsed thyroid follicles admixed with fibrosis and prominent vasculature. Nonspecific findings including histocytes and eosinophilic bodies were present. These changes are consistent with those described in amiodarone-associated thyrotoxicosis” (2). Subsequent hypothyroidism was treated with levothyroxine. In December 1999, he remained in atrial fibrillation, but his ventricular response was 60. Amiodarone is an iodinated benzofuran derivative that is approved for the therapy of life-threatening recurrent ventricular arrhythmias (3) but is also used to treat angina, paroxysmal supraventricular tachycardia, and atrial fibrillation and to maintain normal sinus rhythm after cardioversion for atrial fibrillation (4). Amiodarone contains 75 mg iodine per 200-mg tablet and releases∼ 10% of the iodine as free iodide daily (5). Amiodarone is highly lipophilic and is concentrated in adipose tissue, cardiac and skeletal muscle, as well as the thyroid (6). With prolonged use, amiodarone has an elimination half-life as long as 100 days (6) Amiodarone effects on thyroid function result from iodine release and intrinsic drug properties (7). Pharmacologic iodide administration to euthyroid individuals with intrinsically normal thyroid glands results in transient inhibition of thyroid hormone synthesis and release, decreased thyroidal iodide trapping, and enhanced T4 (3,3′,5,5′ tetraiodothyronine) rather than T3 (3,3′,5 triiodothyronine) production by the thyroid, so-called autoregulatory functions (8). The net effect is a slight serum TSH increase that occasionally exceeds the normal range (9, 10). With chronically higher iodide intake, the prevalence of Hashimoto’s thyroiditis increases in genetically susceptible human and animal populations (11–13). In addition, pharmacologic iodide administration may precipitate hypothyroidism in patients with Hashimoto’s thyroiditis (14). Approximately 6% of patients receiving amiodarone develop iodine-induced hypothyroidism; the prevalence is higher in areas of iodine sufficiency and lower in iodine-deficient areas (15). Hypothyroidism may develop as soon as 2 weeks and as long as 39 weeks after starting amiodarone (7). Iodide supplementation in iodine-deficient endemic goiter populations triggers epidemics of hyperthyroidism in a minority of the population, the so-called Jod-Basedow phenomenon (16). Eighty-five percent of these hyperthyroid patients have nodular goiters. Autonomous areas within the nodular thyroid gland overproduce thyroid hormone when exposed to excess substrate (iodide) but are relatively impervious to the autoregulatory effects of iodine (17). However, some hyperthyroid patients have diffuse thyroidal uptake suggestive of Graves’ disease (18). As in the Hashimoto’s thyroiditis example above, excess iodide seems to trigger or facilitate an immunological attack on the thyroid (19). Additionally, borderline iodine-deficient patients with Graves’ disease in remission commonly relapse after adding 500 μg iodide daily (20), an amount comparable with the daily iodide intake in many iodide-sufficient areas. Pharmacologic doses of iodide may also precipitate hyperthyroidism in euthyroid individuals with nodular thyroid glands in iodine-sufficient regions (21). Case reports (22) and the amiodarone experience suggest that iodine excess may also precipitate Graves’ hyperthyroidism in iodine-sufficient areas, but this conclusion is uncertain. Amiodarone also has powerful effects on thyroid hormone metabolism (7). Amiodarone inhibits the peripheral conversion of T4 to T3 and may inhibit T3 receptor binding and action (23–25). In euthyroid individuals, T4 and free T4 concentrations increase by 42% due to decreased T4 clearance (7). Reverse T3 (3,3′5′ triiodothyronine) concentration rises by 172%. Efficacy and toxicity of amiodarone may be proportional to reverse T3 concentration (26). Serum T3 concentrations initially decline by 20–25%, subsequently an average 16% below baseline, but may be frankly low in some patients (7, 27). Serum TSH rises, occasionally out of the normal range, but with chronic administration generally remains in the normal to high normal range. It is uncertain whether TSH elevation in the 10–20 μU/mL range represents peripheral subclinical hypothyroidism or is a pituitary specific effect of amiodarone. Some authors accept subnormal serum TSH concentrations with normal T3 concentrations as compatible with the euthyroid state. However, I interpret these findings as evidence of amiodarone-induced subclinical hyperthyroidism. The 24-h radioiodine uptake decreases to low levels (<4%) in euthyroid individuals taking amiodarone (28). This is to be expected because 15 mg inorganic iodide daily, after a loading dose of 30 mg, decreases mean 24-h radioiodine uptake to less than 2% after 12 days (10). When added to antithyroid drugs, amiodarone facilitates the treatment of severe hyperthyroidism (29), by inhibiting T4 to T3 conversion, thyroid hormone release, and possibly T3 receptor binding and action. Unfortunately, 3% of patients exposed to amiodarone develop hyperthyroidism (30), with a higher prevalence in iodine-deficient regions (15). AIT may have a male predominance (31), reflecting the higher cardiovascular disease prevalence in men. Hyperthyroidism may occur 4 months to 3 yr after initiating therapy or after drug withdrawal (28) and is not related to cumulative drug dosage (7). Knowledge of three distinct types of AIT is required to understand this case (1, 30). Amiodarone-induced toxic nodular goiter, a form of iodine-induced thyrotoxicosis, was described in Europe where large nodular goiters are more prevalent than in the United States. Despite antithyroid drug therapy, some patients demonstrated refractory hyperthyroidism (28). The addition of perchlorate to antithyroid drugs decreased the time to euthyroidism in uncontrolled trials (32, 33). Perchlorate inhibits the thyroidal iodide trap and permits the back diffusion of free (nonorganified) iodide from the thyroid gland, so-called perchlorate “discharge” (34). Doses of perchlorate higher than 1.5 g per day may cause aplastic anemia, whereas doses of 1 g per day used in these studies are apparently safe. Emergency thyroidectomy was required in some patients, a courageous approach in these critically ill patients. The mechanism of refractory hyperthyroidism is uncertain. Thyroidal iodine stores are much higher in hyperthyroid compared with euthyroid patients receiving amiodarone (34A ). The expanded iodide pool is invoked to explain refractory hyperthyroidism, because antithyroid drugs prevent thyroid hormone synthesis but not hormone release. However, pharmacologic iodide inhibits thyroid hormone release from autonomous nodular thyroid glands when new hormone production is blocked by antithyroid drugs (35). Although amiodarone was often discontinued at the onset of thyrotoxicosis, a continued high iodide environment persisted due to its long half-life. A second group of patients treated with amiodarone developed Graves’ hyperthyroidism characterized by diffuse thyroid enlargement, a prolonged course, and the presence of thyroid autoantibodies (30). T-cell populations specific for Graves’ disease have been demonstated as well (36). Most authors infer that “latent” Graves’ disease was made overt by an iodine-stimulated immune attack on the thyroid. Proof of this assumption requires specific markers for genetic Graves’ disease. Toxic nodular goiter and Graves’ disease comprise Type I AIT, hyperthyroidism in patients with preexisting or “latent” thyroid disease. Type II AIT is a form of “destructive thyroiditis” (37), which develops in patients with baseline normal thyroid glands. Hyperthyroidism is due to release of stored thyroid hormone. The thyroid is usually nontender, but pain may occur. The sedimentation rate is generally within normal limits. Amiodarone, its metabolites, and intrathyroidal iodide have all been implicated in cellular toxicity, however, amiodarone is also toxic to cells that do not incorporate iodine (38, 39). Hyperthyroidism lasts for 1–3 months, until thyroid hormone stores are depleted, but resolves more quickly after glucocorticoid therapy. Transient and rarely permanent hypothyroidism may ensue, but the prevalence is uncertain (37). Subacute lymphocytic thyroiditis (“silent thyroiditis”) and subacute granulomatous thyroiditis (“painful subacute thyroiditis”, de Quervain’s thyroiditis) are worthy of study as other examples of destructive thyroiditis that follow a similar course (40). Hyperthyroidism with a nil 24-h radioiodine uptake is often followed by hypothyroidism. Subacute lymphocytic thyroiditis is an autoimmune disorder with a predilection for the postpartum period (postpartum thyroiditis). Thyroid autoantibodies are generally present, diffuse lymphocytic infiltration is found on biopsy, and permanent hypothyroidism occurs in a significant minority of patients. Subacute granulomatous thyroiditis is characterized by intense thyroid pain, a very high sedimentation rate, severe thyroid follicle disruption, and multinucleate giant cells. Permanent hypothyroidism is rare (41). Amiodarone-induced destructive thyroiditis seems not to be an autoimmune disorder because antithyroid antibodies are generally absent. Hypothyroidism, when it occurs, is usually transient. Although limited numbers of such thyroids have been examined, follicular disruption, zones of fibrosis, and mild inflammatory changes are usually present, but dense lymphocytic infiltration and multinucleated giant cells are usually absent (2, 38). Type II AIT was diagnosed on histological examination of our patient’s thyroid gland; hyperplastic changes of Graves’ disease were absent. Type II is the most common variety of AIT in our clinic. Type I AIT is more common in Europe; the geographic differences likely reflect the higher iodine intake in the United States. Many patients with AIT II demonstrate minimal transient hyperthyroidism, diagnosed by fully suppressed TSH alone (personal observation). Permanent hypothyroidism is rare, even when amiodarone is continued (personal observation). Some episodes of Type II AIT may represent subacute lymphocytic thyroiditis precipitated by amiodarone (42). Occasional patients develop repeated cycles of hypothyroidism, followed by hyperthyroidism (43) Appropriate therapy of AIT requires a clear distinction between Type I and Type II AIT. How can this be accomplished (Table 2)? AIT-differential diagnosis and therapy Based on European experience (see text). AIT-differential diagnosis and therapy Based on European experience (see text). Given the high iodine content of amiodarone, a nil 24-h radioiodine uptake might be expected in all patients taking this drug. However, detectable or normal 24-h radioiodine uptake is found in 80% of patients with amiodarone-associated hypothyroidism in Europe (44). Furthermore, in Europe type I AIT is accompanied by low, normal, or high 24-h radioiodine uptake, a possible consequence of baseline borderline low iodide intake (45, 46). The radioiodine uptake is near zero in all patients with Type II AIT. A normal or high radioiodine uptake effectively excludes Type II AIT, however, a nil uptake cannot distinguish between Type I or Type II. All patients with Type I and Type II AIT seen in our Thyroid Clinic have a near nil uptake. Systemic radiodine studies of Type I AIT are needed in the United States. If confirmed, our observations suggest that 24-h radioiodine uptakes are superfluous in AIT in the United States. A low (0.19%) 20-min 99m pertechnetate uptake was measured in our patient. In contrast to the 24-h radioiodine uptake, this test can be performed while receiving antithyroid drugs, allowing therapy to begin immediately. Thyroid ultrasonography may allow us to discriminate between Type I and Type II AIT. Thyroid nodules are easily diagnosed by ultrasound and in their toxic nodular goiter is effectively However, destructive thyroiditis may with a nodular thyroid Thyroid ultrasound with can thyroid blood Type I AIT with Graves’ disease has normal or increased blood whereas Type II AIT a with decreased In patients with Type I from Type II AIT Many studies on thyroid nodules but not When ultrasonography in patients with AIT, thyroid gland studies be Thyroid as the but experience in iodine-sufficient areas such as the United be before it can be fully other studies antibodies are present in at of patients with Graves’ hyperthyroidism and are generally absent in AIT II. antibodies and are considered specific for Graves’ disease. When thyroid autoantibodies are no can be were found in our Graves’ disease. Serum is a that and T-cell is in Type II AIT and normal to at most slightly in Type in Type II AIT are and in Type I AIT I are However, have seen low concentrations in patients with Type II AIT, reflecting of was not measured in our patient. T3 is a of Graves’ hyperthyroidism. The of serum T3 to T4 concentration is a that can be in Graves’ hyperthyroidism from destructive when radioiodine uptakes cannot be In of patients with Graves’ hyperthyroidism had a T3 to T4 greater than whereas of those with “destructive thyroiditis” and 6% of euthyroid individuals were in this range This has not been in AIT. A low is to be because amiodarone inhibits T4 to T3 conversion, however, a high AIT patients receiving amiodarone have a mean T3 to T4 of whereas AIT patients have a mean of 12 (7). of I and II AIT have not been patient’s T3 to T4 of the diagnosis of Graves’ hyperthyroidism. Type I AIT with Graves’ disease and Type II AIT present with a normal to diffusely enlarged thyroid. or a thyroid Graves’ disease. However, pharmacologic doses of iodide mg/day) thyroidal blood in Graves’ disease and a may within days of iodide administration (personal In our thyroid was to Graves’ hyperthyroidism was diagnosed based on findings and TBII, although this to be We not an ultrasound or in our studies that in might have been The of is uncertain because pathological changes in Type II AIT are often Table 2 the therapy of I and II AIT. of toxic nodular goiter methimazole or perchlorate may be With prolonged hyperthyroidism, or continued amiodarone be considered The of radioiodine therapy in patients with normal or high 24-h radioiodine uptake is uncertain. Type I AIT due to Graves’ disease is treated in a similar 12 patients with Type I AIT (10 with toxic nodular goiters and 2 with Graves’ were treated with a of methimazole and perchlorate All normal free T3 concentrations by 4 weeks A diagnosis of Graves’ hyperthyroidism was made in our patient. Methimazole was and iopanoic acid was added to hormone release and inhibit T4 to T3 conversion, functions also by amiodarone. The 24-h urine iodide was perchlorate was not It is to amiodarone for weeks after starting antithyroid drugs in Type I AIT patients, but this is of Although amiodarone serum half-life is the of T4 to T3 inhibition after drug is Hyperthyroidism in Type II AIT is but some patients critically ill with cardiovascular therapy the hyperthyroidism of Type II AIT and may be treated 12 Type II AIT patients with prednisone (40 mg/day) for with a 3 Free T3 and after an average of and In our many patients euthyroid after weeks of However, hyperthyroidism then prednisone be A response to glucocorticoid therapy is an in difficult a diagnosis seems therapy at Type I and Type II AIT including when from and antibodies often days to weeks to was ill on admission. Amiodarone had been discontinued. Although Graves’ disease was the diagnosis based on his methimazole and iopanoic were all prescribed. When the results prednisone was discontinued. The was attributed to iopanoic acid but may have been due to prednisone therapy. In a course of prednisone therapy have been and might have been A for was made when the was When for the was but the and his a The diagnosis was in and therapy with antithyroid drugs might have been In more with a diagnostic approach might have been amiodarone be discontinued in all cases of When the cardiac amiodarone in AIT but therapy for weeks after starting antithyroid Many authors amiodarone in Type II AIT, however, this is the diagnosis is cases of Type II are had been amiodarone for 9 months, Type II thyroid before starting The drug is usually begun in an or by without for thyroid disease. However, a approach be to a history of autoimmune thyroid disease and serum TSH and antithyroid These studies might be in amiodarone-associated hypothyroidism and possibly allow of “latent” Graves’ disease. Thyroid ultrasound patients with nodular thyroid glands at for AIT but its might be more in Europe where AIT I is more AIT to our Although clear are diagnosis and therapy for an may be studies in the United and in AIT are or 99m pertechnetate uptake is but may be superfluous in the United States. Although in some this case the that with AIT.