Amiodarone, thyroid hormone indexes, and altered thyroid function: Long-term serial effects in patients with cardiac arrhythmias

doi:10.1016/S0002-9149(86)80023-6

The American Journal of Cardiology

Volume 58, Issue 10, 1 November 1986, Pages 981-986

https://doi.org/10.1016/S0002-9149(86)80023-6 Get rights and content

Amiodarone, a drug that has electrophysiologic actions resembling those of hypothyroidism, increases serum levels of T₄ and reverse T₃ (rT₃) and decreases T₃. The drug's long-term effects on thyroid function are poorly defined. Serial thyroid hormone indexes in 76 patients given amiodarone for 6 to 32 months (mean ± standard deviation 16 ± 7) for arrhythmias were determined serially. Over this period, 68 patients (89%) remained euthyroid; hypothyroidism developed in 6 (8%) and hyperthyroidism developed in 2 (3%). In patients who remained euthyroid, thyroid hormone alterations attained steady-state values at 3 months: T₄ increased 42% (p <0.01), rT₃ increased 172% (p <0.01) and T₃ decreased 16% (p <0.05), without significant effect on thyroid stimulating hormone. For the euthyroid patients, the 90% tolerance limits (95% confidence) over the follow-up period for T₄ was 5 to 19 μg/dl (normal 4 to 12), for T₃ 36 to 163 ng/dl (normal 60 to 160), for rT₃ 22 to 131 ng/dl (normal 15 to 50) and for thyroid stimulating hormone 0 to 14 μU/ml (normal 1 to 6). The changes in hormone indexes in hyperthyroid or hypothyroid patients were unrelated to the cumulative dose or duration of drug therapy. The most reliable diagnostic indexes for amiodarone-induced altered thyroid state were: thyroid stimulating hormone level over 20 μU for hypothyroidism and T₄ over 20 ng/dl or high T₃ over 200 ng/dl for hyperthyroidism. All levels were within the 90% tolerance limits derived for these hormones from patients remaining euthyroid on amiodarone long-term. The data provide the basis for diagnosis of abnormal thyroid function in patients with drug-induced changes in thyroid function tests due to amiodarone and suggest the need for baseline and periodic determinations of thyroid function tests during long-term amiodarone therapy.

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Cited by (61)

Prevalence of amiodarone-induced hypothyroidism; A systematic review and meta-analysis
2023, Trends in Cardiovascular Medicine
Citation Excerpt :
58.2% (8158 out of 13999 subjects) of patients were male participants. Hypothyroidism was defined as a combination of elevated thyroid-stimulating hormone (TSH) and reduced T4 levels [21,29–56]. Table 1 provides a summary of all included articles.
Amiodarone is a common anti-arrhythmic agent mostly used to treat and prevent different kinds of arrhythmia with several considerable side effects, most commonly on the thyroid gland. We aimed to assess the frequency of hypothyroidism among chronic amiodarone users. PubMed/Medline, Web of Science, and Scopus databases were screened in the title and abstract sections with no time limitation. Relevant published records reported amiodarone-induced hypothyroidism (AIH) among patients with normal thyroid function at baseline were recruited with further analysis according to gender and study locations. We found 29 records on 14143 individuals. Total population age ranged from 18 to 92 years (males: 58.2% (8158 out of 13,999)). The AIH prevalence was found to be 14% (95% confidence interval (CI): 12–17%). Further gender stratified showed an insignificant higher AIH frequency in females versus males (17%, 95% CI: 13–22% vs. 14%, 95% CI: 11–19% P= 0.304, respectively). Despite no significant difference in AIH prevalence according to different continents, African subjects had marginally lower AIH frequency compared to Asian (7%, 95% CI: 4–13% vs. 15%, 95% CI: 12–19%, P= 0.012) and South American persons (7%, 95% CI: 4–13% vs. 54%, 95% CI: 9–93%, P= 0.038). This review suggests the occurrence of AIH is quite considerable regardless of gender and area of residence, and several periodic thyroid assessment strategies should be developed for earlier recognition and therapeutic interventions in clinical settings.
Short-term amiodarone treatment for atrial fibrillation after catheter ablation induces a transient thyroid dysfunction: Results from the placebo-controlled, randomized AMIO-CAT trial
2016, European Journal of Internal Medicine
Amiodarone is known to affect the thyroid, but little is known about thyroid recovery after short-term amiodarone treatment.
We aimed to evaluate the impact of 8 weeks of amiodarone treatment on thyroid function in patients with atrial fibrillation (AF) undergoing catheter ablation in a randomised, double-blind clinical trial.
212 patients referred for AF ablation at two centres were randomized to 8 weeks of oral amiodarone or placebo. Thyroid function tests (TSH, thyroid stimulating hormone; T4, thyroxine; T3, triiodothyronine; fT4, free T4; fT3, free T3) were performed at baseline and 1, 3 and 6 months.
Study drug was discontinued due to mild thyroid dysfunction in 1 patient in the placebo vs. 3 in the amiodarone group (p = 0.6). In linear mixed models there were significant effects of amiodarone on thyroid function tests, modified by follow-up visit (p < 10^− 9 for both TSH, T4, T3, fT4 and fT3). The amiodarone group had higher TSH, fT4 and T4 after 1 and 3 months compared to placebo, whereas T3 and fT3 were lower. In all cases, the amiodarone-induced thyroid dysfunction was largest at 1 month, declining at 3 months, and with no differences at 6 months, compared to baseline.
We found amiodarone to have a significant impact on thyroid function after only 1 month, but with a fast recovery of thyroid function after amiodarone discontinuation. Our study indicates that short-term amiodarone can be considered safe in patients without prior thyroid dysfunction.
Combined therapy with carvedilol and amiodarone is more effective in improving cardiac symptoms, function, and sympathetic nerve activity in patients with dilated cardiomyopathy: Comparison with carvedilol therapy alone
2008, Journal of Nuclear Cardiology
Citation Excerpt :
Amiodarone has several effects, including an antifibrillatory effect, the ability to prolong the action potential through alterations in potassium transport, a coronary vasodilatory effect, and a noncompetitive inhibition of α-adrenergic receptors.30,31 Furthermore, amiodarone can influence thyroid hormone metabolism, which may have cardioprotective effects.32 Amiodarone can protect cardiac myocytes against oxidative stress-mediated injury by directly scavenging oxygen free radicals.
Carvedilol therapy has been reported to be more effective than other beta-blockers in patients with chronic heart failure (CHF). Amiodarone is an anti-arrhythmic medicine that has also been reported to be effective in patients with CHF. But the usefulness of combined therapy with carvedilol and amiodarone has not been reported.
We compared 15 patients (M/F = 3/12, age = 57 ± 8 y) with dilated cardiomyopathy (DCM) receiving carvedilol and amiodarone with 15 patients (M/F = 3/12, age = 61 ± 9 y) receiving carvedilol alone. Patients were studied before and after 1 year of treatment (1Y). NYHA class and exercise capacity based on the specific-activity-scale (SAS), were assessed. Cardiac sympathetic nerve activity was estimated using total defect score (TDS), H/M ratio and washout rate (WR) of 123I-MIBG imaging. Cardiac function was evaluated using 99mTc-MIBI QGS.
Combined therapy improved several parameters much more than carvedilol alone (p < 0.05) including delta-TDS (15.0 ± 8.6 vs. 7.6 ± 7.2) and delta-WR (15.9 ± 11.0% vs. 7.3 ± 10.0%) for 123I-MIBG imaging, delta-LVEF (26.1 ± 11.4% vs. 15.5 ± 13.8%), delta-end-systolic volume (100 ± 63.8 ml vs. 58.9 ± 47.3 ml), 1Y NYHA class (1.5 ± 0.5 vs. 1.9 ± 0.5), 1Y SAS (7.3 ± 0.7 Mets vs. 6.2 ± 1.0 Mets), and delta-SAS (3.4 ± 0.8 Mets vs. 2.6 ± 1.1 Mets).
Combined therapy with carvedilol and amiodarone is more effective in improving cardiac symptoms, exercise capacity, cardiac function and cardiac sympathetic nerve activity in patients with DCM.
Thyroid Function Abnormalities during Amiodarone Therapy for Persistent Atrial Fibrillation
2007, American Journal of Medicine
Citation Excerpt :
Similarly, at 1 year, approximately 43% of patients in the amiodarone group with overt hypothyroidism were taking levothyroxine, whereas only 9.8% the patients with subclinical hypothyroidism were prescribed levothyroxine (P <.0001). Since amiodarone became available in the United States for anti-arrhythmic therapy in the 1980s, there have been numerous reports of associated changes in thyroid hormone metabolism, as well as clinically significant thyroid dysfunction.10-15 Our study shows that amiodarone-induced hypothyroidism is common among a cohort of older men treated for atrial fibrillation as compared with a control group in a blinded study.
Many patients receiving amiodarone therapy are male. The long-term risk for amiodarone-induced thyroid dysfunction in these patients has not been systematically and prospectively investigated. The purpose of this study was to determine the extent of amiodarone-induced thyroid dysfunction in a large male cohort.
This is a substudy of a prospective randomized controlled trial (SAFE-Trial) in which amiodarone, sotalol, and placebo for persistent atrial fibrillation were evaluated. For the purpose of this substudy, sotalol and placebo groups were combined into a control group. Serial thyroid function tests were performed over 1-4.5 years. Of the 665 patients enrolled in the SAFE-Trial, 612 patients were included in this sub-study.
Subclinical hypothyroidism, thyroid-stimulating hormone (TSH) level 4.5-10 mU/L, was seen among 25.8% of the amiodarone-treated patients and only 6.6% of controls (P <.0001). Overt hypothyroidism, TSH level >10 mU/L, was seen among 5.0% of the amiodarone-treated patients, and only 0.3% of controls (P <.001). By 6 months, 93.8% of the patients who developed TSH elevations above 10 mU/L on amiodarone had been detected. There was a trend toward a greater proportion of hyperthyroidism, defined as a TSH <0.35 mU/L, in the amiodarone group compared with the control group (5.3% vs 2.4%, P = .07).
Hypothyroidism developed in 30.8% of older males treated with amiodarone and in only 6.9% of the controls. Hypothyroidism presented at an early stage of therapy. Hyperthyroidism occurred in 5.3% of amiodarone treated patients, and was a subclinical entity in all but 1 case.
Effects of amiodarone therapy on thryoid function and its current management
2007, Endocrinologia y Nutricion
La amiodarona es un fármaco rico en yodo utilizado como agente antiarrítmico, que puede causar disfunción tiroidea. Sus efectos en la función tiroidea pueden deberse a una acción directa del fármaco y/o del propio yodo. La amiodarona influye sobre la fisiología tiroidea en diferentes áreas: hipofisaria, tiroidea y periférica. Como consecuencia puede causar distintos cambios en las concentraciones séricas de las hormonas tiroideas. Estas modificaciones dependen de varios factores, como dosis y vía de administración del fármaco, duración del tratamiento, enfermedad tiroidea subyacente y aporte habitual de yodo. Aunque la amiodarona puede producir tanto hipotiroidismo como hipertiroidismo, la mayoría de los pacientes permanecen clínicamente eutiroideos. La prevalencia del hipotiroidismo inducido por amiodarona oscila entre el 1-25%. Su aparición no implica la retirada de la amiodarona y, como en otras formas de hipotiroidismo, el tratamiento de elección es la levotiroxina. La prevalencia de la tirotoxicosis inducida por amiodarona (TIA) es del 1-23%. Se han identificado 2 formas clínicas de TIA con implicaciones pronósticas y terapéuticas: la TIA tipo 1 (tirotoxicosis inducida por yodo) y la TIA tipo 2 (tiroiditis destructiva farmacológica). La supresión de la tirotropina (TSH), junto con un aumento de la triyodotironina (T3) y de la tiroxina (T4) libre, y los síntomas de hipertiroidismo son criterios diagnósticos de TIA. La eco-Doppler color de flujo tiroideo es la prueba de elección para establecer el diagnóstico diferencial entre ambos subtipos de TIA. En los casos de TIA, la amiodarona se debería retirar siempre que fuera posible, como en el caso del control de arritmias que no comprometen la vida del paciente. La TIA tipo 1 se controla con tionamidas solas o asociadas a perclorato potásico. La TIA tipo 2 suele responder a esteroides. En las formas mixtas se recomienda la triple terapia con tionamidas, esteroides y perclorato potásico. La tiroidectomía es una buena alternativa terapéutica en los casos de TIA resistente al tratamiento médico.
Amiodarone is an iodine-rich drug used as an antiarrhythmic agent which can cause thyroid dysfunction. The effects of amiodarone on thyroid function can be due to the intrinsic action of the drug and/or iodine-induced effects. Amiodarone influences thyroid physiology at pituitary, thyroid and peripheral level. Consequently, it can produce several changes in thyroid hormone concentrations. These modifications depend on several factors, such as the dose and route of administration of the drug, length of therapy, underlying thyroid disease, and iodine intake. Although amiodarone can produce both hypo-and hyperthyroidism, most patients remain clinically euthyroid. The prevalence of amiodarone-induced hypothyroidism (AIH) ranges from 1 to 25%. In these patients, amiodarone withdrawal is usually not required and, as in other forms of hypothyroidism, the treatment of choice is levothyroxine (LT₄) replacement therapy.
The prevalence of amiodarone-induced thyrotoxicosis (AIT) is between 1 and 23%. Two different clinical forms have been described with therapeutic and prognostic implications: type 1 AIT (iodine-induced thyrotoxicosis) and type 2 AIT (drug-induced destructive thyroiditis). Diagnosis of AIT is established by elevations of free T4 and free T3 with suppression of TSH serum concentrations and clinical symptoms of hyperthyroidism. Color flow Doppler sonography is the most effective procedure to discriminate AIT type 1 from type 2. In patients with AIT, amiodarone therapy should be withdrawn, when feasible, as in the case of non-life-threatening arrhythmias. Type 1 AIT is controlled with antithyroid drugs alone or in combination with potassium perchlorate. Type 2 AIT usually responds to steroids. In mixed forms, triple therapy (antithyroid drugs, steroids and potassium perchlorate) is recommended. Thyroidectomy is an appropriate therapeutic alternative in patients with AIT refractory to medical therapy.
Amiodarone and the thyroid
2005, American Journal of Medicine
Citation Excerpt :
Although amiodarone-induced thyroid dysfunction (hypothyroidism or hyperthyroidism) is a major clinical problem, the majority of patients receiving amiodarone remain euthyroid. In a prospective study from the United States of 76 euthyroid patients started on amiodarone and followed for a mean duration of 16 months, 89% remained euthyroid.20 Because the thyroid gland is exposed to an extraordinary load of iodine, important adjustments are made in thyroidal iodine handling and hormone metabolism in order to maintain normal function, the reflection of which is seen in serum thyroid hormone levels.
Among the drugs affecting the thyroid gland, no drug has puzzled, and at the same time fascinated, endocrinologists more than amiodarone. Amiodarone is a potent class III anti-arrhythmic drug that also possesses beta-blocking properties. It is very rich in iodine, with a 100-mg tablet containing an amount of iodine that is 250 times the recommended daily iodine requirement. Amiodarone produces characteristic alterations in thyroid function tests in euthyroid patients. Understanding these alterations is crucial in avoiding unnecessary investigations and treatment. Amiodarone-induced thyroid dysfunction occurs because of both its iodine content and the direct toxic effects of the compound on thyroid parenchyma. Amiodarone-induced hyperthyroidism is more common in iodine-deficient regions of the world, whereas amiodarone-induced hypothyroidism is usually seen in iodine-sufficient areas. In contrast to amiodarone-induced hypothyroidism, amiodarone-induced thyrotoxicosis is a difficult condition to diagnose and treat. In this review, we discuss the alterations in thyroid function tests seen in euthyroid subjects, the epidemiology and mechanism of amiodarone-induced thyroid dysfunction, treatment options available, and the consequences of amiodarone use in pregnancy and lactation; and finally, we propose a follow-up strategy in patients taking amiodarone.

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^*: This study was supported by grants from the Medical Research Service of the Veterans Administration, Washington, D.C., and the American Heart Association, Greater Los Angeles Affiliate, Los Angeles, California.

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Amiodarone, thyroid hormone indexes, and altered thyroid function: Long-term serial effects in patients with cardiac arrhythmias*

Am J Med

Am Heart J

J Cell Molec Cardiol

Etude clinique d'une nouvelle medication anti-angoreuse

Acta Cardiol Belg

Clinical pharmacology and therapeutic applications of the antiarrhythmic drug, amiodarone

Am Heart J

Side effects of long-term amiodarone therapy

Circulation

Control of tachyarrhythmias associated with the Wolff-Parkinson-White syndrome by amiodarone hydrochloride

Am J Cardiol

Clinical efficacy of amiodarone as an antiarrhythmic agent

Am J Cardiol

Long-term management of sustained recurrent symptomatic ventricular tachycardia with amiodarone

Circulation

Control of refractory life-threatening ventricular arrhythmias by amiodarone

Am Heart J

Amiodarone in refractory life-threatening ventricular arrhythmias

Ann Intern Med

Amiodarone: clinical efficacy and electrophysiology during long-term therapy for recurrent ventricular tachycardia or ventricular fibrillation

N Engl J Med

Amiodarone kinetics after oral doses

Clin Pharmacol Ther

Pharmacology of amiodarone, an antianginal drug with a new biological profile

Arzeimittelforschung

The effect of amiodarone, a new antianginal drug, on cardiac muscle

Br J Pharmacol

Amiodarone pharmacokinetics

Amer Heart J

Effects of amiodarone on thyroid function in patients with ischemic heart disease

Br Heart J

Effect of amiodarone on serum triiodothyroinine, reverse triodothyronine, thyroxine, and thyrotropin: a drug influencing peripheral metabolism of thyroid hormones

J Clin Invest

Low T3 syndrome in patients chronically treated with an iodine-containing drug, amiodarone

Clin Endocrinol

Low T₃ syndrome in patients chronically treated with an iodine-containing drug, amiodarone