Amiodarone and Thyroid Dysfunction

Hema Padmanabhan, MD, FACP


South Med J. 2010;103(9):922-930. 

In This Article

Abstract and Introduction


Amiodarone is a potent antiarrhythmic drug associated with thyroid dysfunction. Its high iodine content causes inhibition of 5′-deiodinase activity. Most patients remain euthyroid. Amiodarone-induced thyrotoxicosis (AIT) or amiodarone-induced hypothyroidism (AIH) may occur depending on the iodine status of individuals and prior thyroid disease. AIT is caused by excess iodine-induced thyroid hormone synthesis (type I AIT) or by destructive thyroiditis (type II AIT). If the medical condition allows it, discontinuation of the drug is recommended in type I AIT. Otherwise, large doses of thioamides are required. Type II AIT is treated with corticosteroids. Mixed cases require a combination of both drugs. Potassium perchlorate has been used to treat resistant cases of type I AIT but use is limited by toxicity. Thyroidectomy, plasmapheresis, lithium, and radioiodine are used in select cases of AIT. AIH is successfully treated with levothyroxine. Screening for thyroid disease before starting amiodarone and periodic monitoring of thyroid function tests are advocated.


Amiodarone is a class III antiarrhythmic drug widely used for the management of various tachyarrhythmias[1] and, to a lesser extent, in the management of severe congestive heart failure.[2] It prolongs myocardial refractoriness, slows heart rate and atrioventricular nodal conduction, and prolongs the QT interval.[3]

Although it has adverse effects on the cornea, lungs, liver, and the skin, the thyroid gland is one of the major organs affected.


It is an iodinated derivative of benzofuran with structural resemblance to the thyroid hormones tri-iodothyronine and thyroxine. Thirty-five percent of its mass is organic iodine. Each 200 mg tablet contains about 75 mg of iodine, 10% of which is released as free iodide. This is approximately 7–21 mg of iodine available each day, resulting in a marked increase in urinary iodide excretion.[4] On an optimal daily iodine intake, there is 50–100 fold excess iodine release per day.[5] The bioavailability of the drug is poor. The drug is highly lipid soluble with a long half life (approximately 100 days) mainly due to storage in adipose tissue.[6] It is also distributed in other tissues, including the liver, lung, and, to a lesser extent, the kidneys, heart, skeletal muscle, thyroid, and brain from where it is slowly released.[7] Total body stores may remain increased for up to 9 months after stopping the drug. Amiodarone is metabolized, by dealkylation, to desethylamiodarone (DEA), which has an elimination half life of 57 ± 27 days. The intrathyroidal concentration of this metabolite is higher,[7] and it is more cytotoxic on thyroid cells than the parent drug.[8] Approximately 66–75% of the drug is eliminated through bile and feces[5] (Table 1). Amiodarone crosses the placenta and reaches measurable levels in breast milk.[9]

Effects on Thyroid

Thyroid toxicity is attributed mainly to the drug's high iodine content[10] but amiodarone and desethylamiodarone have direct cytotoxic effects on the thyroid gland.[8]

Although amiodarone-induced thyroid dysfunction is a major clinical problem, the majority of patients (86%) receiving the drug remain euthyroid[11,12] because of adjustments made in thyroidal iodine handling and hormone metabolism, in order to maintain normal thyroid functions.[13]

Ultrastructural changes indicative of thyroid cytotoxicity include marked distortion of thyroid architecture, apoptosis, necrosis, inclusion bodies, lipofuscinogenesis, macrophage infiltration, and markedly dilated endoplasmic reticulum.[14]

Effects on the thyroid gland range from abnormalities of thyroid function tests to overt thyroid dysfunction and are divided into two unique groups:[6]

a) Intrinsic effects resulting from the inherent properties of the compound and iodine-induced effects (due to the pharmacological effects of a large iodine load) are due to the following (Table 2):

  • Inhibition of thyroid hormone entry into peripheral tissues.[6]

  • Inhibition of type 1 5′-deiodinase activity which removes an atom of iodine from the outer ring of T4 to generate T3 and from the outer ring of rT3 to produce 3, 3′-diiodothyronine (Table 2). This inhibition may persist for several months after the drug is withdrawn.[15]

  • Inhibition of type II 5′-deiodinase which converts T4 to T3 in the pituitary.

The direct effect on thyroidal cells[16] is due to failure to escape from Wolff-Chaikoff effect.[17] Some of its other effects include precipitation or exacerbation of a pre-existing organ, specific autoimmunity,[18] and unregulated hormone synthesis.[19] The alterations in serum thyroid function tests are divided into acute (<3 months) and chronic (>3 months) (Table 3).

Acute Effects

Thyroid-stimulating hormone (TSH) is the first hormone to change, increasing by 39% and 65% after 24 and 48 hours, respectively.[4] After a loading dose of drug by intravenous infusion, it undergoes significant variation even during the first day of therapy.[20,21] The drug may induce a hypothyroid-like condition at the tissue level due to reduction in the number of catecholamine receptors and decrease in the effect of T3 on beta adrenoceptors.[22] TSH concentration rises transiently within a few days of starting amiodarone but rarely rises beyond 20 mU/L.[23,24] The early rise in plasma TSH occurs largely in response to falling intrapituitary T3 concentration due to reduced 5′-deiodination of T4 to T3 within the pituitary and also due to decreasing intracellular T4 transport and inhibition of type 1 5′ deiodinase. Furthermore, desethylamiodarone (DEA), the principal metabolite, binds to intracellular receptors and acts as a T3 antagonist.[25] At the end of the 10th day, serum TSH remains 2.7 times higher than baseline. When administered to euthyroid subjects, there is an immediate decrease in serum T3 levels and an increase in serum T4, free T4, rT3, and TSH. The pharmacological concentration of iodide associated with amiodarone treatment leads to a protective inhibition of thyroidal T4 and T3 synthesis and release by thyroid tissue (called the Wolff-Chaikoff effect) within the first two weeks. Serum total and free T4 concentrations rise and peak on the fifth day. A parallel increase in serum reverse T3 level is seen from day 1 due to inhibition of peripheral metabolism of T3. Serum T3, however, falls significantly during treatment initially due to reduced synthesis and secretion but mainly because of reduced 5′-deiodination of T4 to T3 in the peripheral tissues, especially the liver and decreased clearance of both T4 and reverse T3.[26,27] The inhibition persists during and for several months after the treatment.[23,28,29] The T3 is 19% lower than the baseline value by the end of the 10th day of treatment.[21] As amiodarone has no effect on the serum concentration of thyroid hormone binding globulin, the changes in free T4 and free T3 concentrations reflect those of total hormones.[29]

Chronic Effects

After 3 months of therapy, a steady state is reached. Serum levels of total and free T4 and rT3 remain at the upper end of normal or slightly elevated, and serum T3 level remains low (usually in the low normal range). In contrast, serum TSH levels return to normal after 12 weeks of therapy.[10] The reason for TSH normalization is presumed to be an increase in the T4 production rate,[30,31] possibly the result of increased intrathyroidal iodine stores[4] and escape from the Wolff-Chaikoff effect that partially overcomes the blockade of T3 generation and rising serum T3 levels into the low-normal range.[32] Hypothyroidism at the tissue level, however, cannot be absolutely ruled out.[33]

Amiodarone-induced Thyroid Dysfunction

Irrespective of iodine intake, the overall incidence of amiodarone-induced dysfunction is 4–18%.[34] Various published studies report the overall incidence of amiodarone-induced thyrotoxicosis (AIT) ranges from 1–23%, while the incidence of amiodarone-induced hypothyroidism (AIH) ranges from 1–32%.[35] The clinical presentation of AIH is usually subtle while that of AIT can be dramatic with life-threatening cardiac manifestations. Female sex, complex cyanotic heart disease, previous Fontan type surgery, and a total daily dose above 200 mg are factors that are associated with a higher risk of developing thyroid dysfunction.[36] AIH occurs earlier than AIT.[37]