Thyroid Dysfunction Induced by Amiodarone Therapy 

Amiodarone is a potent antiarrhythmic drug that is used to treat ventricular and supraventricular tachyarrhythmias. It is a benzofuran-derived, iodine-rich compound with some structural similarity to thyroxine (T4). Amiodarone contains approximately 37% iodine by weight. Each 200-mg tablet is estimated to contain about 75 mg of organic iodide, 8-17% of which is released as free iodide. Standard maintenance therapy with 200 mg amiodarone can provide more than 100 times the daily iodine requirement. It is highly lipid-soluble and is concentrated in the adipose tissue, muscle, liver, lung, and thyroid gland.^[1]

The elimination half-life of amiodarone is highly variable, ranging from 50-100 days; total body iodine stores remain increased for up to 9 months after discontinuation of the drug. Thyroid abnormalities have been noted in up to 14-18% of patients receiving long-term amiodarone therapy. However, a meta-analysis suggested that with the lower doses of amiodarone (150-330 mg) incidence of thyroid dysfunction is 3.7%. The effects range from abnormal thyroid function test findings to overt thyroid dysfunction, which may be either amiodarone-induced thyrotoxicosis (AIT) or amiodarone-induced hypothyroidism (AIH).^{[2, 3]} Both can develop in apparently normal thyroid glands or in glands with preexisting abnormalities.

Amiodarone causes a wide spectrum of effects on the thyroid.

• Amiodarone inhibits type 1 5'-deiodinase enzyme activity, thereby decreasing the peripheral conversion of T4 to triiodothyronine (T3) and reducing the clearance of both T4 and reverse T3 (rT3). Consequently, the serum levels of T4 and rT3 increase and the serum levels of T3 decrease by 20-25%.
• Amiodarone inhibits entry of T4 and T3 into the peripheral tissue. Serum T4 levels increase by an average of 40% above pretreatment levels after 1-4 months of treatment with amiodarone. This, in itself, does not constitute evidence of hyperthyroidism (thyrotoxicosis).
• Inhibition of type 2 5'-deiodinase enzyme activity in the pituitary due to feedback regulation is seen in the first 1-3 months and leads to an increase in thyroid-stimulating hormone (TSH) levels. This is not an indication for T4 replacement in these patients. Serum TSH levels return to normal in 2-3 months as T4 concentrations rise sufficiently to overcome the partial block in T3 production. The response of TSH to thyroid-releasing hormone (TRH) may be reduced.
• Amiodarone and its metabolites may have a direct cytotoxic effect on the thyroid follicular cells, which causes a destructive thyroiditis.
• Amiodarone and its metabolite desethylamiodarone can act as a competitive antagonist of T3 at the cardiac cellular level.

In summary, serum T4 levels rise by 20-40% during the first month of therapy and then gradually fall toward high normal. Serum T3 levels decrease by up to 30% within the first few weeks of therapy and remain slightly decreased or low normal. Serum rT3 levels increase by 20% soon afterward and remain increased. Serum thyrotropin (TSH) levels usually rise after the start of therapy but return to normal in 2-3 months.

Two forms of AIT have been described. Type 1 usually affects patients with latent or preexisting thyroid disorders and is more common in areas of low iodine intake. Type 1 is caused by iodine-induced excess thyroid hormone synthesis and release (Jod-Basedow phenomenon). Type 2 occurs in patients with a previously normal thyroid gland and is caused by a destructive thyroiditis that leads to the release of preformed thyroid hormones from the damaged thyroid follicular cells. However, mixed forms of AIT may occur in an abnormal thyroid gland, with features of destructive processes and iodine excess.

The most likely mechanisms of AIH are an enhanced susceptibility to the inhibitory effect of iodine on thyroid hormone synthesis and the inability of the thyroid gland to escape from the Wolff-Chaikoff effect after an iodine load in patients with preexisting Hashimoto thyroiditis. In addition, iodine-induced damage to the thyroid follicles may accelerate the natural trend of Hashimoto thyroiditis toward hypothyroidism. Patients without underlying thyroid abnormalities are postulated to have subtle defects in iodine organification that lead to decreased thyroid hormone synthesis, peripheral down regulation of thyroid hormone receptors, and subsequent hypothyroidism.

Frequency

United States

The prevalence of AIT in the United States is 3%; the prevalence of AIH is 22%. The relative prevalence of the 2 forms of AIT is unknown.

International

Some studies indicate that the incidence varies with the dietary iodine intake in the population. AIT occurs more frequently in geographical areas with low iodine intake, whereas AIH is more frequent in iodine-replete areas. However, in a Dutch study of persons with euthyroidism living in an area with moderately sufficient iodine intake, the incidence of AIT was twice that of AIH.

Mortality/Morbidity

Although amiodarone-associated thyroid dysfunction is usually a mild clinical condition, it can be severe, life threatening, and even lethal. Fatal cases of thyroid storm and myxedema coma have been reported despite various aggressive therapies.

Race

No well-described racial differences exist.

Sex

AIH is more frequent in females, with a female-to-male ratio of 1.5:1. AIT, however, is more frequent in males, with a male-to-female ratio of 3:1.

Age

The risk of AIH is higher in elderly persons,^[4] probably because of the higher prevalence of underlying thyroid abnormality.