AMIODARONE EFFECTS ON THYROID FUNCTION

Amiodarone Effects on Thyroid Function

Amiodarone is a commonly used type III antiarrhythmic agent . It is structurally related to thyroid hormone and contains 39% iodine by weight. Thus, typical doses of amiodarone (200 mg/d) are associated with very high iodine intake, leading to greater than fortyfold increases in plasma and urinary iodine levels. Moreover, because amiodarone is stored in adipose tissue, high iodine levels persist for >6 months after discontinuation of the drug. Amiodarone inhibits deiodinase activity, and its metabolites function as weak antagonists of thyroid hormone action. Amiodarone has the following effects on thyroid function: (1) acute, transient suppression of thyroid function;

                              (2) hypothyroidism in patients susceptible to the inhibitory effects of a high iodine load; and               (3) thyrotoxicosis that may be caused by either a Jod-Basedow effect from the iodine load, in the setting of MNG or incipient Graves' disease, or a thyroiditis-like condition.

The initiation of amiodarone treatment is associated with a transient decrease of T4 levels, reflecting the inhibitory effect of iodine on T₄ release. Soon thereafter, most individuals escape from iodide-dependent suppression of the thyroid (Wolff-Chaikoff effect), and the inhibitory effects on deiodinase activity and thyroid hormone receptor action become predominant. These events lead to the following pattern of thyroid function tests: increased T₄, decreased T₃, increased rT₃, and a transient TSH increase . TSH levels normalize or are slightly suppressed within 1–3 months.

The incidence of hypothyroidism from amiodarone varies geographically, apparently correlating with iodine intake. Hypothyroidism occurs in up to 13% of amiodarone-treated patients in iodine-replete countries, such as the United States, but is less common (<6% incidence) in areas of lower iodine intake, such as Italy or Spain. The pathogenesis appears to involve an inability of the thyroid gland to escape from the Wolff-Chaikoff effect in autoimmune thyroiditis. Consequently, amiodarone-associated hypothyroidism is more common in women and individuals with positive TPO antibodies. It is usually unnecessary to discontinue amiodarone for this side effect, because levothyroxine can be used to normalize thyroid function. TSH levels should be monitored, because T4 levels are often increased for the reasons described above.

The management of amiodarone-induced thyrotoxicosis (AIT) is complicated by the fact that there are different causes of thyrotoxicosis and because the increased thyroid hormone levels exacerbate underlying arrhythmias and coronary artery disease. Amiodarone treatment causes thyrotoxicosis in 10% of patients living in areas of low iodine intake and in 2% of patients in regions of high iodine intake. There are two major forms of AIT, although some patients have features of both. 

Type 1 AIT is associated with an underlying thyroid abnormality (preclinical Graves' disease or nodular goiter). Thyroid hormone synthesis becomes excessive as a result of increased iodine exposure (Jod-Basedow phenomenon). 

Type 2 AIT occurs in individuals with no intrinsic thyroid abnormalities and is the result of drug-induced lysosomal activation leading to destructive thyroiditis with histiocyte accumulation in the thyroid; the incidence rises as cumulative amiodarone dosage increases. Mild forms of type 2 AIT can resolve spontaneously or can occasionally lead to hypothyroidism. Color-flow doppler thyroid scanning shows increased vascularity in type 1 AIT but decreased vascularity in type 2 AIT. Thyroid scintiscans are difficult to interpret in this setting because the high endogenous iodine levels diminish tracer uptake. However, the presence of normal or rarely increased uptake favors type 1 AIT.

In AIT, the drug should be stopped, if possible, although this is often impractical because of the underlying cardiac disorder. Discontinuation of amiodarone will not have an acute effect because of its storage and prolonged half-life. High doses of antithyroid drugs can be used in type 1 AIT but are often ineffective. In type 2 AIT, oral contrast agents, such as sodium ipodate (500 mg/d) or sodium tyropanoate (500 mg, 1–2 doses/d), rapidly reduce T4 and T₃ levels, decrease T₄  T₃ conversion, and may block tissue uptake of thyroid hormones. Potassium perchlorate, 200 mg every 6 h, has been used to reduce thyroidal iodide content. Perchlorate treatment has been associated with agranulocytosis, though the risk appears relatively low with short-term use. Glucocorticoids, as administered for subacute thyroiditis, have modest benefit in type 2 AIT. Lithium blocks thyroid hormone release and can also provide some benefit. Near-total thyroidectomy rapidly decreases thyroid hormone levels and may be the most effective long-term solution if the patient can undergo the procedure safely.





SOURCE: HARRISON INTERNAL MEDICINE 18 TH ED