269-278/Art. 1.1457 16-10-2006 15:24 Pagina 269 European Review for Medical and Pharmacological Sciences 2005; 10: 269-278 Amiodarone-induced thyroid dysfunction in clinical practice S. URSELLA, A. TESTA, M. MAZZONE, N. GENTILONI SILVERI Department of Emergency Medicine, Catholic University of the Sacred Heart, Policlinico “A. Gemelli” – Rome (Italy) Abstract. – Amiodarone is a potent class III ment of ventricular arrhythmias, paroxysmal anti-arrhythmic drug used in clinical practice for supraventicular tachycardia, atrial fibrillation and the prophylaxis and treatment of many cardiac flutter1. rhythm disturbances, ranging from paroxismal As a category type-III anti-arrhythmic drug, its atrial fibrillation to life threatening ventricular tachyarrhythmias. Amiodarone often causes main mechanism of action is to block myocardial changes in thyroid function tests mainly related to potassium channels, but it also possesses some the inhibition of 5’-deiodinase activity resulting in beta-blocking properties2. a decrease in the generation of T3 from T4 with a Although highly effective in patients with ar- consequent increase in rT3 production and a de- rhythmias, its use in clinical practice is associat- crease in its clearance. In a group of amiodarone- ed with a wide array of adverse effects. With the treated patients there is overt thyroid dysfunction, cornea, the lungs, the liver, and the skin, the thy- either amiodarone-induced thyrotoxicosis (AIT) or amiodarone-induced hypothyroidism (AIH). AIT is roid is one of the major organs affected. primarily related to excess iodine-induced thyroid The aim of this review is to analyse the diag- hormone synthesis in an abnormal thyroid gland nostic and therapeutic aspects of amiodarone-in- (type I AIT) or to amiodarone-related destructive duced thyroid dysfunction according to recent lit- thyroiditis (type II AIT). The pathogenesis of AIH is erature. related to a failure to escape from the acute Wolff- All English language articles related to amio- Chaikoff effect due to defects in thyroid hormono- genesis, or, in patients with positive thyroid au- darone and the thyroid were searched in MED- toantibody test, to concomitant Hashimoto’s thy- LINE from 1966 to 2006. The keywords includ- roiditis. Both AIT and AIH may develop either in ed amiodarone and thyroid. The selection criteria apparently normal thyroid glands or in glands included all prospective and retrospective stud- with preexisting, clinically silent abnormalities. ies, all clinical and basic reviews and basic sci- AIT is more common in iodine-deficient regions of ence papers involving the pathophysiology of the world, whereas AIH is usually seen in iodine- amiodarone. sufficient areas. In contrast to AIH, AIT is a diffi- cult condition to diagnose and treat, and discon- tinuation of amiodarone is usually recommended. In this review we analyse, according to data from Pharmacology of Amiodarone current literature, the alterations in thyroid labora- tory tests seen in euthyroid patients under treat- Amiodarone is a benzofuranic derivative ment with amiodarone and the epidemiology and whose structural formula closely resembles that treatment options available of amiodarone-in- duced thyroid dysfunctions (AIT and AIH). of human thyroid hormone T4. It contains ap- proximately 37% iodine by weight. The mainte- Key words: nance daily dose of the drug in clinical practice Amiodarone, Thyroid dysfunction, Thyrotoxicosis, Hy- ranges from 200 to 600 mg and, because approx- pothyroidism. imately 10% of the molecule is deiodinated daily, approximately 7-21 mg iodide are made avail- able each day, resulting in a marked increase in Introduction urinary iodide excretion3. If one considers that the optimal daily iodine Amiodarone is a potent anti-arrhythmic drug intake is 150-200 µg, amiodarone treatment re- used in clinical practice for the acute manage- lease 50- to 100-fold excess iodine daily4. Corresponding Author: Stefano Ursella, MD; e-mail: [email protected]. 269 269-278/Art. 1.1457 16-10-2006 15:24 Pagina 270 S. Ursella, A. Testa, M. Mazzone, N. Gentiloni Silveri Furthermore, amiodarone is distributed in sev- significant variations, even during the first day eral tissues, including adipose tissue, liver, lung, of therapy9,10. and, to a lesser extent, kidneys, heart, skeletal • Amiodarone may induce a hypothyroid-like muscle, thyroid, and brain from which it is slow- condition at the tissue level partly related to a ly released5. reduction in the number of catecholamine re- The elimination half-lives averaged 52 ± 23.7 ceptors and to a decrease in the effect of T3 on days for amiodarone and 61.2 ± 31.2 days for its beta-adrenoreceptors11. metabolite desethylamiodarone (DEA) after cessa- • Direct toxic effect of the drug on thyroidal tion of long term amiodarone therapy5. Those con- cells12. siderations explain why, after amiodarone with- • Failure to escape from Wolff-Chaikoff effect13. drawal, the drug and its metabolites remain avail- • In susceptible individuals amiodarone may able for long period. Amiodarone is metabolised precipitate or exacerbate preexisting organ- through dealkylation, which leads to formation of specific autoimmunity14. DEA and approximately 66-75% of amiodarone is • Unregulated hormone synthesis (Jod-Basedow eliminated through bile and feces3. effect)15. Amiodarone and the Thyroid Effects of Amiodarone in Euthyroid Patients Although the majority of the adverse effects of amiodarone on several organs are due to deposi- Although amiodarone-induced thyroid dys- tion of the drug in the parenchyma, its effects on function represents an important clinical problem, the thyroid gland can be divided in two groups: the majority of patients receiving amiodarone re- intrinsic effects resulting from the inherent prop- main euthyroid. Because the thyroid gland is ex- erties of the compound and iodine-induced ef- posed to an extraordinary load of iodine with fects due solely to the pharmacologic effects of a amiodarone, important adjustments are made in large iodine load (Table I). thyroidal iodine handling and hormone metabo- Amiodarone acts on thyroid function through lism in order to maintain normal function16, the several mechanisms: reflection of which is seen in serum thyroid hor- mone levels. Those alterations in serum thyroid • Inhibits thyroid hormone entry into peripheral function tests can be divided into acute (less than tissues6. 3 months) and chronic (more than 3 months) • Inhibition of type I 5’-deiodinase activity phases that follow amiodarone exposure during which removes an atom of iodine from the the pharmacologic therapy17 (Table II). outer ring of T4 to generate T3 and from the outer ring of rT3 to produce 3,3’-diiodothyro- nine (T2). This inhibition may persist for sev- Acute Effects eral months after amiodarone withdrawal7,8. • Inhibition of type II 5’-deiodinase which con- Serum T4 and T3 verts T4 to T3 in the pituitary. Indeed, after a The pharmacological concentrations of iodide loading dose of amiodarone by intravenous in- associated with amiodarone treatment lead to a fusion, TSH is the first hormone to undergo protective inhibition of thyroidal T4 and T3 syn- Table I. Effects of amiodarone on the thyroid gland. Intrinsic drug effect Iodine-induced effects • Blockade of thyroid hormone entry into cells • Failure to escape from Wolff-Chaikoff effect • Inhibition of type I and type II 5’-deiodinase • Iodine-induced potentiation of thyroid autoimmunity • Decreased T3 binding to its receptor • Unregulated hormone synthesis (Jod-Basedow effect) • Thyroid cytotoxicity Modified from: Basaria S, Cooper DS. Amiodarone and the thyroid. Am J Med 2005;118: 706-714. 270 269-278/Art. 1.1457 16-10-2006 15:24 Pagina 271 Amiodarone-induced thyroid dysfunction in clinical practice Table II. Effects of amiodarone on thyroid function tests in euthyroid subjects. Thyroid Hormone Acute effects (up to 3 months) Chronic effects (> 3 months) Total and free T4 ↑ 50% Remains ↑ 20-40% of baseline Total and free T3 ↓ 15-20%, remains in low-normal range Remains ↓ 20%, remains in low-normal range rT3 ↑ > 200% Remains ↑ > 150% TSH ↑ 20-50%, transient, generally remains Normal < 20 mU/L Modified from: Basaria S, Cooper DS. Amiodarone and the thyroid. Am J Med 2005;118: 706-714. thesis and release by thyroid tissue (called the lin, changes in FT4 and FT3 concentrations re- Wolff-Chaikoff effect) within the first two weeks flect those for total T4 and T320. of treatment18. Amiodarone also inhibits the 5’-deiodination Serum Reverse T3 (rT3) of T4 to T3 in the peripheral tissues, especially The reduction of peripheral metabolism leads to the liver and this inhibition persists during and increased rT3 levels with amiodarone treatment. for several months after the amiodarone treat- ment. The result is that serum T4 rises from pre- Serum Thyroid Stimulating Hormone (TSH) treatment concentrations by an average of 40% Serum TSH concentration rises transiently after two months and remains at this higher level within a few days of starting amiodarone (Table thereafter19,20,21. III), but rarely reaches greater than 20 mU/l (ref- The absolute serum T4 in patients on moderate erence range 0.35-4.3 mU/l)21,25. doses of amiodarone (200 mg/day) is usually to- TSH then gradually return to baseline concen- wards the upper limit of the reference range (71- trations, or even slightly below, over the next one 166 nmol/l). A group of clinically euthyroid pa- to three month21,25,26. tients will have serum T4 concentrations greater The early rise