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The Mechanism for Amiodarone-Induced Hyperthyroidism and Clinical Implications

Summary:

  • Amiodarone (Cordarone) is a commonly prescribed medication for the management of both atrial and ventricular arrhythmias.
  • Each 200 mg tablet of amiodarone contains 74.4 mg (37.3%) of iodine with 7.4mg (10%) per day being released as free iodine. This is roughly 50-fold higher than the daily recommended iodine intake for adults, which is approximately 0.15mg (150 mcg).
  • This increase in iodine delivery and uptake can increase thyroid hormone production and release.  This is a condition called type I amiodarone induced thyrotoxicosis (hyperthyroidism).  In addition, it can also cause type II amiodarone induced thyrotoxicosis, which occurs from actual thyroid tissue destruction.
  • Patients being started on amiodarone should have a baseline TSH (and in some cases free T4 and T3 levels) which is repeated at least every 6-12 months thereafter or based on the emergence of symptoms of hyperthyroidism.  

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA
Last Reviewed: August 2015

Explanation

  • Amiodarone (Cordarone) is a commonly prescribed medication for the management of both atrial and ventricular arrhythmias.  Unfortunately, when amiodarone is given to a euthyroid (normal thyroid function) patient , the normal physiologic process for the formation of the thyroid hormones, thyroxine (T4) and 3,5,3'-triiodothyronine (T3), can be adversely affected.  The following are the generalized steps for normal thyroid hormone production (i.e., a euthyroid patient not on amiodarone): thyroid releasing hormone (TRH) is secreted from the hypothalamus to stimulate the anterior pituitary gland to release thyroid stimulating hormone (TSH); the TSH then travels to the thyroid gland where it causes an increase in production of thyroglobulin and the enzyme thyroid peroxidase; iodide ingested from food or water enters into the thyroid follicular cell via the Na/I cotransporter; once the iodide is inside the thyroid follicle cell it is transported into the follicular lumen via the pendrin transporter.  The iodide is oxidized by thyroid peroxidase into iodine which is then able to iodinate the tyrosine residues within the thyroglobulin to form both monoiodotyrosine and diiodotyrosine.  These products combine to form T4 and T3 and then undergo proteolysis and exocytosis for secretion and recycling.

    How does amiodarone influence thyroid function?
    Amiodarone's influence on the production and secretion of T4 and T3 is multifactorial.  Most importantly, each 200 mg tablet of amiodarone contains 74.4 mg (37.3%) of iodine by weight with 7.4mg (10%) per day being released as free iodine.3  This is roughly 50-fold higher than the daily recommended iodine intake for adults which is approximately 0.15mg (150 mcg).4  As a result of amiodarone use in the first 3 months, there is an increase in iodine delivery and uptake that can increase thyroid hormone production and release.  This is a condition called type I amiodarone induced thyrotoxicosis (hyperthyroidism).5-7 Type I amiodarone induced thyrotoxicosis (AIT) is more likely to occur in patients who live in areas of low iodine intake or have some form of underlying thyroid disease (such as multinodular goiter, latent Grave's disease, etc.) where the iodine exposure could possibly trigger thyroid hormone production.8

    Furthermore, chronic administration (approximately > 3 months) of amiodarone can result in excessive iodine exposure/accumulation that can cause, type II AIT.  This form of hyperthyroidism is different from type I in that it is associated with actual thyroid tissue destruction, inflammation/fibrosis and eventually reductions in thyroid vascularity.7,9-11  The damage or destruction of the thyroid follicular cells can result in the unregulated release of pre-formed thyroid hormone into the circulation.  Of greatest concern during thyrotoxicosis is the development of atrial fibrillation, which as noted above, may have been the reason for amiodarone's initiation.1  To complicate things further, many patients who develop type II AIT will also end up developing subsequent hypothyroidism.8

    What is the incidence of amiodarone-induced thyrotoxicosis and what monitoring parameters should be considered?
    The incidence of AIT has been reported to be 2 to 5.3%.1,2  Therefore, prior to initiation of therapy with amiodarone, patients should have at least a baseline TSH (and possibly a free T4 or T3 level as well) and these should be repeated at least every 6-12 months thereafter or based on the emergence of symptoms of hyperthyroidism.  Unfortunately, laboratory tests for thyroid function do not discriminate type I and type II AIT from each other.8  In general, patients with AIT will present with a low TSH, free T4 levels will be high normal or high and T3 levels will be normal or elevated.8  While not routinely checked in this situation, thyroid autoantibodies are absent unless the patient has underlying Grave's disease.  The onset of hyperthyroidism induced by amiodarone generally occurs within the first 18 months.12 

    If a patient develops amiodarone-induced thyrotoxicosis, what treatment options should be considered?
    In patients who develop type I AIT, it is recommended to discontinue amiodarone if possible.8  In addition, the use of antithyroid medications (such as methimazole or propylthiouracil), perchlorate (not available in the U.S.) and lithium can also be considered.8,13,14  Whereas in type II AIT, discontinuation of amiodarone may not be essential and the use of steroids (such as prednisone) is recommended.7,15,16  While we are not aware of any supporting evidence for this, it plausible that in patients where amiodarone was initiated for atrial fibrillation, amiodarone could possibly be replaced with dronedarone.  Regardless, since it is difficult to distinguish between type I and type II clinically, some have recommended the coadministration of methimazole 40 mg daily along with prednisone 40 mg daily for up to 1-2 months depending on the response.17  If no response is seen with the above, then thyroidectomy may be indicated.

    References:

    1. Amiodarone (Cordarone┬«) product package insert.  Wyeth Pharmaceuticals Inc.  Philadelphia, PA. 
    2. Batcher EL, Tang XL, Singh BN et al. Thyroid function abnormalities during amiodarone therapy for persistent atrial fibrillation. Am J Med 2007; 120:880-885. 
    3. Rao RH, McCready VR, Spathis GS.  Iodine kinetic studies during amiodarone treatment.  J Clin Endocrinol Metab  1986;62:563-8.
    4. United States Department of Agriculture (USDA).  Dietary reference intakes: elements.  Last accessed on 1/23/2009. 
    5. Claxton S, Sinha SN, Donovan S et al. Refractory amiodarone-associated thyrotoxicosis: an indication for thyroidectomy. Aust N Z J Surg 2000; 70:174-8.
    6. Bartelena L, Grasso L, Brogioni S et al.  Serum interleukin-6 in amiodarone-induced thyrotoxicosis.  J Clin Endocrinol Metab  1994;78:423-7.
    7. Bartelena L, Brogioni S, Grasso L et al.  Treatment of amiodarone-induced thyrotoxicosis, a difficult challenge: results of a prospective study.  J Clin Endocrinol Metab  1996;81:2930-3. 
    8. Basaria S, Cooper DS.  Amiodarone and the thyroid.  Am J Med 2005;118:706-14. 
    9. Pitsiavas V, Smerdely P, Li M et al.  Amiodarone induces a different pattern of ultrastructural change in the thyroid to iodine excess alone in both the BB/W rat and the Wistar rat.  Eur J Endocrinol  1997;137:89-98. 
    10. Brennan MD, Erickson DZ, Carney JA et al.  Nongoitrous (type I) amiodarone thyrotoxicosis: evidence of follicular disruption in vitro and in vivo.  Thyroid  1995;5:177-83. 
    11. Smyrk TC, Goellner JR, Brennan MD et al.  Pathology of the thyroid in amiodarone-associated thyrotoxicosis.  Am J Surg Pathol  1987;11:197-204. 
    12. Trip MD, Wiersinga W, Plomp TA et al. Incidence, predictability, and pathogenesis of amiodarone-induced thyrotoxicosis and hypothyroidism. Am J Med 1991; 91:507-11. 
    13. Reichert LJ, de Rooy HA.  Treatment of amiodarone induced hyperthyroidism with potassium perchlorate and methimazole during amiodarone treatment.  BMJ  1989;298:1547-8. 
    14. Newnham HH, Topliss DJ, Le Grand BA et al. Amiodarone-induced hyperthyroidism: assessment of the predictive value of biochemical testing and response to combined therapy using propylthiouracil and potassium perchlorate.  Aust N Z J Med  1988;18:37-44. 
    15. Daniels GH.  Amiodarone-induced thyrotoxicosis.  J Clin Endocrinol Metab  2001;86:3-8. 
    16. Bogazzi F, Bartalena L, Cosci C et al.  Treatment of type II amiodarone-induced thyrotoxicosis by either iopanoic acid or glucocorticoids: a prospective, randomized study.  J Clin Endorinol Metab 2003;88:1999-2002. 
    17. Broussolle C, Ducottet X, Martin C et al.  Rapid effectiveness of prednisone and thionamides combined therapy in severe amiodarone iodine-induced thyrotoxicosis.  Comparison of two groups of patients with apparently normal thyroid glands.  J Endocrinol Invest 1989;12:37-42.

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MESH Terms & Keywords

  • Amiodarone, Cordarone, Hyperthyroidism, Class III Antiarrhythmic