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:
-
Amiodarone (Cordarone®) product
package insert. Wyeth Pharmaceuticals
Inc. Philadelphia, PA.
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Batcher EL, Tang XL, Singh BN et al. Thyroid
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Rao RH, McCready VR, Spathis GS. Iodine kinetic studies during amiodarone
treatment. J Clin Endocrinol Metab 1986;62:563-8.
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United States Department of Agriculture
(USDA). Dietary reference intakes:
elements. Last accessed on
1/23/2009.
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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.
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Bartelena L, Grasso L, Brogioni S et al. Serum interleukin-6 in amiodarone-induced
thyrotoxicosis. J Clin Endocrinol
Metab 1994;78:423-7.
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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.
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Basaria S, Cooper DS. Amiodarone and the thyroid. Am J Med 2005;118:706-14.
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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.
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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.
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Smyrk TC, Goellner JR, Brennan MD et al. Pathology of the thyroid in
amiodarone-associated thyrotoxicosis. Am
J Surg Pathol 1987;11:197-204.
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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.
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Reichert LJ, de Rooy HA. Treatment of amiodarone induced
hyperthyroidism with potassium perchlorate and methimazole during amiodarone
treatment. BMJ 1989;298:1547-8.
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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.
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Daniels GH.
Amiodarone-induced thyrotoxicosis.
J Clin Endocrinol Metab
2001;86:3-8.
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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.
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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.
