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Amiodarone and thyroid dysfunction

AUTHOR: Douglas S Ross, MD
SECTION EDITOR: David S Cooper, MD
DEPUTY EDITOR: Jean E Mulder, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Apr 2025.

This topic last updated: May 20, 2024.

INTRODUCTION

Amiodarone has multiple effects on myocardial depolarization and repolarization that make it
an extremely effective antiarrhythmic drug. However, amiodarone is associated with a number
of side effects, including thyroid dysfunction (both hypo- and hyperthyroidism), which is due to
amiodarone's high iodine content and its direct toxic effect on the thyroid. This topic will review
the major effects of amiodarone on thyroid function. The clinical use and other side effects of
amiodarone are reviewed elsewhere. (See "Amiodarone: Clinical uses" and "Amiodarone:
Adverse effects, potential toxicities, and approach to monitoring".)

PHARMACOLOGY

The effects of amiodarone on thyroid function can be divided into those effects that are intrinsic
properties of the drug and those effects that are due to iodine.

Intrinsic drug properties — Amiodarone is very lipophilic and is concentrated in adipose

tissue, cardiac and skeletal muscle, and the thyroid. Elimination from the body occurs with a
half-life of approximately 100 days [1]. Amiodarone toxicity can therefore occur well after drug
withdrawal [2].

● Amiodarone inhibits outer ring 5'-monodeiodination of thyroxine (T4), thus decreasing

triiodothyronine (T3) production; reverse T3 accumulates since it is not metabolized to T2 [3].

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● Amiodarone (and particularly the metabolite desethylamiodarone) blocks T3-receptor binding

to nuclear receptors [4] and decreases expression of some thyroid hormone-related genes
[5].

● Amiodarone may have a direct toxic effect on thyroid follicular cells, which results in a
destructive thyroiditis [6]. (See 'Types of AIT' below.)

Effects due to iodine — Amiodarone contains two iodine atoms. It is estimated that
amiodarone metabolism in the liver releases approximately 3 mg of inorganic iodine into the
systemic circulation per 100 mg of amiodarone ingested. The average iodine content in a typical
American diet is approximately 0.3 mg/day. Thus, 6 mg of iodine associated with a 200 mg dose
of amiodarone markedly increases the daily iodine load [7,8].

Iodine is a substrate for thyroid hormone synthesis. It is actively transported into thyroid
follicular cells and organified onto tyrosyl residues in thyroglobulin. The normal autoregulation
of iodine prevents individuals with normal thyroid glands from becoming hyperthyroid after
exposure to an iodine load (eg, radiocontrast). When intrathyroidal iodine concentrations reach
a critical high level, iodine transport and thyroid hormone synthesis are transiently inhibited
until intrathyroidal iodine stores return to normal levels (the Wolff-Chaikoff effect). (See "Thyroid
hormone synthesis and physiology" and "Iodine-induced thyroid dysfunction".)

Patients with underlying thyroid disease, however, have defects in autoregulation of iodine:

● Patients with autoimmune thyroid disease "fail to escape" from the Wolff-Chaikoff effect. The
result is the development of goiter and hypothyroidism in Hashimoto's disease [9] and
amelioration of Graves' hyperthyroidism.

● Patients with areas of autonomous function within a nodular goiter do not autoregulate
iodine, and the addition of more substrate may result in excessive thyroid hormone synthesis
and hyperthyroidism (Jod-Basedow) [10].

EPIDEMIOLOGY AND RISK FACTORS

The risk of amiodarone-induced thyroid dysfunction ranges from 2 to 30 percent, depending

upon an individual's underlying thyroid status, dietary iodine intake, and whether cases of
subclinical thyroid disorders (eg, slight rise in thyroid-stimulating hormone [TSH] without
symptoms) are included [7,11-16].

In a cohort study from Denmark evaluating patients without baseline thyroid disease, the
cumulative one-year incidence of any amiodarone-induced thyroid disease was 4.5 percent [17].
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The cumulative five-year incidence ranged from 5.3 to 24.5 percent, with increasing incidence in
those with the highest average daily dose of amiodarone in the first year of treatment.

● Hypothyroidism – In a meta-analysis of studies evaluating chronic amiodarone users with

normal thyroid function at baseline, the prevalence of hypothyroidism was 14 percent [18]. In
one trial, overt hypothyroidism (TSH >10 mU/L) developed in 5 percent of patients receiving
amiodarone, but subclinical hypothyroidism (TSH 4.5 to 10 mU/L) developed in an additional
25 percent [13]. (See 'Hypothyroidism' below.)

Amiodarone-induced hypothyroidism is more likely to occur in iodine-sufficient areas [14,19-

21] and may occur in up to 20 percent of patients from such regions [11,14].

Patients with underlying autoimmune thyroid disease (eg, Hashimoto's thyroiditis or positive
antithyroid antibodies) are more likely to develop persistent hypothyroidism, presumably due
to failure to escape from the Wolff-Chaikoff effect [9,22] (see 'Effects due to iodine' above).
This observation may explain the higher prevalence of amiodarone-induced hypothyroidism
in women compared with men [12].

● Hyperthyroidism – The incidence of hyperthyroidism (amiodarone-induced thyrotoxicosis

[AIT]) is approximately 5 to 10 percent [11,12,23]. The risk increases with higher cumulative
doses of amiodarone [24]. AIT is more common in iodine-deficient regions and in patients
with underlying multinodular goiter or latent Graves' disease [12,14]. The excess iodine from
the amiodarone provides increased substrate, resulting in enhanced thyroid hormone
production [25]. (See 'Amiodarone-induced thyrotoxicosis' below.)

• In the United States (an iodine-sufficient region), 3 to 5 percent of patients treated with
amiodarone become hyperthyroid, usually between four months and three years after the
initiation of the drug [13,22].

• In Dutch patients without thyroid disease at baseline who were from a region with
moderate iodine intake, the incidence of AIT was 12 percent (mean follow-up 21 months)
[12].

• In a study of Japanese patients without preexisting thyroid disease from a region of iodine
sufficiency, 5.8 percent developed AIT during a median follow-up of 3.5 years [26].

One study illustrating the importance of both the underlying thyroid status and dietary iodine
intake in relation to the risk of developing amiodarone-induced thyroid dysfunction showed
that in Worcester, Massachusetts, an area with iodine sufficiency and a high prevalence of
autoimmune thyroid disease, amiodarone was associated with a 22 percent rate of

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hypothyroidism and a 2 percent rate of AIT [14]. In contrast, in Pisa, Italy, an area of borderline
iodine intake and a high prevalence of nodular goiter at the time this study was published,
amiodarone was associated with a 5 percent rate of hypothyroidism and a 9.6 percent rate of
AIT.

MONITORING FOR THYROID DYSFUNCTION

Since thyroid dysfunction is relatively common with amiodarone therapy, all patients should
have thyroid function tests prior to starting amiodarone, several weeks after initiation of
treatment, and at periodic intervals during treatment [12]. Thyroid tests should also be
obtained if new symptoms of hypo- or hyperthyroidism develop.

The optimal frequency of monitoring for thyroid dysfunction is uncertain. Our approach is as
follows [27]:

● Baseline testing – TSH, thyroid peroxidase antibodies

● Four to eight weeks after initiation – TSH, with reflex to free T4 if abnormal, or with free T4
if the laboratory does not provide reflex algorithms

● Every three to six months – TSH

● Development of new symptoms

• Suspected hypothyroidism – TSH, free T4

• Suspected hyperthyroidism – TSH, free T4, total T3

Thyroid dysfunction may occur after amiodarone withdrawal, and therefore, thyroid function
should be assessed for at least one year after the drug is discontinued, and longer in patients
with high cumulative doses or a history of hypothyroidism during treatment. In a study of 71
patients followed after stopping amiodarone, five (7 percent) developed type 2 AIT between 7
and 16 months after withdrawal [28]. Compared with patients who did not develop AIT, they
had been on amiodarone longer (mean 76 versus 16 months) and had been more likely to have
had hypothyroidism during amiodarone therapy.

SPECTRUM OF THYROID DYSFUNCTION

Transient changes in thyroid function tests — Transient changes in thyroid function tests
often occur in euthyroid individuals treated with amiodarone. Acute changes in thyroid function

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tests may include [7,29]:

● Serum T4 and free T4 concentrations rise by 20 to 40 percent during the first month of
therapy.

● Serum T3 concentrations decrease by up to 30 percent within the first few weeks of therapy.

● Serum reverse T3 concentrations increase by 20 percent soon after the initiation of therapy.

● The serum TSH concentration usually rises slightly after the initiation of treatment and may
exceed the upper limit of normal.

If routine monitoring four to eight weeks after initiation of amiodarone reveals a slightly
elevated TSH with a free T4 in the upper normal or elevated range, thyroid function should be
repeated in four weeks as the changes may resolve. A steady state is reached in most patients
who were euthyroid at baseline after three to six months of therapy:

● Serum TSH concentration normalizes

● Serum total T4, free T4, and reverse T3 concentrations remain slightly elevated or in the
upper normal range

● Serum T3 concentrations remain in the low normal range

Transient hypothyroidism may occur in the infants of women treated with amiodarone during
pregnancy. As an example, in a study of 64 pregnancies in which amiodarone was given to the
mother, 11 infants (17 percent) had transient hypothyroidism; 2 of the 11 had a goiter [30].
Hypothyroidism was transient in all cases, and only five infants were treated short term with
thyroid hormones.

Hypothyroidism

Clinical manifestations — The clinical manifestations and diagnosis of amiodarone-

associated hypothyroidism are similar to those of hypothyroidism from any cause.
Hypothyroidism and hypothyroid symptoms may develop as soon as two weeks or as late as
39 months after the initiation of amiodarone therapy [31,32]. (See "Clinical manifestations of
hypothyroidism".)

Diagnosis — Hypothyroidism is usually diagnosed on the basis of routinely monitored thyroid

function tests, preferably before the patient has symptoms.

● Overt hypothyroidism – High TSH and subnormal free T4

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● Subclinical hypothyroidism – High TSH and normal free T4 that persists when remeasured
after two to four weeks

If the TSH is only slightly elevated and the free T4 is in the upper normal or elevated range,
these changes may be transient as discussed above, and thyroid function should be repeated
in four weeks. (See 'Transient changes in thyroid function tests' above.)

Treatment — Thyroid function can be easily normalized by replacement with levothyroxine

while amiodarone is continued.

● Overt hypothyroidism – Initiate treatment with levothyroxine. Initial monitoring and dose
adjustments are similar to those used for primary hypothyroidism unrelated to amiodarone
treatment. However, in addition to patient's age and the suspected duration of
hypothyroidism, they should take into account the severity of the underlying heart disease
(the risk of an ischemic event or arrhythmia) and the higher doses of levothyroxine needed
to normalize TSH when taking amiodarone. Therefore, the starting dose may need to be
reduced to between 50 and 75 percent of the full replacement dose of 1.6 mcg/kg body
weight, depending upon the clinical situation. (See "Treatment of primary hypothyroidism
in adults", section on 'Initial monitoring and dose adjustments'.)

● Subclinical hypothyroidism

• For persistent elevation in TSH ≥7 mU/L, initiate treatment with levothyroxine. The
European guidelines use a TSH threshold of ≥10 mU/L. Since this is usually an older adult
population with underlying cardiac disease, we typically begin treatment of subclinical
hypothyroidism with a dose of 25 to 50 mcg daily, with adjustments at four- to six-week
intervals aiming for a high normal TSH, or slightly elevated TSH in the very elderly. (See
"Subclinical hypothyroidism in nonpregnant adults", section on 'Dosing and monitoring'.)

• For persistent TSH <7 mU/L, the need for treatment is controversial and usually
unnecessary in older adults (see "Subclinical hypothyroidism in nonpregnant adults"). If
the patient is not treated, however, thyroid function should be reassessed in four weeks
to assess stability.

● Goal TSH – The goal of therapy is to restore the serum TSH concentration to normal,
keeping in mind that a larger than usual dose may be required because of the likely effects
of amiodarone on intrapituitary T4 metabolism and T3 production and, possibly, thyroid
hormone action [11]. Overtreatment should be avoided by targeting the upper portion of
the age-adjusted normal range. (See "Treatment of primary hypothyroidism in adults".)

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Amiodarone is usually not discontinued, unless it fails to control the underlying arrhythmia.
However, if amiodarone is stopped, hypothyroidism in patients with no apparent preexisting
thyroid disease often resolves. Therefore, TSH and free T4 should be repeated six months
after discontinuing amiodarone. If there is no evidence of autoimmune thyroid disease (eg,
no antithyroid peroxidase antibodies), the levothyroxine dose may be reduced by 50 percent.
If the TSH is normal six weeks later, levothyroxine may be discontinued and TSH checked after
an additional six weeks.

In patients who have underlying chronic autoimmune thyroiditis with high titers of
antithyroid peroxidase antibodies and goiter, hypothyroidism may persist after withdrawal of
amiodarone, and these patients will require permanent levothyroxine therapy [2,7,11,12,22].

Amiodarone-induced thyrotoxicosis

Clinical manifestations — The clinical manifestations of amiodarone-induced thyrotoxicosis

(AIT) are often masked because its beta-blocking activity minimizes many of the adrenergic
manifestations of thyroid hormone excess and possibly because amiodarone metabolites
may block binding of T3 to its nuclear receptor [5].

Common presenting symptoms and signs include [7]:

● Development or redevelopment of atrial arrhythmias

● Exacerbation of ischemic heart disease or heart failure
● Unexplained weight loss
● Restlessness
● Low-grade fever

Patients with AIT have a threefold higher rate of major adverse cardiovascular events (mostly
ventricular arrhythmias) compared with euthyroid controls [33]. The presence of left
ventricular dysfunction in patients with AIT may be associated with increased mortality [34].

Diagnosis — Hyperthyroidism should be suspected in patients who have a low TSH. Obtain a
repeat TSH, a free T4, and a total T3.

● Overt hyperthyroidism – Low TSH, high free T4, and high or inappropriately normal total
T3

● Subclinical hyperthyroidism – Low TSH, normal free T4 and normal total T3

Types of AIT — There are two types of AIT. However, in some cases, mixed forms of AIT exist,
making both diagnosis and treatment challenging. (See 'Differentiating the two types' below

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and 'Treatment of AIT' below.)

● Type 1 – In type 1 AIT, there is increased synthesis of T4 and T3. Type 1 AIT is typically seen
in patients with preexisting multinodular goiter or latent Graves' disease; the excess iodine
from amiodarone provides increased substrate, resulting in enhanced thyroid hormone
production [25]. While most of these patients have underlying multinodular goiter,
occasional patients have latent Graves' disease that becomes overt upon exposure to large
amounts of iodine [35]. (See "Iodine-induced thyroid dysfunction".)

● Type 2 – In type 2 AIT, there is excess release of T4 and T3 due to a destructive thyroiditis. It
typically occurs in patients without underlying thyroid disease and is caused by a direct
toxic effect of amiodarone on thyroid follicular epithelial cells [36-38].

The hyperthyroid phase may last from several weeks to several months, and it is often
followed by a hypothyroid phase with eventual recovery in most, but not all, patients [6].
(See "Overview of thyroiditis".)

For unclear reasons, the toxic effects of the drug may take two to three years to become
manifest and may occur after amiodarone has been discontinued [39].

The clinical manifestations of each type are similar. However, the types differ in their
pathogenesis, management, and outcome [40]. (See 'Differentiating the two types' below.)

The distribution of AIT by type (1 or 2) varies by geographical region. This is thought to be

primarily due to differences in dietary iodine intake. In the United States, most cases are type
2. In iodine-deficient regions, type 1 AIT usually predominates [11,12,14]. As dietary iodine
intake improves (and perhaps avoidance of amiodarone in patients with known thyroid
disease), the distribution of cases by type in some regions has changed [41]. In a report of
215 consecutive patients with AIT seen at a single institution in Italy over 26 years, the
proportion of new type 2 AIT cases increased from 40 to 86 percent [41].

Differentiating the two types — The distinction between type 1 and type 2 is important
since therapy differs for the two types. (See 'Presumed type 1 AIT' below and 'Presumed type
2 AIT' below.)

The history and physical examination may help to differentiate type 1 and type 2 AIT. In
addition, we routinely measure thyrotropin receptor antibodies (TRAb) using a thyroid-
stimulating immunoglobulin (TSI) assay and assess blood flow on color flow Doppler
ultrasound. However, the distinction may be difficult using these clinical criteria, partly
because some patients may have a mixture of both mechanisms [38].

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Thyroid function tests are not helpful for differentiating type 1 from type 2 AIT.

The following clinical criteria are used to try to distinguish type 1 from type 2 AIT:

● Onset of hyperthyroidism – Type 1, when seen in the setting of an underlying

autonomous nodule or goiter, tends to occur early after amiodarone treatment is started
(at a median 3.5 months in one study), while type 2 occurs much later (median 30 months)
[39]. When thyrotoxicosis initially occurs after amiodarone has been discontinued (19
percent of AIT in this study), it is much more likely to be type 2 (95 percent in this study)
[39].

● Physical examination – Patients with type 1 often have multinodular goiters or diffuse
goiter, whereas those with type 2 usually have no goiter or a small diffuse goiter.

● TRAb – The presence of TRAb suggests Graves' disease. However, in patients suspected of
having type 1 AIT, TRAb measurements to diagnose Graves' disease should be measured
using a TSI assay, if available, and not a thyrotropin-binding inhibitory immunoglobulin
(TBII) assay. TBII assays cannot distinguish between type 1 and 2 AIT.

As an example, in one study, 21 of 309 patients (7 percent) had positive TRAb when
measured in a TBII [42]. Of these, 43 percent appeared to have type 1 AIT based on color
flow Doppler or response to methimazole, while 57 percent appeared to have type 2 AIT
based on response to corticosteroids. TRAb, measured by a TSI assay, was positive in
patients suspected of having type 1 AIT and negative in those suspected of having type 2
AIT.

● Thyroid ultrasound with color flow Doppler – Some studies have reported that color flow
Doppler sonography may distinguish type 1 (increased vascularity) from type 2 (absent
hypervascularity) hyperthyroidism [43-46]. In one study, 80 percent of patients could be
classified by color flow Doppler [44].

However, interpretations of color flow Doppler in AIT require an experienced sonographer.

It is straightforward to separate patients into those with increased and low flow when a
group of patients with AIT are being scanned sequentially, but due to the lack of an
accepted "gold standard," it may be difficult to interpret color flow Doppler of a single
thyroid gland scanned during a typical day of multiorgan ultrasound examinations.

● Technetium-99m (99mTc)-sestamibi thyroid uptake – In some reports, technetium-99m

(99mTc)-sestamibi thyroid uptake and scintigraphy could distinguish type 1 (normal or
increased uptake) from type 2 (decreased uptake) [47-49].

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In patients not taking amiodarone, the 24-hour radioiodine uptake is <1 percent in subacute
thyroiditis and elevated or normal in toxic nodular goiter or Graves' disease. However, the
daily ingestion of 6 mg or more of bioavailable iodine with amiodarone results in sufficiently
high serum levels of iodine that compete with the tracer used to perform the uptake test.

In regions with iodine sufficiency, the radioiodine uptake is not helpful in distinguishing type
1 and type 2 as uptake is undetectable in both types. In regions with iodine insufficiency, the
radioiodine uptake in patients with type 1 AIT may be detectable whereas it will be
undetectable in patients with type 2 AIT [50].

Treatment of AIT

Should amiodarone be discontinued? — When deciding whether to discontinue

amiodarone, we consider the following:

● Amiodarone may be necessary to control a life-threatening arrhythmia.

● Since the half-life of elimination from the body is approximately 100 days, there is no
immediate benefit to stopping amiodarone [51].

● Amiodarone appears to ameliorate hyperthyroidism by blocking T4 to T3 conversion, beta-

adrenergic receptors, and possibly T3 receptors. Stopping amiodarone might actually
exacerbate hyperthyroid symptoms and signs [7].

Our approach is as follows:

● In patients who develop AIT in whom the amiodarone was prescribed for life-threatening
ventricular arrhythmias (and is effective), we suggest continuing the amiodarone and
simultaneously treating the hyperthyroidism, especially for type 2 AIT. Controlling
hyperthyroidism in type 1 AIT may be more difficult if amiodarone is continued.

● For patients with non-life-threatening ventricular arrhythmias, the decision to continue or

discontinue amiodarone should be individualized based on the underlying arrhythmia and
the availability of alternative antiarrhythmic agents.

The decision to continue or discontinue amiodarone should only be done in consultation

with the patient's cardiologist. For type 1 AIT, amiodarone should not be discontinued until
hyperthyroid symptoms are well controlled, if possible, with thionamides, since worsening
hyperthyroid symptoms due to increased T3 levels may occur when the amiodarone is
discontinued.

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There are few data that directly address whether amiodarone should be discontinued. In a
retrospective study from Italy of type 2 AIT, the median time to normalize thyroid function
was similar whether amiodarone was continued (n = 8) or discontinued (n = 32) [52]. However,
five of seven patients taking amiodarone had recurrent thyrotoxicosis compared with 3 of 32
patients in whom the amiodarone was discontinued. In a study from the Netherlands of type
2 AIT in which 36 patients were treated with prednisone, sodium perchlorate, or both, therapy
was effective in all patients receiving prednisone or perchlorate plus prednisone, despite
continuation of amiodarone in all patients [53]. Recurrent thyrotoxicosis occurred in only
three patients (8 percent).

Stable patients

Presumed type 1 AIT — For most stable patients with clinical evidence supporting type 1
AIT (eg, goiter, positive TRAb, increased vascularity on color flow Doppler ultrasound), we
suggest thionamides (eg, methimazole, propylthiouracil, carbimazole). Methimazole is
preferred to PTU because of its longer duration of action, allowing for once-daily dosing,
more rapid efficacy, and lower incidence of side effects. (See "Thionamides in the treatment
of Graves' disease", section on 'Choice of drug'.)

There are observational studies suggesting benefit with thionamides, particularly when
combined with potassium perchlorate [11,23,54]. The addition of potassium perchlorate,
which blocks further iodine uptake by the thyroid, may be of benefit [55], but chronic use
has been associated (rarely) with aplastic anemia, and perchlorate is not currently available
in the United States. The addition of lithium carbonate to the antithyroid drug has also
been reported to speed recovery when the hyperthyroidism is severe [56].

● Thionamide administration and monitoring – Large doses may be required,

presumably because of very high intrathyroidal iodine stores, and the response may be
slow [2,54]. The average initial dose is 30 to 40 mg of methimazole once daily.

Thyroid tests (TSH, free T4, total T3) should be measured every three to six weeks,
depending upon clinical concerns. Once the free T4 and total T3 are normal, the dose can
be slowly decreased to a lower maintenance. Control of hyperthyroidism in type 1 AIT
takes considerably longer than is typical when treating Graves' disease or a toxic nodular
goiter in the absence of amiodarone exposure.

In type 1 AIT, care must be taken not to reduce the dose of thionamide too quickly, or
patients might develop recurrent and prolonged hyperthyroidism. An alternative strategy
is to continue high-dose thionamides and add T4 if patients become hypothyroid. (See

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"Thionamides in the treatment of Graves' disease", section on 'Initiation of therapy' and

"Thionamides in the treatment of Graves' disease", section on 'Monitoring'.)

Careful monitoring for adverse effects such as skin rash, arthralgia, hepatotoxicity, and,
rarely, agranulocytosis is warranted. The side effects of methimazole are dose related.
The risk of agranulocytosis in one study was higher in patients with AIT (8 of 593 [1.35
percent]), compared with patients with thyrotoxicosis unrelated to amiodarone (20 of
14,188 [0.14 percent]) [57]. (See "Thionamides: Side effects and toxicities", section on
'Agranulocytosis'.)

● Duration of therapy – Patients with type 1 AIT who are continuing amiodarone will need
to continue thionamides. If amiodarone is subsequently discontinued (eg, if there is
evidence of toxicity in other organs or if it is ineffective as an antiarrhythmic), the
thionamide should be continued until measurement of urine iodine returns to normal.
This may take 6 to 18 months, after which one could cautiously attempt to taper
antithyroid therapy. In one study, when amiodarone was reintroduced in patients with a
history of type 1 AIT who were not taking a thionamide, 8 of 11 patients (73 percent)
developed recurrent AIT [58].

● Persistent symptoms – For patients who are initially treated with antithyroid drugs for
presumed type 1 AIT who show no improvement after four to six weeks, glucocorticoids
can be added as the presumed mechanism may be incorrect, or the mechanism may be a
mixture of both type 1 and type 2. Patients who are refractory to medical therapy or who
have deterioration of cardiac disease should be treated by thyroidectomy. (See 'Patients
with left ventricular dysfunction or severe underlying cardiac disease' below.)

● Definitive therapy – Once euthyroid, patients with type 1 AIT ideally require definitive
therapy of the underlying thyroid disease with surgery, or if possible, radioiodine. For
patients who need to continue or restart amiodarone therapy with minimal delay, surgery
may be a better option.

If the amiodarone has been discontinued and the radioiodine uptake is high enough, one
could treat the patient with radioiodine. However, it may take 6 to 12 months or longer
after amiodarone discontinuation for the radioiodine uptake to increase sufficiently to
allow radioiodine ablation. In one series of 14 patients in whom amiodarone had been
discontinued due to hyperthyroidism, subsequent radioiodine ablation of the thyroid
allowed reintroduction of amiodarone (and control of recurrent tachyarrhythmias) in 12
of the 14 subjects [59].

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In those patients who are not operative candidates, long-term methimazole can be
utilized, if there are no plans to restart amiodarone. The risk of recurrent hyperthyroidism
if amiodarone is restarted is uncertain. These options for definitive therapy of type 1 AIT
are the same as those for toxic multinodular goiter, toxic adenoma, and Graves' disease.
(See "Treatment of toxic adenoma and toxic multinodular goiter", section on 'Choice of
therapy' and "Graves' hyperthyroidism in nonpregnant adults: Overview of treatment",
section on 'Treatment options'.)

Presumed type 2 AIT — For most stable patients with clinical evidence supporting type 2
AIT (eg, no or small goiter, negative TRAb, absent hypervascularity on color flow Doppler
ultrasound), we suggest initial treatment with glucocorticoids rather than other therapies.
However, for patients with mild hyperthyroidism (eg, TSH ≥0.1 mU/L) and stable cardiac
status, observation is an alternative. Type 2 AIT generally resolves on its own. Patients with
type 2 AIT may develop transient (or sometimes permanent) hypothyroidism when the
hyperthyroidism resolves [6] and benefit from T4 replacement. (See "Overview of
thyroiditis".)

● Glucocorticoid administration and monitoring – Patients with type 2 AIT respond well
to moderately large doses of glucocorticoids (eg, prednisone 40 to 60 mg/day), even if
the amiodarone is continued [40,60-62]. We typically start with oral prednisone, 30 to 40
mg/day. Intravenous administration does not appear to be more effective than oral [63].

Thyroid tests (TSH, free T4, total T3) should be measured initially after 10 to 14 days
because a rapid response to steroids supports the diagnosis of type 2 AIT and allows for a
reduction in the steroid dose [40]. Subsequent testing at three- to four-week intervals will
determine the rate at which steroids can be tapered. In one study of 66 patients, 60
percent were euthyroid within one month and 16 percent remained hyperthyroid for
more than three months [64]. Prolonged hyperthyroidism was associated with higher
serum free T4 levels and goiter.

Glucocorticoids are more effective than methimazole or iopanoic acid. In a retrospective

cohort study in 42 patients with type 2 AIT, there were fewer patients with persistent
thyrotoxicosis at 40 days in the glucocorticoid group (23.8 versus 86.7 percent with
methimazole) [60]. When patients in the methimazole group were switched to
glucocorticoids, 94 percent became euthyroid within 40 days. Amiodarone had been
discontinued in all patients.

In a randomized clinical trial, the addition of perchlorate to prednisone added no benefit

[53].

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● Duration of therapy – The duration of therapy is typically one to three months and is
determined by the response of thyroid function tests to tapering the steroids. Patients on
a prolonged course of steroid may have suppression of the pituitary-adrenal axis. (See
"Determining the etiology of adrenal insufficiency in adults", section on 'History of
exogenous glucocorticoid use'.)

● Persistent symptoms – If there is no improvement in thyroid function tests after two to

three weeks, we add methimazole in case the presumed diagnosis of type 2 AIT was
wrong, or if the mechanism of AIT is a mixture of type 1 and 2. Patients who are
refractory to medical therapy or who have deterioration of cardiac disease should be
treated by thyroidectomy. (See 'Patients with left ventricular dysfunction or severe
underlying cardiac disease' below.)

Mechanism unknown — Some patients may have a "mixed" form of thyrotoxicosis or the
underlying cause (type 1 or type 2) may be uncertain. For example, a patient with an
underlying nodular goiter who developed symptomatic hyperthyroidism after one year of
amiodarone therapy. In such cases, an initial combination of prednisone (40 mg/day) and
methimazole (40 mg/day) is prudent initial therapy. A rapid response suggests type 2 AIT;
the methimazole can then be tapered or stopped. A poor response initially argues for type
1 AIT. If so, steroids can be tapered and, depending upon the subsequent course,
perchlorate (where available), lithium, and/or surgery may be necessary.

Patients who are refractory to medical therapy or who have deterioration of cardiac disease
should be treated by thyroidectomy. (See 'Patients with left ventricular dysfunction or
severe underlying cardiac disease' below.)

Patients with left ventricular dysfunction or severe underlying cardiac

disease — Mortality is increased in patients with AIT and left ventricular dysfunction [34].
Such patients should be treated quickly to restore euthyroidism.

For patients with reduced left ventricular ejection fraction (eg, <40 percent), severe underlying
cardiac disease (eg, malignant arrhythmias), or acute deterioration of cardiac disease, we
suggest thyroidectomy rather than medical therapy. This recommendation is consistent with
the European Thyroid Association guidelines for the management of amiodarone-associated
thyroid dysfunction [65]. When balancing the risk of a surgical procedure during careful
cardiovascular monitoring with the risk of several weeks or months of uncontrolled
thyrotoxicosis while waiting for methimazole and/or glucocorticoids to control
hyperthyroidism, the advantages of surgery in this setting become compelling [66-68].

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In one study of 207 patients, 51 of whom had surgery and 156 of whom were treated
medically, overall and cardiovascular mortality were lower in the surgery group due to
reduced mortality among patients with moderate to severe reductions in left ventricular
ejection fraction (under 40 percent) [69]. In this study, 64 percent of patients who had surgery
for AIT had type 2 AIT. (See "Surgical management of hyperthyroidism".)

Thyroidectomy is also indicated in patients with persistent AIT despite medical therapy with
methimazole and prednisone [23,65].

PATIENTS ON WARFARIN

In patients taking amiodarone who are also being treated with warfarin, the consequences of
amiodarone-induced thyroid dysfunction include a significant influence on warfarin response.
The effect of warfarin is potentiated by thyrotoxicosis and attenuated in hypothyroidism [70]. In
addition, amiodarone itself has effects on warfarin pharmacokinetics, which may be important
if the amiodarone is discontinued because of thyroid dysfunction. In any patient with
amiodarone-induced thyroid dysfunction who is also taking warfarin, the international
normalized ratio (INR) should be monitored closely and appropriate adjustments in warfarin
dosing made. (See "Warfarin and other VKAs: Dosing and adverse effects".)

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Hyperthyroidism" and
"Society guideline links: Hypothyroidism".)

SUMMARY AND RECOMMENDATIONS

● Monitoring for thyroid dysfunction – Thyroid dysfunction is relatively common with

amiodarone therapy due to direct effects of the drug on the thyroid, as well as its high iodine
content. All patients should have regular monitoring of thyroid function tests. We obtain
thyroid tests prior to starting amiodarone, several weeks after initiation of treatment, at
three- to six-month intervals during treatment, and with development of new thyroid-related
symptoms. (See 'Monitoring for thyroid dysfunction' above.)

In asymptomatic patients, we typically measure thyroid-stimulating hormone (TSH) with reflex

to free thyroxine (T4) if abnormal. If the laboratory does not provide a reflex free T4 option,

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we measure TSH with free T4. For patients with symptoms suggestive of hyperthyroidism, we
also measure a total triiodothyronine (T3).

● Spectrum of thyroid dysfunction – Patients initiating amiodarone may develop transient

changes in thyroid function tests, hypothyroidism, or hyperthyroidism (amiodarone-induced
thyrotoxicosis [AIT]). (See 'Spectrum of thyroid dysfunction' above.)

● Hypothyroidism – Amiodarone-induced hypothyroidism is more common in iodine-sufficient

regions and in patients with underlying autoimmune thyroid disease.

• Clinical manifestations and diagnosis – The clinical manifestations and diagnosis of

amiodarone-associated hypothyroidism are similar to those of hypothyroidism from any
cause. Hypothyroidism is diagnosed based on routinely monitored thyroid function tests,
preferably before the patient has symptoms. The biochemical diagnosis is the same as for
other patients with primary hypothyroidism. (See 'Clinical manifestations' above and
'Diagnosis' above.)

• Treatment – Hypothyroidism is treated with levothyroxine replacement. Larger than

normal doses are often required. (See 'Treatment' above.)

We suggest continuing amiodarone therapy in patients who develop amiodarone-induced

hypothyroidism (Grade 2C). Amiodarone should only be discontinued if it fails to control the
underlying arrhythmia. If amiodarone is discontinued in a patient without preexisting
autoimmune thyroid disease, the hypothyroidism often resolves. (See 'Treatment' above
and 'Should amiodarone be discontinued?' above.)

● Amiodarone-induced thyrotoxicosis – AIT is more common in iodine-deficient regions and

in patients with underlying multinodular goiter or latent Graves' disease.

• Clinical manifestations and diagnosis – The clinical manifestations of AIT are often
masked because its beta-blocking activity minimizes many of the adrenergic manifestations
of thyroid hormone excess. The development or redevelopment of atrial arrhythmias
and/or exacerbation of ischemic heart disease or heart failure are common findings. The
biochemical diagnosis is the same as for other patients with hyperthyroidism. (See 'Clinical
manifestations' above and 'Diagnosis' above.)

• Types of hyperthyroidism – There are two types of AIT. (See 'Types of AIT' above.)

- Type 1 – In type 1, there is increased synthesis of thyroid hormone (excess iodine

provides the increased substrate).

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- Type 2 – In type 2, there is excess release of T4 and T3 due to a destructive thyroiditis

(direct toxic effect of amiodarone on the thyroid gland). For patients with type 2 AIT, the
hyperthyroid phase may last from several weeks to several months and is often followed
by a hypothyroid phase and then recovery.

• Differentiating the two types – The distinction between type 1 and type 2 is important
since therapy differs for the two types. The history and physical examination may help to
differentiate type 1 and type 2 AIT. We routinely measure thyrotropin receptor antibodies
(TRAb) using a thyroid-stimulating immunoglobulin (TSI) assay and assess blood flow on
color flow Doppler ultrasound to help differentiate two types of AIT. (See 'Differentiating the
two types' above.)

• Treatment

- Should amiodarone be discontinued? – In patients who develop AIT in whom the

amiodarone was prescribed for life-threatening ventricular arrhythmias (and is effective),
we suggest continuing the amiodarone and simultaneously treating the hyperthyroidism
(Grade 2C). (See 'Should amiodarone be discontinued?' above.)

For patients with non-life-threatening ventricular arrhythmias, the decision to continue or

discontinue amiodarone should be individualized based on the underlying arrhythmia
and the availability of alternative antiarrhythmic agents.

The decision to continue or discontinue amiodarone should only be done in consultation

with the patient's cardiologist. For type 1 AIT, amiodarone should not be discontinued
until hyperthyroid symptoms are well controlled with thionamides since worsening
hyperthyroid symptoms due to increased T3 levels may occur when the amiodarone is
discontinued. (See 'Should amiodarone be discontinued?' above.)

- Stable patients, presumed type 1 – For the treatment of stable patients with type 1 AIT,
we suggest thionamides (whether amiodarone is continued or discontinued) rather than
other therapies (Grade 2C). The average initial dose is 30 to 40 mg of methimazole daily.
Although radioiodine ablation has been reported to have been used (in rare patients with
high enough radioiodine uptake), this is usually not an option due to low radioiodine
uptake in the majority of type 1 patients. Surgery is an option but is generally reserved
for definitive therapy in stable patients, for patients with AIT refractory to medical
therapy, or for patients with severe cardiac disease. (See 'Presumed type 1 AIT' above.)

- Stable patients, presumed type 2 – For the treatment of stable patients with type 2 AIT,
we suggest glucocorticoid therapy (whether amiodarone is continued or discontinued)

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rather than other therapies (Grade 2C). We typically start with prednisone (30 to 40
mg/day) and continue therapy for one to two months before tapering (to avoid
exacerbations of hyperthyroidism). For patients with mild hyperthyroidism (eg, TSH ≥0.1
mU/L) and stable cardiac function, observation is an option as type 2 AIT typically
resolves on its own. (See 'Presumed type 2 AIT' above.)

- Stable patients, mechanism unknown – When the mechanism of AIT is unclear, we

suggest initial combination therapy with prednisone and methimazole (Grade 2C). A
rapid response suggests type 2 AIT; the methimazole can then be tapered or stopped. A
poor or slow initial response argues for type 1 AIT. (See 'Mechanism unknown' above.)

- Patients with left ventricular dysfunction or severe cardiac disease – For patients
with type 1 or type 2 AIT with left ventricular dysfunction (ejection fraction <40 percent)
or with deterioration of cardiac disease, we suggest thyroidectomy rather than medical
therapy (Grade 2C). Mortality is increased in patients with AIT and left ventricular
dysfunction, and surgery is the most rapid way to restore euthyroidism. (See 'Patients
with left ventricular dysfunction or severe underlying cardiac disease' above.)

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Topic 7834 Version 24.0

Contributor Disclosures
Douglas S Ross, MD Consultant/Advisory Boards: Medullary Thyroid Cancer Registry Consortium [Thyroid
cancer]. All of the relevant financial relationships listed have been mitigated. David S Cooper,
MD Speaker's Bureau: MacLeod Pharma [Hypothyroidism]. All of the relevant financial relationships listed
have been mitigated. Jean E Mulder, MD No relevant financial relationship(s) with ineligible companies to
disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.

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