Endocrine Reviews 22 (2): 240-254
Copyright © 2001 by The Endocrine Society
The Effects of Amiodarone on the Thyroid1
Enio Martino,
Luigi Bartalena,
Fausto Bogazzi and
Lewis E. Braverman
Dipartimento di Endocrinologia e Metabolismo (E.M., F.B.),
University of Pisa, Pisa, Italy 56124; Cattedra di Endocrinologia
(L.B.), University of Insubria, Varese, Italy; Section of
Endocrinology, Diabetes and Nutrition (L.E.B.), Boston Medical Center,
Boston, Massachusetts 02118-2393
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Abstract
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Amiodarone is a benzofuranic-derivative iodine-rich drug widely used
for the treatment of tachyarrhythmias and, to a lesser extent, of
ischemic heart disease. It often causes changes in thyroid function
tests (typically an increase in serum T4 and
rT3, and a decrease in serum T3,
concentrations), mainly related to the inhibition of 5'-deiodinase
activity, resulting in a decrease in the generation of T3
from T4 and a decrease in the clearance of rT3.
In 14–18% of amiodarone-treated patients, there is overt thyroid
dysfunction, either amiodarone-induced thyrotoxicosis (AIT) or
amiodarone-induced hypothyroidism (AIH). Both AIT and AIH may develop
either in apparently normal thyroid glands or in glands with
preexisting, clinically silent abnormalities. Preexisting Hashimoto’s
thyroiditis is a definite risk factor for the occurrence of AIH. The
pathogenesis of iodine-induced AIH is related to a failure to escape
from the acute Wolff-Chaikoff effect due to defects in thyroid
hormonogenesis, and, in patients with positive thyroid autoantibody
tests, to concomitant Hashimoto’s thyroiditis. AIT is primarily
related to excess iodine-induced thyroid hormone synthesis in an
abnormal thyroid gland (type I AIT) or to amiodarone-related
destructive thyroiditis (type II AIT), but mixed forms frequently
exist. Treatment of AIH consists of L-T4
replacement while continuing amiodarone therapy; alternatively, if
feasible, amiodarone can be discontinued, especially in the absence of
thyroid abnormalities, and the natural course toward euthyroidism can
be accelerated by a short course of potassium perchlorate treatment. In
type I AIT the main medical treatment consists of the simultaneous
administration of thionamides and potassium perchlorate, while in type
II AIT, glucocorticoids are the most useful therapeutic option. Mixed
forms are best treated with a combination of thionamides, potassium
perchlorate, and glucocorticoids. Radioiodine therapy is usually not
feasible due to the low thyroidal radioiodine uptake, while
thyroidectomy can be performed in cases resistant to medical therapy,
with a slightly increased surgical risk.
I. Introduction
II. Pharmacology of Amiodarone
III. Amiodarone and the Thyroid
A. Pituitary-thyroid function tests during amiodarone therapy
B. Thyroid cytotoxicity
C. Effect on thyroid autoimmunity
D. Interaction of amiodarone and its metabolites with thyroid hormone
receptors
E. Amiodarone-induced thyroid dysfunction
IV. Recommendations for Following Patients Receiving Amiodarone Therapy
V. Amiodarone and Pregnancy
VI. Conclusions
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I. Introduction
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AMIODARONE is an iodine-rich drug widely used for the
management of ventricular arrhythmias, paroxysmal supraventricular
tachycardia, and atrial fibrillation and flutter (1). The drug is, to a
lesser extent, also employed for severe congestive heart failure
because of its minimal negative inotropic action (2). In addition, it
may decrease cardiac-related mortality after myocardial infarction (3),
although the latter effect has been questioned (4); decrease the
immediate and late complications of atrial fibrillation in patients
undergoing elective cardiac surgery (5); prevent recurrence of atrial
fibrillation (6); and decrease cardiac arrhythmia death when given to
patients upon arrival of emergency medical technicians (EMTs) (7).
However, amiodarone also has effects on the thyroid and other organs
that may counterbalance its beneficial effects on the heart (8, 9)
(Table 1
). The complex effects on the
thyroid range from abnormalities of thyroid function tests to overt
thyroid dysfunction, either thyrotoxicosis or hypothyroidism (10, 11, 12).
The aim of this review is to analyze the pathophysiology of
amiodarone-induced changes in thyroid function and to present the
diagnostic and therapeutic aspects of amiodarone-induced thyroid
dysfunction.
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II. Pharmacology of Amiodarone
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Amiodarone is a benzofuranic derivative whose structural formula
closely resembles that of T4 (Fig. 1). It contains approximately 37% iodine
by weight. Because approximately 10% of the molecule is deiodinated
daily, and the maintenance daily dose of the drug ranges from 200 to
600 mg, approximately 7–21 mg iodide are made available each day,
resulting in a marked increase in urinary iodide excretion (13). If one
considers that the optimal daily iodine intake is considered to be
150–200 µg (14), amiodarone treatment releases 50- to 100-fold
excess iodine daily. Furthermore, amiodarone is distributed in several
tissues, including adipose tissue, liver, lung, and, to a lesser
extent, kidneys, heart, skeletal muscle, thyroid, and brain (15), from
which it is slowly released. In the analysis of a variety of postmortem
tissues, intrathyroidal concentrations of amiodarone and its
metabolite, desethylamiodarone (DEA), were 14 mg/kg and 64 mg/kg,
respectively, compared with 316 mg/kg and 76 mg/kg in the adipose
tissue and 391 mg/kg and 2354 mg/kg in the liver (15). Terminal
elimination half-lives averaged 52.6 ± 23.7 (±SD)
days for amiodarone and 61.2 ± 31.2 days for DEA in eight
patients after cessation of long-term amiodarone therapy (15). In
another study the mean (±SDD) elimination half-lives were
40 ± 10 days for amiodarone and 57 ± 27 days for DEA (16).
The above results explain why, after amiodarone withdrawal, the drug
and its metabolites remain available for a long period.
Amiodarone is metabolized through different pathways, the most
important being dealkylation, which leads to formation of DEA (17)
(Fig. 1
). Approximately 66–75% of amiodarone is eliminated through
bile and feces (13).
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III. Amiodarone and the Thyroid
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A. Pituitary-thyroid function tests during amiodarone therapy
In peripheral tissues, particularly the liver, amiodarone inhibits
type I 5'-deiodinase (5'-D) activity, which removes an atom of iodine
from the outer ring of T4 to generate
T3 and from the outer ring of
rT3 to produce 3,3'-diiodothyronine
(T2) (18, 19, 20). This inhibition of 5'-D activity
may persist for several months after amiodarone withdrawal (9, 10, 11).
Apparently, amiodarone does not affect the distribution and fractional
removal of T3 from the plasma pool (21). In
addition, the drug inhibits thyroid hormone entry into peripheral
tissues (22). Both mechanisms contribute to the increased serum
T4 concentration and the decreased serum
T3 concentration in euthyroid subjects given
long-term amiodarone therapy (9, 10, 11, 12). Serum T4
concentrations are often at the upper limit of the normal range, but
may be increased, especially in patients receiving higher daily doses
of the drug (23). The decrease in serum T3, due
to decreased production from T4, and the
concomitant increase in serum rT3 concentrations,
due to decreased clearance, are often found as early as 2 weeks after
institution of amiodarone therapy (24, 25). The increase in serum
rT3 levels is usually far greater than the
decrease in serum T3 concentrations (17, 23, 26).
Indeed, serum T3 concentrations often remain
within the low normal range.
Amiodarone administration is also associated with dose- and
time-dependent changes in serum TSH concentration. With a daily dose of
200–400 mg of the drug, serum TSH levels are usually normal, although
an increased TSH response to intravenous TRH administration is
frequently observed (10). With higher doses of the drug, an increase in
serum TSH concentration may occur during the early months of treatment,
but this is generally followed by a return to normal (24, 25). These
changes in serum TSH concentration are believed to be related to the
variations of serum thyroid hormone levels; amiodarone may also
directly affect TSH synthesis and secretion at the pituitary level
(27). The increased serum TSH concentration may also result from the
inhibition of type II 5'-D, which converts T4 to
T3 in the pituitary, by either amiodarone or
desethylamiodarone (28). Indeed, after a loading dose of amiodarone by
intravenous infusion, TSH is the first hormone to undergo significant
variations, even during the first day of therapy (29). During long-term
amiodarone therapy, clinically euthyroid patients may show modest
increases or decreases in serum TSH concentration, possibly reflecting
episodes of subclinical hypo- or hyperthyroidism, respectively.
The above description of changes in thyroid function tests occurring
during chronic amiodarone therapy underscore the important concept that
standard thyroid function tests in euthyroid patients receiving
amiodarone have a different range than those observed in euthyroid
subjects not receiving amiodarone. Appropriate reference values for
thyroid function tests in patients receiving amiodarone are shown in
Table 2.
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Table 2. Reference values for serum thyroid hormones and TSH
concentrations in euthyroid untreated subjects and in euthyroid
patients receiving long-term amiodarone therapy
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B. Thyroid cytotoxicity
In addition to the above effects on enzymatic activities relevant
to pituitary-thyroid physiology, amiodarone and its metabolites also
have cytotoxic effects on the thyroid. Chiovato et al. (30)
reported that amiodarone had a cytotoxic effect on thyroid cells (Fig. 2), although this occurred at a lower
molar concentration in freshly prepared human thyroid follicles, which
trap and organify iodide, than in rat FRTL-5 cells, which have an
active iodide pump but are unable to organify iodide. In human thyroid
follicles, lysis of 50% of thyroid cells occurred at concentrations of
amiodarone (
200 µmol/liter) much lower than potassium iodide (30).
Methimazole, which inhibits iodide organification, partially, but
significantly reduced the cytotoxic effects of amiodarone in human
thyroid follicles (30). Finally, amiodarone cytotoxicity was also shown
in Chinese hamster ovary cells, a nonthyroid cell line (30). These
data, taken together, suggest that amiodarone-related thyroid
cytotoxicity is mainly due to a direct effect of the drug on thyroid
cells, although excess iodide released from amiodarone may contribute
to its toxic action. DEA, the main amiodarone metabolite, is even more
cytotoxic for thyroid cells than amiodarone (31), and its
intrathyroidal concentration is higher than that of the parental drug
(15). It has been shown recently that in thyroid cells (both primary
thyroid cells and the cell line TAD-2 derived from human fetal thyroid
cells infected with Simian virus 40), iodide excess induced apoptosis
through a p53-independent mechanism involving oxidative stress and
associated with production of reactive oxygen species and a marked
increase in lipid peroxide levels (32). Whether these mechanisms
contribute to amiodarone-associated thyroid histopathological
abnormalities remains to be established. Finally, it is unclear whether
nonthyroid amiodarone-induced abnormalities are more common in patients
with amiodarone thyroid toxicity.
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Figure 2. Cytotoxicity of amiodarone on freshly prepared
human thyroid follicles. Cells were incubated for 24 h in the
standard medium added with amiodarone in the concentrations shown.
Black bars, viable cells; white bars,
cell lysis. [Derived from L. Chiovato et al.:
Endocrinology 134: 2277–82, 1994 (30 ). © The Endocrine
Society.]
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In the rat, it was shown that amiodarone administration is associated
with ultrastructural changes indicative of thyroid cytotoxicity, which
were distinct from those induced by excess iodine alone (33). These
included marked distortion of thyroid architecture, apoptosis,
necrosis, inclusion bodies, lipofuscinogenesis, macrophage
infiltration, and markedly dilated endoplasmic reticulum (33) (Table 3). The latter findings might be
compatible with the disruption of protein sorting pathways leading to a
drug-induced form of endoplasmic reticulum storage disease. The fact
that amiodarone, being amphiphilic, strongly binds to intralysosomal
phospholipids, making them indigestible by phospholipases, may
contribute to these subcellular changes (34). Similar subcellular
abnormalities have been observed during amiodarone treatment in other
organs, such as liver, lung, heart, skin, cornea, and in peripheral
nerve fibers and blood leukocytes (9). Accumulation of amiodarone in
the different tissues and the long terminal half-lives of amiodarone
and its metabolites (15) represent important factors for the occurrence
of the above changes.
Amiodarone-induced tissue changes seem to be associated with prolonged
drug treatment. In dogs, thyroid subcellular changes were not observed
after a single, high-dose intravenous amiodarone injection, while they
became apparent after multiple injections for 1 week (35).
C. Effect on thyroid autoimmunity
The effect of amiodarone on thyroid autoimmunity is a matter of
disagreement. Iodine may induce thyroid autoimmunity in man (36) and
animals (37, 38); therefore, the excess iodine released from amiodarone
might be involved in the occurrence of thyroid autoimmune phenomena. In
a prospective study of 37 patients randomly assigned to either placebo
or amiodarone treatment after myocardial infarction, antithyroid
peroxidase antibodies de novo occurred in the serum of 6 of
13 (55%) amiodarone-treated patients and in no placebo-treated
patients (39). Interestingly, these autoantibodies, appearing early
during amiodarone treatment, could no longer be detected 6 months after
withdrawal of the drug (39). This phenomenon was attributed to early
and transient toxic effects of amiodarone on the thyroid, leading to
release of thyroid autoantigens and subsequent triggering of thyroid
autoimmune reactions (39). These results were not, however, confirmed
in several subsequent prospective or cross-sectional studies (40, 41, 42, 43, 44).
Safran et al. (40) failed to find an increased incidence of
antithyroid autoantibodies in 47 patients submitted to both short-term
and long-term amiodarone treatment in geographical areas of different
ambient iodine intake. Foresti et al. (43) found positive
thyroid autoantibody tests at low titer in only 2 of 23
amiodarone-treated patients, a figure not different from that found in
patients receiving other antiarrhythmic drugs. Thus, the majority of
studies indicate that it is unlikely that thyroid autoantibodies appear
in subjects who have negative tests before treatment. The finding that
amiodarone treatment may be associated with an increase in certain
lymphocyte subsets may indicate, however, that in susceptible
individuals amiodarone may precipitate or exacerbate preexisting
organ-specific autoimmunity (45). This appears to be particularly
important in amiodarone-induced hypothyroidism (AIH), where the
majority of patients have circulating thyroid autoantibodies before
amiodarone treatment (9, 10).
D. Interaction of amiodarone and its metabolites with thyroid
hormone receptors
In addition to the inhibition of type I and type II 5'-D
activities, amiodarone may induce a hypothyroid-like condition at the
tissue level. This is partly related partly to a reduction in the
number of catecholamine receptors (46, 47) and to a decrease in the
effect of T3 on ß-adrenoceptors (48). In the
heart of amiodarone-treated pigs, the maximum binding capacity of
ß-adrenoceptors and calcium channels was diminished, whereas the
maximum T3 binding capacity was unchanged,
indicating that amiodarone did not induce any functional decrease in
the number of T3 receptors (49). Amiodarone has
no effect on ß-adrenoceptor number in hypothyroid animals; however,
the drug inhibits the increase in receptor density after
T3 administration (48, 50). This suggests that
thyroid hormone is required for the effect of amiodarone on
ß-adrenoceptors, and that amiodarone does not exert a direct action
on ß-adrenoceptors. Tissue and ß-adrenoceptor subtype
differences may also exist. In the brown adipose tissue of
thyroidectomized rats, amiodarone did not inhibit the positive
T3 effect on ß1-adrenoceptor expression, but it
antagonized the effect on ß3-adrenoceptors number (51).
In the liver it was shown that amiodarone causes a decreased
transcription of the T3-responsive gene encoding
for the low density lipoprotein receptor (52, 53). In pituitary cell
cultures, amiodarone inhibited in a dose-dependent manner the
T3-induced increase in GH mRNA (54).
The molecular mechanisms underpinning this antagonistic action of
amiodarone on thyroid hormone effects are not completely understood.
They might be related to a down-regulation of thyroid hormone receptors
(TR) caused by amiodarone. Myocardial nuclear T3
receptor maximum binding was reduced to a similar degree in hypothyroid
and amiodarone-treated rats (55). In mice treated with this drug,
certain TR subtypes (TR
1 and TRß1) were effectively down-regulated
in a dose-dependent manner (56). However, other TR subtypes, such as
TR2 (which has the highest density in the mouse heart) and TRß2,
were not affected by amiodarone treatment (56). DEA, but not
amiodarone, has been reported to affect the binding of
T3 to chicken TR1, but not to TRß1 expressed
in Escherichia coli (57, 58). Inhibition of
T3 binding appeared to be competitive for TR1
and noncompetitive for TRß1 (57, 58). Studies using TRß1 mutants
would suggest that DEA does not bind to the T3
binding pocket (59). This would be in keeping with the noncompetitive
feature of the DEA inhibition on T3 binding to
TRß1. We have recently observed that in NIH3T3 cells DEA (but not
amiodarone) behaves as a weak thyroid hormone agonist, using both TR
and TRß, and antagonizes the effect of T3 only
when present in large excess (60). Bakker et al. (61) have
also reported that DEA has a thyroid hormone agonist effect. Thus, DEA,
the main amiodarone metabolite, might act both as thyroid hormone
agonist and antagonist, possibly depending upon TR expression in
different tissues. The high tissue levels reached by the drug during
chronic amiodarone treatment might explain the prevailing antagonist
effect and the "hypothyroid-like" situation observed in tissue such
as the heart and liver (9).
E. Amiodarone-induced thyroid dysfunction
Although the majority of patients given amiodarone remain
euthyroid, some develop thyroid dysfunction, i.e.,
thyrotoxicosis and hypothyroidism (10). Amiodarone-induced
thyrotoxicosis (AIT) appears to occur more frequently in geographical
areas with low iodine intake, whereas AIH is more frequent in
iodine-sufficient areas (62, 63, 64). In particular, in a study carried out
simultaneously in Western Tuscany (moderately low iodine intake) and
Massachusetts (normal iodine intake), it was found that the incidence
of AIT was about 10% in Italy and 2% in the United States, while the
incidence of AIH was 5% in Italy and 22% in the United States (61)
(Fig. 3). Two studies have prospectively
evaluated the incidence of amiodarone-induced thyroid dysfunction. In a
study of 58 consecutive euthyroid patients residing in a Dutch region
with moderately sufficient iodine intake, AIT occurred in 12.1% of
cases and AIH in 6.9% (44). In a prospective study carried out in a
moderately iodine-deficient Italian area, AIT occurred in 2 of 13
patients (15%) and AIH in 5 of 7 patients (71%) who had evidence of
Hashimoto’s thyroiditis before treatment (65). A high prevalence of
thyroid dysfunction was recently reported in an iodine-deficient area
(Sardinia, Italy) in a young adult population with ß-thalassemia
major who received amiodarone therapy (66). Five of 22 patients
(23%) developed overt hypothyroidism, compared with 3 of 73 (4%)
control ß-thalassemic patients not receiving amiodarone therapy, and
3 amiodarone-treated patients (14%) developed AIT (2 overt, one
subclinical) (66). In the case of ß-thalassemia, thyroid damage
related to increased intrathyroidal iron deposits probably contributed
to the high rate of amiodarone-associated thyroid dysfunction,
particularly hypothyroidism.
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Figure 3. Prevalence of amiodarone-induced hyperthyroidism
and hypothyroidism in an iodine-deficient area of Northern Tuscany,
Italy, and in an iodine-sufficient area of Worcester, Massachusetts.
[Derived from E. Martino et al.: Ann Intern
Med 101:28–34, 1984 (62 ).]
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In general, the various published studies reported an overall incidence
of AIT ranging from 1% to 23% and of AIH ranging from 1% to 32%
(11). Thus, irrespective of iodine intake, it may be estimated that the
overall incidence of amiodarone-induced thyroid dysfunction be between
2% and 24% (11), most commonly in the range of 14–18% (10). It is
worth mentioning that in one study the addition of phenytoin to
amiodarone was associated with a 49% incidence of thyroid dysfunction
after a prolonged follow-up (67). Likewise, evaluation of a large
series of adults with congenital heart disease revealed a prevalence of
thyroid dysfunction in 36% of patients (68): female sex, complex
cyanotic heart disease, previous Fontan-type surgery, and a dose of
amiodarone >200 mg/day appeared to be significant risk factors for the
occurrence of amiodarone-associated thyroid dysfunction (68).
1. Amiodarone-induced thyrotoxicosis. AIT may develop, often
suddenly and explosively, early or after many years of amiodarone
treatment (69). Trip et al. (44) observed that the average
length of amiodarone treatment before the occurrence of AIT was about 3
yr, with a probability of 0.025 after 18 months and 0.335 after 48
months. In the prospective study by Martino et al. (65), two
patients developed AIT 12 and 29 months after institution of therapy.
Mariotti et al. (66) reported the occurrence of AIT after
21–47 months of amiodarone therapy. An interesting feature of AIT is
that, due to tissue storage of the drug and its metabolites and to
their slow release, the effect of amiodarone can persist for a long
period of time. It is, therefore, not surprising that AIT may develop
even many months after drug withdrawal (63). The daily or cumulative
dose of amiodarone does not seem to be relevant for the occurrence of
AIT. There are no parameters allowing predictability of AIT (44),
although it has been suggested that the baseline lack of a TSH response
to TRH may represent a risk factor for the subsequent occurrence of AIT
(70). A relative predominance of AIT among men, with a M:F ratio of
3:1, has been reported (67, 71).
a. Pathogenesis.
The pathogenesis of AIT is complex and not
completely understood. The disease may develop both in a normal thyroid
gland or in a gland with preexisting abnormalities. In a study in a
moderately iodine-deficient area, diffuse goiter was found in 29% of
AIT, and nodular goiter occurred in 38%, but the thyroid was
apparently normal in the remaining 33% of cases (63). The occurrence
of AIT in apparently normal thyroid glands was also reported in studies
from iodine-sufficient areas (26, 44, 69, 72). Humoral thyroid
autoimmunity seems to play little, if any, role in the development of
AIT in patients without underlying thyroid disorders. Circulating
antithyroglobulin, antithyroid peroxidase, and TSH-receptor (TRAb)
antibodies were found only in AIT patients with preexisting thyroid
abnormalities (mostly diffuse goiter), but not in those with apparently
normal thyroid glands (Fig. 4) (73).
While most studies failed to observe the development of TRAb in AIT
patients (44, 72, 73), in a study of 12 Japanese patients, 1 patient
developed thyrotoxicosis associated with transient positivity for TRAb,
which was, however, devoid of any thyroid hormone-releasing activity in
cultured human thyroid follicles (74).
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Figure 4. Fig. 4. TSH-receptor antibody (assessed by the
increase in adenylate-cyclase activity) in 46 patients with AIT and in
35 normal controls.
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A possible pathogenic hypothesis suggests that AIT is due to excessive
thyroid hormone synthesis induced by the iodine load. Intrathyroidal
iodine content, assessed by x-ray fluorescence, was found to be
markedly increased in AIT patients, irrespective of the presence of an
intrinsic thyroid abnormality (75). The perchlorate discharge test is
negative, indicating that there is no relevant impairment of iodine
organification (76, 77). Interestingly, a normalization of
intrathyroidal iodine content has been reported after the restoration
of euthyroidism in AIT patients (69). In patients with preexisting
thyroid abnormalities (diffuse or nodular goiter, latent Graves’
disease), the 24-h thyroid radioactive iodine uptake (RAIU) values were
in some cases higher than 8% (and as high as 64%) despite the iodine
load (78), although in iodine-sufficient areas such as the United
States, the RAIU is almost always very low. This suggests that in
patients with an underlying thyroid disorder and residing in a mildly
iodine-deficient area, the thyroid gland may fail to adapt normally to
the excess iodine load, resulting in inappropriately elevated RAIU
values despite the presence of excess plasma iodine. This subgroup of
AIT patients usually have normal or slightly elevated serum
interleukin-6 (IL-6) levels (79) (Fig. 5). This cytokine is a good marker of
thyroid-destructive processes and, therefore, increases in the
circulation after radioiodine therapy, intranodular ethanol injection,
and fine needle aspiration (80). An increased IL-6 concentration is
also found in subacute thyroiditis (81). The fact that serum IL-6
levels are normal or slightly increased in this subgroup of AIT
patients suggests that thyroid-destructive processes do not represent
an important pathogenetic mechanism in most of these cases. This form
of AIT with an underlying thyroid abnormality, normal/elevated RAIU
values but low values in iodine sufficient regions, and normal/slightly
elevated serum IL-6 levels, has been defined as type I AIT (79) (Table 4). Further support to the concept that
type I AIT is due to excess iodine-associated excessive thyroid hormone
synthesis comes from the observation that these patients have color
flow Doppler sonography (CFDS) patterns (pattern I-III) that indicate a
hyperfunctioning gland with hypervascularity, as seen in spontaneous
hyperthyroidism (82, 83) (Fig. 6).
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Figure 5. Serum IL-6 in amiodarone-treated patients and in
control groups. AmEu, Euthyroid amiodarone-treated patients; AIH,
amiodarone-induced hypothyroidism; AIT-, AIT in the absence of
underlying thyroid abnormalities; AIT+, AIT with underlying thyroid
abnormalities; GD, Graves’ disease; TA, toxic adenoma; NTG, nontoxic
goiter. [Reproduced with permission from L. Bartalena et
al.: J Clin Endocrinol Metab 78:423–427,
1994 (79 ). © The Endocrine Society.]
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Figure 6. Color flow Doppler sonography (CFDS) pattern in
AIT patients, in euthyroid amiodarone-treated subjects, in Graves’
disease, in subacute thyroiditis, and in control subjects. Pattern 0,
Absent hypervascularity; pattern I, presence of parenchymal blood flow
with patchy uneven distribution); pattern II, mild increase of color
flow Doppler signal with patchy distribution); pattern III, markedly
increased color flow Doppler signal with diffuse homogeneous
distribution). [Reproduced with permission from F. Bogazzi et
al.: Thyroid 7:541–545, 1997 (82 ).]
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If excessive thyroid hormone synthesis can explain the occurrence of
hyperthyroidism in patients with preexisting (subclinical) thyroid
disorders, what is the mechanism leading to AIT in patients with
apparently normal thyroid glands? These patients usually have no
detectable thyroid abnormalities on physical examination or
ultrasonography, although in some cases there may be a small, tender
goiter, and thyroid autoantibody tests are negative. In addition they
have very low (usually <2–3%) RAIU values (77, 78). Serum IL-6
concentrations are usually markedly elevated (78) (Fig. 5), and pattern
0 (indicating the absence of hypervascularity) is observed on CFDS (82, 83) (Fig. 6). Both the above features are typically encountered in
thyroid-destructive processes, such as subacute thyroiditis (81, 83).
Further support to the concept that this form of AIT, defined as type
II (79) (Table 4), is related to a thyroid-destructive process is
provided by the histopathological examination of the thyroids of a few
patients. While euthyroid amiodarone-treated patients showed minimal or
no evidence of thyroid follicular damage, the glands of two patients
with AIT showed moderate to severe follicular damage and disruption
(84). Other small surgical series showed signs of thyroid damage, with
swelling of follicular cells, vacuolization of the cytoplasm, and
fibrosis (85, 86, 87, 88) (Table 5). Therefore,
type II AIT appears to be a form of destructive thyroiditis with
associated leakage of preformed hormones from damaged follicles. This
is in keeping with the in vitro studies demonstrating the
cytotoxic effect of amiodarone and its metabolites (30, 32). Further
support comes from the observation that in this subgroup of AIT
patients, the thyrotoxic phase is sometimes followed by mild
hypothyroidism (89), as may happen after subacute thyroiditis. This
progression may be accelerated by reexposure of the patient to an
iodine load (90).
To summarize, two main forms of AIT exist. Type I AIT usually occurs in
abnormal thyroid glands and is due to iodine-induced excessive thyroid
hormone synthesis and release; type II AIT is a destructive thyroiditis
leading to release of preformed thyroid hormones from the damaged
thyroid follicular cells. The relative prevalence of the two forms of
AIT is unknown, but it may depend on the ambient iodine intake. For
example, in Japan, an iodine-sufficient area with a very low incidence
of toxic multinodular goiter, only destructive-type AIT was observed
(91) Definitions of AIT may not be so absolute, and indeed mixed forms
often exist, in which the different features of type I and type II AIT
may coexist. This is suggested, for example, by the observation that
some patients with type I AIT may have markedly increased serum IL-6
levels (79). Nevertheless, the effort to identify the different
subgroups of AIT has important clinical implications regarding the
difficult management of this challenging situation (see below).
b. Clinical manifestations.
Classical symptoms of
thyrotoxicosis may be absent, due to the antiadrenergic action of
amiodarone and its impairment of conversion of T4
to T3; goiter may be present or absent, with or
without pain in the thyroid region; ophthalmopathy is usually absent,
unless AIT occurs in a patient with Graves’ disease (9, 10, 11, 12). AIT may
be heralded by a worsening of the underlying cardiac disorder, with
tachyarrhythmias or angina (63). The occurrence or recurrence of
tachycardia or atrial fibrillation in a patient treated with amiodarone
should be considered a good reason to investigate thyroid function
(92). Diagnosis of AIT may be a difficult challenge in patients with
severe nonthyroidal illness, because the latter may dominate the
clinical picture (84) and result in increased serum free
T4, decreased/suppressed serum TSH, and decreased
serum total and free T3 concentrations (62):
under these circumstances, measurement of serum free
T3 concentration may, however, be useful in
establishing the diagnosis (93). Serum thyroglobulin is often increased
in AIT, but this may not represent a good marker of thyroid destruction
in goitrous patients. In addition, unexplained suppression of serum
thyroglobulin secretion has been reported in a few AIT patients (94).
Serum sex hormone binding globulin (SHBG) concentration is increased in
AIT patients but not in euthyroid amiodarone-treated subjects with
hyperthyroxinemia (95); however, this assay is of limited importance in
individual patients, due to the numerous factors affecting serum SHBG
levels.
c. Treatment.
Treatment of AIT is a major challenge. The high
intrathyroidal iodine content reduces the effectiveness of conventional
thionamide drug therapy (63). The generally low or suppressed RAIU
values makes the administration of radioiodine therapy not feasible. An
increase in RAIU values has been reported after administration of
exogenous TSH (96). This possibility should be reevaluated using
recombinant human TSH. Thyroidectomy may represent a valid option for
AIT patients resistant to medical treatment, although the underlying
cardiac conditions and the thyrotoxic state may increase the surgical
risk or even exclude surgery in some patients. About 30 AIT patients
treated by thyroidectomy have been reported: this procedure was
associated with a prompt control of thyrotoxicosis, and no death
occurred (72, 87, 88, 97, 98, 99). Plasmapheresis, aimed at removing the
excess thyroid hormones from the circulation, has been reported to be
efficacious (100), but this is usually transient and followed by an
exacerbation of AIT (101, 102).
The identification of the different subtypes of AIT may provide a
rational basis for the choice of the appropriate medical treatment in
an effort to improve the therapeutic outcome. In type I AIT the goal of
treatment should be, on one hand, to block further organification of
iodine and synthesis of thyroid hormones. Since the iodine-rich thyroid
is more resistant to the therapeutic efficacy of the thionamides,
larger than usual daily doses of methimazole (40–60 mg) or
propylthiouracil (600–800 mg) are often necessary. On the other hand,
one should also decrease the entrance of iodine into the thyroid and
deplete intrathyroidal iodine stores to improve the therapeutic
efficacy of thionamides and to allow subsequent radioiodine therapy.
The latter effect can be achieved by potassium perchlorate, a drug that
inhibits thyroid iodine uptake (103). Treatment of AIT by the
simultaneous administration of potassium perchlorate and methimazole
was first reported by our group (104). In this study, 23 AIT patients
were treated with methimazole (40 mg daily) alone, with methimazole and
potassium perchlorate (1 g daily), or were not treated (104). Only the
combined treatment controlled thyrotoxicosis in all cases. In addition,
the time required for the attainment of euthyroidism was shorter than
that in patients responsive to conventional thionamide treatment (104).
The combined treatment was associated with a transient rise in serum
thyroid hormone levels and urinary iodine excretion (104). These
results were subsequently confirmed by other studies (69, 105). The
limitation of potassium perchlorate is its toxicity, particularly
agranulocytosis and aplastic anemia, and renal side effects. Trotter
(106) compared the toxicity of thionamides and perchlorate and reported
that the total incidence of reactions to perchlorate was 2–3%.
Agranulocytosis occurred in 0.3% of 1,200 perchlorate-treated patients
compared with 0.94% of the 10,131 thionamide-treated patients (106).
However, when the daily dose of perchlorate exceeded 1 g, the
incidence of toxicity increased to 16–18% (106). More recently,
Wenzel and Lente (107) treated patients with Graves’ disease for 2 yr
with initial doses of 900 mg daily decreasing to 40–120 mg, and no
hematological toxicity was recorded. A complete blood count should be
done every few weeks in patients receiving thionamide and perchlorate
to detect the potential development of anemia and/or agranulocytosis.
In addition, it seems prudent to withdraw potassium perchlorate if
euthyroidism is achieved, frequently by 6 weeks, associated with
removing the refractoriness to thionamides related to excess
intrathyroidal iodine stores. Shorter periods of perchlorate therapy (8
days) seem to result in a high risk of recurrent thyrotoxicosis (108).
The addition of lithium carbonate (900–1350 mg/day for 4–6 weeks) to
propylthiouracil has been reported in a small series of AIT patients to
shorten substantially the time period necessary to achieve euthyroidism
(109). The latter results will require confirmation in controlled
studies enrolling a larger number of patients.
Thionamides with or without potassium perchlorate are not an
appropriate form of therapy for type II AIT, which is a destructive
thyroiditis induced by amiodarone. Steroids are a good and effective
therapeutic approach in these cases because of their
membrane-stabilizing and antiinflammatory effects (110). In addition,
they are beneficial because of their inhibition of 5'-D activity.
Steroids have been employed in AIT at different doses (15–80 mg
prednisone or 3–6 mg dexamethasone daily) and different time schedules
(7–12 weeks) (9, 10, 11, 12). Results of steroid treatment, either alone or in
combination with antithyroid drugs or plasmapheresis, have been
favorable in most studies in patients with type II AIT (96, 110, 111, 112, 113, 114),
whereas the data in type I AIT are scant but seem to indicate limited
effectiveness (110). It is worth mentioning the possible recurrence of
thyrotoxicosis when steroid treatment is discontinued (111, 112, 115);
steroid treatment must be reinstituted in these patients. For a
subgroup of patients with mixed forms of AIT, a combination of
methimazole, potassium perchlorate, and steroids is probably the most
beneficial therapeutic regimen.
A relevant problem is whether amiodarone therapy should be
discontinued or not. Obviously, amiodarone is a very effective drug for
the underlying cardiac problem, and quite often these patients are
resistant to other antiarrhythmic drugs. This may make withdrawal of
amiodarone impossible, especially in patients in whom the original
indication for this pharmacological treatment was a life-threatening
tachyarrhythmia, such as ventricular tachycardia or fibrillation. In
addition, even discontinuation of amiodarone therapy does not prevent a
continuing effect on the thyroid due to its long half-life.
Furthermore, in view of the hypothyroid-like effect of amiodarone and
its metabolites on the heart (9), amiodarone might, to some extent,
paradoxically protect the heart from thyroid hormone excess; therefore,
withdrawal of the drug might be associated with an exacerbation of
"heart thyrotoxicosis" (116). Indeed, a worsening of thyrotoxic
symptoms and cardiac conditions has occasionally been reported after
amiodarone was discontinued (72, 96). There are a few reports in the
literature demonstrating successful management of AIT with antithyroid
drugs while amiodarone therapy was continued (105, 117, 118). Since AIT
is widely accepted to be much more difficult to treat than "normal"
hyperthyroidism, we believe that withdrawal of amiodarone, when
feasible as in the case of non-life-threatening arrhythmias, should be
part of the management of AIT patients, although some patients have
mild disease and respond to thionamide and/or glucocorticoid therapy,
depending upon the type of AIT. In these patients amiodarone may be
continued since the AIT seems to be self-limited.
A rational approach might be the following (Table 6): 1) Identify the subtype of AIT (type
I, type II, mixed forms) if possible; 2) Treat type II with steroids
for 3 months, with a starting dose of 30–40 mg prednisone (or
equivalent) and a gradual, slow reduction to minimize the risk of
recurrences; 3) Treat type I AIT with methimazole and potassium
perchlorate (1 g daily for no more than 30–40 days); 4) If the two
types cannot be distinguished (mixed forms), triple therapy with a
thionamide, potassium perchlorate, and glucocorticoids is a practical
solution. In cases in which withdrawal of amiodarone is not feasible
and medical therapy has failed, thyroidectomy represents a useful
alternative. Definitive treatment of the underlying thyroid disorder
will usually be required in most type I AIT patients; this can
occasionally be accomplished by radioiodine, provided the RAIU values
become adequate (Table 6). Most type II patients will remain euthyroid
after resolution of the thyrotoxicosis; some of them may eventually
develop hypothyroidism, either spontaneously or after reexposure to
iodine (89, 90). The hypothyroidism that occasionally occurs may be
more prolonged than that which occurs after postpartum lymphocytic
thyroiditis or painful, subacute thyroiditis since the excess iodine
and amiodarone persist, even if the amiodarone is discontinued. In
patients with a history of AIT in whom amiodarone becomes necessary
after it has been discontinued, ablation of the thyroid with
radioiodine before resuming amiodarone should be strongly considered.
2. Amiodarone-induced hypothyroidism. AIH occurs more
frequently than AIT in iodine-sufficient areas (62). In contrast to
AIT, AIH is slightly more frequent in females, with a female to male
ratio of 1.5:1 (25, 44, 62, 119, 120). AIH patients are older than AIT
patients (119, 120). AIH usually develops earlier than AIT, both in
patients with apparently normal thyroid glands and in patients with
preexisting thyroid abnormalities (44, 64, 121, 122, 123). Among 28 AIH
patients, underlying thyroid abnormalities were found in 19 (68%),
while the remaining 9 (32%) had no detectable abnormalities (64).
Among preexisting abnormalities, the presence of circulating thyroid
autoantibodies appears to be particularly relevant, since they were
detected in 53% of AIH patients with underlying thyroid abnormalities
(64). Indeed, female sex or the presence of circulating anti-thyroid
peroxidase (TPO) antibodies represented a relative risk of 7.9 and 7.3,
respectively, for the occurrence of AIH; the combination of female sex
and antithyroid antibodies increased the risk to 13.5 (44). In another
series, five of seven patients (71%) with baseline positive
antithyroid antibody tests developed hypothyroidism during long-term
amiodarone treatment (65). Thus, preexisting Hashimoto’s thyroiditis
is an established risk factor for the occurrence of hypothyroidism in
amiodarone-treated patients (64). This is in keeping with previous
observations showing that patients with Hashimoto’s thyroiditis
chronically treated with iodine have an enhanced susceptibility to
develop myxedema (124). It is also possible that the cytotoxicity
induced by amiodarone would decrease the possibility of a goiter
developing while receiving amiodarone.
a. Pathogenesis.
The most likely pathogenic mechanism is that
the thyroid gland of these patients, damaged by preexisting
Hashimoto’s thyroiditis, is unable to escape from the acute
Wolff-Chaikoff effect after an iodine load (125) and to resume normal
thyroid hormone synthesis. A subtle defect in thyroid hormonogenesis
may explain the enhanced susceptibility to the inhibitory effect of
iodine on thyroid hormone synthesis and the inability to escape from
the acute Wolff-Chaikoff effect (64). In cell cultures,
amiodarone had a more potent and persistent inhibitory effect on
TSH-stimulated cAMP production in vitro than iodine (126).
The hypothesis of a defect in the hormonogenetic process seems to be
tenable in view of the observation that these patients have a positive
perchlorate discharge test, indicating a defect in iodine
organification (64, 123). In addition, while normally the increase in
iodine intake causes a low RAIU because of dilution of the tracer by
the increased stable iodide pool, in patients with AIH the thyroid
iodine uptake may not be inhibited, although such findings are rare in
the United States where ambient iodine intake is sufficient (76, 77)
(Fig. 7). This may be due to excess TSH
stimulation of the thyroid. In addition to these functional changes,
AIH occurring in patients with Hashimoto’s thyroiditis may also be
related to the fact that iodine-induced nonspecific damage to the
thyroid follicles may add to that caused by the preexisting autoimmune
thyroiditis, thus accelerating the natural trend of Hashimoto’s
thyroiditis toward hypothyroidism (64). In AIH patients without
underlying thyroid abnormalities and with negative thyroid autoantibody
tests, subtle defects in iodine organification and thyroid hormone
synthesis are likely the best explanation for the occurrence of AIH. It
has been reported that AIH may spontaneously remit (120, 123, 127, 128). In 20 patients followed prospectively, AIH was transient in 12
and persistent in 8; 7 of the latter patients had positive anti-TPO
antibody tests (64).
View larger version (15K):
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Figure 7. Twenty-four-hour thyroidal RAIU in patients with
spontaneous (SPONT HYPO) or amiodarone-induced (AIH) hypothyroidism,
and in euthyroid subjects chronically treated with amiodarone (EUAM).
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b. Clinical manifestations.
Similar to spontaneous
hypothyroidism, AIH patients frequently have vague symptoms and signs,
such as fatigue, cold intolerance, mental sluggishness, and dry skin
(123). A case of myxedema coma occurring during long-term amiodarone
therapy has been reported (122). In patients already on
L-T4 replacement therapy, the dose of
L-T4 may need to be increased due to
the inhibition of the generation of T3 from
T4 induced by amiodarone (129). Laboratory
findings are similar to those in spontaneous hypothyroidism, with
decreased serum free T4 and increased serum TSH
concentrations (11). Serum thyroglobulin is often increased, probably
because of the enhanced thyroid stimulation by TSH (64).
c. Treatment.
Management of AIH does not have the complexity
observed with AIT (Table 7). If
amiodarone is necessary for the underlying cardiac disorder, it can be
continued in association with L-T4
replacement. L-T4 is the drug of
choice, particularly in these patients with cardiac problems, because
it requires only once-daily administration and is not associated with
the spikes in serum thyroid hormone concentrations observed in patients
given L-T3. The serum TSH
concentration is the most important parameter to monitor therapy. If
discontinuance of amiodarone therapy is feasible, spontaneous remission
of hypothyroidism often occurs, particularly in patients without
underlying thyroid abnormalities, while this outcome is less likely to
occur in patients with Hashimoto’s thyroiditis (64). Thus, it is our
policy to continue amiodarone and to treat with
L-T4, often requiring larger doses of
L-T4 to normalize the serum TSH in
view of the inhibitory effects of amiodarone on
T4 conversion to T3. In
view of the fact that these patients often have severe underlying
cardiac disease, it is advisable to maintain the serum TSH
concentration in the upper half of the normal range. If amiodarone is
discontinued, to shorten the period of time between discontinuing
amiodarone and the attainment of hypothyroidism, a short course (10–30
days) of potassium perchlorate (1 g daily) can be given (130). This
treatment was associated with a prompt restoration of euthyroidism in
six of nine patients, although a second course of potassium perchlorate
was required in the remaining three patients to achieve persistent
euthyroidism (130). The rationale for this treatment resides in the
fact that potassium perchlorate inhibits thyroid iodide uptake, thereby
blocking further entrance of iodide into the thyroid and decreasing the
inhibitory effect of excess intrathyroidal iodine.
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IV. Recommendations for Following Patients Receiving Amiodarone
Therapy
|
|---|
It is essential to carefully evaluate patients before and during
amiodarone therapy (Fig. 8). A careful
thyroid gland examination, and perhaps a thyroid ultrasound on initial
evaluation, is essential since the presence of a nodular or diffuse
goiter increases the risk of AIT, which can occur up to years after
amiodarone is begun. Baseline serum TSH, total and free
T4 or free T4 index, total
and free T3 concentrations and thyroid peroxidase
antibodies (TPOAb) are recommended so that changes in thyroid function
during amiodarone administration can be carefully monitored. The
presence of TPOAb markedly increases the risk of developing AIH since
chronic autoimmune thyroiditis predisposes the patient for the
development of iodine-induced hypothyroidism, which most often occurs
during the first year of therapy.
Repeat serum TSH, total and free T4 or free
T4 index, total and free T3
concentrations and a careful thyroid gland examination should be done
every 6 months or sooner should symptoms of hyper- or hypothyroidism
develop. Refractoriness to antiarrhythmic therapy may reflect the
development of AIT. Although the serum TSH may occasionally be low in
euthyroid amiodarone-treated patients, it remains the single best test
to monitor thyroid function. If the serum TSH becomes low and the serum
T4 and T3 do not rise above
previous values on amiodarone and the patient remains clinically
euthyroid, more frequent evaluations are necessary but definitive
therapy should be withheld. As noted earlier, serum
T4 is often in the high normal range or slightly
elevated during amiodarone therapy. A high normal or slightly elevated
serum T3, however, is extremely helpful in the
diagnosis of AIT in these patients. An elevated serum TSH value during
chronic amiodarone therapy strongly suggests the occurrence of AIH.
|
V. Amiodarone and Pregnancy
|
|---|
If amiodarone therapy is required, it can be administered
during pregnancy, although it may cause changes in fetal thyroid
function. Among a total of 64 pregnant women treated with amiodarone
(131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150), abnormalities in thyroid function were found in 13 neonates
(20%), 2 of whom had transient hyperthyroxinemia and 11 (17%) had
AIH, associated with goiter in 2 cases. Congenital hypothyroidism
related to amiodarone therapy in the mother is likely to be transient,
but it seems wise to promptly start
L-T4 therapy in the newborn. In one
case L-T4 was given in
utero via intraamniotic administration (148). The reason to start
L-T4 treatment is that
growth and motor and mental development were normal in some instances
(142, 149, 150), but impaired in others (143, 146). In a recent
long-term follow-up of eight toddlers exposed transplacentally to
amiodarone, all subjects had normal social competence and favorable
global IQ scores, but showed some problems in reading comprehension,
written language, and arithmetic, a picture reminiscent of the
Nonverbal Learning Disability Syndrome (151). The effects of amiodarone
during pregnancy on subsequent neonatal thyroid function and
development have been recently reviewed in greater detail (152).
Since amiodarone is secreted in the milk, breast feeding is not
absolutely contraindicated but carries a risk because he fetus is very
sensitive to iodine-induced hypothyroidism (9, 143). Therefore, thyroid
function in the neonate must be carefully monitored to rule out the
possible occurrence of AIH.
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VI. Conclusions
|
|---|
Amiodarone is a very effective drug, widely used for
tachyarrhythmias and, to a lesser extent, ischemic heart disease. Its
use is associated with variations in thyroid function tests that do not
reflect true changes in thyroid status. However, a substantial
proportion (14–18%) of amiodarone-treated patients develop either
hypothyroidism or thyrotoxicosis. Both abnormalities may occur in
apparently normal glands or in glands with preexistent abnormalities.
The occurrence of AIH does not necessitate withdrawing amiodarone while
instituting L-T4 replacement therapy,
although many cases are transient and will spontaneously remit after
amiodarone withdrawal. AIT is a far more complex diagnostic and
therapeutic challenge. Therapeutic options include thionamides (alone
or in association with potassium perchlorate), glucocorticoids, and
thyroidectomy. The identification of two main subtypes of AIT and of
the respective pathogenic mechanisms provides the basis for a rational
approach to medical treatment. In type I AIT, occurring in abnormal
thyroid glands and related to excessive iodine-induced thyroid hormone
synthesis, the present best initial treatment is a combination of
thionamides and potassium perchlorate. In type II AIT, a form of
destructive thyroiditis associated with very high serum IL-6 levels,
glucocorticoid administration is the treatment of choice. Mixed forms
of AIT, in which thionamides, potassium perchlorate, and
glucocorticoids are administered simultaneously, are probably more
common than formerly realized. In patients in whom amiodarone
must be continued and medical therapy has failed, thyroidectomy is a
valid alternative and does not carry a markedly higher surgical risk.
Radioiodine is not feasible in most cases, due to the low RAIU values.
Amiodarone, if absolutely necessary, can be administered to pregnant
women, but thyroid function in the neonate must be carefully monitored
because of the possible occurrence of AIH.
|
Acknowledgments
|
|---|
We are grateful to Professor Aldo Pinchera for his continuous
encouragement and advice.
|
Footnotes
|
|---|
Address reprint requests to: Professor Enio Martino, Dipartimento di Endocrinologia e Metabolismo, University of Pisa, Ospedale di Cisanello, via Paradisa, 2, 56124 Pisa, Italy. E-mail:
e.martino{at}endoc med.unipi.it; or Dr. Lewis E. Braverman, Boston
1 This work was supported in part and by grants from the University of
Pisa (Fondi d’Ateneo) to Enio Martino e Luigi Bartalena, and from the
Ministero della Università e della Ricerca Scientifica e
Tecnologica (M.U.R.S.T.), Rome to Enio Martino. 
|
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Abstract
I. Introduction
