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The Journal of Clinical Endocrinology & Metabolism 86(10):4707– 4710
Copyright © 2001 by The Endocrine Society
Use of Oral Cholecystographic Agents in the Treatment
of Amiodarone-Induced Hyperthyroidism
INDER J. CHOPRA
AND
KHANSA BABER
Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, University of California Center for Health
Sciences, Los Angeles, California 90024
We describe here five cardiac patients with type II amiodarone-induced hyperthyroidism who were treated prospectively with a combination of an oral cholecystographic agent
(sodium ipodate, Oragrafin, or sodium iopanoate, Telepaque)
and a thionamide (propylthiouracil or methimazole); amiodarone was discontinued in all patients. All patients improved
substantially clinically within a few days of treatment and
became euthyroid or hypothyroid in 15–31 wk when treatment
was discontinued. Four of the five became hypothyroid and
required long-term treatment with L-T4; the remaining patient
A
MIODARONE IS AN effective, iodine-rich, antiarrhythmic agent that may cause both hyper- and hypothyroidism (1). It was approved by the FDA in 1985 for the
treatment of serious ventricular arrhythmias; it reduces complex ventricular ectopy and cardiac-related mortality (2, 3).
It is also effective in the treatment of paroxysmal supraventricular tachycardia and atrial fibrillation and flutter (2).
Amiodarone is a benzofuron derivative with some structural
similarities to thyroid hormone. It has two iodine atoms, and
iodine accounts for 39.3% of its mol wt (4). Some 8 –17% of
iodine in amiodarone is converted daily to inorganic iodine
(5). Chronic treatment with amiodarone is associated with
hyperthyroidism in up to 23% and with hypothyroidism in
up to 32% of patients (6).
Amiodarone-induced hyperthyroidism (AIH) is particularly common in regions with underlying iodine deficiency,
e.g. Europe, where the incidence of hyperthyroidism approximates 20% of patients taking amiodarone (6). In iodine-rich
regions, the incidence of AIH is generally less than 10% (7).
Two types of AIH have been described. Type I AIH (AIH I)
is associated with an underlying disorder of the thyroid
gland, and hyperthyroidism is triggered by the large amount
of iodine liberated from the metabolism of amiodarone. Both
nodular goiter and autoimmune thyroid disease can be associated with this type of AIH (8). In contrast, type II AIH
(AIH II) is characterized by thyroiditis, a form of toxic thyroiditis, wherein the inflammatory process of the thyroid and
the associated derangement of its follicular parenchyma lead
to the leakage of thyroid hormones into the circulation. This
clinical picture is similar to that in subacute thyroiditis (8).
Because of the fat solubility and long half-life (⬃20 –100 d)
of amiodarone (7–9), the treatment of AIH is often more
Abbreviations: AIH, Amiodarone-induced hyperthyroidism; AIH I,
type I amiodarone-induced hyperthyroidism; AIH II, type II amiodarone-induced hyperthyroidism; FT3I, free T3 index; 5⬘-MD, 5⬘-monodeiodinases; OCA, oral cholecystographic agent.
was euthyroid, but died from cardiomyopathy and congestive
heart failure at 29 wk, when he had been off oral cholecystographic agent and thionamide for 6 wk. We did not find any
clinical or biochemical adverse effects of the treatment. Our
study suggests that a combination of oral cholecystographic
agent and thionamide is a safe and effective treatment of type
II amiodarone-induced hyperthyroidism. Data also suggest
that hypothyroidism is a common end result of type II amiodarone-induced hyperthyroidism. (J Clin Endocrinol Metab
86: 4707– 4710, 2001)
difficult and prolonged than that of the other forms of iodineinduced hyperthyroidism (10 –18). We describe in this report
the combined use of oral cholecystography agents (OCAs)
and antithyroid drugs (thionamides) in the management of
AIH. OCAs are very potent inhibitors of iodothyronine 5⬘monodeiodinases (5⬘-MD) that catalyze the activation of the
prohormone T4 to the more potent T3 (19). OCAs have previously been shown to be effective in the management of
other forms of hyperthyroidism, e.g. Graves’ disease, thyroiditis, and thyrotoxicosis factitia (20 –24).
Materials and Methods
We studied prospectively five consecutive patients (42–71 yr old)
with AIH II between 1995–2000. All patients were from clinical practice
of I. J. Chopra. The diagnostic criteria for the AIH II included biochemical
hyperthyroidism, normal-sized thyroid, no clinically discernible nodules, and undetectable antithyroid (anti-Tg and antithyroid peroxidase)
autoantibodies. Patients were all males, who presented with clinical
features of weight loss, muscle weakness, finger tremors, palpitation,
and/or dyspnoea. The underlying cardiac diagnosis was cardiomyopathy in three cases and congenital heart disease in two cases with
congestive heart failure and cardiac arrhythmias. Initial thyroid function
test data are shown in Table 1. Patients had a history of long-term
ingestion of amiodarone for 30 months or longer. Thyroid radioiodine
uptake was measured in one patient, and it was markedly decreased
(⬍1%). Amiodarone was discontinued after the diagnosis of AIH in all
cases. All patients were started on treatment of hyperthyroidism using
OCAs [sodium ipodate (Oragrafin, Bracco Diagnostics, Princeton, NJ;
500 mg/d; three patients) or sodium tyropanoate (Telepaque, Nycomed,
Princeton, NJ; 500 mg 1–2 times/d; two patients)] and an antithyroid
drug [propylthiouracil (100 –150 mg, three times per d; four patients) or
methimazole (Tapazole; 15 mg, twice daily; one patient)]. Case 3 was
treated first with ipodate for about 10 wk and later with iopanoate for
5 wk because ipodate was no longer available. Glucocorticoids were not
used to treat our patients.
The serum concentration of free T3 and/or the free T3 index (FT3I) was
decreased to normal or near normal in four of five patients when first
measured after initiation of treatment; the response of serum free T3 or
FT3I was slow in the remaining patient (Fig. 1). The dose of the drugs
for treatment of hyperthyroidism was decreased gradually as the serum
concentration of free T4 decreased to normal or near normal. Treatment
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J Clin Endocrinol Metab, October 2001, 86(10):4707– 4710
Chopra and Baber • Oral Cholecystographic Agents in Treatment of AIH
TABLE 1. Clinical data and initial serum levels of TSH, free T4 index (FT4I), free T3 index (FT3I), free T4 (FT4) by dialysis, free T3 (FT3)
by dialysis, and/or antithyroid antibodies in patients with AIH under study
Case no.
1
2
3
4
5
Reference range
Age
(yr, sex)
42,
64,
63,
59,
59,
M
M
M
M
M
Weight
(lbs)
TSH
(mIU/liter)
237
244
179
250
180
0.1
⬍0.02
⬍0.02
0.07
0.02
0.3– 4.7
FT4I
FT3I
19.3
25.0
45.6
12.3
181
301
716
216
5–11
80 –175
FT4a
(ng/dl)
8.4
5.3
24.9
0.7–2.2
FT3a (pg/
dl)
620
754
210 – 440
Antithyroid
antibodies
Thyroid 123I
uptake
UD
UD
UD
UD
UD
⬍2 IU/ml
ND
ND
ND
very low
ND
M, Male; UD, undetectable; ND, not done.
FT4 and FT3 by dialysis, measurements done by RIA after equilibrium dialysis (Ref. 25).
a
was needed for 15–31 wk before both serum free T4 and free T3 (or FT3I)
decreased to normal and stayed normal or became subnormal after the
drugs were discontinued. Serum levels of free T3 and free T4 by dialysis,
FT4I, FT3I, TSH, and antithyroid antibodies were measured in the clinical
laboratories of University of California-Los Angeles as described previously (25). The study was approved by the institutional review board
at University of California-Los Angeles.
Results
Figure 1 shows the data from thyroid function tests performed during and after treatment with the drug combination studied. All patients studied reported marked improvement in symptoms at their first visit (8 –15 d) after initiation
of treatment with OCA. We observed no side effects of treatment with OCA. Four of five patients became hypothyroid
in 15–31 wk (Table 2) and have required treatment with T4
to maintain euthyroid status. The remaining patient became
euthyroid with normal serum free T4 and TSH levels at 20 wk
of treatment and remained euthyroid when treatment was
gradually tapered off at 23 wk. However, he died 6 wk later
from cardiomyopathy and congestive heart failure. Two of
the four hypothyroid patients (cases 1 and 3) treated with T4
were, after about 1 yr of treatment, asked to discontinue T4
for 1 month, and their serum TSH levels were measured. Both
demonstrated elevated serum TSH, suggesting prolonged,
possibly permanent, hypothyroidism. All four patients who
became hypothyroid are stable and/or feel improved on
continued T4 treatment.
Discussion
Amiodarone is a very effective antiarrhythmic agent, but
it has several adverse effects, including thyroid dysfunction.
Chronic treatment with amiodarone is associated with hyperthyroidism (AIH) in up to 23% of patients and with hypothyroidism in up to 32% of patients (6). It can be difficult
to manage hyperthyroidism, and thyroidectomy has been
employed in some cases (26). We find that thyroidectomy is
often a significant challenge in seriously ill AIH patients with
compromised cardiac status. AIH I has been treated with a
combination of a thionamide and potassium perchlorate (18),
whereas AIH II has been responsive to treatment with corticosteroids (27). However, several patients continue to manifest prolonged hyperthyroidism and its adverse cardiac effects despite these treatments (18), whereas several patients
treated with corticosteroids suffer from their side effects.
Furthermore, potassium perchlorate is a potentially toxic
agent with some side effects as serious as aplastic anemia and
agranulocytosis (12, 28). Fortunately, however, these serious
side effects of potassium perchlorate are uncommon (29).
Our study demonstrated that OCAs are safe and effective
agents to quickly lower serum free T3 levels to normal or near
normal levels in AIH patients. OCAs act by strongly inhibiting iodothyronine 5⬘-MD (19, 30). Thus, on a molar or
weight basis, sodium ipodate (Oragrafin) is among the most
potent inhibitors of iodothyronine 5⬘-MD, followed by sodium tyropanoate (Telepaque) (19). Ipodate inhibits this
deiodinase competitively with respect to T4. It inhibits iodothyronine 5⬘-MD in all tissues where it is present, including liver, kidney, and thyroid (19, 31). It has previously been
shown to be effective in the management of hyperthyroidism
in Graves’ disease, thyroiditis, and thyrotoxicosis factitia
(20 –24). It reduces the serum T3 concentration markedly and
to near-normal levels in hyperthyroid patients within 24 –36
h of initiation of treatment (19 –21). Thus, in hyperthyroid
patients with Graves’ disease, ipodate treatment caused an
average 70% reduction in the serum T3 concentration within
48 h (20). Additionally, OCAs improve hyperthyroidism by
other mechanisms. Thus, ipodate has been shown to reduce
tissue uptake of thyroid hormones (32). It is also a known
inhibitor of the nuclear building of T3 (33). Its effects on the
thyroid gland include reduced thyroid hormone synthesis,
decreased proteolysis of Tg, decreased thyroidal response to
TSH, and decreased release of thyroid hormone from the
thyroid gland (34). Although the thyroidal effects of ipodate
are of interest, they probably play a minor role in improving
hyperthyroidism caused by leakage of thyroid hormones
observed in thyroiditis or by ingestion of T4 in thyrotoxicosis
factitia. The peripheral tissue effects of ipodate mentioned
above are apparently mainly responsible for the systemic
improvement observed after treatment with OCAs in these
disorders (25). Another study of five hyperthyroid patients
with severe heart failure treated with methimazole (45
mg/d) and a single dose of ipodate (3 g) demonstrated a
marked improvement in cardiovascular parameters measured by the Swan-Ganz catheter (35). Thus, there was a
significant decrease in systolic pressure and pulse pressure
within 24 h after the administration of ipodate. Heart rate
decreased from a mean of 132 to 110 beats/min, cardiac index
fell 36.7% within 12 h after ipodate treatment, and there was
a near normalization of the stroke volume and total systemic
resistance. Additionally, left ventricular work improved progressively, while right ventricular work remained normal. T3
levels decreased in parallel with these improvements by 67%
Chopra and Baber • Oral Cholecystographic Agents in Treatment of AIH
J Clin Endocrinol Metab, October 2001, 86(10):4707– 4710 4709
TABLE 2. Duration of treatment with OCAs and thionamides
and final outcome of AIH patients studied
Case
No.
Duration of
treatment with
OCAs (wk)a
Duration of
treatment with
thionamide
(wk)b
1
2
3
4
22
26
15
23
31
26
15
23
5
17
17
Final outcome
Hypothyroid
Hypothyroid
Hypothyroid
Euthyroid at 23 wk, and
then died at 29 wk
Hypothyroid
a
The OCA used was sodium ipodate (Oragrafin) in cases 1, 2, and
4 and sodium tyropanoate (Telepaque) in cases 3 and 5.
b
The thionamide used was propylthionrocil in cases 1– 4 and carbimazole in case 5.
however, because the iodine liberated from the metabolism
of amiodarone may actually worsen hyperthyroidism. In a
previous study several treatment modalities for hyperthyroidism, including ipodate, were tried without success in a
patient with AIH (26). This case may have had type I or a
combination of type I and type II AIH; he had to be treated
with thyroidectomy (26).
Interestingly, we observed no appreciable adverse effects
of treatment with OCAs in our patients. Our study suggests
that the combination of an OCA and a thionamide should be
a useful treatment of AIH as in selected cases of other forms
of hyperthyroidism. Curiously, we also discerned a high
incidence of hypothyroidism in four of five cases of AIH II
studied. Hypothyroidism was prolonged and persisted for
over a year in two cases studied. Others have reported hypothyroidism after AIH even when patients were not treated
with OCAs (36, 37).
Acknowledgments
Received February 22, 2001. Accepted May 10, 2001.
Address all correspondence and requests for reprints to: Inder J. Chopra, M.D., Division of Endocrinology, Metabolism, Diabetes, and Metabolism, 900 Veteran Avenue, Suite 24-130, Warren Hall, Los Angeles,
California 90095-7073. E-mail: [email protected].
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FIG. 1. Serum FT3I and free T4 determined by dialysis and of TSH in
five patients with AIH II studied during treatment with a combination of an OCA (sodium ipodate, Oragrafin, or sodium tyropanoate,
Telepaque) and a thionamide (propylthiouracil or methimazole).
Treatment was discontinued when patients were euthyroid or hypothyroid. L-T4 treatment was added when serum TSH was elevated.
after 24 h (35). These effects of OCAs may represent additional benefits for cardiac patients with AIH who are treated
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Our study suggested that OCAs are safe and effective in
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