Download Amiodarone Induced Thyroid Dsyfunction

MEDICINE
REVIEW ARTICLE
Amiodarone Induced
Thyroid Dsyfunction
George J. Kahaly, Markus Dietlein, Roland Gärtner,
Klaus Mann, Henning Dralle
SUMMARY
Introduction: Amiodarone, an iodine containing antiarrhythmic, induces functional thyroid
dysfunction in circa 40% of patients receiving it.These disorders can be iodine-induced, or due
to immunotoxic effects on thyrocytes. Methods: Selective literature review. Results: 2 types of
amiodarone-induced hyperthyroidism are recognized. Type 1 is caused by unregulated
hormonal synthesis; type 2 is due to the release of preformed hormone by inflammatory
destruction of the gland. Color-flow doppler sonography is a helpful diagnostic tool. In type 1,
amiodarone should be discontinued where possible, although this will not immediately restore
normal thyroid function. Thionamides, potassium perchlorate, and lithium can be used to treat
type 1, and steroids to treat type 2. Patients with mixed forms should be managed with
combination therapy. Thyroidectomy is advisable for patients with severe type 1. Amiodarone
need not be discontinued in amiodarone-induced hypothyroidism. Discussion: Amiodaroneinduced thyroid complications are best prevented through accurate monitoring of thyroid
morphology and function both before and during amiodarone treatment.
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Key words: amiodarone, thyroid, thyroid function, interdisciplinary, evidence based
R
esults of randomized trials have confirmed the superiority of amiodarone in the
management of atrial and ventricular arrhythmias (1). The problem with amiodarone
therapy, however, is its organotoxicity. Complications that give grounds for concern
include therapy refractory thyroid dysfunction (2, 3).
Based on recent findings relating to the diagnosis and therapy of thyroid abnormalities
associated with amiodarone, up-to-date, evidence based and interdisciplinary recommendations
for prophylaxis and practical procedure are offered below. So far, there is a lack of standards
approved by all members of the Thyroid Section of the German Society for Endocrinology.
This survey article is based on a selective literature review by George J. Kahaly and his
co-authors.
Prevalence and predisposing factors
The prevalence and incidence of amiodarone related thyroid dysfunction are geographically
variable and correlate with iodine supply (2). Hypothyroidism tends to be more prevalent
in countries with a sufficient iodine supply, such as the USA (22% versus 2% hyperthyroidism), while it is rarer in countries with lower iodine uptake, such as Italy (5%) or the
Netherlands (6%) (versus 12% to 13% hyperthyroidism). Worldwide, hyperthyroidism has
been described in 1% to 23% and hypothyroidism in 1% to 36% of patients treated with
amiodarone (3). The main predisposing factors for amiodarone induced hyperthyroidism
are high iodine intake and/or nodular goiter with low basal thyroid stimulating hormone
(TSH) (functional autonomy) due to years of iodine deficiency. Genetic factors (such as
HLA anti-gens as risk markers for the development of immunothyropathy) are also implicated
but are not responsible for a large proportion of the explained variance (see box). The
presence of thyroid antibodies and subclinical hypothyroidism predispose individuals with
simultaneously elevated iodine intake to develop amiodarone induced hypothyroidism (4).
I. Medizinische Univ.-Klinik und Poliklinik, Mainz: Prof. Dr. med. Kahaly; Klinik und Poliklinik für Nuklearmedizin, Universität zu
Köln: Prof. Dr. med. Dietlein; Medizinische Univ.-Klinik, Klinikum Innenstadt, LMU München: Prof. Dr. med. Gärtner; Klinik für Endokrinologie, Universitätsklinikum Essen: Prof. Dr. med. Mann; Klinik und Poliklinik für Allgemein-, Viszeral- und Gefäßchirurgie,
MLU Halle: Prof. Dr. med. Dralle
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MEDICINE
Pharmacology and molecular activity
Amiodarone (2-n-butyl-3-[3, 5 diiodo-4-diethylaminoethoxybenzoyl]-benzofuran) is a
structural congener of the thyroid hormones (diagram 1) and contains 39% parts by weight
of iodine. With every tablet (200 mg amiodarone) about 75 mg bound iodine is ingested,
with the free portion (9 mg) selectively entering the thyroid gland. This high iodine intake
leads to a 40 fold rise in ioduria. The high iodine levels persist for 6 months after discontinuing
the medication because amiodarone as a lipophilic substance is stored in fatty tissue (5).
The main metabolite is desethylamiodarone, which in most tissues is present in a higher
concentration than the parent compound. The half-life of amiodarone is 20 to 100 days.
Amiodarone has a wide range of effects on the thyroid gland (table 1):
Acute, transient changes in thyroid function
Hypothyroidism in patients susceptible to the inhibitory effect of large amounts of iodine
Hyperthyroidism due to
– iodine induced hyperthyroidism in nodular goiter
– an inflammatory destructive condition
– immune hyperthyroidism.
Amiodarone and its dealkylated metabolites competitively inhibit the extrathyroid
conversion of T4 to the active T3 (6). Because of their structural similarity to iodothyronines
they continue to be active deiodase inhibitors. Type I 5'-deiodase is preferentially inhibited.
Amiodarone and its metabolites also bind to nuclear T3 receptors and change their interaction
with co-activators or co-repressors of the transcription T3 regulated genes.
Laboratory parameter changes during amiodarone therapy
The initial phase of amiodarone therapy is accompanied by a temporary decrease in the
fT4 levels and a usually transient TSH elevation due to the inhibitory effect of iodine on the
thyroid gland (Wolff-Chaikoff effect). During the course of amiodarone therapy the inhibitory
effect of the drug on deiodase activity and the thyroid hormone receptor predominates (6).
This leads to increased fT4, reduced fT3, elevated reverse T3, and a temporary rise in TSH
(up to 20 mU/L). During the further course the TSH levels normalize or remain slightly
suppressed, with the result that the commonest laboratory parameter constellation during
long term therapy is as follows: fT4 increase by 20% to 30%, fT3 decrease into the lower
range of normal, basal TSH in the lower range of normal or suppressed (7). The case history
of a 68-year-old patient presents the findings observed during amiodarone therapy.
Thyroid examinations before and during amiodarone therapy
Because of the impairments of thyroid function commonly caused by amiodarone, basal
TSH, serum-fT3/ -fT4 and thyroid peroxidase (TPO) antibodies should be determined and a
thyroid sonographic examination performed before commencing therapy to ensure timely
identification of pre-disposed patients and to allow possible subsequent changes in thyroid
BOX
Predisposing factors for
amiodarone induced thyroid
dysfunction
Hyperthyroidism
Nodular goiter
Functional autonomy
Years of iodine deficiency
Subclinical hyperthyroidism
Genetic risk factors
Hypothyroidism
Thyroperoxidase (TPO) antibodies
Subclinical hypothyroidism
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MEDICINE
Structural similarity
between amiodarone
and T3/T4
DIAGRAM 1
TABLE 1
Relative risk of amiodarone
induced side effects, especially
thyroid dysfunction*
Total patient years: amiodarone 2580, placebo 2545
Odds Ratio
P=
Hypothyroidism
7.3
0.00005
Hyperthyroidism
2.5
0.0043
Pulmonary fibrosis
3.1
0.0003
Neuropathy
2.8
0.071
Hepatopathy
2.7
0.0072
Bradycardia
2.6
0.0003
*based on a meta-analysis of a large patient
and control population. Reference 1
function to be conclusively attributed to the amiodarone therapy (5, 8). If thyroid nodules
with a diameter >1 cm are present or if there is nodular goiter, thyroid scintigraphy is
additionally valuable, because hyperfunctional nodules can also be present when TSH values
are normal. As a general principle, radioiodide therapy cannot be performed in amiodarone
treated patients for up to 1 year after discontinuing the medication (9). The protracted
release of iodine from amiodarone prevents the uptake of the radioiodide into the thyroid in
therapeutically relevant levels. If TPO antibodies are present, there is an increased risk of
developing either clinically overt hypothyroidism or immunogenic hyperthyroidism. Close
functional monitoring of the thyroid is required in such cases (diagram 2).
During long term amiodarone therapy, regular monitoring of thyroid (fT3/ fT4, TSH and
once annually TOP antibodies) and hepatic function is necessary, even in patients with
initially normal thyroid function. After the cumulative total dose is reached, these tests
should be performed after 3 months and then every 6 months. In several studies, concentrations
of amiodarone and its metabolites in plasma showed no clinically relevant correlation with
the antiarrhythmic action of the substance. Plasma level concentrations are also without
evidential value in regard to tolerability.
Side effects and interactions
Side effects of amiodarone – depending on the dose and duration of treatment – include not
only thyroid dysfunction but also corneal deposits, photosensitization and hyperpigmentation
of the skin, pulmonary and hepatic toxicity, and optic neuropathies (table 2). Clinically
relevant interactions are an increase in digitalis levels and a potentially increased bleeding
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MEDICINE
Diagnosis before
and during
amiodarone therapy
DIAGRAM 2
TABLE 2
Prevalence of side effects of amiodarone*
(dose/time dependent)
Cases (in percent)
Corneal deposits
> 90
Photosensitivity
50–75
Thyroid dysfunction
30–40
Toxic hepatitis
20–50
Gastrointestinal complaints
20–30
Neuropathy, tremor
5–30
Interstitial pneumonia
5–20
*based on Reference 10
tendency in anticoagulated patients (10). In digitalized patients it is recommended to
reduce the dose by half. If the patient is anticoagulated, the international normalized ratio
(INR) value should be checked twice weekly and the dose reduction determined with
reference to the target INR. The simultaneous use of drugs metabolized by cytochrome
P4503A4 (ciclosporin, statins) and amiodarone – an inhibitor of CYP3A4 – can result in
higher plasma levels. If severe complications develop on amiodarone therapy, the
administration of colestyramine (3 × 4 to 8 g) or sucralfate (2 × 2 g) can accelerate
biodegradation (3). Colestyramine and sucralfate significantly reduce the enterohepatic
circulation and therefore accelerate elimination both in acute and long term treatment.
Differential diagnosis of AIH
The diagnosis of amiodarone induced hyperthyroidism (AIH) requires the determination
of basal TSH and fT3 (11). A suppressed TSH (<0.1 mU/L) and elevated fT3 values are
decisive for the diagnosis of AIH. Two forms of AIH are distinguished (table 3). Type I
is characterized by previous thyroid conditions such as Basedow's disease and nodular
goiter as well as increased production of thyroid hormones. The excess thyroid hormone
synthesis is the consequence of increased iodine exposure. Since a thyroid diagnostic
program is routinely performed prior to initiating elective amiodarone therapy, type I is
now rarely observed. Type II usually develops without prior thyroid disease. In this case
the mechanism is either an inflammatory destructive effect on the thyroid with increased
release of thyroid hormones or the result of drug induced lysosomal activation which
leads to destructive thyroiditis with accumulation of histiocytes in the thyroid gland
(12). The development of type II AIH cannot be ruled out in advance. Mild forms of
Type II can remit spontaneously or lead to hypothyroidism. Color Doppler sonography
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MEDICINE
CASE
A 68-year-old patient attended our thyroid outpatient department
for clarification of de novo thyroid dysfunction. There was a
3 year history of absolute arrhythmia successfully treated with
amiodarone (200 mg/day). The patient reported effort dyspnea,
sleep problems and digital tremor. Inspection and palpatory
examinations revealed no neck abnormalities. Ultrasonographic
thyroid volume was 17 mL with echo-deficient, inhomogeneous
internal structure and duplex sonography showed slightly
increased vascularization. Laboratory tests showed overt
hyperthyroidism: TSH < 0.01 mU/L, fT3 6.8 pg/mL, fT4 3.9
ng/dL, thyroperoxidase and thyroglobulin antibodies were
elevated, IL-6 also increased at 10 pg/mL (reference value
< 6). From these findings we concluded the presence of
amiodarone induced immunothyropathy with hyperthyroid
metabolic situation (Type II AIH). Prednisolone (initially 50 mg/
day) was therefore prescribed. The amiodarone dose was
retained. Control tests soon thereafter showed decreasing but
still abnormal peripheral thyroid values and symptoms and we
therefore recommended 20 mg/day metamizole. 2 weeks later,
fT3 and fT4 were in the normal range.
of the thyroid shows increased vascularization in type I and reduced to absent vascularization
in type II (13–14). Interleukin 6 levels may be elevated in type II (15) but, like serum
thyroglobulin, are unreliable differentiation markers. The thyroid scintigram is
characterized by absent technetium storage (11) because the high endogenous iodine
levels reduce the uptake of technetium pertechnate. Normal or increased uptake is a rarity
and suggests type I. Thyroid scintigraphy is not usually helpful in the differential
diagnosis of AIH.
Treatment of type I AIH
The treatment of AIH is impeded by the fact that the usual thionamides act competitively
against iodine in the thyroid, which means that very high doses are needed. Moreover, the
side effects of the thionamides on the liver and bone marrow must be considered. Radioiodide
therapy is generally ruled out because of the reduced uptake of radioactive iodine. In type I
AIH, amiodarone should be discontinued if an alternative antiarrhythmic therapy (beta
blockers, flecainide, propafenone) is available. However, amiodarone inhibits the
peripheral conversion of T4 to T3, i.e. also exerts thyrostatic action, so that discontinuation
can aggravate the hyperthyroidism. Prospective, controlled studies (16–17) and a recent
European survey (11) have underlined the role of thionamides in type I AIH (table 4) (18)
and that of glucocorticoids in type II AIH.
Thionamides
Thionamides inhibit thyroperoxidase and the synthesis of thyroid hormones
competitively to iodine. In AIH, thionamides have to be highly dosed (metamizole
beginning with 40 to 60 mg daily by the oral route, carbimazole 60 to 90 mg daily,
propylthiouracil 400 to 600 mg daily). Despite the long half-life of metamizole, a 2 to 3
times daily divided dose schedule is recommended (as for propylthiouracil) with
a night interval of about 8 hours. The onset of action is observed after several days
(diagram 3).
Perchlorate
Potassium perchlorate blocks thyroid iodine uptake by directly inhibiting the sodium iodide
symporter and hence active thyroid iodine transport (19). The combination of perchlorate
and thionamides is more effective. 600 to 1000 mg perchlorate is administered orally in
2 daily doses to reduce the intrathyroid iodine content.
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MEDICINE
TABLE 3
Features of amiodarone induced hyperthyroidism (AIH)
Characteristics
Type I AIH
Type II AIH
Pre-existing thyroid disease
Common
No
Diffuse/nodular goiter
Common
No
Onset
Early (weeks)
Late (months)
Mechanism (thyroid hormones)
Production increased
Release
Color Doppler sonography
Blood flow increased
Blood flow decreased
Tc uptake (thyroid scan)
Unchanged
Lowered
Serum interleukin-6 levels
Unchanged
Slightly increased
Serum thyroglobulin level
Greatly increased
Slightly increased
Thyroid antibodies
(Increased)
Normal to elevated
Course
Severe
Mild to severe
Histology
Inflammatory
Destructive
Discontinuation of amiodarone
Yes
No
Response to therapy
Poor
Good
Definitive therapy necessary
Yes
No
Transition to hypothyroidism
No
Possible
Risk in later iodine exposure
Hyperthyroidism
Hypothyroidism
Lithium
Lithium reduces the release both of the thyroid hormones and iodine and additionally
inhibits T4 deiodination (2). In type I, combination therapy with thionamides and lithium
normalizes the thy-roid metabolic situation more rapidly (about 4 weeks) than thionamide
monotherapy (about 10 weeks). An evening dose of 600 to 900 mg (86 to 130 mmol) and
weekly monitoring of blood lithium levels (therapeutic range 0.4 to 1.3 mmol/L) are
recommended. Lithium therapy is contraindicated in patients with severe heart failure.
Thyroidectomy
If thyroid autonomy is causally responsible for type I AIH, it cannot be permanently treated
pharmacologically. Only surgical removal of the thyroid tissue remains, provided the patient
can be safely subjected to this procedure. The main advantage of surgical management of
AIH is the immediate elimination of the hyperthyroidism combined with the possibility of
continuing the amiodarone therapy. Although subtotal thyroidectomy can save patients the
necessity for lifelong LT4 substitution therapy, there is a risk of relapse. Almost total
thyroidectomy is therefore preferable. Perioperative mortality and morbidity are increased
in emergency hyperthyroidism, which is why thyroid operations should whenever possible
be performed at a center specializing in thyroid surgery (21).
Management of type II AIH
Glucocorticoids have proved effective in type II AIH because of their anti-inflammatory
effects on the destructive inflammatory process and their inhibition of proteolytic lysosomal
enzyme activities (22). The additional action of the steroids resulting from inhibition of
5'-deiodase is less decisive, because amiodarone itself is a potent deiodase inhibitor. An
initial weight related dose of 1 mg/kg bodyweight prednisolone for 2 weeks is recommended,
followed by gradual dose reduction every 2 weeks over a total period of 20 weeks. Steroid
therapy is also superior to the oral contrast medium iopanoic acid with a blocking property
of T4/T3 conversion.
The more pronounced the inflammatory destruction of the organ, the more self limiting
is type II AIH. Renewed administration of amiodarone after achieving euthyroid status in
type II AIH is therefore justifiable (23).
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MEDICINE
TABLE 4
Evidence based recommendations for diagnosis and treatment of type I
and II amiodarone induced hyperthyroidism*
Evidence grade
Recommendation
Diagnosis
Color Doppler sonography
1a
A
Interleukin-6 (serum)
2a
C
Thyroid antibodies (serum)
3a
B
Tc uptake (scan)
3b
C
Thyroglobulin (serum)
4
D
Treatment
Methimazole (in type I)
1a
A
Perchlorate (in type I)
1b
A
Steroids (in type II)
1b
A
Thyroidectomy (in type I)
3a
B
* These recommendations correspond to those of the Thyroid Section of the
German Society for Endocrinology.
Evidence grade and grades of recommendation based on Reference 18.
Evidence grade: 1a) several randomized prospective studies and meta-analyses
with positive detection; 1b) No meta-analysis; 2a) Individual prospective controlled studies
with positive detection; 3a) Positive expert opinion with recommendation;
3b) Neutral expert opinion; 4) Individual case reports.
Recommendations: A) highly recommended, B) recommended,
C) neutral or possible, D) not recommended
Management of mixed forms
If the differential diagnosis of AIH is not conclusive or if a mixed form is suspected,
combined therapy with thionamides and glucocorticoids is recommended (for example
metamizole and prednisolone, each beginning with 40 mg daily or 0.5 mg/kg body
weight/day [2–3, 10]). Since mixed forms are on the increase, some research groups
recommend treating all 3 forms of AIH immediately with the combination therapy (8).
Management of amiodarone induced hypothyroidism
The transient TSH elevation at the start of treatment is physiological and only needs to
be treated if hypothyroidism develops during the course. If amiodarone is indicated,
intake need not be discontinued in amiodarone induced hypothyroidism (8, 10). Because
of the underlying cardiomyopathy, it is generally recommended to initiate thyroxine
substitution of the overt hyperthyroidism with a low initial dose and not to exceed the
maintenance dose of 1.5 µg LT4/kg body weight/day. On LT4 therapy, basal serum TSH
should be in the upper range of normal. Amiodarone induced subclinical hypothyroidism
can be controlled rather by adopting a temporizing approach if clinical symptoms are
absent (diagram 4).
Amiodarone therapy in pregnancy and lactation
Amiodarone crosses the placenta and is excreted in breast milk. The main risks for the
fetus are bradycardia, QT interval prolongation and hypothyroidism with goiter. The
treatment of 64 pregnant women with amiodarone, however, resulted in the
development of goiter in only 3% and transient hypothyroidism in 17% of newborns
(24). Mild, scarcely symptomatic neurological retardation and slight speech disorders
were observed in a small number of newborns. Otherwise, despite measured high
concentrations of amiodarone and desethylamiodarone in breast milk, transient
hypothyroidism was observed in only one infant, whose thyroid function normalized
after the medication was discontinued. In consideration of these data and the low rate of
side effects, the administration of amiodarone appears justified in pregnant women with
life threatening cardiac arrhythmias and in the absence of effective alternative
medications.
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MEDICINE
Procedure for
amiodarone
induced
hypothyroidism
DIAGRAM 3
Procedure for
amiodarone
induced
hypothyroidism
DIAGRAM 4
Prospects
A substance with effective and similar electrophysiological and arrhythmogenic actions
and which is iodine-free (dronedarone) is currently in the clinical trials stage. Dronedarone
is less lipophilic and has a shorter half-life than amiodarone. Clinical studies suggest that
there may well soon be a successor compound for amiodarone (25).
Acknowledgement
The authors express their very sincere thanks to all the members of the Interdisciplinary Thyroid Section of the German Society
for Endocrinology for their critical review of the manuscript and constructive comments.
Conflict of Interest Statement
The authors declare that no conflict of interest exists according to the guidelines of the International Committee of Medical
Journal Editors.
Manuscript received on 30 November 2006, revised version accepted on 8 August 2007.
Translated from the original German by mt-g.
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Corresponding author
Prof. Dr. med. George J. Kahaly
I. Medizinische Universitätsklinik und Poliklinik
55101 Mainz, Germany
[email protected]
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