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Clinical Studies |
Laboratory of Cardiovascular Endocrinology, National Research Council Institute of Clinical Physiology (G.I., Al.C., R.B., C.M., S.B., M.R., C.P., An.C. A.B.), Pisa, Italy; and Division of Endocrinology, Department of Medicine (I.C.), University of California at Los Angeles School of Medicine, Los Angeles, California 90026-1682
Address all correspondence and requests for reprints to: G. Iervasi, National Research Council Institute of Clinical Physiology, Via Savi 8, 56100 Pisa, Italy.
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Abstract |
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Introduction |
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Earlier prospective studies on short-term effects of amiodarone have been limited to a small number of normal subjects rather than cardiac patients (10, 11), and/or did not include data on free hormone concentrations when performed in arrhythmic patients (12). Furthermore, most data (10, 11, 12) on TSH release were based on relatively a insensitive RIA method and/or TRH test, which was performed under basal condition and after 4 (10) or 24 (11) weeks of treatment, respectively. One prospective study examined patients with symptomatic ventricular tachyarrhythmias treated with oral doses of amiodarone and documented effects of the amiodarone at or after 7 days of treatment; this study did not evaluate free thyroid hormone levels (13).
Clinical interest in amiodarone has been increasing recently because of its effectiveness in a wide range of cardiac disturbances, including prophylaxis of life-threatening ventricular tachyarrhythmias in myocardial infarction survivors (sudden death cardiac prophylaxis), because it does not show the hemodynamic disadvantages of other antiarrhythmic drugs (14, 15, 16). More recent protocols of amiodarone treatment provide the use of an iv loading dose of the drug to rapidly reach an effective plasma concentration (14, 15, 16, 17). However, to our knowledge, the mechanism of the acute interaction of the drug with the thyroid function is not well understood in amiodarone-treated arrhythmic patients.
We describe here a prospective study designed to gather information on acute changes in serum TSH and thyroid hormone levels after an iv loading dose of amiodarone in patients with cardiac arrhythmias; a group of well-matched patients, who were not treated with the drug, served as control group.
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Methods |
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Serum T4 and T3 concentrations were
measured by the fully automated immunoenzymometric assay AIA 600 system
(TOSOH Corp., Tokyo, Japan). Serum TSH was measured by a
third-generation (sensitivity 
0.005 µIU/mL immunoluminometric
assay (ILMA) method BeriLux human TSH (Behringwerke AG, Marburg,
Germany). Serum T3 and T4 free concentrations
were measured using both the microparticle enzyme immunoassay by means
of a fully automated IMx apparatus (Abbott Labs., Diagnostic Division,
Abbott Park, IL) and the gel equilibration procedure (Liso Phase RIA
system, Techno Genetics, Cassina de’ Pecchi, Milano, Italy). Serum
reverse T3 (rT3) was measured by a RIA method (BIODATA
Diagnostic, manufactured by Biodata S.p.A., Guidonia Montecelio, Roma,
Italy). To minimize the assay error, each serum sample was assayed more
than once in the same assay; consequently, the values used in the study
are the mean result of all of these determinations. The sensitivity and
between-assay precision of these methods were previously reported (8, 9).
In our laboratory the normal ranges for serum hormone concentrations are the following: total T4: 58–154 nmol/L (4.5–12 µg/100 mL); total T3: 1.2–3.0 nmol/L (80–200 ng/100 mL); free T4: 9–24 pmol/L (7.0–18.5 pg/mL); free T3: 3.9–8.3 pmol/L (2.6–5.4 pg/mL); TSH: 0.3–4.2 µIU/mL; rT3: 0.14–0.55 nmol/L (9–35 ng/100 mL).
Amiodarone assay
Serum concentrations of amiodarone and its major metabolite N-desethyl-amiodarone were measured by a high performance liquid chromatography method, using as internal standard the trifluoperazine, as previously described in detail (17). Each unknown serum sample was triple assayed. The sensitivity of the assay is 0.15 µg/mL of amiodarone. We considered an acceptable therapeutical range to be when the serum amiodarone levels ranged from 0.5–2 µg/mL (2, 17).
Experimental subjects
Patients. Twenty-four patients who had been chosen for
treatment with amiodarone because of their cardiac arrhythmia were
sequentially enrolled in the study. The most important clinical data of
these patients were reported in Table 1
. Five patients
showed overt cardiac failure (NYHA functional class 
III and/or left
ventricular ejection fraction <20%, patients 1, 2, 6, 12, and 22 in
Table 1); the other patients were in NYHA functional class < III or II
with left ventricular ejection fraction 40%. Inclusion criteria
were: 1) presence of cardiac arrhythmias evaluated by 48-h Holter
monitoring; 2) documented inadequate efficiency of at least two
different antiarrhythmic drugs; 3) absence of clinical, echographic,
and laboratory evidence of thyroid diseases (including thyroid hormone
concentrations and titers of antithyroid antibodies); and 4) no
consumption of any other drug known to affect thyroid function.
Myocardial contractility, dimensions, and function were assessed by
two-dimensional echocardiography and radionuclide ventriculography. The
weight of patients was monitored daily and did not significantly vary
during the study.
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In all 24 patients studied, two serum samples for amiodarone and hormonal assays were collected before the start of therapy (basal sample), and then other serum samples were collected at least every 12 h in the first 2 days after amiodarone administration and at least once a day in the following days. In 16 patients who had been hospitalized for a long time because of their cardiac disease, serum samples were also collected at 0800 h of the 10th day. Finally, in 16 patients who had been chronically treated with amiodarone, at least one other serum sample was collected 3 months after the start of therapy.
Control group. Twenty arrhythmic patients (14 men and 6 women), matched for age (66.6 ± 9.8 yr; range 46–81 yr) and gender, as well as for underlying heart disease, were enrolled in the study as the patients’ control group. These patients were hospitalized in the same clinical ward and for the same period of the study as the amiodarone-treated patients; these patients, even if they suffered from cardiac arrhythmias, were not given for treatment with amiodarone and did not take any medications that may have affected thyroid function.
Serum samples for hormone assays were collected throughout 5 consecutive days in the clinical ward.
Statistical analysis
The statistical analysis was carried out by a Macintosh IIsi personal computer using the Stat-View 4.0 and SuperANOVA programs (Abacus Concepts, Berkeley, CA). Data were analyzed by ANOVA for paired data (repeated measures), and the significant differences between the pairs of means were tested by the Bonferroni/Dunn test for paired data. The results were expressed as the mean ± SD in the text and as the mean ± SEM in the figures.
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Results |
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There was no significant variation in serum concentrations of TSH
and of thyroid hormones (total and free concentration) throughout the 5
days of the study in the arrhythmic patients not treated with
amiodarone (data not shown). Moreover, the mean hormone levels of these
patients were not significantly different from basal hormone values
found in patients treated with amiodarone (Table 1
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Amiodarone-treated patients
Baseline hormone values. On average, basal levels of total and
free thyroid hormones and TSH were found to be in the normal range
(Table 1). However, as expected (18, 19), the analysis of individual
values indicates that several patients (with NYHA functional class
III) showed evidence of euthyroid sick syndrome, as demonstrated by
low levels of both total and/or free T3 and/or
T4 concentrations (patients 1, 2, 6, 12, and 22 in Table 1).
Serum drug levels. The mean (± SEM) time course
of serum amiodarone and of its main metabolite
N-desethyl-amiodarone throughout the first 10 days of
therapy in patients treated with amiodarone is shown in Fig. 1. The peak of amiodarone concentration observed in the
first 12–36 h was caused by the loading iv dose of the drug. It is
important to note that a detectable concentration of the main and
pharmacologically active metabolite was on average found within 24
h after the start of amiodarone administration. By using the
therapeutical protocol described in this study, the plateau of the
circulating levels of amiodarone was generally reached in 5–12 days
(on average in 9 days) (Fig. 1). The mean concentration of amiodarone
after 3 months of therapy was 0.73 ± 0.25 µg/mL, and that of
its metabolite was 0.63 ± 0.11 µg/mL; the mean ratio, found in
chronically treated patients (for at least 3 months) between
N-desethyl-amiodarone and amiodarone concentrations was
0.84 ± 0.34. All of these findings are consistent with previously
described data (17).
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Acute effects of amiodarone administration. The time courses
of the daily mean values of serum total and free T3 and
T4 concentrations, observed in the first 10 days of therapy
with amiodarone, are shown in Figs. 2 and 3, respectively. Total and free concentrations of
T4 tended to significantly (P < 0.0001, by
ANOVA) increase in the first 5 days of therapy, reaching a maximum at
the fifth day after the start of therapy (free T4 = +15.3%
and total T4 = +11.5%, on average, compared with basal
values). On the contrary, total T3 levels progressively and
significantly fell throughout the study (P < 0.0001,
by ANOVA), whereas free T3 did not significantly change.
However, after 10 days of therapy, the free T3 levels were,
on average, 88.4%, and the total T3 were 81.3% compared
with basal values.
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. TSH levels early and
significantly (P < 0.001, by ANOVA) increased
throughout the study, starting from the first day of therapy and at 10
days reaching a value that was on average 2.7 times higher than the
basal value (Fig. 4). rT3 levels progressively and
significantly (after 2 days of treatment) increased and paralleled the
TSH values, at the 10th day reaching a value that was about two times
higher than basal value (Fig. 4).
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Discussion |
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Our studies describe the early effects of amiodarone treatment in
arrhythmic patients. Our findings indicate that in arrhythmic patients
short-term amiodarone treatment induced a significant decrease in serum
total T3. Interestingly, in our patients free
T3 showed a pattern not parallel to that of total
T3, mainly in the first 4 days of treatment (Fig. 2). The
basis for this observation is not known. This finding may reflect the
displacement by amiodarone of T3 bound to serum proteins
(15).
It is noteworthy that, unlike previous data in normal subjects (10), which showed an early decline in T4 concentrations, our data showed a significant increase in plasma T4 (both total and free) with the drug; a similar tendency for total T4 increase was also previously observed in arrhythmic patients after 7 days of treatment with an oral dose of amiodarone by other authors (13). The early decline of T4 concentrations in normal subjects given amiodarone has been suggested to be responsible for the subsequent increase in TSH (20). However, our data do not support this possibility.
We have documented a rise in serum TSH concentration in our patients
earlier (first day) than previously reported in normal subjects (second
day) (10) or arrhythmic patients (eighth day) (12). It is not clear
whether this discrepancy can be related to the different modality (oral
vs. iv) and/or amount of drug administration, improved TSH
techniques, the difference in the study population, and/or a more
frequent collection of blood samples in the first days of the study.
Indeed, by frequent sampling, we were able to clearly show that TSH is
the first hormonal parameter to be affected by amiodarone
administration. The use of a third-generation assay for TSH measurement
provided a suitable sensitivity to determine the minimal hormonal
changes observed after amiodarone treatment. An increment of 39%, on
average, was found in serum TSH at 24 h of treatment, and a
significant increment (65%) of TSH levels was clearly demonstrated on
the second day of amiodarone administration (Fig. 4). The basis for the
measured TSH increase after amiodarone is not known. It may be caused
by an early inhibition of type II 5'-deiodinase in the pituitary cells;
other possible effects may include a direct TSH secretory effect of the
drug and a competition between amiodarone, its metabolite, and specific
nuclear receptors for T3 (3). In this respect, there are
indications that desethylamiodarone (and not amiodarone) competes with
T3 for receptors in most tissues (21). Our data showing a
rapid appearance of desethylamiodarone in plasma within 24 h after
iv amiodarone, and the parallel rise with the rise of TSH levels lend
further support to this possibility.
The later increase in the serum total T4 and free T4 levels (which reach statistical significance at 4 days) may be explained by a direct stimulation of T4 secretion by increased TSH. However, in the absence of kinetic studies, it is not possible to exclude an important role of an alteration in T4 to T3 metabolism (5).
The progressive significant increase in rT3, as well as the concomitant and parallel fall in serum total T3 levels, which reach a statistical significance after 48 h of treatment, suggest an inhibition by amiodarone or its metabolite of type I 5' deiodinase resulting in a decrease in peripheral conversion of T4 to T3 and metabolic clearance of rT3.
The inhibitory action of amiodarone on iodothyronine deiodinase activity seems to persist during chronic treatment with the drug, as demonstrated by a persistent increase of TSH and rT3 associated with some decrease in total T3 concentrations. This is in accordance with our previous double-tracer kinetic study in which a direct measurement of T4 to T3 conversion was performed before and during chronic amiodarone treatment, and an inhibition of T4 to T3 peripheral conversion was demonstrated (9). These alterations in thyroid hormone metabolism may contribute to changes observed during the first 24–120 h after amiodarone iv loading dose in this study.
Received May 1, 1996.
Revised July 1, 1996.
Revised August 27, 1996.
Accepted September 10, 1996.
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This article has been cited by other articles:
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  E. Martino, L. Bartalena, F. Bogazzi, and L. E. Braverman The Effects of Amiodarone on the Thyroid Endocr. Rev., April 1, 2001; 22(2): 240 - 254. [Abstract] [Full Text]
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 K.-C. Loh Current concepts in medicine: Amiodarone-induced thyroid disorders: a clinical review Postgrad. Med. J., March 1, 2000; 76(893): 133 - 140. [Abstract] [Full Text]
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