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Clin Drug Investig
DOI 10.1007/s40261-017-0582-4
ORIGINAL RESEARCH ARTICLE
Association between Serum Amiodarone
and N-Desethylamiodarone Concentrations and Development
of Thyroid Dysfunction
Mikie Yamato1,2 • Kyoichi Wada1 • Tomohiro Hayashi3,4 • Mai Fujimoto2
Kouichi Hosomi2 • Akira Oita1 • Mitsutaka Takada2
•
Ó Springer International Publishing AG 2017
Abstract
Objective This retrospective cohort study was performed
to examine the association between serum amiodarone
(AMD) and N-desethylamiodarone (DEA) concentrations
and the development of thyroid dysfunction.
Methods Patients treated with AMD from January 2012 to
April 2016 were identified from the computerized hospital
information system database at the National Cerebral and
Cardiovascular Center. Only patients whose serum AMD
and DEA concentrations had been determined at least once
were included in the study.
Results A total of 377 patients were enrolled. Consequently, 54 (14.3%) and 60 (15.9%) patients who developed AMD-induced thyrotoxicosis and hypothyroidism
were included. The mean DEA/AMD ratio during the preindex period in the thyrotoxicosis group (0.86 ± 0.24) was
significantly higher than in the hypothyroidism
(0.68 ± 0.27) and euthyroidism (0.78 ± 0.30; p\0.0001)
Electronic supplementary material The online version of this
article (doi:10.1007/s40261-017-0582-4) contains supplementary
material, which is available to authorized users.
& Mitsutaka Takada
[email protected]
1
Department of Pharmacy, National Cerebral and
Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, Osaka,
Japan
2
Division of Clinical Drug Informatics, Kindai University
School of Pharmacy, 3-4-1, Kowakae, Higashi-osaka, Osaka
577-8502, Japan
3
Department of Cardiovascular Medicine, National Cerebral
and Cardiovascular Center, Suita, Japan
4
Division of Cardiovascular Medicine, Department of Internal
Medicine, Kobe University Graduate School of Medicine,
Kobe, Japan
groups. In addition, the mean DEA/AMD ratio during the
post-index period in the thyrotoxicosis group (1.05 ± 0.40)
was significantly higher than in the hypothyroidism
(0.81 ± 0.24) and euthyroidism (0.88 ± 0.22; p\0.0001)
groups. A persistently higher DEA/AMD ratio was
observed throughout the study period in the thyrotoxicosis
group. In addition, good correlations between the DEA/
AMD ratio and the levels of free thyroxine, free triiodothyronine levels, and log (thyroid-stimulating hormone) were observed in the thyrotoxicosis and
euthyroidism groups.
Conclusion Patients with AMD-induced thyrotoxicosis
had an increased DEA/AMD ratio and patients with AMDinduced hypothyroidism had a decreased DEA/AMD ratio
before the development of thyroid dysfunction. The DEA/
AMD ratio may be a predictive marker for AMD-induced
thyroid dysfunction.
Key Points
Although several potential predictors for amiodarone
(AMD)-induced thyroid dysfunction are known, the
association between AMD and Ndesethylamiodarone (DEA) concentrations and
thyroid dysfunction remain unknown.
This study revealed that patients with AMD-induced
thyrotoxicosis had an increased DEA/AMD ratio and
patients with AMD-induced hypothyroidism had a
decreased DEA/AMD ratio.
The DEA/AMD ratio may be a predictive marker for
AMD-induced thyroid dysfunction.
M. Yamato et al.
1 Introduction
2 Methods
Amiodarone (AMD) is a class III antiarrhythmic drug used
in the treatment of life-threatening arrhythmias. Thyroid
dysfunction, including thyrotoxicosis and hypothyroidism,
is a major problem in patients undergoing AMD therapy
[1, 2]. Although previous studies reported that younger age,
male sex, thyroid autoantibody production, goiter, or low
body mass index (BMI) were associated with AMD-induced thyrotoxicosis [3–8], and that older age, higher
baseline thyroid-stimulating hormone (TSH) level, lower
left ventricular ejection fraction, diabetes mellitus, and
thyroid autoantibody production in women are possible risk
factors for AMD-induced hypothyroidism [5, 6, 9–12],
definitive predictors for AMD-induced thyrotoxicosis and
hypothyroidism remain unknown.
AMD-induced thyrotoxicosis occurs more frequently in
geographical areas with low iodine intake, whereas AMDinduced hypothyroidism is more common in iodine-sufficient areas [9, 13, 14]. In Japan, a daily iodine intake of
1–3 mg results in a 6- to 15-fold excess in the recommended daily intake [15]. Therefore, in Japan, the incidence of AMD-induced hypothyroidism may be higher
than that of AMD-induced thyrotoxicosis. Meanwhile, it
has been reported that AMD-related thyroid cytotoxicity
may be mainly due to a direct effect of the drug on thyroid
cells [16]. AMD is predominantly metabolized to an active
metabolite, N-desethylamiodarone (DEA), by cytochrome
P450 (CYP) 3A4 [17–20], and both the parent compound
and the metabolite exhibit long half-lives, 55 and 62 days,
respectively [21]. CYP3A4 activity is responsible for both
the DEA concentration and DEA/AMD ratio in patients
treated with AMD. AMD and DEA are very highly lipidsoluble substances and are thought to be concentrated in
various tissues and organs, and these long half-lives are
attributable to drug accumulation. DEA is even more
cytotoxic to thyroid cells than AMD [22], and its
intrathyroidal concentration is higher than that of the parent
drug [23]. These findings suggested that DEA may play an
important role in the development of thyroid dysfunction in
patients treated with AMD.
Recently, a data mining study of AMD and DEA concentrations and thyroid-related hormone concentrations has
suggested that the increased and decreased DEA/AMD
ratios were associated with increased and decreased thyroid-related hormone levels, respectively [24]; however, a
causal relationship between AMD and DEA concentrations
and the development of thyroid dysfunction remains
unclear. To address this question, alterations in both AMD
and DEA concentrations and the DEA/AMD ratio before
and after the development of AMD-induced thyroid dysfunction were investigated in the study.
2.1 Study Design and Patients
This retrospective cohort study was performed to examine
the association between serum AMD and DEA concentrations and the development of thyroid dysfunction at the
National Cerebral and Cardiovascular Center (NCVC) in
Japan. Patients treated with AMD from January 2012 to
April 2016 were identified from the computerized hospital
information system database. Only patients whose serum
AMD and DEA concentrations had been determined at
least once were included in the study. Patients under the
age of 18 years were excluded, as were patients who were
treated with drugs for thyroid dysfunction (antithyroid
drugs and thyroid hormone preparations) or diagnosed
with thyroid dysfunction during the 6 months prior to the
initiation of AMD treatment. To restrict study patients to
those with normal thyroid function, patients with abnormal TSH levels during the 6 months prior to the initiation
of AMD treatment were also excluded, as were patients
positive for antithyroid hormone antibodies. It is known
that AMD administration may cause transient thyroid
dysfunction within 3 months after the initiation of therapy
[25], therefore thyroid dysfunction observed within
3 months after the initiation of AMD was ruled out.
Patients without thyroid function data after the initiation
of AMD therapy were also excluded from the study.
Furthermore, patients who had not been treated with
AMD for \3 months were excluded. Patients who discontinued AMD therapy in the post-index period were
included in the study; however, follow-up was finished
when AMD therapy was interrupted for more than
3 months. The index date for each patient was defined as
the first date on which thyroid dysfunction was found
during the study period, while, for euthyroid patients, the
index date was defined as the first date on which euthyroidism was confirmed after the central day of the
observation period. One-year periods before and after the
index date were defined as the pre- and post-index periods, respectively. Associations between AMD and DEA
concentrations and DEA/AMD ratio and thyroid-related
hormones were examined using data in the pre- and postindex periods.
Demographic, clinical, and biochemical data were
retrieved from the computerized hospital information system, as well as medical records. For patients who developed thyroid dysfunction during the study period, the
duration of AMD therapy was defined as the period
between the date of initiation of AMD administration and
the date when thyroid dysfunction was observed.
Amiodarone Concentration and Thyroid Dysfunction
2.2 Measurement of Thyroid-Related Hormones
and Definition of Thyroid Dysfunction
Serum free thyroxine (FT4) levels, free triiodothyronine
(FT3) levels, and TSH levels were measured using an
electrochemiluminescence immunoassay (Elecsys FT4 II,
Elecsys FT3 III, and Elecsys TSH; Roche Diagnostics,
Japan). Serum FT4 levels of 1.1–1.8 ng/dL and TSH levels
of 0.5–5.5 lIU/mL were defined as the normal range in our
hospital. Patients with suppressed TSH levels (\0.5 lIU/
mL) and elevated FT4 levels ([1.8 ng/dL) were classified
into the thyrotoxicosis group, patients with elevated TSH
([5.5 lIU/mL) and suppressed FT4 levels (\1.1 ng/dL)
were classified into the hypothyroidism group, and those
with elevated TSH ([5.5 lIU/mL) and normal FT4
(1.1–1.8 ng/dL) levels were classified into the subclinical
hypothyroidism group. Furthermore, patients with suppressed TSH (\0.5 lIU/mL) and normal FT4 (1.1–1.8 ng/
dL) levels were classified into the subclinical hyperthyroidism group, and patients with normal TSH levels were
classified into the euthyroidism group.
2.3 Measurement of Amiodarone (AMD) and Ndesethylamiodarone (DEA) Concentrations
Serum AMD and DEA concentrations were determined
using a high-performance liquid chromatographic (HPLC)
system [26]. In brief, AMD and DEA were extracted with
diethyl ether followed by evaporation. The residue was
reconstituted in methanol prior to injection into the HPLC
system. The mobile phase, a mixture of methanol, water,
and 28% ammonia water (91:8.8:0.2 by volume), was
pumped at 1.5 mL/min, with detection at 242 nm. Standard
curves were linear for AMD and DEA over the concentration range of 0.1–5.0 lg/mL.
2.4 Statistical Analysis
Results are expressed as mean ± standard deviation (SD)
for quantitative data and frequency (%) for categorical
data. Student’s t test was used to compare continuous
variables. Mean values for more than two groups were
compared by one-way analysis of variance (ANOVA),
followed by a post hoc Tukey–Kramer test. Categorical
variables were compared using the Chi-square test or
Fisher’s exact test.
Linear regression analyses were performed to examine
the correlation between the AMD and DEA concentrations
and the DEA/AMD ratio and levels of thyroid-related
hormones using all individual data sets. Additional linear
regression analyses were performed to examine the correlation between mean AMD and DEA concentrations and
DEA/AMD ratio and mean thyroid-related hormones. Data
during both the pre- and post-index periods were used in
the correlation analyses.
Multivariable logistic regression analysis was performed
using data closest to the index date in the pre-index period
to assess the association between clinical variables and the
development of AMD-induced thyrotoxicosis and
hypothyroidism. All variables were entered into the logistic
models, and removed by employing the stepwise backward
elimination method if the p value exceeded 0.1. Adjusted
odds ratios (ORs), their 95% confidence intervals (CIs),
and p values were calculated. JMPÒ 11.2.0 (SAS Institute
Inc., Cary, NC, USA) was used for all statistical analyses.
All procedures performed in studies involving human
participants were in accordance with the ethical standards
of the institutional research committee and the 1964 Helsinki declaration and its later amendments or comparable
ethical standards. This study was approved by the Ethics
Committees of the NCVC and the Kindai University.
3 Results
3.1 Study Population
A total of 1021 patients treated with oral AMD were
identified during the study period (electronic supplementary Fig. S1). Of these, 124 patients whose serum AMD
and DEA concentrations had not been measured were
excluded from the study. In addition, 422 patients who
were either diagnosed with thyroid dysfunction, treated
with drugs for thyroid dysfunction, or positive for
antithyroid hormone antibodies at the initiation of AMD
therapy were excluded. Furthermore, one patient without
thyroid function tests after the initiation of AMD therapy
was also excluded. In addition, patients under 18 years of
age at the index date (11 patients) and patients who had not
been treated for more than 3 months with AMD at the
index date (86 patients) were also excluded from the study.
A total of 377 patients fulfilled the inclusion criteria and
were enrolled in the study. Consequently, 54 and 60
patients who developed AMD-induced thyrotoxicosis and
hypothyroidism, respectively, were included in the study.
Among our study patients, the incidence of AMD-induced
thyrotoxicosis and hypothyroidism was 14.3 and 15.9%,
respectively. At the end of the follow-up period, 145, 13,
99, and 6 patients were classified into the euthyroidism,
subclinical hyperthyroidism, subclinical hypothyroidism,
and undetermined groups, respectively.
Of 54 patients in the thyrotoxicosis group, 14 and 3
patients were treated with corticosteroid and antithyroid
drugs after the development of AMD-induced thyrotoxicosis, respectively. In addition, of 60 patients in the
hypothyroidism group, 51 were treated with levothyroxine.
M. Yamato et al.
Patients who received any therapeutic interventions were
enrolled in the study, and the association between AMD
and DEA concentrations and DEA/AMD ratio and thyroidrelated hormones were examined with or without therapeutic intervention.
Characteristics of the study patients are summarized in
Table 1. Significant differences in mean age were observed
at the initiation of AMD therapy (ANOVA; p\0.0001)
and index date (ANOVA; p\0.0001) among the three
different thyroid function groups. The mean age of the
thyrotoxicosis group (49.9 ± 14.2 years) at the initiation of
AMD therapy was significantly younger than those of the
hypothyroidism (62.0 ± 16.6 years; p\0.0001) and
euthyroidism (61.5 ± 13.8 years; p\0.0001) groups. The
mean age of the thyrotoxicosis group (53.4 ± 14.0 years) at
the index date was significantly younger than that of the
hypothyroidism (64.7 ± 16.3 years; p\0.0001) and
euthyroidism (63.9 ± 13.5 years; p\0.0001) groups. The
duration of AMD therapy in the thyrotoxicosis group was
significantly longer than that of the euthyroidism group
(41.9 ± 31.7 vs. 27.6 ± 28.9 months; p = 0.0073), and
there was no significant difference in mean AMD dose at
the index date among the three different thyroid function
groups.
3.2 Association Between Serum AMD and DEA
Concentrations and the DEA/AMD Ratio
and Thyroid-Related Hormone Levels
Changes in both serum AMD and DEA concentrations and
the DEA/AMD ratio during the pre- and post-index period
are presented in Fig. 1. Mean AMD and DEA concentrations and DEA/AMD ratio during the pre- and post-index
period are presented in Table 2 and electronic supplementary Figs. S2 and S3. The mean DEA concentration
during the pre-index period in the thyrotoxicosis group
(0.67 ± 0.32 lg/mL) was significantly higher than in the
euthyroidism (0.57 ± 0.35 lg/mL) and hypothyroidism
(0.56 ± 0.33 lg/mL) groups. Meanwhile, the mean AMD
concentration in the thyrotoxicosis group (0.68 ± 0.37 lg/
mL) during the post-index period was significantly lower
than in the hypothyroidism (0.95 ± 0.49 lg/mL) and
euthyroidism (0.91 ± 0.47 lg/mL) groups. The mean DEA
concentration in the thyrotoxicosis group (0.63 ± 0.25 lg/
mL) during the post-index period was significantly lower
than in the euthyroidism group (0.75 ± 0.34 lg/mL). In
addition, the mean DEA/AMD ratio during the pre-index
period in the thyrotoxicosis group (0.86 ± 0.24) was significantly higher than in the hypothyroidism (0.68 ± 0.27)
and euthyroidism (0.78 ± 0.30) groups, and the mean DEA/
AMD ratio during the post-index period in the thyrotoxicosis group (1.05 ± 0.40) was significantly higher than in
the hypothyroidism (0.81 ± 0.24) and euthyroidism
(0.88 ± 0.22) groups. The difference in the DEA/AMD
ratio became more prominent after the development of
thyroid dysfunction.
As shown in electronic supplementary Figs. S4–S6, the
levels of thyroid-related hormones appear to change in
conjunction with the DEA/AMD ratio. In addition, the
mean DEA/AMD ratio significantly correlated with the
mean levels of thyroid-related hormones in the thyrotoxicosis and euthyroidism groups (Table 3). Meanwhile, liner
regression analyses using all individual data showed significant correlations between AMD and DEA concentrations and DEA/AMD ratio and thyroid-related hormones in
some different combinations (electronic supplementary
Fig. S7); however, these correlations were weak and were
not definitive. Additionally, receiver operating characteristic (ROC) curve analysis of thyrotoxicosis indicated an
AUC of 0.624 and showed a sensitivity of 0.358, specificity
of 0.875, positive predictive value of 46.6%, and negative
predictive value of 81.7% using a DEA/AMD ratio cut-off
of 1.08. Moreover, ROC curve analysis of hypothyroidism
indicated an AUC of 0.615 and showed a sensitivity of
0.465, specificity of 0.734, positive predictive value of
21.7%, and negative predictive value of 89.7% using a
DEA/AMD ratio cut-off of 0.615 (electronic supplementary Table S1).
A stepwise multivariable logistic regression analysis
identified age at the initiation of AMD therapy (adjusted
OR 0.96, 95% CI 0.94–0.98), dilated cardiomyopathy
(adjusted OR 2.04, 95% CI 1.06–3.94), and ischemic cardiomyopathy (adjusted OR 4.80, 95% CI 1.65–13.11) as
predictors of AMD-induced thyrotoxicosis (Table 4).
Although the DEA/AMD ratio was not identified as a
significant predictor, it had an interesting value (adjusted
OR 3.25, 95% CI 0.96–11.04; p = 0.0583). In the analysis
of AMD-induced hypothyroidism, AMD concentration
(adjusted OR 2.01, 95% CI 1.13–3.56) was identified as a
significant predictor (Table 5).
4 Discussion
This study revealed that the levels of thyroid-related hormones changed in conjunction with the DEA/AMD ratio,
and the mean DEA/AMD ratio significantly correlated with
the mean levels of thyroid-related hormones in the thyrotoxicosis and euthyroidism groups. Additionally, the ROC
analyses suggested that the DEA/AMD ratio may be a
potential predictive marker for the development of AMDinduced thyrotoxicosis and hypothyroidism. These findings
suggest that the thyroid-related hormone levels were
associated with the DEA/AMD ratio in the thyrotoxicosis
and hypothyroidism groups; however, a causal relationship
between the development of thyroid dysfunction and the
281 (74.5)
Male sex
199 (52.8)
298 (79.0)
Atrial arrhythmia
Ventricular arrhythmias
64.7 ± 16.3
48 (88.9)
26 (48.1)
23 (42.6)
34 (63.0)
16 (29.6)
4 (7.4)
7 (13.0)
6 (11.1)
26 (48.1)
43 (79.6)
1.10 ± 0.48
41.9 ± 31.7
e
49 (81.7)
32 (53.3)
33 (55.0)
43 (71.7)
24 (40.0)
2 (3.3)
4 (6.7)
12 (20.0)
18 (30.0)
46 (76.7)
27.6 ± 28.9
106 (73.1)
79 (54.5)
85 (58.6)
102 (70.3)
50 (34.5)
14 (9.7)
11 (7.6)
23 (15.9)
39 (26.9)
104 (71.7)
1.34 ± 1.07
Significantly increased compared with the euthyroidism group (Tukey–Kramer test)
0 (0)
0 (0)
10 (77.0)
4 (30.8)
8 (61.5)
8 (61.5)
10 (76.9)
0.4201d
0.5371d
0.507d
0.1297d
0.7263d
0.0432d
5 (38.5)
0.3449d
0.4305
d
5 (38.5)
12 (92.3)
0.4759d
0.0157d
1.1 ± 1.0
25.0 ± 24.1
111.5 ± 36.3
57.5 ± 9.8
55.3 ± 11.0
13
Subclinical
hyperthyroidism
0.2717c
0.0073
0.7633c
\0.0001
\0.0001
p value
82 (82.8)
50 (50.5)
43 (4.34)
62 (62.6)
34 (34.3)
6 (6.1)
1 (1.0)
17 (17.2)
36 (36.4)
72 (72.7)
1.3 ± 0.9
31.6 ± 34.8
144.7 ± 55.6
62.7 ± 14.7
60.0 ± 14.8
99
Subclinical
hypothyroidism
One value was missing in the euthyroidism group
A significant difference was observed among the hyperthyroidism, hypothyroidism, and euthyroidism groups (Chi-square test or Fisher’s exact test)
No significant difference was observed among the hyperthyroidism, hypothyroidism, and euthyroidism groups (ANOVA)
d
c
31.9 ± 28.9
1.33 ± 0.97
125.1 ± 43.2
63.9 ± 13.5
61.5 ± 13.8
145
Euthyroidism
Significantly decreased compared with the hypothyroidism and euthyroidism groups (Tukey–Kramer test)
b
a
AMD amiodarone, ANOVA analysis of variance
b
130.0 ± 43.4
53.4 ± 14.0a
126.4 ± 45.4
60
62.0 ± 16.6
54
Hypothyroidism
49.9 ± 14.2a
Thyrotoxicosis
Data are expressed as mean ± standard deviation or n (%)
194 (51.5)
26 (6.9)
Cardiac sarcoidosis
Dyslipidemia
24 (6.4)
Ischemic cardiomyopathy
254 (67.3)
128 (34.0)
63 (16.7)
Hypertrophic cardiomyopathy
Hypertension
Diabetes mellitus
128 (34.0)
Dilated cardiomyopathy
Cardiac diagnoses
1.29 ± 0.95
AMD dose (mg) at index date
31.2 ± 30.9
131.1 ± 47.6
Age at index date (years)
Duration (months)
61.7 ± 14.8
Age at initiation of AMD therapy (years)
Serum creatinine (mg/dL)e
377
59.1 ± 15.1
Number of patients
All patients
Patients
Table 1 Characteristics of the study patients
3 (50.0)
4 (66.7)
2 (33.3)
3 (50)
0 (0)
0 (0)
1 (16.7)
0 (0)
4 (66.7)
4 (66.7)
1.0 ± 1.1
19.8 ± 21.8
150.0 ± 44.7
46.8 ± 14.0
45.2 ± 15.1
6
Undetermined
Amiodarone Concentration and Thyroid Dysfunction
M. Yamato et al.
Fig. 1 Changes in serum AMD and DEA concentrations and DEA/AMD ratio during the pre- and post-index periods. AMD amiodarone, DEA
N-desethylamiodarone, down-pointing triangle indicates development of thyroid dysfunction
Table 2 AMD and DEA concentrations and the DEA/AMD ratio in the different thyroid function groups
Thyrotoxicosis
n
Mean ± SD
t test
(p values)
Hypothyroidism
n
Mean ± SD
t test
(p values)
Euthyroidism
n
Mean ± SD
t test
(p values)
ANOVA
(p values)
AMD (lg/mL)
Pre-index period
127
0.83 ± 0.44
Post-index
period
162
0.68 ± 0.37a
127
0.67 ± 0.32b
162
c
0.63 ± 0.25
127
0.86 ± 0.24b
162
b
0.002
114
0.89 ± 0.50
128
0.95 ± 0.49
114
0.56 ± 0.33
128
0.72 ± 0.34
114
0.68 ± 0.27d
128
0.81 ± 0.24
0.4236
259
0.81 ± 0.56
293
0.91 ± 0.47
259
0.57 ± 0.35
293
0.75 ± 0.34
259
0.78 ± 0.30
293
0.88 ± 0.22
0.0189
0.3492
\0.0001
DEA (lg/mL)
Pre-index period
Post-index
period
0.3147
0.0003
\0.0001
0.0182
0.0008
DEA/AMD ratio
Pre-index period
Post-index
period
1.05 ± 0.40
\0.0001
\0.0001
\0.0001
\0.0001
\0.0001
Data are expressed as mean ± SD
AMD amiodarone, DEA N-desethylamiodarone, ANOVA analysis of variance, SD standard deviation
a
Significantly decreased compared with the hypothyroidism and euthyroidism groups (Tukey–Kramer test)
b
Significantly increased compared with the hypothyroidism and euthyroidism groups (Tukey–Kramer test)
c
Significantly decreased compared with the euthyroidism groups (Tukey–Kramer test)
d
Significantly decreased compared with the hyperthyroidism and euthyroidism groups (Tukey–Kramer test)
AMD and DEA concentrations and the DEA/AMD ratio
was unknown. To resolve this question, the AMD and DEA
concentrations and the DEA/AMD ratio were analyzed
during the pre- and post-index periods. The thyrotoxicosis
group had a higher DEA/AMD ratio compared with the
hypothyroidism and euthyroidism groups during the preindex period, and this characteristic became more
prominent during the post-index period. A persistently
higher DEA/AMD ratio was observed throughout the study
period in the thyrotoxicosis group. In contrast, the
hypothyroidism group had a lower DEA/AMD ratio compared with the thyrotoxicosis and euthyroidism groups
during the pre-index period. Consequently, higher and
lower DEA/AMD ratios during the pre-index period may
Significant trend
Significant
b
a
FT4 = 1.44 - 0.30 DEA/AMD
0.132
LOG (TSH) = 0.36 ? 0.93 DEA/AMD
DEA/AMD
AMD amiodarone, DEA N-desethylamiodarone, TSH thyroid-stimulating hormone, FT4 free thyroxine, FT3 free triiodothyronine
0.335
0.2092
0.071
FT3 = 2.03 ? 0.45 DEA/AMD
0.1561
0.7893
0.0811b
0.089
0.042
0.003
FT3 = 2.32 ? 0.04 AMD
FT3 = 2.23 ? 0.20 DEA
0.1762
0.4671
FT4 = 1.33 - 0.16 DEA
0.024
FT4 = 1.29 - 0.07 AMD
0.1103
0.0127a
0.112
0.251
LOG (TSH) = 0.69 ? 0.37 AMD
LOG (TSH) = 0.56 ? 0.73 DEA
AMD
DEA
Hypothyroidism
0.082
0.0127a
0.2423
0.062
0.251
FT3 = 0.69 ? 2.22 DEA/AMD
FT3 = 4.09 - 1.95 DEA
0.2892
0.0514b
0.162
FT4 = 0.46 ? 1.52 DEA/AMD
0.051
FT4 = 2.89 - 1.51 DEA
0.263
LOG (TSH) = 2.05 - 1.44 DEA/AMD
0.0104a
0.004
LOG (TSH) = 0.47 - 0.32 DEA
DEA
DEA/AMD
0.7639
0.0489a
0.165
FT3 = 4.13 - 1.73 AMD
0.1322
0.100
FT4 = 2.78 - 1.14 AMD
0.1119
0.111
LOG (TSH) = -0.01 ? 0.90 AMD
Hyperthyroidism
0.142
LOG (TSH) = 0.58 - 0.27 DEA/AMD
DEA/AMD
AMD
FT4 = 1.25 ? 0.43 DEA/AMD
b
0.360
LOG (TSH) = 0.52 - 0.23 DEA
DEA
0.0694
FT4 = 1.36 ? 0.34 DEA
0.224
0.0691b
0.381
0.0124a
0.252
FT3 = 3.10 - 0.81 DEA/AMD
0.0195
a
0.142
0.035
FT3 = 2.57 - 0.16 AMD
FT3 = 2.66 - 0.33 DEA
0.0001a
0.0046a
a
0.311
FT4 = 1.36 ? 0.26 AMD
0.0112a
0.259
LOG (TSH) = 0.53 - 0.19 AMD
Euthyroidism
AMD
R
Regression formula
p value
R
Regression formula
0.498
R2
Regression formula
p value
FT3
2
FT4
2
Log (TSH)
Table 3 Correlation between AMD, DEA, and DEA/AMD and thyroid-related hormones
0.0019
p value
Amiodarone Concentration and Thyroid Dysfunction
be discriminative characteristics for patients who develop
AMD-induced thyrotoxicosis and hypothyroidism,
respectively.
Some experimental studies have demonstrated that
thyroid hormones have an impact on CYP3A4 expression
[27–30]. In accordance with the effect of thyroid hormones
on CYP3A expression, patients with AMD-induced thyrotoxicosis have increased CYP3A4 expression and an
increased DEA/AMD ratio, with associated reductions in
DEA and AMD concentrations. In contrast, patients with
AMD-induced hypothyroidism have decreased CYP3A4
expression and a decreased DEA/AMD ratio, with an
associated reduction in the DEA concentration. The alterations in thyroid hormones themselves have an influence
on the expression of CYP3A4 and are likely to affect drug
metabolism, resulting in the alteration of AMD and DEA
concentrations and the DEA/AMD ratio. Lower AMD and
DEA concentrations and a higher DEA/AMD ratio
observed after the development of thyrotoxicosis may be
attributable to enhanced metabolism of AMD by increased
levels of thyroid hormones. AMD metabolism is enhanced
after the development of thyrotoxicosis, resulting in
decreased concentration of AMD and increased concentration of DEA. Subsequently, DEA metabolism may also
be enhanced after the development of thyrotoxicosis,
resulting in decreased concentration of DEA. Consequently, DEA concentration in the post-index period might
not change compared with the pre-index period. Meanwhile, our study revealed that alterations in the DEA/AMD
ratio occurred prior to the development of thyroid dysfunction. This finding suggests that patients who develop
AMD-induced thyroid dysfunction may have naturally
occurring AMD metabolic alterations or may have
obtained such alterations prior to the development of their
thyroid dysfunction.
In addition, our study revealed that mean age at the
initiation of AMD therapy in the thyrotoxicosis group was
significantly younger than in the euthyroidism and
hypothyroidism groups. Our previous study showed that
younger patients have a higher DEA/AMD ratio compared
with older patients [24]; the higher DEA/AMD ratio in
younger patients may be attributable to higher CYP3A4
activity. Of note, younger age is a predominant risk factor
for the development of thyrotoxicosis in patients treated
with AMD. There is a possibility that the increased risk of
AMD-induced thyrotoxicosis in young patients is related to
the higher activity of CYP3A4 that contributes to higher
DEA concentrations and DEA/AMD ratios.
Some studies have suggested that DEA is even more
cytotoxic to thyroid cells than AMD, and DEA exerts a
direct cytotoxic effect on human thyroid cells at concentrations near those found in the plasma of patients [22]. In
addition, the intrathyroid concentration of DEA is higher
M. Yamato et al.
Table 4 Logistic regression analysis including risk factors for the development of AMD-induced thyrotoxicosis
Variables
Crude OR (95% CI)
p value
Male sex
1.40 (0.71–2.96)
0.3435
Age at initiation of AMD therapy
0.96 (0.94–0.97)
\0.0001
AMD
0.88 (0.44–1.66)
0.7113
DEA
1.34 (0.53–3.28)
0.5347
DEA/AMD ratio
3.09 (0.99–9.52)
0.052
Hypertension
0.80 (0.44–1.47)
0.4591
Diabetes mellitus
0.79 (0.41–1.46)
0.4644
Dilated cardiomyopathy
2.01 (1.12–3.61)
0.0197
Hypertrophic cardiomyopathy
0.58 (0.22–1.33)
0.2132
Ischemic cardiomyopathy
2.68 (0.99–6.58)
0.0517
Cardiac sarcoidosis
1.09 (0.31–3.01)
0.874
Adjusted OR (95% CI)
p value
0.96 (0.94–0.98)
\0.0001
3.25 (0.96–11.04)
0.0583
2.04 (1.06–3.94)
0.032
4.80 (1.65–13.11)
0.005
Multivariate logistic regression analysis was performed using data closest to the index date in the pre-index period
AMD amiodarone, DEA N-desethylamiodarone, OR odds ratio, CI confidential interval
Table 5 Logistic regression
analysis including risk factors
for the development of AMDinduced hypothyroidism
Variables
Crude OR (95% CI)
p value
Male sex
1.15 (0.61–2.26)
0.6771
Age at AMD initiation
1.02 (1.00–1.04)
0.0959
1.02 (1.00–1.04)
0.0656
AMD
1.93 (1.09–3.38)
0.0253
2.01 (1.13–3.56)
0.0178
DEA
2.01 (0.85–4.74)
0.1126
DEA/AMD ratio
0.55 (0.17–1.72)
0.3078
Hypertension
1.27 (0.70–2.39)
0.4347
Diabetes mellitus
Dilated cardiomyopathy
1.37 (0.77–2.40)
0.81 (0.43–1.45)
0.2856
0.4771
Hypertrophic cardiomyopathy
1.30 (0.62–2.56)
0.4652
Ischemic cardiomyopathy
1.06 (0.30–2.93)
0.9176
Cardiac sarcoidosis
0.42 (0.07–1.47)
0.1967
Adjusted OR (95% CI)
p value
Multivariate logistic regression analyses was performed using data closest to the index date in the pre-index
period
AMD amiodarone, DEA N-desethylamiodarone, OR odds ratio, CI confidential interval
than that of AMD [23]. These findings suggest that DEA
may play an important role in the development of AMDinduced thyrotoxicosis. In our study, the mean DEA concentration during the pre-index period in the thyrotoxicosis
group was significantly higher than in the euthyroidism and
hypothyroidism groups. A higher DEA concentration and
DEA/AMD ratio are likely associated with the development of thyrotoxicosis, and a higher AMD concentration
and a lower DEA/AMD ratio are likely associated with the
development of hypothyroidism. Furthermore, multivariable logistic regression analysis revealed that a higher
AMD concentration was identified as a risk factor for
hypothyroidism, and a higher DEA/AMD ratio was identified as an almost significant risk factor for thyrotoxicosis
(adjusted OR 3.25, 95% CI 0.96–11.04; p = 0.0583).
Although the factors responsible for the development of
thyroid dysfunction are unclear, our study implied that
CYP3A4 activity and expression are involved in the
development of AMD-induced thyrotoxicosis and
hypothyroidism. Patients who developed thyroid dysfunction may naturally have discriminative characteristics of
CYP3A4 activity and expression prior to the development
of thyroid dysfunction, resulting in the alteration of AMD
concentrations and the DEA/AMD ratio. If patients who
develop AMD-induced thyroid dysfunction have naturally
different AMD metabolic characteristics, the AMD and
DEA concentrations and the DEA/AMD ratio may be
useful for predicting the development of thyroid
dysfunction.
Several potential limitations should be taken into
account when interpreting the results obtained from this
study. First, this was an observational study with a retrospective design. Since the time to development of thyroid
dysfunction during long-term therapy was unknown, serum
Amiodarone Concentration and Thyroid Dysfunction
AMD and DEA concentrations and thyroid-related hormone levels before and after the development of thyroid
dysfunction were not necessarily measured in all months
for all patients. Second, patients diagnosed with thyroid
dysfunction at the initiation of AMD therapy were excluded from the study; therefore, our study population consisted of patients with normal thyroid function at the
initiation of AMD therapy. However, we could not be
completely assured that patients with autoimmune disease
were not included in the study. Third, AMD-induced thyrotoxicosis is divided into two subtypes. Type I AMDinduced thyrotoxicosis develops in patients with latent
Graves’ disease or nodular goiters, and is due to excess
iodine-induced thyroid hormone synthesis. Type II AMDinduced thyrotoxicosis develops in an apparently normal
thyroid as a destructive thyroiditis. The rare incidence of
type I AMD-induced thyrotoxicosis would be accounted
for by a sufficient intake of iodine and a rare incidence of
toxic multinodular goiter in Japan [31]. Although a
definitive diagnosis of the type of AMD-induced thyrotoxicosis was not made in this study, patients with abnormal thyroid function who were positive for antithyroid
antibodies at the initiation of AMD therapy were excluded
from the study; therefore, it was expected that patients with
type I AMD-induced thyrotoxicosis were not included in
the study. Finally, any interventions for thyroid dysfunction
may affect the results; however, therapeutic intervention
for thyroid dysfunction was not controlled in the study. The
exclusion of patients who received interventions was not a
realistic approach because most patients who developed
thyroid dysfunction received any type of therapeutic
interventions. Our findings show the association between
AMD and DEA concentrations and DEA/AMD ratio and
thyroid-related hormones under the actual therapeutic
intervention, which is a major limitation of the study.
5 Conclusions
Our study revealed that age at the initiation of AMD
therapy, dilated cardiomyopathy, and ischemic cardiomyopathy were significant predictors of AMD-induced thyrotoxicosis, and AMD concentration was a significant
predictor of AMD-induced hypothyroidism. In addition,
patients with thyrotoxicosis had an increased DEA/AMD
ratio compared with patients with hypothyroidism and
euthyroid. Meanwhile, patients in the hypothyroidism
group had a decreased DEA/AMD ratio compared with
those in the euthyroidism group. Furthermore, the levels of
thyroid-related hormones changed in conjunction with the
DEA/AMD ratio, and the DEA/AMD ratio significantly
correlated with thyroid-related hormones in the thyrotoxicosis and euthyroidism groups during AMD therapy.
Additionally, ROC analyses showed that the DEA/AMD
ratio may be a potential predictive marker for the development of AMD-induced thyrotoxicosis and hypothyroidism. Hence, these findings suggest that the DEA/AMD
ratio may be a potential predictive marker for AMD-induced thyroid dysfunction.
Compliance with Ethical Standards
Funding No source of funding was used to conduct this study.
Conflict of interest Mikie Yamato, Kyoichi Wada, Tomohiro
Hayashi, Mai Fujimoto, Kouichi Hosomi, Akira Oita, and Mitsutaka
Takada declare that they have no conflicts of interest.
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