The onset time of amiodarone-induced thyrotoxicosis (AIT) depends on AIT type

Abstract

Objective:
Considering the different pathogenic mechanisms of the two main forms of amiodarone-induced thyrotoxicosis (AIT), we ascertained whether this results in a different onset time as well.

Design and methods:
We retrospectively analyzed the clinical records of 200 consecutive AIT patients (157 men and 43 women; mean age 62.2±12.6 years) referred to our Department from 1987 to 2012. The onset time of AIT was defined as the time elapsed from the beginning of amiodarone therapy and the first diagnosis of thyrotoxicosis, expressed in months. Factors associated with the onset time of AIT were evaluated by univariate and multivariate analyses.

Results:
The median onset time of thyrotoxicosis was 3.5 months (95% CI 2-6 months) in patients with type 1 AIT (AIT1) and 30 months (95% CI 27-32 months, P<0.001) in those with type 2 AIT (AIT2). Of the total number of patients, 5% with AIT1 and 23% with AIT2 (P=0.007) developed thyrotoxicosis after amiodarone withdrawal. Factors affecting the onset time of thyrotoxicosis were the type of AIT and thyroid volume (TV).

Conclusions:
The different pathogenic mechanisms of the two forms of AIT account for different onset times of thyrotoxicosis in the two groups. Patients with preexisting thyroid abnormalities (candidate to develop AIT1) may require a stricter follow-up during amiodarone therapy than those usually recommended. In AIT1, the onset of thyrotoxicosis after amiodarone withdrawal is rare, while AIT2 patients may require periodic tests for thyroid function longer after withdrawing amiodarone.

Full text

AUTHOR COPY ONLY
The onset time of amiodarone-induced
thyrotoxicosis (AIT) depends on AIT type
Luca Tomisti, Giuseppe Rossi
2
, Luigi Bartalena
1
, Enio Martino and Fausto Bogazzi
Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Ospedale Cisanello,
Via Paradisa, 2, 56124 Pisa, Italy,
1
Endocrine Unit, Department of Clinical and Experimental Medicine,
University of Insubria, 21100 Varese, Italy and
2
Unit of Epidemiology and Biostatistics, Institute of Clinical
Physiology, National Research Council, 56184 Pisa, Italy
Correspondence
should be addressed
to F Bogazzi
Emails
fausto.bogazzi@med.unipi.it
or fbogazzi@hotmail.com
Abstract
Objective: Considering the different pathogenic mechanisms of the two main forms of amiodarone-induced
thyrotoxicosis (AIT), we ascertained whether this results in a different onset time as well.
Design and methods: We retrospectively analyzed the clinical records of 200 consecutive AIT patients (157 men and
43 women; mean age 62.2G12.6 years) referred to our Department from 1987 to 2012. The onset time of AIT was defined
as the time elapsed from the beginning of amiodarone therapy and the first diagnosis of thyrotoxicosis, expressed in months.
Factors associated with the onset time of AIT were evaluated by univariate and multivariate analyses.
Results: The median onset time of thyrotoxicosis was 3.5 months (95% CI 2–6 months) in patients with type 1 AIT (AIT1) and
30 months (95% CI 27–32 months, P!0.001) in those with type 2 AIT (AIT2). Of the total number of patients, 5% with AIT1
and 23% with AIT2 (PZ0.007) developed thyrotoxicosis after amiodarone withdrawal. Factors affecting the onset time of
thyrotoxicosis were the type of AIT and thyroid volume (TV).
Conclusions: The different pathogenic mechanisms of the two forms of AITaccount for different onset times of thyrotoxicosis in
the two groups. Patients with preexisting thyroid abnormalities (candidate to develop AIT1) may require a stricter follow-up
during amiodarone therapy than those usually recommended. In AIT1, the onset of thyrotoxicosis after amiodarone
withdrawal is rare, while AIT2 patients may require periodic tests for thyroid function longer after withdrawing amiodarone.
European Journal of
Endocrinology
(2014) 171, 363–368
Introduction
Amiodarone-induced thyrotoxicosis (AIT) develops in
w15% of patients under amiodarone therapy (1, 2). Two
main forms of AIT may occur: type 1 is a form of iodine-
induced hyperthyroidism occurring in patients with
underlying thyroid abnormalities, and type 2 is a destruc-
tive thyroiditis mainly due to direct cytotoxic effects of
amiodarone on thyroid follicular cells of a normal thyroid
gland (1, 3, 4, 5). The prevalence of the two main forms of
AIT has changed over the last 30 years in Italy with a current
predominance of the type 2 AIT (AIT2) (6).
Occurrence of AIT is usually considered to be unpre-
dictable, often sudden, and explosive, occurring either early
or long after initiation of amiodarone treatment. In a group
of 58 patients,Trip et al.(7) observed that average duration of
amiodarone treatment before AIT occurrence was w3 years,
with a probability of 2.5% after 18 months and 33.5% after
48 months. In addition, Ahmed et al.(8) have recently
reported an AIT incidence rate per 100 persons/year of 1.9 in
a series of 303 patients taking amiodarone. Other small
prospective studies described the onset of AIT after
12–47 months of amiodarone therapy (9, 10). AIT may also
develop months after drug withdrawal, because of tissue
storage of the drug and its metabolites and their slow release
into the circulation.
Owing to the different pathogenic mechanisms of the
two forms of AIT, we aimed at evaluating whether AIT1
and AIT2 may have different onset times in a large series
of patients. This information might be useful in clinical
European Journal of Endocrinology
Clinical Study L Tomisti and others Onset time of AIT depends
on type
171:3 363–368
www.eje-online.org Ñ2014 European Society of Endocrinology
DOI: 10.1530/EJE-14-0267 Printed in Great Britain
Published by Bioscientifica Ltd.

AUTHOR COPY ONLY
practice for planning a different surveillance program of
thyroid function.
Materials and methods
Study design
We retrospectively analyzed the clinical records of AIT
patients referred to the Department of Clinical and
Experimental Medicine, Endocrinology Section,
University of Pisa, from January 1987 to December 2012.
Each patient gave her/his written informed consent, at
the first clinical visit at our Department, for the use of
anonymous data for research purpose. The Internal
Review Board of our Department approved the study.
Subjects and diagnosis of AIT
A total of 200 consecutive AIT patients (157 men and
43 women; mean (GS.D.), age 62.2G12.6 years, range
24–87 years) were included in the study.
Diagnosis of AIT was based on clinical grounds (signs
and symptoms of thyrotoxicosis) and laboratory findings,
including increased serum free thyroxine (FT
4
) and free
tri-iodothyronine (FT
3
) concentrations, undetectable
serum TSH levels, and increased urinary iodine excretion
(UIE). Diagnosis of AIT2 was based on the following
criteria (1): normal or slightly increased TV without
nodules (R1 cm) at conventional ultrasonography, absent
hypervascularity at color-flow Doppler sonography,
absence of circulating thyroid-directed autoantibody
(anti-thyroglobulin (TgAb), anti-thyroid peroxidase
(TPOAb), anti-TSH receptor (TRAb)), and low/undetect-
able thyroid radioiodine uptake (RAIU) values (!5% at
24 h), as reported previously (11, 12).
The remaining subjects, including patients with Graves’
disease, toxic adenoma, and multinodular goiter, did not
meet the above criteria and were classified as type 1 AIT
(AIT1). For the purpose of this study, all non-AIT2 patients
were designated as AIT1, as reported previously (6).These
criteria were applied retrospectively to patients diagnosed
with AIT before 1990, when differentiation of the two main
types of AIT had not yet been clearly established (6).
Clinical and biochemical findings of the two groups
are given in Table 1.
Time definitions
Onset time of AIT was defined as the period elapsed from
initiation of amiodarone therapy and first diagnosis of
thyrotoxicosis. Onset time after amiodarone withdrawal
was defined as the period elapsed from the withdrawal of
amiodarone therapy and first diagnosis of thyrotoxicosis
in patients who developed thyrotoxicosis after amiodar-
one discontinuation.
Thyroid status
Serum FT
4
,FT
3
(Vitros Immunodiagnostics, The Broad-
way, Amersham), TSH (Immulite 2000, third generation
TSH; Diagnostic Products Corp., Los Angeles, CA, USA),
Table 1 Clinical and biochemical features of the study groups.
Data are expressed as meanGS.D.Normalvaluesinour
laboratory are as follows: FT
4
, 7–17 pg/ml; FT
3
, 2.7–4.5 pg/ml;
TSH, 0.4–3.4 mU/l; TPOAb, !10 IU/ml; and 3rd and 24th h RAIU,
in our area, 15–30 and 30–45% respectively. To convert serum
FT
4
and FT
3
values from pg/ml to pmol/l, multiply by 1.29 and
1.54 respectively.
Variable
AIT1 (nZ42)
meanGS.D.
AIT2 (nZ158)
meanGS.D.P
Sex (female/male) 11/31 32/126 0.41
Age (years) 65.3G10.6 61.4G13 0.07
BSA (m
2
) 1.85G0.23 1.88G0.21 0.52
BMI 26.1G4.6 25.4G3.9 0.35
Basal FT
4
(pg/ml) 28.2G15.3 41.7G16.4 !0.001
Basal FT
3
(pg/ml) 7.2G4.7 10.2G5.2 !0.001
FT
4
/FT
3
4.2G2.2 4.4G1.3 0.50
TSH (mIU/l) !0.01 !0.01 1.00
TPOAb (IU/ml) 138G384 !10 !0.001
UIE (mg/l) 5769G10 999 7967G8045 0.24
TG (ng/ml) 218.3G492.2 136.1G203.9 0.32
3rd h RAIU (%) 7.1G8 1.5G1.1 !0.001
24th h RAIU (%) 12.8G13.3 1.1G1.3 !0.001
TV (ml) 56.7G39.7 19.6G8.8 !0.001
TV norm (ml/m
2
) 30.5G20.1 10.5G4.6 !0.001
CFDS pattern
(0/1/2/3)
3/11/23/5 154/4/0/0 !0.001
Duration of
amiodarone
treatment
(months)
9.9G11.8 28.7G16.1 !0.001
Daily dose of amio-
darone (mg)
193G38 192G54 0.96
Cumulative dose of
amiodarone (g)
46.8G31.7 134.4G108.8 0.001
AIT post AMIO (%) 2/40 (4.76) 36/122 (22.8) 0.007
Basal FT
4
and basal FT
3
, serum thyroid hormone concentrations at
diagnosis; UIE, urinary iodine excretion; TG, serum thyroglobulin; 3rd
and 24th h RAIU, 3rd and 24th h thyroid radioiodine uptake; BSA, body
surface area calculated using the Mosteller formula, as described
previously; TV, thyroid volume estimated by ultrasonography; TV norm,
normalized thyroid volume obtained by dividing thyroid volume by body
surface area; CFDS pattern, color-flow Doppler sonography pattern
expressed as the number of patients having pattern 0/1/2/3; AIT after
AMIO, number of patients (and percentage) developing AIT after
amiodarone withdrawal.
European Journal of Endocrinology
Clinical Study L Tomisti and others Onset time of AIT depends
on type
171:3 364
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TG (Access Immunoassay Systems; Beckman Coulter, Inc.,
Brea, CA, USA), TRAb (TRAK human; Brahms, Hennigs-
dorf, Germany), TgAb (AIA-Pack TgAb; Tosoh, Tokyo,
Japan), and TPOAb (AIA-Pack TPOAb; Tosoh) were assayed
using commercial kits. Normal values in our laboratories
are as follows: FT
4
, 7–17 pg/ml (9.0–22.0 pmol/l); FT
3
,
2.7–4.5 pg/ml (4.2–7.0 pmol/l); TSH, 0.4–3.4 mU/l; TRAb,
!1 U/l; TgAb, !30 IU/ml; and TPOAb, !10 IU/ml.
Random morning urinary samples were collected for
iodine measurements using an autoanalyzer apparatus
(Technicon, Rome, Italy). Median UIE in our area is
110 mg/l.
Thyroid ultrasound and RAIU
TV was measured by ultrasonography and calculated by the
ellipsoid model (width!length!thickness!0.52 for each
lobe) as described previously (13, 14). TV was normalized by
body surface area (TV norm) calculated using the Mosteller
formula (BSA (m
2
)ZOheight (m)!weight (kg)/3600) (15),
because, as reported previously (16), BSA accounts for the
main variations in TVs, including sex-related differences;
normal values in our areas are 3.5–13 ml/m
2
.
Thyroid RAIU was measured at 3 and 24 h after the
administration of a tracer dose (50 mCi) of
131
I. The normal
3 and 24 h RAIU values in our area are 10–20 and 30–45%
respectively.
Statistical analysis
Results are expressed as meanGS.D. for quantitative data
and percentage for categorical data. The comparison
between the two study groups (AIT1 vs AIT2) for clinical
and biochemical features was performed by the Wilcoxon
rank-sum test for quantitative variables and by Fisher’s
exact test for categorical variables. The onset time of AIT
was analyzed by the Kaplan–Mayer survival curve and the
comparison between groups was performed by the log-rank
test. Factors associated with onset time were evaluated by
univariate and multivariate analyses using the Cox
regression model. Hazard ratio (HR) and 95% CI were also
reported. A two-sided Pvalue of !0.05 was considered
statistically significant. Statistical analysis was performed
using the JMP4 (SAS Institute, Inc.,Cary, NC, USA) software.
Results
Out of 200 patients evaluated in this study, 42 (21%) were
diagnosed with AIT1 and 158 (79%) with AIT2. The
clinical and biochemical features of the two groups of
patients are given in Table 1. As expected, patients with
AIT2 had lower 3 and 24-h RAIU values and a smaller TV
than those with AIT1. In addition, patients with AIT2 had
significantly higher serum thyroid hormone concen-
trations (FT
4
41.7G16.4 pg/ml and FT
3
10.2G5.2 pg/ml)
than those with AIT1 (FT
4
28.2G15.3 pg/ml and FT
3
7.2G
4.7 pg/ml, P!0.001 and P!0.001 respectively). Eight
patients with AIT1 had Graves’ disease, six a toxic
adenoma, and 28 a multinodular goiter.
Median onset time of thyrotoxicosis in the AIT1 group
was 3.5 months (range 1–61 months) and 30 months in
AIT2 group (range 1–95 months, log-rank !0.001, Fig. 1).
Distribution of onset time of AIT in the two groups of
patients is shown in Fig. 2.
Out of 200 patients, 38 (19%) developed thyrotoxi-
cosis after amiodarone withdrawal: two patients in the
AIT1 group (4.8%) and 36 patients in the AIT2 group
(22.9%, PZ0.007). The two patients with AIT1 developed
thyrotoxicosis at 1 and 12 months (median time 6.5
months) after the withdrawal of amiodarone. The time
elapsed from the withdrawal of amiodarone therapy and
the first diagnosis of thyrotoxicosis in the AIT2 group
(median time 5.5 months, range 1–18 months) is
summarized in Fig. 3. In the AIT2 group, no difference
was found between patients developing thyrotoxicosis
before or after amiodarone withdrawal in TV, normalized
TV, BMI, and sex, whereas patients developing thyrotoxi-
cosis after amiodarone withdrawal were significantly
younger (56.8G11.9 vs 62.8G13 years respectively;
PZ0.014). In addition, the onset time of thyrotoxicosis
Percentage of patients remaining euthyroid
100
90
80
70
60
50
40
30
20
10
0
0 1020304050
Months
60 70 80 90 100
Figure 1
The Kaplan–Meier event-free survival estimates the onset time
of thyrotoxicosis in type 1 AIT (dotted line) and type 2 AIT
(continuous line). Onset time of thyrotoxicosis was significantly
shorter in type 1 AIT patients (log rank, P!0.001).
European Journal of Endocrinology
Clinical Study L Tomisti and others Onset time of AIT depends
on type
171:3 365
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did not significantly differ in patients who developed AIT
during amiodarone therapy or after therapy withdrawal
(median time 31 months, range 1–200 months, and
median time 26 months, range 2–63 months respectively;
log-rank PZ0.066).
Factors affecting the onset time of thyrotoxicosis were
evaluated by the univariate and multivariate analyses, as
reported in Table 2. In the univariate analysis, a shorter
onset time was related to AIT1 (P!0.0001) and to a larger
normalized TV (P!0.0001). When patients were divided
based on the type of AIT, the univariate analysis confirmed
the significant effect of the normalized TV on the onset
time of thyrotoxicosis (HR 1.01, 95% CI 1.00–1.03,
PZ0.04 in the AIT1 group and HR 1.05, 95% CI 1.01–
1.09, PZ0.01 in the AIT2 group).
After adjusting for age, sex, and BMI, in the multi-
variate analysis, the type of AIT and the normalized TV
were confirmed as the main independent factors affecting
the onset time of thyrotoxicosis with a HR of 2.88 (95% CI
1.76–4.55, P!0.0001) and 1.03 (95% CI 1.01–1.04,
P!0.0001) per unit of increment respectively. No
interaction was found between the type of AIT and
normalized TV (PZ0.42).
Discussion
Onset of thyrotoxicosis during amiodarone therapy is
usually considered to be unpredictable (1, 3, 7) and has
been reported to occur at any time during therapy as well
as after drug withdrawal. However, no studies have so far
investigated as to whether differences exist in the onset
time of the two main forms of AIT.
The present retrospective study of a large cohort of
patients is the first report of a significant difference in the
onsettime of thyrotoxicosis of the twoforms of AIT. The time
elapsed from initiation of amiodarone therapy and occur-
rence of thyrotoxicosis was much shorter in AIT1 than in
AIT2, themedian time being 3.5and 30 months respectively.
This observation is consistent with previous limited
observations in small series and the different pathogenic
mechanisms of the two forms of AIT (6, 12, 17). AIT1 is
a form of iodine-induced hyperthyroidism arising in
a thyroid gland with underlying functional autonomy;
in these patients, iodine load may rapidly trigger
an increased thyroid hormone synthesis. Conversely,
AIT2, being a destructive thyroiditis due to a direct
cytotoxic effect of amiodarone or iodine (1, 3, 18, 19),
may imply that a high intrathyroid drug concentration
may be reached before the damage of thyroid follicular
cells becomes evident at a clinical level (20).
0
0
20
15
10
5
0
0 5 10 15 20 25 30 35 40 45
Months
50 55 60 65 70 75 80 85 90 95
10
20
Percentage of patientsPercentage of patients
30
40A
B
5 1015202530
Months
35 40 45 50 55 60 65
Figure 2
Percentage of patients developing amiodarone-induced
thyrotoxicosis (AIT) from the beginning of amiodarone
therapy in type 1 AIT (nZ42 patients, A) and type 2 AIT
(nZ158 patients, B).
50
40
30
20
Percentage of patients
10
0
5 101520
Months
Figure 3
Time distance from the withdrawal of amiodarone therapy and
the onset of thyrotoxicosis in the 36 type 2 AIT patients
developing thyrotoxicosis after amiodarone withdrawal.
European Journal of Endocrinology
Clinical Study L Tomisti and others Onset time of AIT depends
on type
171:3 366
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However, AIT2 may also have an abrupt and explosive
onset at any time during amiodarone therapy (21). In fact,
although the mean onset time was 30 months in AIT2
patients, w15% of subjects developed thyrotoxicosis
after !12 months of amiodarone therapy.
In addition, we observed that w20% of AIT2 patients
developed thyrotoxicosis after amiodarone withdrawal,
probably due to the long storage time and the slow release
of amiodarone and its main metabolite, desethylamiodar-
one, from the adipose tissue, which prolong and maintain
exposure of the thyroid gland to amiodarone. This is in
keeping with the observation that onset time of thyro-
toxicosisinthissubsetofpatientsdidnotdiffer
significantly from that of patients who developed thyro-
toxicosis during amiodarone therapy. This event was
rarely observed in AIT1 (!5%), which is associated with
an earlier occurrence of thyrotoxicosis.
Despite the clear-cut difference in the average onset
time of AIT1 and AIT2, there was a partial overlap between
the two forms. A possible reason for the presence of a
longer onset time in a small subset of AIT1 patients may be
a concomitant destructive process (mixed forms) accoun-
table for a longer onset time. However, w70% of AIT1
patients but only 5% of AIT2 patients developed AIT
within 6 months. At variance, in 70% of AIT2 patients,
thyrotoxicosis developed after 2 years, while only 10%
of AIT1 has such a long onset time. The interval between
initiation of amiodarone therapy and occurrence of AIT,
nevertheless, cannot be used, alone, to distinguish the two
forms of AIT in individual patients.
Another independent determinant of the onset time of
thyrotoxicosis was the TV. We have previously reported that
the normalized TV is an independent factor affecting the
response to glucocorticoid therapy in AIT2 patients (11).
In this study, we have found that a larger TV was related to a
shorter onset time of thyrotoxicosis, confirming that the
thyroid size plays a role in development and severity of AIT.
It is noteworthy that the TV is calculated at the moment of
the diagnosis of AIT. This is a limitation of our study due to its
retrospective design. However, no data regarding modifi-
cation of the TV in patients under amiodarone therapy have
been currently reported. Thus, being so we have considered
the TV, estimated at the timeof diagnosis of AIT, to be a good
proxy for thebasal TV. As a matter of fact, a prospective study
by Silva et al.(22) did not find any correlation among the
time of use, the daily dose and the cumulative dose of
amiodarone, and the detection of goiter in a subset of
patients taking amiodarone because of Chagas disease. This
information may support the concept that TV should not be
significantly affected by the amiodarone therapy.
It has been previously observed that a lower BMI may
be an independent risk factor for the development of AIT
(23). However, our study failed to find a relationship
between the onset time of thyrotoxicosis and BMI. It is
worth noting that patients described in the study by Stan
et al.(23) had congenital cardiomyopathy and a normal to
low BMI, at variance with patients of the present series.
In conclusion, our data showed that patients with AIT1
have a shorter median onset time of thyrotoxicosis than
those with AIT2. In patients under amiodarone therapy,
evaluation of thyroid function is usually recommended
at 6-month intervals (1,2,3,24). Based on the present data,
we suggest a closer follow-up (i.e. every 1–3 months) for
the patients with preexisting thyroid abnormalities
(autonomous multinodular goiter or latent Graves’ disease)
who may develop AIT1.
By contrast, in patients with a normal thyroid gland
we cannot provide a follow-up plan able to guarantee an
early diagnosis of AIT because of the large variability of
their onset time. In addition, the onset of thyrotoxicosis is
often sudden and the clinical features of thyrotoxicosis
may be atypical and mild, mainly in older patients. As
a result, evaluation of thyroid function should be
performed, at any time, in patients under amiodarone
therapy showing an unexpected worsening of cardiac
conditions and in patients, also taking warfarin therapy,
showing an unexplained increased sensitivity to antico-
agulant therapy (25).
However, in patients under amiodarone therapy
showing no signs of thyrotoxicosis, we believe that a
thyroid function test should be periodically performed
because the diagnosis of thyrotoxicosis might be strongly
delayed by the atypical clinical features often observed.
Table 2 Factors associated with the onset time, evaluated by
the Cox regression model. Factors associated with the onset
time were evaluated using univariate analysis by the Cox
regression model.
Variables
Univariate
HR 95% CI P
AIT type 4.20 2.90–5.96 !0.0001
Age (years) 0.99 0.98–1.00 0.435
Sex 0.81 0.58–1.16 0.257
BMI 1.02 0.98–1.05 0.206
TV norm 1.05 1.03–1.06 !0.0001
Type 1 AIT, a larger thyroid volume, and a larger body surface area were
associated with a shorter onset time; BSA, body surface area calculated
using the Mosteller formula, as described previously; TV norm, normalized
thyroid volume obtained by dividing thyroid volume by body surface area;
HR, hazard ratio.
European Journal of Endocrinology
Clinical Study L Tomisti and others Onset time of AIT depends
on type
171:3 367
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Finally, thyroid function should be monitored for at
least 2 years after amiodarone withdrawal, particularly in
patients without apparent thyroid abnormalities.
Declaration of interest
The authors declare that there is no conflict of interest that could be
perceived as prejudicing the impartiality of the research reported.
Funding
This research did not receive any specific grant from any funding agency
in the public, commercial or not-for-profit sector.
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Received 2 April 2014
Revised version received 30 May 2014
Accepted 16 June 2014
European Journal of Endocrinology
Clinical Study L Tomisti and others Onset time of AIT depends
on type
171:3 368
www.eje-online.org