Int J Clin Pharm (2014) 36:405–411 DOI 10.1007/s11096-013-9910-9
RESEARCH ARTICLE
Amiodarone-induced thyroid dysfunction in Taiwan: a retrospective cohort study Chun-Jui Huang • Po-Ju Chen • Jing-Wen Chang • De-Feng Huang • Shih-Lin Chang • Shih-Ann Chen Tjin-Shing Jap • Liang-Yu Lin
•
Received: 9 September 2013 / Accepted: 27 December 2013 / Published online: 11 February 2014 Koninklijke Nederlandse Maatschappij ter bevordering der Pharmacie 2014
Abstract Background The incidence and risk factors of amiodarone-induced thyroid dysfunction are variable in the literature. Objective The aim of this study was to investigate the clinical and biochemical features and risk factors of amiodarone-induced thyroid dysfunction in Taiwan. Setting This study was conducted at a tertiary referral center for arrhythmia. Method Retrospective analysis of patients treated with amiodarone during the years 2008–2009 was performed. Main outcome measure Incidence and risk factors of amiodarone-induced thyrotoxicosis (AIT) and amiodaroneinduced hypothyroidism (AIH) were assessed. Results Of the 527 patients, 437 (82.9 %) remained euthyroid, 21 (4.0 %) C.-J. Huang P.-J. Chen T.-S. Jap L.-Y. Lin (&) Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei City, Taiwan e-mail: [email protected] C.-J. Huang D.-F. Huang S.-L. Chang S.-A. Chen T.-S. Jap L.-Y. Lin Faculty of Medicine, National Yang-Ming University, Taipei City, Taiwan
developed AIT, and 69 (13.1 %) were affected with AIH. In univariate analysis, AIT was associated with younger age, and the risk factors for AIH included older age, higher baseline thyroid stimulating hormone (TSH) titer, lower baseline free T4 level, lower cumulative amiodarone dosage, and shorter amiodarone treatment duration. Cox regression analysis was performed to determine the different risk categories in the elderly population of age 65–74 (young-old), 75–84 (old-old), and C85 years old (oldest-old). Additionally increased risk of AIH was found in the groups of old-old (HR 2.09, 95 % CI 1.11–3.96) and oldest-old (HR 2.57, 95 % CI 1.21–4.75). In the multivariate analysis of risk factors for AIH, baseline TSH level (HR 1.38, 95 % CI 1.12–1.70) and cumulative amiodarone dosage (HR 0.95, 95 % CI 0.93–0.97) remained statistically significant. Conclusion AIH was much more common than AIT in Taiwan, an area with sufficient iodine intake. Higher baseline TSH level was the predominant independent risk factor for the development of AIH. Keywords Amiodarone Hypothyroidism Thyrotoxicosis
J.-W. Chang Department of Medicine, Kaohsiung Armed Forces General Hospital, Kaohsiung City, Taiwan D.-F. Huang Division of Allergy, Immunology and Rheumatology, Department of Medicine, Taipei Veterans General Hospital, Taipei City, Taiwan S.-L. Chang S.-A. Chen Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei City, Taiwan L.-Y. Lin Institute of Pharmacology, National Yang-Ming University, Taipei City, Taiwan
Impact of findings on practice •
•
Amiodarone-induced thyroid dysfunction is not uncommon and warrants the need for routine measurement of thyroid function after amiodarone is being prescribed. Elderly patients with higher baseline thyroid stimulating hormone (TSH) level may need to be even closer monitored for early detection of amiodarone-induced thyroid dysfunction.
123
406
Int J Clin Pharm (2014) 36:405–411
Introduction
Method
Amiodarone is one of the most common anti-arrhythmic agents for treating supraventricular and ventricular arrhythmia. It is a benzofuran derivative with 37 % iodine content (by weight), and its structure is similar to that of the thyroid hormone. Adverse drug reactions, including elevated transaminase levels, pulmonary fibrosis, arrhythmia, and thyroid dysfunction have been reported to occur even on low-dose amiodarone therapy [1]. The high iodine content of amiodarone and its intrinsic drug properties, such as inhibition of type I 50 -deiodinase, may lead to the development of thyroid dysfunctions, including amiodarone-induced thyrotoxicosis (AIT) and amiodaroneinduced hypothyroidism (AIH) [2, 3]. The risk factors for amiodarone-induced thyroid dysfunction are variable in different areas; younger age, male gender, thyroid auto-antibody production, goiter, or low body mass index (BMI) were reported to be associated with AIT [4–9]; whereas older age, higher baseline TSH level, diabetes mellitus, poor heart function, and thyroid autoantibody production in women were the possible risk factors for AIH [6, 7, 10–13]. Ambient iodine intake may also be an independent contributing factor for this variation. When urinary iodine excretion was used as the determinant of iodine intake, West Tuscany in Italy was found to be an area with iodine deficiency, and local studies showed a higher incidence of AIT in this area [14]. In Worchester, USA, sufficient iodine intake was reported to be associated with a higher incidence of AIH [14]. However, the association between the development of thyroid dysfunction and amiodarone treatment duration and dosage has been inconsistently reported in the literature [6, 7, 15, 16]. A great majority of the studies on amiodarone-induced thyroid dysfunction has been conducted in Europe and America, with only one report from Asia [6]. The incidence and risk factors for amiodarone-induced thyroid dysfunction in Taiwan, an area with sufficient iodine intake [17], remain to be elucidated.
Study design and data collection The study was carried out at Taipei Veterans General Hospital, a tertiary referral center for arrhythmia control in Taiwan. The hospital receives patients with new-onset arrhythmia from general practice and provides evaluation, treatment and follow-ups at the hospital. The medical records of 558 patients initially prescribed with amiodarone due to arrhythmia at the hospital with thyroid function data available from January 1, 2008 to December 31, 2009 were retrospectively retrieved from the computer database of the hospital. Thirty-one patients with a previous history of thyroid diseases, including papillary thyroid carcinoma (n = 7), Graves’ disease (n = 5), hypothyroidism (n = 4), prior thyroid surgery for goiter (n = 2), subclinical hypothyroidism with a TSH titer [10 mU/l (n = 9), and subclinical hyperthyroidism with a TSH titer \0.1 mU/l (n = 4) were excluded. In total, 527 patients were recruited for analysis. Indications for amiodarone therapy included supraventricular tachycardia (n = 469, 89.0 %) and ventricular tachycardia (n = 58, 11.0 %). The demographic, clinical, and biochemical metrics; thyroid function data before and after amiodarone therapy; and information on co-morbidities such as diabetes mellitus, hypertension, chronic obstructive pulmonary disease, peripheral arterial disease, and various heart diseases were collected. Data on thyroid autoantibody level, thyroid sonography, and I131 thyroid uptake and scans were also recorded if the tests had been performed. The treatment duration and cumulative and average daily dosage of amiodarone were also analyzed. The duration of amiodarone therapy was defined as the period between the date of amiodarone prescription and the date when thyroid dysfunction developed, or the date of amiodarone withdrawal if thyroid dysfunction did not occur. The cumulative dosage was the effective dose taken by the patient, while the average daily dose was calculated from the cumulative dosage and duration of amiodarone therapy.
Aim of the study Definition of thyroid dysfunction The aim of this study was to investigate the clinical and biochemical features and risk factors for AIT and AIH in Taiwan.
Ethical approval This study was approved by the local Institutional Review Board (VGH IRB No: 2011-12-003IC).
123
AIT was defined as TSH titer \0.1 mU/l and free thyroxin (T4) level [24.5 pmol/l, while AIH in need of treatment was ascertained by serum TSH titer[10 mU/l regardless of the free T4 level, or TSH titer between 4 and 10 mU/l with a lowered free T4 level \10.3 pmol/l. In cases showing an abnormal thyroid function test result within 3 months of amiodarone initiation, a subsequent abnormal result was considered necessary to make the diagnosis.
Int J Clin Pharm (2014) 36:405–411 Table 1 Univariate analysis of risk factors of the 527 patients taking amiodarone
407
Number (%)
Euthyroidism 437 (82.9)
AIT 21 (4.0)
AIH 69 (13.1)
Total 527 (100) 69.1 ± 14.9
Age (years)
68.9 ± 14.7
54.7 ± 18.1***
74.6 ± 11.8**
Male (%)
286 (65.4)
11 (52.4)
51 (73.9)
348 (66.0)
Body mass index (kg/m2)
24.3 ± 4.8
24.8 ± 7.5
23.8 ± 3.9
24.2 ± 4.8
Diabetes mellitus (%)
94 (21.5)
4 (19.0)
17 (24.6)
115 (21.8)
Hypertension (%)
259 (59.3)
8 (38.1)
47 (68.1)
314 (59.6)
COPD (%)
15 (3.4)
0 (0.0)
2 (2.9)
17 (3.2)
PAD (%)
9 (2.1)
1 (4.8)
3 (4.3)
13 (2.5)
Coronary artery disease (%)
120 (27.5)
5 (23.8)
24 (34.8)
149 (28.3)
Valvular heart disease (%)
43 (9.8)
3 (14.3)
6 (8.7)
52 (9.9)
Congenital heart disease (%) Congestive heart failure (%)
17 (3.9) 92 (21.1)
1 (4.8) 3 (14.3)
0 (0.0) 18 (26.1)
18 (3.4) 113 (21.4)
Sick sinus syndrome (%)
14 (3.2)
1 (4.8)
5 (7.2)
20 (3.8)
Baseline free T4 (pmol/l) (n = 151)
18.1 ± 3.3
20.0 ± 4.3
16.4 ± 3.7*
18.0 ± 3.5
Baseline TSH (mU/l) (n = 181)
2.06 ± 1.64
1.79 ± 1.27
4.64 ± 2.83***
2.43 ± 2.05
Duration (days)
424 ± 372
456 ± 350
304 ± 245**
410 ± 359
Cumulative dose (g)
86.2 ± 73.2
117.7 ± 128.3
66.6 ± 58.1*
84.9 ± 74.8
Average dose(mg/day)
244.9 ± 105.1
231.9 ± 109.2
255.9 ± 162.8
245.8 ± 114.2
Heart disease
AIT amiodarone-induced thyrotoxicosis, AIH amiodarone-induced hypothyroidism, COPD chronic obstructive pulmonary disease, PAD peripheral arterial disease * P \ 0.05, ** P \ 0.01, *** P \ 0.001
Amiodarone use
Measurement of thyroid function
Results
Serum TSH level was measured with a chemiluminescent immunometric assay (DPC Immulite 2000; Seracon Diagnostic Co., Brownsville, TX, USA), while free T4 level was determined using a chemiluminescent, competitive analogue immunoassay (DPC Immulite 2000; Seracon Diagnostic Co., Brownsville, TX, USA). The normal reference range of thyroid function tests in our laboratory was as follows: free T4, 10.3–24.5 pmol/l; TSH, 0.4–4.0 mU/l.
The baseline demographic and clinical characteristics of the 527 enrolled patients are summarized in Table 1. The mean age was 69.1 ± 14.9 years and 66.0 % of patients were male. The mean duration of amiodarone treatment was 410 ± 359 days with a cumulative dosage of 84.9 ± 74.8 g and an average daily dose of 245.8 ± 114.2 mg/day. AIT developed in 21 patients (4.0 %), and AIH occurred in 69 patients (13.1 %), while the remaining 437 patients (82.9 %) maintained a euthyroid state throughout the study period.
Statistical analysis
Correlation between amiodarone usage and thyroid dysfunction
Statistical analysis was performed using the Statistical Product and Service Solutions (SPSS) software, version 18.0. Descriptive statistics were expressed as the mean ± standard deviation (SD) for continuous variables, and as the number of cases and percentage (%) for categorical variables. The analyses for differences between groups were performed using the Pearson Chi Square or Student’s t test. Cox regression hazard model was used for multivariate analysis and to identify the risk categories of AIH in different elderly age groups. A two-tailed P value of less than 0.05 was considered statistically significant.
Compared to patients who remained euthyroid, the patients who developed AIH received amiodarone therapy for a shorter duration (mean duration, 424 ± 372 days vs. 304 ± 245 days, P = 0.001), while there was no difference in treatment duration between the euthyroid and AIT groups (mean duration, 424 ± 372 vs. 456 ± 350 days, P = 0.71). In addition to the duration of amiodarone therapy, the cumulative dosage in the AIH group was also found to be significantly lower than that in the euthyroid group (86.2 ± 73.2 g vs. 66.6 ± 58.1 g, P = 0.013) (Table 1). In patients who took amiodarone for less than 365 days, the odds ratio of developing AIH was 1.89 (95 %
123
408
Int J Clin Pharm (2014) 36:405–411 Table 3 Multivariate analysis of risk factor for the development of AIH Variable
Adjusted HR (95 % CI)
P value
Amiodarone cumulative dose (g)
0.95 (0.93–0.97)
\0.001
Baseline TSH (mU/l)
1.38 (1.12–1.70)
0.003
Age (years old)
1.01 (0.97–1.05)
0.739
Free T4 (pmol/l)
1.00 (0.86–1.17)
0.983
Cox proportional hazard regression model was used
Fig. 1 Kaplan-Meier curve of event-free probability of AIH in patients treated with amiodarone. Statistically significant difference between the age groups of age \65, 65–74 (young-old), 75–84 (old-old), and age C85 years old (oldest-old) were found (Log rank test, P = 0.047)
Table 2 Analysis of age as a risk factor for the development of AIH Age (years)
n (%)
HR (95 % CI)
P value
\65
204 (38.7)
1
0.25
65–74 75–84
96 (18.2) 140 (26.6)
1.54 (0.73–3.24) 2.09 (1.11–3.96)
0.02* 0.01*
87 (16.5)
2.57 (1.25–5.25)
C85
Cox proportional hazard regression model was used * P \ 0.05
CI 1.10–3.24, P = 0.02) compared to those whose treatment duration was more than 1 year. A cumulative dosage of \73 g (in a patient taking 200 mg of amiodarone per day for 1 year) was associated with a 1.87-fold increased risk for AIH (95 % CI 1.09–3.18, P = 0.02). Association of age, gender, and BMI with thyroid dysfunction
increased risk for occurrence of AIH (95 % CI 1.28–4.27, P = 0.006); in younger adults of age \50 years, a 5.32-fold increased risk for developing AIT (95 % CI 2.14–13.22, P \ 0.001) was found. To determine the different risk categories in the elderly population, patients with age 65 years or more were further divided into three groups: age 65–74 (young-old), age 75–84 (old-old), and age C85 years old (oldest-old). Logrank test showed statistically significant difference between the event-free probability of AIH in the four different age groups as shown in Fig. 1 (P = 0.04). In the investigation of hazard ratio, substantially increased risk of AIH was found in the group of old-old (HR 1.92, 95 % CI 1.03–3.56, P = 0.04) and oldest-old (HR 2.40, 95 % CI 1.25–5.25, P = 0.01) (Table 2). Influence of baseline thyroid status With reference to the euthyroid group, AIH was significantly associated with higher baseline TSH titer (mean TSH titer, 2.06 ± 1.64 vs. 4.64 ± 2.83 mU/l, P \ 0.001) and lower free T4 level (mean free T4 level, 18.1 ± 3.3 vs. 16.4 ± 3.7 mU/l, P = 0.03) (Table 1). There was no statistically significant difference in thyroid status between the euthyroid and AIT groups. While determining the cutoff value for increased risk for the development of AIH, a baseline TSH titer [1.5 mU/l was found to be associated with AIH (HR 3.3, 95 % CI 1.25–8.73, P = 0.016). An increase of 1 mU/l in the baseline TSH titer was further associated with increased incidence of AIH (HR 1.36, 95 % CI 1.21–1.54, P \ 0.001). Independent risk factors for AIH
There were no statistically significant differences in gender and BMI between the euthyroid, AIT, and AIH groups. Compared to the euthyroid individuals, AIT patients were younger (68.9 ± 14.7 years vs. 54.7 ± 18.1 years, P \ 0.001), while AIH patients were typically older (68.9 ± 14.7 years vs. 74.6 ± 11.8 years, P = 0.001) (Table 1). When odds ratio was evaluated, age C65 years was associated with a 2.34-fold
123
Multivariate analysis showed baseline TSH titer (HR 1.38, 95 % CI 1.12–1.70, P = 0.003) and cumulative amiodarone dosage (HR 0.95, 95 % CI 0.93–0.97, P \ 0.001) to be correlated with the development of AIH (Table 2). Free T4 level and age did not show statistically significant correlations (Table 3).
Int J Clin Pharm (2014) 36:405–411
409
Table 4 Summary of risk analysis of amiodarone-induced thyroid dysfunction Author, country (year)
n
AIT (%)
AIH (%)
Risk factor of AIT
Risk factor of AIH
Ref.
1. Martino et al., Italy (1987)
467
N.A.
6
N.A
Thyroid Ab
10
Women with thyroid Ab
2. Trip et al. Netherlands (1991)
58
12.1
6.9
N.A
3. Thorne et al., UK (1999)a,
92
20.7
15.2
Female; complex cyanotic heart disease; Fontan-type surgery; average dose [200 mg/d
15
b
11
4. Sidhu et al., UK (2003)
216
5.6
7
Male
N.A.
4
5. Schaan et al., Brazil (2005)
195
2.1
25.1
Male; microsomal Ab
N.A.
5
21.3c
12.5c
6. Hofmann et al., Austria (2008)b
None
None
30
7. Lee et al., Hong Kong (2010)
390
6
22
Younger age
Baseline TSH [4.0 mU/l
6
8. Ahmed et al., Netherlands (2011)
303
8
6
Age \62 years
Baseline TSH [1.4 mU/lc; LVEF \45 %c; DMc; age C62 years
7
9. Aleksic´ et al., Serbia (2011)b
248
6
9.7
Goiterc, thyroid peroxidase antibodiesc
12
a
72
169
13.6
N.A.
BMI \21; goiter
N.A.
8
11. Zosin et al., Romania (2012)
229
20.5
17.9
Younger age, goiter
Older age, goiter, higher thyroid volume
9
12. Current study, Taiwan (2014)
527
4
13.1
Younger age
Older age, higher baseline TSHc, lower baseline free T4, shorter amiodarone duration, less amiodarone cumulative dosagec
–
10. Stan et al., USA (2012)
AIT amiodarone-induced thyrotoxicosis, AIH amiodarone-induced hypothyroidism, Ref. reference number, N.A not available, Ab antibody, LVEF left ventricular ejection fraction, DM diabetes mellitus, BMI body mass index a
Only adult patients with congenital heart disease were evaluated in these two studies
b
Comparison was made between the group of euthyroidism and thyroid dysfunction
c
Independent risk factors in multivariate analysis
Discussion To our knowledge, this is the first study to evaluate the incidence and risk factors for amiodarone-induced thyroid dysfunction in Taiwan. Previous studies on the risk factor analysis of amiodarone-induced thyroid dysfunction are summarized in Table 4 [4–12, 15, 18]. The positive association between younger age and AIT in our study was similar to the findings of reports from Hong Kong, the Netherlands, and Romania [6, 7]. Risk factors associated with AIH in our study included older age, higher baseline TSH titer, lower baseline free T4 level, shorter amiodarone treatment duration, and lower amiodarone cumulative dosage. Elevated baseline TSH titer being a risk factor for AIH [6, 7], and the association between older age and AIH were found in previous reports [7, 9]. However, risk analysis in different elderly age groups has not been done. The novelty of this study lies in the finding that substantial increased risk of AIH is present in the elderly groups of old-old and oldest-old. Other novel findings include the associations between AIH and lower baseline free T4 level, shorter amiodarone treatment duration, and lower amiodarone cumulative dosage. Higher baseline TSH level and
lower amiodarone cumulative dosage were the independent factors showing significance in multivariate analysis. The reported incidence of AIT and AIH varies in the literature. Studies from Europe showed that AIT was more frequent than AIH, but reports from America and Asia revealed the opposite [19–21]. This discrepancy may be due to differences in diagnostic criteria, follow-up periods, ethnicity, geographic variations, or ambient iodine intake. A higher incidence of AIT was found in areas with iodine deficiency, and sufficient iodine intake was associated with AIH [14]. Local data on urinary iodine excretion showed that the amount of iodine intake was sufficient in Taiwan [17], which may explain the higher incidence of AIH in our study. The data on amiodarone dose/duration and thyroid dysfunction are conflicting. A cumulative dose exceeding 144 g was previously reported to be associated with AIT (OR 12.9), but the dose–effect was less pronounced for AIH [16]. In patients with congenital heart disease, an average amiodarone dose over 200 mg/day appeared to be a risk factor for thyroid dysfunction [15]. However, a correlation between amiodarone treatment duration and dose and AIH or AIT was not observed in many other studies, as summarized in Table 4. Our study revealed an association
123
410
between lower amiodarone cumulative dosage (mean dosage, 66.6 ± 58.1 g) and shorter treatment duration (mean duration, 304 ± 245 days) and the development of AIH. The shorter period to AIH diagnosis was not related to the transient thyroid function alterations frequently observed during the first 3 months following amiodarone administration [22]. This may indicate that AIH is an early event in the course of amiodarone therapy, in accordance with the prospective studies by Trip et al. [11], Bongard et al. [23], and Batcher et al. [24], showing that AIH typically occurs no later than after 1 year of therapy. When baseline TSH level was considered as a risk factor, a cutoff value of [2 mU/l was observed to predict hypothyroidism in a 20-year follow-up study of the Wickham Survey [25]. Recent epidemiological studies also confirmed that individuals with a TSH level within the high-normal range are at increased risk for hypothyroidism [26, 27]. The situation in patients taking amiodarone is unknown. In the current study, baseline TSH titer[1.5 mU/l was associated with AIH progression (HR = 3.3). A similar baseline cutoff TSH value of [1.4 mU/l was shown to predict AIH in previous report [7]. Whether the association was partially related to autoimmune thyroid disease could not be evaluated due to limited measurements of baseline thyroid auto-antibodies by cardiologists. Nevertheless, individuals with high-normal baseline TSH value warrant special attention and frequent monitoring when using amiodarone. The findings that younger age is a risk factor for AIT and older age for AIH were similar to those obtained in previous reports [6, 7, 9]. An explanation was not provided in most studies and could also be difficult to determine in our study due to the limited data on thyroid auto-antibodies, color Doppler, and radioactive iodine uptake studies. Further risk analysis in the elderly age groups revealed additionally increased risk in the group of old-old (age 75–84) and oldest-old (age over 85). According to previous evaluation on the relationship between age and serum TSH level in asymptomatic older people in Taiwan, the mean serum TSH level was similar between the groups of young-old (age 65–79) and old-old (age over 80) [28]. This suggests that factors other than higher baseline mean TSH level may have contributed to the additional risk for AIH in the older population. The clinical manifestations of AIH in the geriatric population are subjective enough to be vague and can lead to delayed diagnosis in daily clinical practice [29, 30]. Considering that subclinical hypothyroidism with a TSH value above 10 mU/l should be treated, and inadequate thyroid function monitoring during amiodarone therapy occurs due to lack of awareness of current guidelines [31, 32], active surveillance and close follow-up is needed, especially in the population with the highest risk, the elderly group of old-old (age 75–84) and oldest-old (age C85).
123
Int J Clin Pharm (2014) 36:405–411
The limitations of this study are related to its retrospective nature. The incidence of AIT and AIH may be overestimated because patients with suspected symptoms may more likely to have thyroid function tested compared to those who remained asymptomatic on amiodarone therapy. Case numbers with data related to thyroid auto-antibodies, thyroid sonography, and I131 scintigraphy were too small to be included for analysis. The AIT subtype could not be classified based on available information. Amount of individual iodine intake could not be determined. We also believe that interpretation of the positive findings in a small event group, such as a group size of 21 patients with AIT, needs to be validated in future cohorts with a larger patient population. A further prospective study is therefore needed.
Conclusion Our study shows a higher incidence of AIH than AIT in Taiwan, which is comparable to the findings in other iodine-sufficient areas. It is advised that patients, especially the old-old and oldest-old, or those with higher baseline TSH level, be closely followed for early detection of hypothyroidism during amiodarone therapy.
Funding This study was partly supported by research Grants V100B-039, V101B-023, V102B-048 to L.Y.L. and V100A-013 to P.J.C from Taipei Veterans General Hospital, Taipei, Taiwan. Conflicts of interest
None.
References 1. Vorperian VR, Havighurst TC, Miller S, January CT. Adverse effects of low dose amiodarone: a meta-analysis. J Am Coll Cardiol. 1997;30:791–8. 2. Han TS, Williams GR, Vanderpump MP. Benzofuran derivatives and the thyroid. Clin Endocrinol. 2009;70:2–13. 3. Cohen-Lehman J, Dahl P, Danzi S, Klein I. Effects of amiodarone therapy on thyroid function. Nat Rev Endocrinol. 2010;6:34–41. 4. Sidhu J, Jenkins D. Men are at increased risk of amiodaroneassociated thyrotoxicosis in the UK. QJM. 2003;96:949–50. 5. Schaan BD, Cunha CP, Francisconi A, Zottis B, Brum G, Bruch RS, et al. Amiodarone-induced thyroid dysfunction in a tertiary center in south Brazil. Arq Bras Endocrinol Metabol. 2005;49:916–22. 6. Lee KF, Lee KM, Fung TT. Amiodarone-induced thyroid dysfunction in the Hong Kong Chinese population. Hong Kong Med J. 2010;16:434–9. 7. Ahmed S, Van Gelder IC, Wiesfeld AC, Van Veldhuisen DJ, Links TP. Determinants and outcome of amiodarone-associated thyroid dysfunction. Clin Endocrinol. 2011;75:388–94. 8. Stan MN, Ammash NM, Warnes CA, Brennan MD, Thapa P, Nannenga MR, et al. Body mass index and the development of amiodarone-induced thyrotoxicosis in adults with congenital heart disease-A cohort study. Int J Cardiol. 2013;167:821–6.
Int J Clin Pharm (2014) 36:405–411 9. Zosin I, Balas M. Amiodarone-induced thyroid dysfunction in an iodine-replete area: epidemiological and clinical data. Endokrynol Pol. 2012;63:2–9. 10. Martino E, Aghini-Lombardi F, Mariotti S, Bartalena L, Lenziardi M, Ceccarelli C, et al. Amiodarone iodine-induced hypothyroidism: risk factors and follow-up in 28 cases. Clin Endocrinol. 1987;26:227–37. 11. Trip MD, Wiersinga W, Plomp TA. Incidence, predictability, and pathogenesis of amiodarone-induced thyrotoxicosis and hypothyroidism. Am J Med. 1991;91:507–11. 12. Aleksic Z, Aleksic A. Incidence of amiodarone-induced thyroid dysfunction and predictive factors for their occurrence. Med Pregl. 2011;64:533–8. 13. Martino E, Aghini-Lombardi F, Bartalena L, Grasso L, Loviselli A, Velluzzi F, et al. Enhanced susceptibility to amiodaroneinduced hypothyroidism in patients with thyroid autoimmune disease. Arch Intern Med. 1994;154:2722–6. 14. Martino E, Safran M, Aghini-Lombardi F, Rajatanavin R, Lenziardi M, Fay M, et al. Environmental iodine intake and thyroid dysfunction during chronic amiodarone therapy. Ann Intern Med. 1984;101:28–34. 15. Thorne SA, Barnes I, Cullinan P, Somerville J. Amiodaroneassociated thyroid dysfunction: risk factors in adults with congenital heart disease. Circulation. 1999;100:149–54. 16. Bouvy ML, Heerdink ER, Hoes AW, Leufkens HG. Amiodaroneinduced thyroid dysfunction associated with cumulative dose. Pharmacoepidemiol Drug Saf. 2002;11:601–6. 17. Lin HD, Lo JG, Ching KN. Amount of urinary iodine excretion in residents of Taipei City: a hospital-based study. J Chin Med Assoc. 1991;48:20–4. 18. Hofmann A, Nawara C, Ofluoglu S, Holzmannhofer J, Strohmer B, Pirich C. Incidence and predictability of amiodarone-induced thyrotoxicosis and hypothyroidism. Wien Klin Wochenschr. 2008;120:493–8. 19. Diehl LA, Romaldini JH, Graf H, Bartalena L, Martino E, Albino CC, et al. Management of amiodarone-induced thyrotoxicosis in Latin America: an electronic survey. Clin Endocrinol. 2006;65:433–8. 20. Tanda ML, Piantanida E, Lai A, Liparulo L, Sassi L, Bogazzi F, et al. Diagnosis and management of amiodarone-induced thyrotoxicosis: similarities and differences between North American and European thyroidologists. Clin Endocrinol. 2008;69:812–8. 21. Bartalena L, Wiersinga WM, Tanda ML, Bogazzi F, Piantanida E, Lai A, et al. Diagnosis and management of amiodarone-
411
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
induced thyrotoxicosis in Europe: results of an international survey among members of the European Thyroid Association. Clin Endocrinol. 2004;61:494–502. Bogazzi F, Bartalena L, Gasperi M, Braverman LE, Martino E. The various effects of amiodarone on thyroid function. Thyroid. 2001;11:511–9. Bongard V, Marc D, Philippe V, Jean-Louis M, Maryse LM. Incidence rate of adverse drug reactions during long-term followup of patients newly treated with amiodarone. Am J Ther. 2006;13:315–9. Batcher EL, Tang XC, Singh BN, Singh SN, Reda DJ, Hershman JM, et al. Thyroid function abnormalities during amiodarone therapy for persistent atrial fibrillation. Am J Med. 2007;120:880–5. Vanderpump MP, Tunbridge WM, French JM, Appleton D, Bates D, Clark F, et al. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clin Endocrinol. 1995;43:55–68. Walsh JP, Bremner AP, Feddema P, Leedman PJ, Brown SJ, O’Leary P. Thyrotropin and thyroid antibodies as predictors of hypothyroidism: a 13-year, longitudinal study of a communitybased cohort using current immunoassay techniques. J Clin Endocrinol Metab. 2010;95:1095–104. Asvold BO, Vatten LJ, Midthjell K, Bjoro T. Serum TSH within the reference range as a predictor of future hypothyroidism and hyperthyroidism: 11-year follow-up of the HUNT Study in Norway. J Clin Endocrinol Metab. 2012;97:93–9. Huang CC, Chen YC, Chen LK, Hwang SJ, Lin HD. Relationship between age and serum thyrotropin among asymptomatic older people in Taiwan. Arch Gerontol Geriatr. 2010;51:117–20. Gheri RG, Pucci P, Falsetti C, Luisi ML, Cerisano GP, Gheri CF, et al. Clinical, biochemical and therapeutical aspects of amiodarone-induced hypothyroidism (AIH) in geriatric patients with cardiac arrhythmias. Arch Gerontol Geriatr. 2004;38:27–36. Maselli M, Inelmen EM, Giantin V, Manzato E. Hypothyroidism in the elderly: diagnostic pitfalls illustrated by a case report. Arch Gerontol Geriatr. 2012;55:82–4. Burgess C, Blaikie A, Ingham T, Robinson G, Narasimhan S. Monitoring the use of amiodarone: compliance with guidelines. Intern Med J. 2006;36:289–93. Raebel MA, Carroll NM, Simon SR, Andrade SE, Feldstein AC, Lafata JE, et al. Liver and thyroid monitoring in ambulatory patients prescribed amiodarone in 10 HMOs. J Manag Care Pharm. 2006;12:656–64.
123
RESEARCH ARTICLE
Amiodarone-induced thyroid dysfunction in Taiwan: a retrospective cohort study Chun-Jui Huang • Po-Ju Chen • Jing-Wen Chang • De-Feng Huang • Shih-Lin Chang • Shih-Ann Chen Tjin-Shing Jap • Liang-Yu Lin
•
Received: 9 September 2013 / Accepted: 27 December 2013 / Published online: 11 February 2014 Koninklijke Nederlandse Maatschappij ter bevordering der Pharmacie 2014
Abstract Background The incidence and risk factors of amiodarone-induced thyroid dysfunction are variable in the literature. Objective The aim of this study was to investigate the clinical and biochemical features and risk factors of amiodarone-induced thyroid dysfunction in Taiwan. Setting This study was conducted at a tertiary referral center for arrhythmia. Method Retrospective analysis of patients treated with amiodarone during the years 2008–2009 was performed. Main outcome measure Incidence and risk factors of amiodarone-induced thyrotoxicosis (AIT) and amiodaroneinduced hypothyroidism (AIH) were assessed. Results Of the 527 patients, 437 (82.9 %) remained euthyroid, 21 (4.0 %) C.-J. Huang P.-J. Chen T.-S. Jap L.-Y. Lin (&) Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei City, Taiwan e-mail: [email protected] C.-J. Huang D.-F. Huang S.-L. Chang S.-A. Chen T.-S. Jap L.-Y. Lin Faculty of Medicine, National Yang-Ming University, Taipei City, Taiwan
developed AIT, and 69 (13.1 %) were affected with AIH. In univariate analysis, AIT was associated with younger age, and the risk factors for AIH included older age, higher baseline thyroid stimulating hormone (TSH) titer, lower baseline free T4 level, lower cumulative amiodarone dosage, and shorter amiodarone treatment duration. Cox regression analysis was performed to determine the different risk categories in the elderly population of age 65–74 (young-old), 75–84 (old-old), and C85 years old (oldest-old). Additionally increased risk of AIH was found in the groups of old-old (HR 2.09, 95 % CI 1.11–3.96) and oldest-old (HR 2.57, 95 % CI 1.21–4.75). In the multivariate analysis of risk factors for AIH, baseline TSH level (HR 1.38, 95 % CI 1.12–1.70) and cumulative amiodarone dosage (HR 0.95, 95 % CI 0.93–0.97) remained statistically significant. Conclusion AIH was much more common than AIT in Taiwan, an area with sufficient iodine intake. Higher baseline TSH level was the predominant independent risk factor for the development of AIH. Keywords Amiodarone Hypothyroidism Thyrotoxicosis
J.-W. Chang Department of Medicine, Kaohsiung Armed Forces General Hospital, Kaohsiung City, Taiwan D.-F. Huang Division of Allergy, Immunology and Rheumatology, Department of Medicine, Taipei Veterans General Hospital, Taipei City, Taiwan S.-L. Chang S.-A. Chen Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei City, Taiwan L.-Y. Lin Institute of Pharmacology, National Yang-Ming University, Taipei City, Taiwan
Impact of findings on practice •
•
Amiodarone-induced thyroid dysfunction is not uncommon and warrants the need for routine measurement of thyroid function after amiodarone is being prescribed. Elderly patients with higher baseline thyroid stimulating hormone (TSH) level may need to be even closer monitored for early detection of amiodarone-induced thyroid dysfunction.
123
406
Int J Clin Pharm (2014) 36:405–411
Introduction
Method
Amiodarone is one of the most common anti-arrhythmic agents for treating supraventricular and ventricular arrhythmia. It is a benzofuran derivative with 37 % iodine content (by weight), and its structure is similar to that of the thyroid hormone. Adverse drug reactions, including elevated transaminase levels, pulmonary fibrosis, arrhythmia, and thyroid dysfunction have been reported to occur even on low-dose amiodarone therapy [1]. The high iodine content of amiodarone and its intrinsic drug properties, such as inhibition of type I 50 -deiodinase, may lead to the development of thyroid dysfunctions, including amiodarone-induced thyrotoxicosis (AIT) and amiodaroneinduced hypothyroidism (AIH) [2, 3]. The risk factors for amiodarone-induced thyroid dysfunction are variable in different areas; younger age, male gender, thyroid auto-antibody production, goiter, or low body mass index (BMI) were reported to be associated with AIT [4–9]; whereas older age, higher baseline TSH level, diabetes mellitus, poor heart function, and thyroid autoantibody production in women were the possible risk factors for AIH [6, 7, 10–13]. Ambient iodine intake may also be an independent contributing factor for this variation. When urinary iodine excretion was used as the determinant of iodine intake, West Tuscany in Italy was found to be an area with iodine deficiency, and local studies showed a higher incidence of AIT in this area [14]. In Worchester, USA, sufficient iodine intake was reported to be associated with a higher incidence of AIH [14]. However, the association between the development of thyroid dysfunction and amiodarone treatment duration and dosage has been inconsistently reported in the literature [6, 7, 15, 16]. A great majority of the studies on amiodarone-induced thyroid dysfunction has been conducted in Europe and America, with only one report from Asia [6]. The incidence and risk factors for amiodarone-induced thyroid dysfunction in Taiwan, an area with sufficient iodine intake [17], remain to be elucidated.
Study design and data collection The study was carried out at Taipei Veterans General Hospital, a tertiary referral center for arrhythmia control in Taiwan. The hospital receives patients with new-onset arrhythmia from general practice and provides evaluation, treatment and follow-ups at the hospital. The medical records of 558 patients initially prescribed with amiodarone due to arrhythmia at the hospital with thyroid function data available from January 1, 2008 to December 31, 2009 were retrospectively retrieved from the computer database of the hospital. Thirty-one patients with a previous history of thyroid diseases, including papillary thyroid carcinoma (n = 7), Graves’ disease (n = 5), hypothyroidism (n = 4), prior thyroid surgery for goiter (n = 2), subclinical hypothyroidism with a TSH titer [10 mU/l (n = 9), and subclinical hyperthyroidism with a TSH titer \0.1 mU/l (n = 4) were excluded. In total, 527 patients were recruited for analysis. Indications for amiodarone therapy included supraventricular tachycardia (n = 469, 89.0 %) and ventricular tachycardia (n = 58, 11.0 %). The demographic, clinical, and biochemical metrics; thyroid function data before and after amiodarone therapy; and information on co-morbidities such as diabetes mellitus, hypertension, chronic obstructive pulmonary disease, peripheral arterial disease, and various heart diseases were collected. Data on thyroid autoantibody level, thyroid sonography, and I131 thyroid uptake and scans were also recorded if the tests had been performed. The treatment duration and cumulative and average daily dosage of amiodarone were also analyzed. The duration of amiodarone therapy was defined as the period between the date of amiodarone prescription and the date when thyroid dysfunction developed, or the date of amiodarone withdrawal if thyroid dysfunction did not occur. The cumulative dosage was the effective dose taken by the patient, while the average daily dose was calculated from the cumulative dosage and duration of amiodarone therapy.
Aim of the study Definition of thyroid dysfunction The aim of this study was to investigate the clinical and biochemical features and risk factors for AIT and AIH in Taiwan.
Ethical approval This study was approved by the local Institutional Review Board (VGH IRB No: 2011-12-003IC).
123
AIT was defined as TSH titer \0.1 mU/l and free thyroxin (T4) level [24.5 pmol/l, while AIH in need of treatment was ascertained by serum TSH titer[10 mU/l regardless of the free T4 level, or TSH titer between 4 and 10 mU/l with a lowered free T4 level \10.3 pmol/l. In cases showing an abnormal thyroid function test result within 3 months of amiodarone initiation, a subsequent abnormal result was considered necessary to make the diagnosis.
Int J Clin Pharm (2014) 36:405–411 Table 1 Univariate analysis of risk factors of the 527 patients taking amiodarone
407
Number (%)
Euthyroidism 437 (82.9)
AIT 21 (4.0)
AIH 69 (13.1)
Total 527 (100) 69.1 ± 14.9
Age (years)
68.9 ± 14.7
54.7 ± 18.1***
74.6 ± 11.8**
Male (%)
286 (65.4)
11 (52.4)
51 (73.9)
348 (66.0)
Body mass index (kg/m2)
24.3 ± 4.8
24.8 ± 7.5
23.8 ± 3.9
24.2 ± 4.8
Diabetes mellitus (%)
94 (21.5)
4 (19.0)
17 (24.6)
115 (21.8)
Hypertension (%)
259 (59.3)
8 (38.1)
47 (68.1)
314 (59.6)
COPD (%)
15 (3.4)
0 (0.0)
2 (2.9)
17 (3.2)
PAD (%)
9 (2.1)
1 (4.8)
3 (4.3)
13 (2.5)
Coronary artery disease (%)
120 (27.5)
5 (23.8)
24 (34.8)
149 (28.3)
Valvular heart disease (%)
43 (9.8)
3 (14.3)
6 (8.7)
52 (9.9)
Congenital heart disease (%) Congestive heart failure (%)
17 (3.9) 92 (21.1)
1 (4.8) 3 (14.3)
0 (0.0) 18 (26.1)
18 (3.4) 113 (21.4)
Sick sinus syndrome (%)
14 (3.2)
1 (4.8)
5 (7.2)
20 (3.8)
Baseline free T4 (pmol/l) (n = 151)
18.1 ± 3.3
20.0 ± 4.3
16.4 ± 3.7*
18.0 ± 3.5
Baseline TSH (mU/l) (n = 181)
2.06 ± 1.64
1.79 ± 1.27
4.64 ± 2.83***
2.43 ± 2.05
Duration (days)
424 ± 372
456 ± 350
304 ± 245**
410 ± 359
Cumulative dose (g)
86.2 ± 73.2
117.7 ± 128.3
66.6 ± 58.1*
84.9 ± 74.8
Average dose(mg/day)
244.9 ± 105.1
231.9 ± 109.2
255.9 ± 162.8
245.8 ± 114.2
Heart disease
AIT amiodarone-induced thyrotoxicosis, AIH amiodarone-induced hypothyroidism, COPD chronic obstructive pulmonary disease, PAD peripheral arterial disease * P \ 0.05, ** P \ 0.01, *** P \ 0.001
Amiodarone use
Measurement of thyroid function
Results
Serum TSH level was measured with a chemiluminescent immunometric assay (DPC Immulite 2000; Seracon Diagnostic Co., Brownsville, TX, USA), while free T4 level was determined using a chemiluminescent, competitive analogue immunoassay (DPC Immulite 2000; Seracon Diagnostic Co., Brownsville, TX, USA). The normal reference range of thyroid function tests in our laboratory was as follows: free T4, 10.3–24.5 pmol/l; TSH, 0.4–4.0 mU/l.
The baseline demographic and clinical characteristics of the 527 enrolled patients are summarized in Table 1. The mean age was 69.1 ± 14.9 years and 66.0 % of patients were male. The mean duration of amiodarone treatment was 410 ± 359 days with a cumulative dosage of 84.9 ± 74.8 g and an average daily dose of 245.8 ± 114.2 mg/day. AIT developed in 21 patients (4.0 %), and AIH occurred in 69 patients (13.1 %), while the remaining 437 patients (82.9 %) maintained a euthyroid state throughout the study period.
Statistical analysis
Correlation between amiodarone usage and thyroid dysfunction
Statistical analysis was performed using the Statistical Product and Service Solutions (SPSS) software, version 18.0. Descriptive statistics were expressed as the mean ± standard deviation (SD) for continuous variables, and as the number of cases and percentage (%) for categorical variables. The analyses for differences between groups were performed using the Pearson Chi Square or Student’s t test. Cox regression hazard model was used for multivariate analysis and to identify the risk categories of AIH in different elderly age groups. A two-tailed P value of less than 0.05 was considered statistically significant.
Compared to patients who remained euthyroid, the patients who developed AIH received amiodarone therapy for a shorter duration (mean duration, 424 ± 372 days vs. 304 ± 245 days, P = 0.001), while there was no difference in treatment duration between the euthyroid and AIT groups (mean duration, 424 ± 372 vs. 456 ± 350 days, P = 0.71). In addition to the duration of amiodarone therapy, the cumulative dosage in the AIH group was also found to be significantly lower than that in the euthyroid group (86.2 ± 73.2 g vs. 66.6 ± 58.1 g, P = 0.013) (Table 1). In patients who took amiodarone for less than 365 days, the odds ratio of developing AIH was 1.89 (95 %
123
408
Int J Clin Pharm (2014) 36:405–411 Table 3 Multivariate analysis of risk factor for the development of AIH Variable
Adjusted HR (95 % CI)
P value
Amiodarone cumulative dose (g)
0.95 (0.93–0.97)
\0.001
Baseline TSH (mU/l)
1.38 (1.12–1.70)
0.003
Age (years old)
1.01 (0.97–1.05)
0.739
Free T4 (pmol/l)
1.00 (0.86–1.17)
0.983
Cox proportional hazard regression model was used
Fig. 1 Kaplan-Meier curve of event-free probability of AIH in patients treated with amiodarone. Statistically significant difference between the age groups of age \65, 65–74 (young-old), 75–84 (old-old), and age C85 years old (oldest-old) were found (Log rank test, P = 0.047)
Table 2 Analysis of age as a risk factor for the development of AIH Age (years)
n (%)
HR (95 % CI)
P value
\65
204 (38.7)
1
0.25
65–74 75–84
96 (18.2) 140 (26.6)
1.54 (0.73–3.24) 2.09 (1.11–3.96)
0.02* 0.01*
87 (16.5)
2.57 (1.25–5.25)
C85
Cox proportional hazard regression model was used * P \ 0.05
CI 1.10–3.24, P = 0.02) compared to those whose treatment duration was more than 1 year. A cumulative dosage of \73 g (in a patient taking 200 mg of amiodarone per day for 1 year) was associated with a 1.87-fold increased risk for AIH (95 % CI 1.09–3.18, P = 0.02). Association of age, gender, and BMI with thyroid dysfunction
increased risk for occurrence of AIH (95 % CI 1.28–4.27, P = 0.006); in younger adults of age \50 years, a 5.32-fold increased risk for developing AIT (95 % CI 2.14–13.22, P \ 0.001) was found. To determine the different risk categories in the elderly population, patients with age 65 years or more were further divided into three groups: age 65–74 (young-old), age 75–84 (old-old), and age C85 years old (oldest-old). Logrank test showed statistically significant difference between the event-free probability of AIH in the four different age groups as shown in Fig. 1 (P = 0.04). In the investigation of hazard ratio, substantially increased risk of AIH was found in the group of old-old (HR 1.92, 95 % CI 1.03–3.56, P = 0.04) and oldest-old (HR 2.40, 95 % CI 1.25–5.25, P = 0.01) (Table 2). Influence of baseline thyroid status With reference to the euthyroid group, AIH was significantly associated with higher baseline TSH titer (mean TSH titer, 2.06 ± 1.64 vs. 4.64 ± 2.83 mU/l, P \ 0.001) and lower free T4 level (mean free T4 level, 18.1 ± 3.3 vs. 16.4 ± 3.7 mU/l, P = 0.03) (Table 1). There was no statistically significant difference in thyroid status between the euthyroid and AIT groups. While determining the cutoff value for increased risk for the development of AIH, a baseline TSH titer [1.5 mU/l was found to be associated with AIH (HR 3.3, 95 % CI 1.25–8.73, P = 0.016). An increase of 1 mU/l in the baseline TSH titer was further associated with increased incidence of AIH (HR 1.36, 95 % CI 1.21–1.54, P \ 0.001). Independent risk factors for AIH
There were no statistically significant differences in gender and BMI between the euthyroid, AIT, and AIH groups. Compared to the euthyroid individuals, AIT patients were younger (68.9 ± 14.7 years vs. 54.7 ± 18.1 years, P \ 0.001), while AIH patients were typically older (68.9 ± 14.7 years vs. 74.6 ± 11.8 years, P = 0.001) (Table 1). When odds ratio was evaluated, age C65 years was associated with a 2.34-fold
123
Multivariate analysis showed baseline TSH titer (HR 1.38, 95 % CI 1.12–1.70, P = 0.003) and cumulative amiodarone dosage (HR 0.95, 95 % CI 0.93–0.97, P \ 0.001) to be correlated with the development of AIH (Table 2). Free T4 level and age did not show statistically significant correlations (Table 3).
Int J Clin Pharm (2014) 36:405–411
409
Table 4 Summary of risk analysis of amiodarone-induced thyroid dysfunction Author, country (year)
n
AIT (%)
AIH (%)
Risk factor of AIT
Risk factor of AIH
Ref.
1. Martino et al., Italy (1987)
467
N.A.
6
N.A
Thyroid Ab
10
Women with thyroid Ab
2. Trip et al. Netherlands (1991)
58
12.1
6.9
N.A
3. Thorne et al., UK (1999)a,
92
20.7
15.2
Female; complex cyanotic heart disease; Fontan-type surgery; average dose [200 mg/d
15
b
11
4. Sidhu et al., UK (2003)
216
5.6
7
Male
N.A.
4
5. Schaan et al., Brazil (2005)
195
2.1
25.1
Male; microsomal Ab
N.A.
5
21.3c
12.5c
6. Hofmann et al., Austria (2008)b
None
None
30
7. Lee et al., Hong Kong (2010)
390
6
22
Younger age
Baseline TSH [4.0 mU/l
6
8. Ahmed et al., Netherlands (2011)
303
8
6
Age \62 years
Baseline TSH [1.4 mU/lc; LVEF \45 %c; DMc; age C62 years
7
9. Aleksic´ et al., Serbia (2011)b
248
6
9.7
Goiterc, thyroid peroxidase antibodiesc
12
a
72
169
13.6
N.A.
BMI \21; goiter
N.A.
8
11. Zosin et al., Romania (2012)
229
20.5
17.9
Younger age, goiter
Older age, goiter, higher thyroid volume
9
12. Current study, Taiwan (2014)
527
4
13.1
Younger age
Older age, higher baseline TSHc, lower baseline free T4, shorter amiodarone duration, less amiodarone cumulative dosagec
–
10. Stan et al., USA (2012)
AIT amiodarone-induced thyrotoxicosis, AIH amiodarone-induced hypothyroidism, Ref. reference number, N.A not available, Ab antibody, LVEF left ventricular ejection fraction, DM diabetes mellitus, BMI body mass index a
Only adult patients with congenital heart disease were evaluated in these two studies
b
Comparison was made between the group of euthyroidism and thyroid dysfunction
c
Independent risk factors in multivariate analysis
Discussion To our knowledge, this is the first study to evaluate the incidence and risk factors for amiodarone-induced thyroid dysfunction in Taiwan. Previous studies on the risk factor analysis of amiodarone-induced thyroid dysfunction are summarized in Table 4 [4–12, 15, 18]. The positive association between younger age and AIT in our study was similar to the findings of reports from Hong Kong, the Netherlands, and Romania [6, 7]. Risk factors associated with AIH in our study included older age, higher baseline TSH titer, lower baseline free T4 level, shorter amiodarone treatment duration, and lower amiodarone cumulative dosage. Elevated baseline TSH titer being a risk factor for AIH [6, 7], and the association between older age and AIH were found in previous reports [7, 9]. However, risk analysis in different elderly age groups has not been done. The novelty of this study lies in the finding that substantial increased risk of AIH is present in the elderly groups of old-old and oldest-old. Other novel findings include the associations between AIH and lower baseline free T4 level, shorter amiodarone treatment duration, and lower amiodarone cumulative dosage. Higher baseline TSH level and
lower amiodarone cumulative dosage were the independent factors showing significance in multivariate analysis. The reported incidence of AIT and AIH varies in the literature. Studies from Europe showed that AIT was more frequent than AIH, but reports from America and Asia revealed the opposite [19–21]. This discrepancy may be due to differences in diagnostic criteria, follow-up periods, ethnicity, geographic variations, or ambient iodine intake. A higher incidence of AIT was found in areas with iodine deficiency, and sufficient iodine intake was associated with AIH [14]. Local data on urinary iodine excretion showed that the amount of iodine intake was sufficient in Taiwan [17], which may explain the higher incidence of AIH in our study. The data on amiodarone dose/duration and thyroid dysfunction are conflicting. A cumulative dose exceeding 144 g was previously reported to be associated with AIT (OR 12.9), but the dose–effect was less pronounced for AIH [16]. In patients with congenital heart disease, an average amiodarone dose over 200 mg/day appeared to be a risk factor for thyroid dysfunction [15]. However, a correlation between amiodarone treatment duration and dose and AIH or AIT was not observed in many other studies, as summarized in Table 4. Our study revealed an association
123
410
between lower amiodarone cumulative dosage (mean dosage, 66.6 ± 58.1 g) and shorter treatment duration (mean duration, 304 ± 245 days) and the development of AIH. The shorter period to AIH diagnosis was not related to the transient thyroid function alterations frequently observed during the first 3 months following amiodarone administration [22]. This may indicate that AIH is an early event in the course of amiodarone therapy, in accordance with the prospective studies by Trip et al. [11], Bongard et al. [23], and Batcher et al. [24], showing that AIH typically occurs no later than after 1 year of therapy. When baseline TSH level was considered as a risk factor, a cutoff value of [2 mU/l was observed to predict hypothyroidism in a 20-year follow-up study of the Wickham Survey [25]. Recent epidemiological studies also confirmed that individuals with a TSH level within the high-normal range are at increased risk for hypothyroidism [26, 27]. The situation in patients taking amiodarone is unknown. In the current study, baseline TSH titer[1.5 mU/l was associated with AIH progression (HR = 3.3). A similar baseline cutoff TSH value of [1.4 mU/l was shown to predict AIH in previous report [7]. Whether the association was partially related to autoimmune thyroid disease could not be evaluated due to limited measurements of baseline thyroid auto-antibodies by cardiologists. Nevertheless, individuals with high-normal baseline TSH value warrant special attention and frequent monitoring when using amiodarone. The findings that younger age is a risk factor for AIT and older age for AIH were similar to those obtained in previous reports [6, 7, 9]. An explanation was not provided in most studies and could also be difficult to determine in our study due to the limited data on thyroid auto-antibodies, color Doppler, and radioactive iodine uptake studies. Further risk analysis in the elderly age groups revealed additionally increased risk in the group of old-old (age 75–84) and oldest-old (age over 85). According to previous evaluation on the relationship between age and serum TSH level in asymptomatic older people in Taiwan, the mean serum TSH level was similar between the groups of young-old (age 65–79) and old-old (age over 80) [28]. This suggests that factors other than higher baseline mean TSH level may have contributed to the additional risk for AIH in the older population. The clinical manifestations of AIH in the geriatric population are subjective enough to be vague and can lead to delayed diagnosis in daily clinical practice [29, 30]. Considering that subclinical hypothyroidism with a TSH value above 10 mU/l should be treated, and inadequate thyroid function monitoring during amiodarone therapy occurs due to lack of awareness of current guidelines [31, 32], active surveillance and close follow-up is needed, especially in the population with the highest risk, the elderly group of old-old (age 75–84) and oldest-old (age C85).
123
Int J Clin Pharm (2014) 36:405–411
The limitations of this study are related to its retrospective nature. The incidence of AIT and AIH may be overestimated because patients with suspected symptoms may more likely to have thyroid function tested compared to those who remained asymptomatic on amiodarone therapy. Case numbers with data related to thyroid auto-antibodies, thyroid sonography, and I131 scintigraphy were too small to be included for analysis. The AIT subtype could not be classified based on available information. Amount of individual iodine intake could not be determined. We also believe that interpretation of the positive findings in a small event group, such as a group size of 21 patients with AIT, needs to be validated in future cohorts with a larger patient population. A further prospective study is therefore needed.
Conclusion Our study shows a higher incidence of AIH than AIT in Taiwan, which is comparable to the findings in other iodine-sufficient areas. It is advised that patients, especially the old-old and oldest-old, or those with higher baseline TSH level, be closely followed for early detection of hypothyroidism during amiodarone therapy.
Funding This study was partly supported by research Grants V100B-039, V101B-023, V102B-048 to L.Y.L. and V100A-013 to P.J.C from Taipei Veterans General Hospital, Taipei, Taiwan. Conflicts of interest
None.
References 1. Vorperian VR, Havighurst TC, Miller S, January CT. Adverse effects of low dose amiodarone: a meta-analysis. J Am Coll Cardiol. 1997;30:791–8. 2. Han TS, Williams GR, Vanderpump MP. Benzofuran derivatives and the thyroid. Clin Endocrinol. 2009;70:2–13. 3. Cohen-Lehman J, Dahl P, Danzi S, Klein I. Effects of amiodarone therapy on thyroid function. Nat Rev Endocrinol. 2010;6:34–41. 4. Sidhu J, Jenkins D. Men are at increased risk of amiodaroneassociated thyrotoxicosis in the UK. QJM. 2003;96:949–50. 5. Schaan BD, Cunha CP, Francisconi A, Zottis B, Brum G, Bruch RS, et al. Amiodarone-induced thyroid dysfunction in a tertiary center in south Brazil. Arq Bras Endocrinol Metabol. 2005;49:916–22. 6. Lee KF, Lee KM, Fung TT. Amiodarone-induced thyroid dysfunction in the Hong Kong Chinese population. Hong Kong Med J. 2010;16:434–9. 7. Ahmed S, Van Gelder IC, Wiesfeld AC, Van Veldhuisen DJ, Links TP. Determinants and outcome of amiodarone-associated thyroid dysfunction. Clin Endocrinol. 2011;75:388–94. 8. Stan MN, Ammash NM, Warnes CA, Brennan MD, Thapa P, Nannenga MR, et al. Body mass index and the development of amiodarone-induced thyrotoxicosis in adults with congenital heart disease-A cohort study. Int J Cardiol. 2013;167:821–6.
Int J Clin Pharm (2014) 36:405–411 9. Zosin I, Balas M. Amiodarone-induced thyroid dysfunction in an iodine-replete area: epidemiological and clinical data. Endokrynol Pol. 2012;63:2–9. 10. Martino E, Aghini-Lombardi F, Mariotti S, Bartalena L, Lenziardi M, Ceccarelli C, et al. Amiodarone iodine-induced hypothyroidism: risk factors and follow-up in 28 cases. Clin Endocrinol. 1987;26:227–37. 11. Trip MD, Wiersinga W, Plomp TA. Incidence, predictability, and pathogenesis of amiodarone-induced thyrotoxicosis and hypothyroidism. Am J Med. 1991;91:507–11. 12. Aleksic Z, Aleksic A. Incidence of amiodarone-induced thyroid dysfunction and predictive factors for their occurrence. Med Pregl. 2011;64:533–8. 13. Martino E, Aghini-Lombardi F, Bartalena L, Grasso L, Loviselli A, Velluzzi F, et al. Enhanced susceptibility to amiodaroneinduced hypothyroidism in patients with thyroid autoimmune disease. Arch Intern Med. 1994;154:2722–6. 14. Martino E, Safran M, Aghini-Lombardi F, Rajatanavin R, Lenziardi M, Fay M, et al. Environmental iodine intake and thyroid dysfunction during chronic amiodarone therapy. Ann Intern Med. 1984;101:28–34. 15. Thorne SA, Barnes I, Cullinan P, Somerville J. Amiodaroneassociated thyroid dysfunction: risk factors in adults with congenital heart disease. Circulation. 1999;100:149–54. 16. Bouvy ML, Heerdink ER, Hoes AW, Leufkens HG. Amiodaroneinduced thyroid dysfunction associated with cumulative dose. Pharmacoepidemiol Drug Saf. 2002;11:601–6. 17. Lin HD, Lo JG, Ching KN. Amount of urinary iodine excretion in residents of Taipei City: a hospital-based study. J Chin Med Assoc. 1991;48:20–4. 18. Hofmann A, Nawara C, Ofluoglu S, Holzmannhofer J, Strohmer B, Pirich C. Incidence and predictability of amiodarone-induced thyrotoxicosis and hypothyroidism. Wien Klin Wochenschr. 2008;120:493–8. 19. Diehl LA, Romaldini JH, Graf H, Bartalena L, Martino E, Albino CC, et al. Management of amiodarone-induced thyrotoxicosis in Latin America: an electronic survey. Clin Endocrinol. 2006;65:433–8. 20. Tanda ML, Piantanida E, Lai A, Liparulo L, Sassi L, Bogazzi F, et al. Diagnosis and management of amiodarone-induced thyrotoxicosis: similarities and differences between North American and European thyroidologists. Clin Endocrinol. 2008;69:812–8. 21. Bartalena L, Wiersinga WM, Tanda ML, Bogazzi F, Piantanida E, Lai A, et al. Diagnosis and management of amiodarone-
411
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
induced thyrotoxicosis in Europe: results of an international survey among members of the European Thyroid Association. Clin Endocrinol. 2004;61:494–502. Bogazzi F, Bartalena L, Gasperi M, Braverman LE, Martino E. The various effects of amiodarone on thyroid function. Thyroid. 2001;11:511–9. Bongard V, Marc D, Philippe V, Jean-Louis M, Maryse LM. Incidence rate of adverse drug reactions during long-term followup of patients newly treated with amiodarone. Am J Ther. 2006;13:315–9. Batcher EL, Tang XC, Singh BN, Singh SN, Reda DJ, Hershman JM, et al. Thyroid function abnormalities during amiodarone therapy for persistent atrial fibrillation. Am J Med. 2007;120:880–5. Vanderpump MP, Tunbridge WM, French JM, Appleton D, Bates D, Clark F, et al. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clin Endocrinol. 1995;43:55–68. Walsh JP, Bremner AP, Feddema P, Leedman PJ, Brown SJ, O’Leary P. Thyrotropin and thyroid antibodies as predictors of hypothyroidism: a 13-year, longitudinal study of a communitybased cohort using current immunoassay techniques. J Clin Endocrinol Metab. 2010;95:1095–104. Asvold BO, Vatten LJ, Midthjell K, Bjoro T. Serum TSH within the reference range as a predictor of future hypothyroidism and hyperthyroidism: 11-year follow-up of the HUNT Study in Norway. J Clin Endocrinol Metab. 2012;97:93–9. Huang CC, Chen YC, Chen LK, Hwang SJ, Lin HD. Relationship between age and serum thyrotropin among asymptomatic older people in Taiwan. Arch Gerontol Geriatr. 2010;51:117–20. Gheri RG, Pucci P, Falsetti C, Luisi ML, Cerisano GP, Gheri CF, et al. Clinical, biochemical and therapeutical aspects of amiodarone-induced hypothyroidism (AIH) in geriatric patients with cardiac arrhythmias. Arch Gerontol Geriatr. 2004;38:27–36. Maselli M, Inelmen EM, Giantin V, Manzato E. Hypothyroidism in the elderly: diagnostic pitfalls illustrated by a case report. Arch Gerontol Geriatr. 2012;55:82–4. Burgess C, Blaikie A, Ingham T, Robinson G, Narasimhan S. Monitoring the use of amiodarone: compliance with guidelines. Intern Med J. 2006;36:289–93. Raebel MA, Carroll NM, Simon SR, Andrade SE, Feldstein AC, Lafata JE, et al. Liver and thyroid monitoring in ambulatory patients prescribed amiodarone in 10 HMOs. J Manag Care Pharm. 2006;12:656–64.
123
