Risk factors for amiodarone-induced thyroid dysfunction in Japan☆

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Abstract

Background

Amiodarone is associated with a number of significant adverse effects, including elevated transaminase levels, pulmonary fibrosis, arrhythmia, and thyroid dysfunction. Although thyroid dysfunction is considered to be a common and potentially serious adverse effect of amiodarone therapy, the exact pathogenesis remains unknown because of its complex manifestations. Therefore, the prevalence of, and risk factors for, amiodarone-induced thyroid dysfunction in Japanese patients were investigated in the present study.

Methods

A retrospective analysis of patients treated with amiodarone between January 2012 and December 2013 was performed. A total of 317 patients with euthyroidism, or subclinical hyperthyroidism or hypothyroidism, were enrolled in this study.

Results

After being treated with amiodarone, 30 (9.5%) and 60 patients (18.9%) developed amiodarone-induced hyperthyroidism and amiodarone-induced hypothyroidism, respectively. Ten (33.3%) patients with amiodarone-induced hyperthyroidism and 40 (66.6%) with amiodarone-induced hypothyroidism were diagnosed within two years of the initiation of amiodarone therapy. Dilated cardiomyopathy (DCM) [Adjusted odds ratio (OR) 3.30 (95% confidence interval (CI): 1.26–8.90)], and cardiac sarcoidosis [Adjusted OR 6.47 (95% CI: 1.60–25.77)] were identified as predictors of amiodarone-induced hyperthyroidism. The baseline free thyroxine (T4) level [Adjusted OR 0.13 (95% CI: 0.03–0.68)], and thyroid-stimulating hormone (TSH) level [Adjusted OR1.47 (95% CI: 1.26–1.74)] were identified as predictors of amiodarone-induced hypothyroidism.

Conclusion

DCM and cardiac sarcoidosis were identified as risk factors for amiodarone-induced hyperthyroidism. Risk factors for amiodarone-induced hypothyroidism included higher baseline TSH level and lower baseline free T4 level, suggesting that subclinical hypothyroidism may be a potential risk factor for the development of amiodarone-induced hypothyroidism.

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Most cited references 41

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Assessment of Japanese iodine intake based on seaweed consumption in Japan: A literature-based analysis

Theodore Zava, David Zava (2011)

Japanese iodine intake from edible seaweeds is amongst the highest in the world. Predicting the type and amount of seaweed the Japanese consume is difficult due to day-to-day meal variation and dietary differences between generations and regions. In addition, iodine content varies considerably between seaweed species, with cooking and/or processing having an influence on iodine content. Due to all these factors, researchers frequently overestimate, or underestimate, Japanese iodine intake from seaweeds, which results in misleading and potentially dangerous diet and supplementation recommendations for people aiming to achieve the same health benefits seen by the Japanese. By combining information from dietary records, food surveys, urine iodine analysis (both spot and 24-hour samples) and seaweed iodine content, we estimate that the Japanese iodine intake--largely from seaweeds--averages 1,000-3,000 μg/day (1-3 mg/day).

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Adverse effects of low dose amiodarone: a meta-analysis.

Vicken R Vorperian, Thomas C Havighurst, Stephen Miller … (1997)

We sought to assess the odds of experiencing adverse effects with low dose amiodarone therapy compared with placebo. An estimate of the likelihood of experiencing amiodarone-related adverse effects with exposure to low daily doses of the drug is lacking in the published reports, and little information is available on adverse effect event rates in control groups not receiving the drug. Data from four published trials involving 1,465 patients were included in a meta-analysis design. The criteria for inclusion were 1) double-blind, placebo-controlled design; 2) absence of a crossover design between patient groups; 3) mean follow-up of at least 12 months; 4) maintenance amiodarone dose < or = 400 mg/day; and 5) presence of an explicit description of adverse effects. Data were pooled after testing for homogeneity of treatment effects across trials, and summary odds ratios were calculated by the Peto-modified Mantel-Haenszel method for each adverse effect. The mean amiodarone dose per day ranged from 152 to 330 mg; 738 patients were randomized to receive amiodarone and 727 placebo. Exposure to amiodarone in this dose range, for a minimal duration of 12 months, resulted in odds similar to those of placebo for hepatic and gastrointestinal adverse effects, but in significantly higher odds than those of placebo (p < 0.05) for experiencing thyroid (odds ratio [OR] 4.2, 95% confidence interval [CI] 2.0 to 8.7), neurologic (OR 2.0, 95% CI 1.1 to 3.7), skin (OR 2.5, 95% CI 1.1 to 6.2), ocular (OR 3.4, 95% CI 1.2 to 9.6) and bradycardic (OR 2.2, 95% CI 1.1 to 4.3) adverse effects. A trend toward increased odds of pulmonary toxicity was noted (OR 2.0, 95% CI 0.9 to 5.3), but this did not reach statistical significance (p = 0.07). The unadjusted total incidence of drug discontinuation was 22.9% in the amiodarone group and 15.4% in the placebo group. The odds of discontinuing the drug in the amiodarone group was approximately 1.5 times that of the placebo group (OR 1.52, 95% CI 1.2 to 1.9) (p = 0.003). Compared with placebo, there is a higher likelihood of experiencing several amiodarone-related adverse effects with exposure to low daily doses of the drug. Thus, although low dose amiodarone may be well tolerated, it is not free of adverse effects.

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The effects of amiodarone on the thyroid.

L Braverman, F. Bogazzi, L. Bartalena … (2001)

Amiodarone is a benzofuranic-derivative iodine-rich drug widely used for the treatment of tachyarrhythmias and, to a lesser extent, of ischemic heart disease. It often causes changes in thyroid function tests (typically an increase in serum T(4) and rT(3), and a decrease in serum T(3), concentrations), mainly related to the inhibition of 5'-deiodinase activity, resulting in a decrease in the generation of T(3) from T(4) and a decrease in the clearance of rT(3). In 14-18% of amiodarone-treated patients, there is overt thyroid dysfunction, either amiodarone-induced thyrotoxicosis (AIT) or amiodarone-induced hypothyroidism (AIH). Both AIT and AIH may develop either in apparently normal thyroid glands or in glands with preexisting, clinically silent abnormalities. Preexisting Hashimoto's thyroiditis is a definite risk factor for the occurrence of AIH. The pathogenesis of iodine-induced AIH is related to a failure to escape from the acute Wolff-Chaikoff effect due to defects in thyroid hormonogenesis, and, in patients with positive thyroid autoantibody tests, to concomitant Hashimoto's thyroiditis. AIT is primarily related to excess iodine-induced thyroid hormone synthesis in an abnormal thyroid gland (type I AIT) or to amiodarone-related destructive thyroiditis (type II AIT), but mixed forms frequently exist. Treatment of AIH consists of L-T(4) replacement while continuing amiodarone therapy; alternatively, if feasible, amiodarone can be discontinued, especially in the absence of thyroid abnormalities, and the natural course toward euthyroidism can be accelerated by a short course of potassium perchlorate treatment. In type I AIT the main medical treatment consists of the simultaneous administration of thionamides and potassium perchlorate, while in type II AIT, glucocorticoids are the most useful therapeutic option. Mixed forms are best treated with a combination of thionamides, potassium perchlorate, and glucocorticoids. Radioiodine therapy is usually not feasible due to the low thyroidal radioiodine uptake, while thyroidectomy can be performed in cases resistant to medical therapy, with a slightly increased surgical risk.

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Author and article information

Contributors

Kyoichi Wada

Journal

Journal ID (nlm-ta): J Arrhythm

Journal ID (iso-abbrev): J Arrhythm

Title: Journal of Arrhythmia

Publisher: Elsevier

ISSN (Print): 1880-4276

ISSN (Electronic): 1883-2148

Publication date PMC-release: 05 May 2016

Publication date (Print): December 2016

Publication date (Electronic): 05 May 2016

Volume: 32

Issue: 6

Pages: 474-480

Affiliations

[a ]Department of Pharmacy, National Cerebral and Cardiovascular Center, 5-7-1, Fujishiro-dai, Suita, Osaka 565-8565, Japan

[b ]Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, 5-7-1, Fujishiro-dai, Suita, Osaka 565-8565, Japan

[c ]Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan

[d ]Division of Clinical Drug Informatics, School of Pharmacy, Kinki University, 3-4-1, Kowakae, Higashiosaka, Osaka 577-0818, Japan

Author notes

[* ]Corresponding author. Tel.: +81 6 6833 5012; fax:+81 6 6872 8074. kwada@ 123456ncvc.go.jp

Article

Publisher ID: S1880-4276(16)30031-X

DOI: 10.1016/j.joa.2016.03.008

PMC ID: 5129120

PubMed ID: 27920832

SO-VID: ef5bd968-b78e-4f35-b002-35626211aff7

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 29 December 2015

Date revision received : 15 March 2016

Date accepted : 24 March 2016

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