The effects of amiodarone on the thyroid

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.     

The effect of amiodarone on thyroid gland function

Plasma concentrations of T4, FT4, T3, rT3 and TBG, as well as of TSH before and after stimulation with TRH were studied in 25 patients, who had been treated with amiodarone for up to nine years. At the beginning of therapy, all the parameters mentioned above were found to be in the normal range in all patients. After two months of therapy, T4 had increased from 100 nmol/l +/- 24 nmol/l to 155 nmol/l +/- 32 nmol/l (p less than 0.01), and FT4 from 22 pmol/l +/- 10.5 pmol/l to 32 pmol/l +/- 8 pmol/l (p less than 0.01). T3 had decreased to the lower normal range (n.s.). TBG showed no significant changes. The TRH-tests had been normal in the beginning, but they remained positive in only 20% of the cases. At the end of the study, rT3 exceeded the normal range in all 25 patients. Two patients developed definite hyperthyroidism with elevations of T3 up to 4.7 nmol/l and 7.5 nmol/l, respectively. In one of them, we decided to discontinue amiodarone. Testing of thyroid function under antithyroid drug therapy revealed a hyperfunctioning autonomous adenoma, which was successfully eliminated by radioactive iodine therapy. In the other patient, it was not possible to withdraw amiodarone, so we initiated long-term treatment with antithyroid drugs. Our data support the assumption that amiodarone causes an impairment of the peripheral conversion of T4 to T3. As a result, one finds elevated serum concentrations of T4, which, in combination with the mainly negative TRH-test, must not be interpreted as proof of a hyperthyroid metabolic state being present. Hyperthyroidism is confirmed only if serum concentrations of T3 are also elevated.     

Effect of long-term amiodarone therapy on thyroid hormone levels and thyroid function

Both hyperthyroidism and hypothyroidism have been noted to occur in some patients treated with amiodarone for cardiac arrhythmias. To determine the frequency of the development of thyroidal abnormalities in patients receiving amiodarone, 45 euthyroid patients were prospectively evaluated. Serum samples were obtained for measurement of thyroxine, thyrotropin, triiodothyronine, and triiodothyronine resin uptake prior to initiation of amiodarone treatment and serially over a 12- to 27-month period during which amiodarone was administered. The patients were divided into four subgroups as follows: Group I (n = 22) had elevated thyroxine levels, Group IIA (n = 13) had normal thyroxine levels and normal thyrotropin levels, Group IIB (n = 7) had normal thyroxine levels and elevated thyrotropin levels, and Group III (n = 3) had subnormal thyroxine levels. Demographic factors (such as route of administration, cardiac diagnosis, sex of the patient, or indication for amiodarone therapy) and amiodarone levels had no significant effect on the thyroid hormone parameters. However, Group I patients were statistically older than the patients in the other groups. Linear regression analysis revealed a negative correlation for thyroxine levels and a positive correlation with thyrotropin levels with age for the whole group. The various groups were not statistically affected by duration of therapy, but a positive trend existed for increasing thyroxine levels. Although virtually all patients showed changes in their thyroid hormone levels, chemical hyperthyroidism (elevated thyroxine and triiodothyronine levels without symptoms) developed in only two patients (4 percent), and clinical hyperthyroidism (elevated thyroxine and triiodothyronine levels with symptoms) developed in no patients. Four patients (9 percent) became biochemically and clinically hypothyroid. Thus, amiodarone frequently influences thyroid hormonal parameters, but less commonly causes a change in actual thyroid function. However, hyperthyroidism and hypothyroidism do occur in a significant number of patients.     

Effects of amiodarone on thyroid function in patients with ischaemic heart disease.

Thyroid function was evaluated clinically and biochemically in 12 patients with ischaemic heart disease receiving 200 mg oral amiodarone three times daily for periods up to 6 weeks. During drug administration, no patient developed clinical or laboratory evidence of hypothyroidism, but serum levels of T3 tended to fall and those of T4 increased but not to levels outside the normal range. Amiodarone produced a significant reduction in heart rate with prolongation of the QTc interval of the electrocardiogram without altering either the PR interval or the QRS duration. These effects of the drug were still present 4 weeks after cessation of treatment. In spite of the high iodine content, amiodarone does not, therefore, depress thyroid function to any important degree during chronic administration and its antianginal action does not appear to be caused by the production of generalized hypothyroidism.     

Effects of amiodarone on thyroid function in patients with ischaemic heart disease.

Thyroid function was evaluated clinically and biochemically in 12 patients with ischaemic heart disease receiving 200 mg oral amiodarone three times daily for periods up to 6 weeks. During drug administration, no patient developed clinical or laboratory evidence of hypothyroidism, but serum levels of T3 tended to fall and those of T4 increased but not to levels outside the normal range. Amiodarone produced a significant reduction in heart rate with prolongation of the QTc interval of the electrocardiogram without altering either the PR interval or the QRS duration. These effects of the drug were still present 4 weeks after cessation of treatment. In spite of the high iodine content, amiodarone does not, therefore, depress thyroid function to any important degree during chronic administration and its antianginal action does not appear to be caused by the production of generalized hypothyroidism.     

二甲双胍对甲状腺功能的影响

二甲双胍作为一个经典的抗高血糖药物,在临床应用已走过了50余年的辉煌历史.近年来,有研究显示,二甲双胍对甲状腺功能减退症(甲减)患者的血清促甲状腺素(TSH)具有抑制作用,但不影响游离甲状腺素的水平,对于无甲状腺疾病的糖尿病患者的TSH水平亦无明显影响.推测可能与药物的相互作用、体重的改变、下丘脑-垂体-甲状腺轴的调节等因素有关,但尚缺乏令人信服的理论依据.虽然如此,这一意外的发现有可能对临床工作产生深远的影响,如二甲双胍有望作为甲状腺癌术后的辅助治疗措施.     

The effect of short-term low-dose perchlorate on various aspects of thyroid function.

Perchlorate (ClO4) salts are found in rocket fuel, fireworks, and fertilizer. Because of ground water contamination, ClO4 has recently been detected in large public water supplies in several states in the 4-18 microg/L (parts per billion [ppb]) range. The potential adverse effect of chronic low level ClO4 ingestion on thyroid function is of concern to the Environmental Protection Agency (EPA). The daily ingestion of ClO4 at these levels would be magnitudes below the therapeutic effect level of hundreds of milligrams of ClO4 used in treating hyperthyroidism. Studies were carried out in nine healthy male volunteers who had normal thyroid function and negative thyroid antibodies to determine whether the ingestion of 10 mg of ClO4 daily (approximately 300 times the estimated maximum amount of ClO4 consumed from the affected water supplies) would affect any aspect of thyroid function. They ingested 10 mg of ClO4 dissolved in a liter of spring water during waking hours for 14 days. Baseline serum thyrotropin (TSH), free thyroxine index (FTI), total triiodothyronine (TT3), 4-, 8-, and 24-hour thyroid 123I uptakes (RAIU), serum and 24-hour urine ClO4, 24-hour urine iodine, complete blood count (CBC), and chemistry profile were determined. All blood and urine tests were repeated on days 7 and 14 of ClO4 administration and thyroid RAIU on day 14 of ClO4 administration. All tests were repeated 14 days after ClO4 was discontinued. No effect of ClO4 on serum thyroid hormone or TSH concentrations, urinary iodine excretion, CBC, or blood chemistry was observed. Urine and serum ClO4 levels were appropriately elevated during the course of ClO4 ingestion in all subjects, demonstrating compliance. By day 14 of ClO4 administration, the 4-, 8-, and 24-hour thyroid RAIU values decreased in all nine subjects by a mean value of 38% from baseline and rebounded above baseline values by 25% at 14 days after ClO4 withdrawal (p < 0.01 analysis of variance (ANOVA) and Tukey). It is well known that the major effect of ClO4 on the thyroid is a decrease in the thyroid iodide trap by competitive inhibition of the sodium iodide symporter (NIS). The present study demonstrates the sensitivity of the thyroid iodide trap to ClO4 because a low dose of 10 mg daily significantly decreased the thyroid RAIU without affecting circulating thyroid hormone or TSH concentrations. It is possible, however, that the daily consumption of low levels of ClO4 in drinking water over a prolonged period of time could adversely affect thyroid function but no evidence of hypothyroidism was observed at 10 mg of ClO4 daily in this 2-week study. It is now of interest to determine a no effect level for ClO4 on the inhibition of the thyroid RAIU and to carry out a long-term ClO4 exposure study.     

Outcome of thyroid function in newborns from mothers treated with amiodarone.

Amiodarone, a drug extensively used as an antiarrhythmic agent, contains 37% iodine and causes several thyroid abnormalities. The transplacental passage of amiodarone occurs with chronic therapy; we describe in this report the outcome of 9 pregnant women who used amiodarone (200 mg/day) for treatment of resistant tachycardia and the follow-up of their newborns. All women were clinically euthyroid at the 3rd trimester and showed expected values of thyroid hormones (mean +/- SD: total T4, 228 +/- 45 nmol/L; total T3, 4.0 +/- 0.65 nmol/L; TSH, 4.0 +/- 1.8 mU/L; negative thyroid antibodies). At birth all newborns were normal on routine examination with no goiter or corneal changes. T4 and TSH, measured on dried umbilical blood spots were normal or borderline-normal in 8 of 9 babies. Only 1 neonate presented clearly abnormal values of T4 and TSH (96 mU/L); on clinical grounds the baby was normal, without signs of hypothyroidism. At 1 month of life, T4 and TSH were normal. Follow-ups at 3, 6, and 12 months were normal. We conclude that is not necessary to discontinue treatment with amiodarone in pregnant women with resistant tachycardia, but it is imperative to evaluate the thyroid function of the newborn, since transient hypothyroidism may occur.     

Thyroid dysfunction in long-term amiodarone administration. Correlation of the antiarrhythmic activity of amiodarone with its effect on thyroid function

Relationship between amiodarone-associated thyroid dysfunction and antiarrhythmic activity of amiodarone was studied in 27 patients (13 with hypothyroidism, 8 with hyperthyroidism, 6 with euthyroid hyperthyroxinemia). Amiodarone-associated hypothyroidism and euthyroid hyperthyroxinemia were not associated with loss of antiarrhythmic efficacy of amiodarone. Hypothyroidism did not require amiodarone withdrawal and therapy with L-thyroxin was conducted at the background of continued amiodarone intake. Achievement of euthyroid state was not followed by recurrence of heart rhythm disturbances. Development of amiodarone-associated thyrotoxicosis was accompanied with loss of antiarrhythmic efficacy of amiodarone in all cases. In 87.5% of patients with thyrotoxicosis correction of the thyroid status was conducted under conditions of continued amiodarone intake as this drug had been given because of life threatening arrhythmias or proven resistance to other antiarrhythmic therapy. In 12.5% of patients it was possible to substitute other drugs for amiodarone. Correction of thyroid status and achievement of euthyroidosis in these patients was associated with restoration of amiodarone antiarrhythmic activity.     

胺碘酮对老年心律失常患者甲状腺功能的影响

目的探讨口服小剂量胺碘酮(AD)对老年心律失常患者甲状腺功能的作用和影响.方法老年冠心病心律失常住院患者56例,均给予负荷量AD(600mg/d),6d后渐减至维持剂量(50～100mg/d);放射免疫法测定甲状腺激素水平.结果服用AD第6天即可见甲状腺激素水平变化,与用药前相比较,总三碘甲状腺原氨酸(TT3)和游离三碘甲状腺原氨酸(FT3)1个月时下降幅度最大,分别由(1.7±0.7)nmol/L、(3.1±1.1)pmol/L下降为(1.4±0.6)nmol/L、(2.3±1.6)pmol/L,下降了17.2%和27.6%(均为P<0.01);促甲状腺激素(TSH)、游离甲状腺激素(FT4)3个月时上升达峰值,由(2.1±1.6)mU/L和(16.2±4.0)pmol/L升为(4.4±4.7)mU/L及(20.7±4.8)pmol/L,分别为118.8%和15.2%(均为P<0.01),总甲状腺素(TT4)于6个月达峰,由(126.3±20.5)nmol/L升为(154.1±32.6)nmol/L(22.0%,P<0.01).监测1年,仅有12例出现TSH异常上升,6例TSH>15.0mU/L者给予左旋甲状腺片后,有4例逐渐恢复正常.结论老年心律失常患者、特别是安装心脏起搏器的老年患者服用AD第6天即可检测到甲状腺激素水平的变化,1～6个月变化最显著,但大多数变化是在正常值范围内.     

The effects of lysophosphatidate on thyrotropin-mediated differentiated thyroid function in FRTL-5 thyroid cells.

Lysophosphatidate (LPA; 1-acyl-sn-glycero-3-phosphate) is a novel lipid mediator with diverse biological activity. The intracellular mechanisms that mediate the actions of LPA include activation of phospholipase C and protein kinase C (PKC), increases in intracellular Ca2+, inhibition of adenylyl cyclase, and activation of phospholipase D (PLD). We have shown that thyrotropin (TSH) mediated PLD activation involves both the cyclic adenosine monophosphate (cAMP) and PKC pathways. We determined the effects of LPA (10 or 50 microM; 30 minutes) on TSH- and forskolin-mediated cAMP production in FRTL-5 thyroid cells. Basal cAMP was unaffected by LPA. However, both 10 microM and 50 microM LPA inhibited TSH-mediated cAMP production by 66% and 64%, respectively (p < 0.01, ANOVA). A similar inhibition of forskolin-mediated cAMP production was observed following LPA (p < 0.01, ANOVA). After 30-minutes exposure to 50 microM LPA, TSH-mediated iodide uptake (IU) was unaffected. However, 50 microM LPA enhanced TSH-IU after 24-hour exposure by 23%+/-8% (p < 0.03, ANOVA) and inhibited TSH-IU following 72-hour exposure by 43%+/-10% (p < 0.02, ANOVA). There was no effect of LPA on basal IU. To determine whether PLD activation mediated the effects of LPA, PLD activity was examined in FRTL-5 thyroid cells 30 minutes after LPA exposure. While PLD was increased 3.5-fold compared to control values following 50 microM LPA (p < 0.05, ANOVA), no increase in PLD activation was seen following treatment with 10 microM LPA. Preliminary evidence revealed no effect of a protein kinase C inhibitor on LPA inhibition of cAMP generation. To examine the products of PLD activation, we measured the production of phosphatidate (PA) and diacylglycerol (DAG) in FRTL-5 thyroid cells following treatment with 50 microM LPA or 100 microU/mL TSH. Within 1 minute following LPA, a rapid spike of DAG production was observed (1.5- +/- 0.2-fold above basal, p < 0.05, ANOVA). No similar increases in PA or bisPA were demonstrated. However, TSH caused a steady increase in PA and DAG that reached a maximum after 30 minutes. In summary, the effects of LPA on differentiated thyroid function in FRTL-5 thyroid cells are complex. LPA inhibits TSH- and forskolin-mediated cAMP generation most likely via a direct inhibition of adenylyl cyclase, whereas its effects on TSH-IU involve other mechanisms, possibly including PLD activation.     

Impact of long-term administration of amiodarone on the thyroid function of patients with Chagas' disease.

The effect of long-term treatment with amiodarone on patients with Chagas' disease has seldom been reported. This nonrandomized observational study attempted to analyze the follow-up of patients with Chagas' disease regarding their clinical evolution, thyroid dysfunction, and goiter. We compared 72 patients with long-term use (11 +/- 5 years) of amiodarone, including 22 patients who developed goiter, to 33 patients who did not use amiodarone, followed-up for 2 to 20 years (7 +/- 11 years). Follow-up of 72 patients for 9 +/- 5.4 years with periodic cardiac and thyroid function evaluations showed that only 26 maintained normal serum thyrotropin (TSH) levels; 24 presented with elevated levels; 4 had low levels, and 18 patients presented with fluctuations of TSH level. Among the 22 patients with goiter, only 3 (14%) patients maintained normal TSH, 8 (36%) had elevated TSH, 2 (9%) had low TSH, and 9 (41%) patients presented with fluctuating serum TSH levels. Most individuals remained clinically euthyroid with no evidence of cardiac impairment that could be attributed to thyroid dysfunction and the arrhythmias were adequately controlled by amiodarone. We suggest that amiodarone treatment may be continued for patients with Chagas' disease with arrhythmias, even in those who develop thyroid function abnormalities or goiter.     

The effects of amiodarone on serum thyroid hormones and hepatic thyroxine 5'-monodeiodination in rats

Amiodarone (2-n-butyl-3,4'-diethylaminoethoxy-3', 5'-diiodobenzoyl-benzofurane) is an antiarrhythmic drug which increases serum T4 and rT3 levels in patients and lowers serum T3 levels. To investigate its effects on T4 metabolism and its cardiac action, we fed amiodarone to male Fisher rats at doses of 5, 15, and 45 mg/kg BW X day; controls received potassium iodide for 4-7 weeks, and another group received sodium ipodate. At 4 weeks, amiodarone caused a dose-dependent increase in the serum T4 concentration and a slight reduction of serum TSH without a change in the serum T3 concentration. These changes were not present at 7 weeks. Sodium ipodate raised serum T4 concentrations at both times. Rats treated with T4 (150 micrograms/kg BW X day) to suppress thyroidal secretion of hormone and with amiodarone (15 mg/kg) had marked reduction of serum T3 concentrations compared with controls receiving T4 without amiodarone. Liver homogenates from rats treated with amiodarone showed marked reduction on T4 5'-monodeiodinase activity in a dose-related manner. Amiodarone added to liver homogenates in vitro at concentrations of 0.001-1 mM did not inhibit T3 production from T4, whereas ipodate added in vitro (0.01-1 mM) did inhibit T3 production. Rats treated with amiodarone showed a lowering of the resting heart rate and a reduction of the increment in heart rate after iv isoproterenol administration. The cardiac Ca++ myosin ATPase activity was reduced in rats receiving amiodarone (45 mg/kg) compared with that in controls. The data indicate that rats treated with amiodarone have reduced peripheral conversion of T4 to T3 owing to impaired hepatic T4 5'-monodeiodinase activity. In addition, these rats have slowing of heart rate and reduction of cardiac Ca++ myosin ATPase activity. These findings are consistent with the hypothesis that amiodarone blocks some effects of thyroid hormone on the heart, but additional studies are needed to test this hypothesis.     

Effects of amiodarone administration during pregnancy on neonatal thyroid function and subsequent neurodevelopment

Amiodarone, a benzofuranic derivative, iodine-rich drug, has been used in pregnancy for either maternal or fetal tachyarrhythmias. Amiodarone, its main metabolite (desethylamiodarone) and iodine are transferred, albeit incompletely, through the placenta, resulting in a relevant fetal exposure to the drug and iodine overload. Since the fetus acquires the capacity to escape from the acute Wolff-Chaikoff effect only late in gestation, the iodine overload may cause fetal/neonatal hypothyroidism and goiter. Among the reported 64 pregnancies in which amiodarone was given to the mother, 11 cases (17%) of hypothyroidism in the progeny (10 detected at birth, 1 in utero) were reported, 9 non-goitrous (82%) and 2 (18%) associated with goiter. Hypothyroidism was transient in all cases, and only 5 infants were treated short-term with thyroid hormones. Only 2 newborns had transient hyperthyroxinemia, associated with low serum TSH concentrations in one. Neurodevelopment assessment of the hypothyroid infants, when carried out, showed in some instances mild abnormalities, most often reminiscent of the Non-verbal Learning Disability Syndrome; however, these features were also reported in some amiodarone-exposed euthyroid infants, suggesting that there might be a direct neurotoxic effect of amiodarone during fetal life. Breast-feeding was associated with a substantial ingestion of amiodarone by the infant, but in the few cases followed it did not cause changes in the newborn's thyroid function. In conclusion, amiodarone therapy during pregnancy may cause fetal/neonatal hypothyroidism and, less frequently, goiter. Thus, the use of amiodarone in pregnancy should be limited to maternal/fetal tachyarrhythmias which are resistant to other drugs or life-threatening. If amiodarone is used during gestation, a careful fetal/neonatal evaluation of thyroid function and morphology is warranted. It seems prudent to advise that fetal/neonatal hypothyroidism be treated, as soon as the diagnosis is made, even in utero, to avoid neurodevelopment abnormalities, although the latter may occur independently of hypothyroidism. If breast-feeding is allowed, careful evaluation of the infant's thyroid function and morphology is required because of the continuing exposure of the infant to the drug.     

Clinical and chemical assessment of thyroid function during therapy with amiodarone

Clinical and chemical variables of thyroid function were studied in 26 patients with symptomatic ventricular tachyarrhythmias before and during long-term oral treatment with amiodarone. The mean (+/-SEM) pretreatment thyroxine (T4) level in the 26 patients was 7.32 +/- 0.33 micrograms/dL, and increased notably to 10.15 +/- 0.47 micrograms/dL by 30 to 120 days after treatment. The free thyroxine index (FT4I) was also notably elevated. Clinical hyperthyroidism or goiter did not develop, but clinical hypothyroidism occurred in four patients during and in one patient after discontinuation of amiodarone treatment. Notable titers of antithyroid antibodies were found in the serum of two of the five and a family history of thyroid disease was present in three of the five hypothyroid patients. An elevation of both the T4 level and the FT4I above the normal range is an expected finding in patients receiving amiodarone and does not by itself indicate hyperthyroidism. Patients with positive antithyroid antibodies or a family history of thyroid disease prior to treatment with amiodarone may be at an increased risk of hypothyroidism developing when treated with this drug.     

Chronic administration of amiodarone and thyroid function: a follow-up study

In order to evaluate the effects of amiodarone on thyroid function in chronically treated patients, 43 consecutive patients, who had been taking a mean weekly dose of 1420 +/- 488 mg for more than 9 months (mean 16.5 months), were studied. In a first evaluation, three patients with hypothyroidism and two with hyperthyroidism were discovered. In the remaining 38 patients, mean T4 (131 +/- 38 nmol/L) and rT3 (0.85 +/- 0.3 nmol/L) levels were significantly higher than reference values (p less than 0.05 and p less than 0.001, respectively), and mean T3 levels (1.89 +/- 0.73 nmol/L) were significantly lower (p less than 0.001). Thirteen patients showed hyperresponsiveness to thyrotropin-releasing hormone (TRH) stimulation testing. In a second evaluation, performed 12 to 18 months later, two new cases of hypothyroidism were discovered. T3 levels showed significantly lower values (p less than 0.02) than in the first evaluation, whereas basal thyroid-stimulating hormone levels and levels 30 and 60 minutes after TRH stimulation were significantly higher than those in the first evaluation (p less than 0.001). Five new hyperresponders to TRH were found. In the present series, the progressive appearance of clinical thyroid dysfunction with an elevated total incidence (16%) is demonstrated. Moreover, a progressively high prevalence of hyperresponsiveness to TRH stimulation is shown. These findings indicate that chronic amiodarone administration may carry a high risk of thyroid dysfunction.