Thyroid Dysfunction Induced by Amiodarone Therapy

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Practice Essentials

Amiodarone is a potent antiarrhythmic drug that is used to treat ventricular and supraventricular tachyarrhythmias. It is a benzofuran-derived, iodine-rich compound with some structural similarity to thyroxine (T4). Amiodarone contains approximately 37% iodine by weight. Each 200-mg tablet is estimated to contain about 75 mg of organic iodide, 8-17% of which is released as free iodide. Standard maintenance therapy with 200-mg amiodarone can provide more than 100 times the daily iodine requirement. It is highly lipid-soluble and is concentrated in the adipose tissue, muscle, liver, lung, and thyroid gland.[1]

The elimination half-life of amiodarone is highly variable, ranging from 50-100 days; total body iodine stores remain increased for up to 9 months after discontinuation of the drug. Thyroid abnormalities have been noted in up to 14-18% of patients receiving long-term amiodarone therapy. However, a meta-analysis suggested that with lower doses of amiodarone (150-330 mg), the incidence of thyroid dysfunction is 3.7%. The effects range from abnormal thyroid function test findings to overt thyroid dysfunction, which may be either amiodarone-induced thyrotoxicosis (AIT) or amiodarone-induced hypothyroidism (AIH).[2, 3, 4, 5] Both can develop in apparently normal thyroid glands or in glands with preexisting abnormalities.

Signs and symptoms of thyrotoxicosis and hypothyroidism induced by amiodarone

Signs and symptoms of AIT include the following:

Signs and symptoms of AIH include the following:

Workup in thyrotoxicosis and hypothyroidism induced by amiodarone

Lab findings for AIH are similar to those for spontaneous hypothyroidism and include decreased levels of serum free T4 and increased levels of serum thyroid-stimulating hormone (TSH). Serum thyroglobulin levels are often increased, probably because of TSH-enhanced thyroid stimulation.

Lab findings for AIT include elevated levels of serum total and free T4 and triiodothyronine (T3), and undetectable levels of TSH. Low TSH levels and elevated free T4 levels are also commonly seen in the early phases of amiodarone therapy and in patients with severe nonthyroidal illness who have euthyroidism and are treated with amiodarone. Therefore, the measurement of free T3 levels may be helpful in differentiating conditions, because free T3 levels are increased in hyperthyroidism, while they are decreased in early phases of treatment with amiodarone.

Although lab studies can confirm a diagnosis of thyrotoxicosis, further studies are necessary to recognize the correct type of AIT.[6] An ultrasonogram of the thyroid that shows abnormalities such as hypoechoic or nodular patterns or increased gland size is more indicative of type 1.

Management of thyrotoxicosis and hypothyroidism induced by amiodarone

The initial management of AIT involves deciding whether to discontinue amiodarone therapy. This depends on the patient's cardiac condition, the availability of alternate therapies, and the type of AIT present in the patient.

Mild AIT subsides spontaneously in up to 20% of cases upon discontinuation of amiodarone therapy.

Type 1 thyrotoxicosis is treated with high doses of thionamides (eg, methimazole [40-60 mg/d] or propylthiouracil [600-800 mg/d]) to block thyroid hormone synthesis. Adding potassium perchlorate may block iodide uptake by the thyroid and deplete intrathyroidal iodine stores. Because potassium perchlorate is a drug that potentially causes aplastic anemia, limit it to patients whose condition cannot be controlled by methimazole alone.

Type 2 thyrotoxicosis is treated with a relatively long course of glucocorticoids.

If thyrotoxicosis is exacerbated after initial control, it is usually treated with steroids. In type 1 AIT, this exacerbation may be due to mixed forms, which respond to the addition of steroids. In type 2 AIT, relapse can occur after discontinuation of corticosteroid treatment, and steroid treatment may need to be restarted.

Hypothyroidism in patients with no preexisting thyroid disease often resolves after discontinuation of amiodarone therapy. However, hypothyroidism may persist after discontinuation of treatment in patients with underlying chronic autoimmune thyroiditis and high titers of anti-thyroid peroxidase (anti-TPO) antibodies. In this case, the patient may require permanent T4 replacement therapy.

Total or near-total thyroidectomy is performed in cases of AIT that fail to respond to combination therapy with thionamides, perchlorate, and corticosteroids. Thyroidectomy is also performed in patients who need amiodarone therapy but whose resulting hyperthyroidism does not respond to medical treatment. In addition, it is carried out for immediate control of a thyrotoxic state (eg, during thyroid storm), as well as in patients with intractable arrhythmias.

Pathophysiology

Amiodarone causes a wide spectrum of effects on the thyroid.

In summary, serum T4 levels rise by 20-40% during the first month of therapy and then gradually fall toward high normal. Serum T3 levels decrease by up to 30% within the first few weeks of therapy and remain slightly decreased or low normal. Serum rT3 levels increase by 20% soon afterward and remain increased. Serum thyrotropin (TSH) levels usually rise after the start of therapy but return to normal in 2-3 months.

Two forms of AIT have been described. Type 1 usually affects patients with latent or preexisting thyroid disorders and is more common in areas of low iodine intake. Type 1 is caused by iodine-induced excess thyroid hormone synthesis and release (Jod-Basedow phenomenon). Type 2 occurs in patients with a previously normal thyroid gland and is caused by a destructive thyroiditis that leads to the release of preformed thyroid hormones from the damaged thyroid follicular cells. However, mixed forms of AIT may occur in an abnormal thyroid gland, with features of destructive processes and iodine excess.

The most likely mechanisms of AIH are an enhanced susceptibility to the inhibitory effect of iodine on thyroid hormone synthesis and the inability of the thyroid gland to escape from the Wolff-Chaikoff effect after an iodine load in patients with preexisting Hashimoto thyroiditis. In addition, iodine-induced damage to the thyroid follicles may accelerate the natural trend of Hashimoto thyroiditis toward hypothyroidism. Patients without underlying thyroid abnormalities are postulated to have subtle defects in iodine organification that lead to decreased thyroid hormone synthesis, peripheral down-regulation of thyroid hormone receptors, and subsequent hypothyroidism.

Epidemiology

Frequency

United States

The prevalence of AIT in the United States is 3%; the prevalence of AIH is 22%. The relative prevalence of the two forms of AIT is unknown.

International

Some studies indicate that the incidence varies with the dietary iodine intake in the population. AIT occurs more frequently in geographic areas with low iodine intake, whereas AIH is more frequent in iodine-replete areas. However, in a Dutch study of persons with euthyroidism living in an area with moderately sufficient iodine intake, the incidence of AIT was twice that of AIH.

In a Danish study of 43,724 patients receiving first-time amiodarone therapy, including 16,939 with heart failure, Ali et al found that at 1-year follow-up, the cumulative incidence of the study’s primary outcome (“a composite of thyroid diagnoses and initiation of thyroid drugs”) was slightly higher in individuals with heart failure than in those without it (5.3% vs 4.2%, respectively).[7]

Mortality/Morbidity

Although amiodarone-associated thyroid dysfunction is usually a mild clinical condition, it can be severe, life threatening, and even lethal. Fatal cases of thyroid storm and myxedema coma have been reported despite various aggressive therapies.

Race

No well-described racial differences exist.

Sex

AIH is more frequent in females, with a female-to-male ratio of 1.5:1. AIT, however, is more frequent in males, with a male-to-female ratio of 3:1.

Age

The risk of AIH is higher in elderly persons,[8] probably because of the higher prevalence of underlying thyroid abnormality.

Prognosis

The prognosis for AIT may be very poor even though a wide range of antithyroid therapies are available. This prognosis emphasizes the need for careful monitoring of patients receiving amiodarone treatment.

The long-term prognosis for AIH is usually good.

A randomized, double-blind study by Diederichsen et al indicated that in patients without previous thyroid dysfunction, short-term amiodarone use can be safe. The study looked at the effects of 8 weeks of either amiodarone or placebo therapy in 212 patients with atrial fibrillation undergoing catheter ablation. Although the amiodarone patients had higher levels of TSH, T4, and free T4, as well as lower levels of T3 and free T3, than did the placebo group, thyroid dysfunction peaked at 1 month, was declining at 3 months, and returned to baseline levels by 6 months.[9]

A study by Wang et al indicated that in patients with paroxysmal atrial fibrillation and AIT, early catheter ablation is safe and effective, although the rate of atrial tachyarrhythmia recurrence is higher than in controls for as long as 3 months after pulmonary vein isolation.[10]

Patient Education

Instruct patients about the adverse effects of amiodarone therapy. Give them a list of potential symptom manifestations. Because the development of thyrotoxicosis is sudden and explosive, instruct patients to watch for symptoms and to seek treatment promptly.

Patients should also be aware of the potential side effects of antithyroid medications. Instruct patients to watch for signs such as fever, sore throat, jaundice, or oral ulcers.

History

The clinical presentation of AIH is usually subtle, while that of AIT can be dramatic, with life-threatening cardiac manifestations without antecedent subclinical biochemical findings. Suspect AIT in a patient who was previously stable while receiving amiodarone but who starts to show signs of cardiac decompensation, tachyarrhythmias, or angina. However, patients may lack cardiac manifestations because of amiodarone's intrinsic effect on the heart, and other signs of hyperthyroidism such as weight loss and fatigue may predominate. Thyrotoxicosis can occur while a patient receives amiodarone and even several months after discontinuation of treatment. Hypothyroidism is rare after the first 18 months of therapy.

Physical

The physical signs of thyrotoxicosis or hypothyroidism induced by amiodarone therapy do not differ from those observed in states of thyroid excess or deficiency attributable to other causes.

Causes

The risk of developing hypothyroidism or thyrotoxicosis is thought to be independent of the daily or cumulative dose of amiodarone. However, some studies have shown the contrary. For example, in the aforementioned study by Ali and colleagues, patients who underwent first-time amiodarone therapy who did not experience thyroid problems in the first year were followed up for the next 5 years, with the investigators reporting that “[a] dose-response relationship was observed between the 1-year accumulated amiodarone dose and the subsequent 5-year cumulative incidence of thyroid dysfunction.”[7]

Autoimmune thyroid disease is the principal risk factor for the development of hypothyroidism. High dietary intake and a positive family history of thyroid disease may also be predisposing factors. Females with thyroid peroxidase or thyroglobulin antibodies have a relative risk of 13.5% for the development of hypothyroidism.

A Japanese study, by Kinoshita et al, indicated that in patients receiving amiodarone, the presence of dilated cardiomyopathy and cardiac sarcoidosis are risk factors for amiodarone-induced hyperthyroidism, while higher baseline TSH levels and lower baseline free thyroxine levels are predictors for amiodarone-induced hypothyroidism. The investigators also stated that because the TSH and free thyroxine levels are apparent risk factors, subclinical hypothyroidism may be a predictor for amiodarone-induced hypothyroidism.[11]

A literature review by Zhong et al indicated that new-onset AIH is particularly likely to occur in older women and in regions with a high environmental iodine content. The incidence of AIH in women was reported to be 19.2%, compared with 13.3% in men, with mean age found to correlate positively with the percentage of women. In areas with a high iodine content, the incidence of AIH was 20.3%, compared with 8.7% in regions with a low iodine content.[12]

A retrospective study by Chaturvedi et al indicated that in patients who undergo heart transplantation, the pre-transplantation use of amiodarone is strongly associated with the development of post-transplantation chronic thyroiditis. Fifty percent of study patients in whom chronic thyroiditis arose after transplantation had been on amiodarone therapy prior to surgery, compared with 21.6% of the group that did not develop chronic thyroiditis. Multivariate analysis revealed that in patients who underwent pre-transplantation amiodarone therapy, the odds ratio for the occurrence of chronic thyroiditis following transplantation was 3.65. In most of the thyroiditis cases, the condition manifested as hypothyroidism.[13]

Laboratory Studies

Lab findings for AIH are similar to those for spontaneous hypothyroidism and include decreased levels of serum free T4 and increased levels of serum TSH. Serum thyroglobulin levels are often increased, probably because of TSH-enhanced thyroid stimulation.

Lab findings for AIT are elevated levels of serum total and free T4 and T3, and undetectable levels of TSH. Low TSH levels and elevated free T4 levels are also commonly seen in the early phases of amiodarone therapy and in patients with severe nonthyroidal illness who have euthyroidism and are treated with amiodarone. Therefore, the measurement of free T3 levels may be helpful in differentiating conditions, because free T3 levels are increased in hyperthyroidism, while they are decreased in early phases of treatment with amiodarone. Serum rT3 levels are also markedly increased. However, serum rT3 levels are not part of a routine workup.

Because amiodarone has no effect on the serum concentration of thyroid hormone–binding globulin, changes in the levels of free T4 and free T3 mirror those for total T4 and total T3.

In the absence of hypothyroid symptoms, moderately elevated serum TSH levels with high normal or raised serum free T4 levels may reflect subclinical hypothyroidism. Close monitoring and repeat testing after 6 weeks is recommended.

Serum sex hormone–binding globulin concentration is increased in patients with AIT but not in patients with hyperthyroxinemia and euthyroidism who are treated with amiodarone therapy. This assay is of limited importance, however, because of the numerous factors that affect the serum levels.

Serum thyroglobulin levels are not diagnostic because they are usually higher in type 2 AIT but can be elevated in both types of AIT. Thyroglobulin levels can be increased in patients with goiters independent of the association with destructive thyroiditis.

In some studies, serum interleukin-6 levels were lower in type 1 AIT and markedly elevated in type 2 AIT. The fact that interleukin 6 is also increased in patients with severe nonthyroidal illnesses limits the specificity of interleukin-6 determination.

Thyroid autoantibodies are generally absent in type 2 AIT. The presence of autoantibodies supports the diagnosis of type 1 AIT. However, a test negative for autoantibodies does not rule out type 1 AIT.

Urinary iodine excretion is not helpful in the initial assessment but may be useful long after the withdrawal of amiodarone, to assess whether excess iodine levels are present.

Imaging Studies

Although the above lab studies can confirm a diagnosis of thyrotoxicosis, further studies are necessary to recognize the correct type of AIT.[6] This distinction is important when choosing treatment modalities.

Color flow Doppler ultrasonography visualizes the amount of blood flow within the thyroid. However, the accuracy of this tool is limited by the proficiency of the sonographer.

Most patients with AIH have been reported to have positive results on the perchlorate discharge test, indicating defects in intrathyroidal iodide organification. People with AIT have negative test results. These tests are rarely indicated or performed outside an academic setting.

A study found technetium-99m – sestamibi (99m Tc-MIBI) thyroid scintigraphy to be effective in the differential diagnosis of AIT.[6, 14] According to the report, which utilized patients with either type 1 or type 2 AIT, or with an indefinite form of the condition, this modality proved superior to a variety of diagnostic tools, including color flow Doppler ultrasonography and radioactive iodine, in differentiating one form of AIT from another.

Histologic Findings

A biopsy of the thyroid gland is unnecessary in most patients. The histologic changes that occur with amiodarone administration have been studied in a research setting and include the following:

Patients with euthyroidism treated with amiodarone therapy showed minimal or no evidence of thyroid follicular damage.

Medical Care

AIT presents a therapeutic challenge because data on optimal treatment are limited (due to the lack of randomized, controlled trials).

Hypothyroidism in patients with no preexisting thyroid disease often resolves after discontinuation of amiodarone therapy. However, hypothyroidism may persist after the discontinuation of treatment in patients with underlying chronic autoimmune thyroiditis and high titers of anti-TPO antibodies. In this case, the patient may require permanent T4 replacement therapy. Amiodarone therapy is usually continued while T4 is used to normalize the TSH level. In view of the often-severe, underlying cardiac disease, consider maintaining the serum TSH concentration in the upper half of the reference range. Levothyroxine is the drug of choice because it is not associated with the spikes in serum thyroid hormone concentrations observed in patients given liothyronine (L-T3, a synthetic form of T3), which also requires multiple daily doses. However, if amiodarone therapy is continued, larger doses of T4 are required to offset the inhibitory effects of amiodarone on the conversion of T4 to T3.

Surgical Care

Total or near-total thyroidectomy is performed in cases of AIT that fail to respond to combination therapy with thionamides, perchlorate, and corticosteroids. Thyroidectomy is also performed in patients who need amiodarone therapy but whose resulting hyperthyroidism does not respond to medical treatment. In addition, it is carried out for immediate control of a thyrotoxic state (eg, during thyroid storm), as well as in patients with intractable arrhythmias. Treat the resulting hypothyroidism with thyroid hormone replacement. Despite the minimally elevated risk due to underlying heart disease, surgery is reasonably safe in these patients and can even be performed with local anesthesia.

A retrospective cohort study by Cappellani et al indicated that in patients with AIT and a left ventricular ejection fraction (LVEF) of less than 40%, those who undergo total thyroidectomy after euthyroidism has been restored, and thus have longer exposure to thyrotoxicosis, have a higher mortality rate (peritreatment mortality rate: 40%; 5-year cardiovascular mortality rate: 53.3%) than do those who undergo the surgery while still thyrotoxic (0% and 12.3% mortality rates, respectively). In contrast, survival rates in study patients with an LVEF of 40% or above did not significantly differ with regard to whether or not they were euthyroid when total thyroidectomy was performed.[16]

Similar results were obtained in a study by Frey et al, which also indicated that in persons with AIT, a longer period of time until total thyroidectomy in those with an LVEF of under 40% has a significant link to cardiac mortality. The median time to surgery referral for all patients in the study, including those with an LVEF of 40% or greater and those with an LVEF below 40%, was 3.1 months, with 47.1% of the patients undergoing surgery after euthyroidism was restored. The report found that in patients with an LVEF of under 40%, the 5-year cardiac mortality rate was 47.0%, compared with 2.9% in those with the higher LVEF values. According to the investigators, these outcomes support the strategy that, if surgery is chosen for patients with an LVEF below 40%, the procedure be performed quickly.[17]

Consultations

Consultation with an endocrinologist is recommended. Consult with a cardiologist to decide whether or not to continue amiodarone therapy.

Diet

No dietary restrictions apply, but excess amounts of iodide found in some expectorants, contrast dyes, seaweed tablets, and health food supplements should be avoided.

Activity

Restriction of activity is prudent in elderly persons or in patients with severe thyrotoxicosis with cardiovascular symptoms. Otherwise, no activity restrictions are necessary.

Complications

Complications include the following:

Prevention

Test baseline thyroid function in all patients starting amiodarone therapy to exclude underlying gland dysfunction that may predispose them to thyroid abnormalities after therapy begins. The serum levels of TSH, free T4, and free T3 may be reassessed after 3 months of amiodarone therapy. In patients with euthyroidism, thyroid function results may be used as reference for future comparisons. Periodically monitor serum TSH levels and other thyroid indices if TSH levels are abnormal or clinical suspicion of thyroid dysfunction exists. The threshold for performing thyroid function tests should be low in patients who are taking amiodarone or who have in the past, as type 2 AIT has an abrupt onset. Continue to measure thyroid function for at least a year after amiodarone therapy is discontinued.

Research indicates that another benzofuran-derived drug, dronedarone (Multaq), may be a useful alternative treatment for arrhythmia. Although apparently not as effective an antiarrhythmic as amiodarone, dronedarone seems to be less toxic to the thyroid.[18]  Dronedarone was approved by the FDA on July 2, 2009.

Long-Term Monitoring

Prolonged monitoring of thyroid function tests is necessary in patients with AIT, even if they become euthyroid, as they may become hypothyroid. Recurrences are common in type 2 AIT.

Guidelines Summary

In 2018, the European Thyroid Association published guidelines concerning amiodarone-related thyroid dysfunction management. Recommendations include the following[19] :

What is amiodarone-associated thyroid dysfunction?What is the role of amiodarone in the pathophysiology of thyroid dysfunction?What is the prevalence of amiodarone-associated thyroid dysfunction in the US?What is the global prevalence of amiodarone-associated thyroid dysfunction?What is the disease progression of amiodarone-associated thyroid dysfunction?What are the racial predilections of amiodarone-associated thyroid dysfunction?What are the sexual predilections of amiodarone-associated thyroid dysfunction?Which age groups have the highest prevalence of amiodarone-associated thyroid dysfunction?What is the prognosis of amiodarone-associated thyroid dysfunction?What is included in patient education about amiodarone-associated thyroid dysfunction?Which clinical history findings are characteristic of amiodarone-associated thyroid dysfunction?What are the signs and symptoms of amiodarone-induced thyrotoxicosis (AIT)?What are the signs and symptoms of amiodarone-induced hypothyroidism (AIH)?Which family history findings are characteristic of amiodarone-associated thyroid dysfunction?Which physical findings are characteristic of amiodarone-associated thyroid dysfunction?What are the risk factors for amiodarone-associated thyroid dysfunction?What are the differential diagnoses for Thyroid Dysfunction Induced by Amiodarone Therapy?What is the role of lab testing in the diagnosis of amiodarone-associated thyroid dysfunction?What is the role of imaging studies in the diagnosis of amiodarone-associated thyroid dysfunction?What is the role of color flow Doppler ultrasonography in the diagnosis of amiodarone-associated thyroid dysfunction?What is the role of nuclear medicine imaging in the diagnosis of amiodarone-associated thyroid dysfunction?Which histologic findings are characteristic of amiodarone-associated thyroid dysfunction?How are amiodarone-induced thyrotoxicosis (AIT) and amiodarone-induced hypothyroidism (AIH) treated?What is the role of surgery in the treatment of amiodarone-induced thyrotoxicosis (AIT)?Which specialist consultations are beneficial to patients with amiodarone-associated thyroid dysfunction?What dietary restrictions are indicated in patients with amiodarone-associated thyroid dysfunction?Which activity modifications are used in the treatment of amiodarone-associated thyroid dysfunction?What are the possible complications of amiodarone-associated thyroid dysfunction?How is amiodarone-associated thyroid dysfunction prevented?What is included in the long-term monitoring of patients with amiodarone-associated thyroid dysfunction?What are the ETA treatment guidelines for amiodarone-associated thyroid dysfunction?

Author

Mini Gopalan, MD, Consulting Physician, Department of Internal Medicine, Midland Community Healthcare Services; Clinical Assistant Professor, Department of Medicine, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

James Burks, MD, FACP, FACE, Professor of Medicine, Program Director, Department of Medicine, Texas Tech University Health Sciences Center

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Arthur B Chausmer, MD, PhD, FACP, FACE, FACN, CNS, Professor of Medicine (Endocrinology, Adj), Johns Hopkins School of Medicine; Affiliate Research Professor, Bioinformatics and Computational Biology Program, School of Computational Sciences, George Mason University; Principal, C/A Informatics, LLC

Disclosure: Nothing to disclose.

Chief Editor

Romesh Khardori, MD, PhD, FACP, (Retired) Professor, Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Eastern Virginia Medical School

Disclosure: Nothing to disclose.

Acknowledgements

Robert A Gabbay, MD, PhD Associate Professor of Medicine, Division of Endocrinology, Diabetes and Metabolism, Laurence M Demers Career Development Professor, Penn State College of Medicine; Director, Diabetes Program, Penn State Milton S Hershey Medical Center; Executive Director, Penn State Institute for Diabetes and Obesity

Robert A Gabbay, MD, PhD is a member of the following medical societies: American Association of Clinical Endocrinologists, American Diabetes Association, and Endocrine Society

Disclosure: Novo Nordisk Honoraria Speaking and teaching; Merck Honoraria Speaking and teaching

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