Amiodarone-induced Thyroid Disorders

The thyroid gland produces three hormones, thyroxine (T4), triiodothyronine (T3), and calcitonin. Thyroxine is the main hormone produced by the thyroid gland. While triiodothyronine is the more active form, the majority of this hormone is produced peripherally via the breakdown of thyroxine.

Thyroid hormones play an important role in development, growth, and metabolism. In adults, the main effects of thyroid disorders are metabolic. Hypothyroidism may present with fatigue, weight gain, cold intolerance, and depression. Symptoms of hyperthyroidism may include heart palpitations, hyperactivity, increased sweating, heat hypersensitivity, fatigue, increased appetite, weight loss, insomnia, and frequent bowel movements.

The production of thyroid hormones is regulated by thyroid stimulating hormone (TSH), produced by the anterior pituitary. Thyroid stimulating hormone is under negative feedback control by the circulating levels of free thyroid hormone and under positive control by hypothalamic thyrotropin-releasing hormone (TRH). The production of thyroid hormones is also affected by the extrathyroidal deiodination of T4 to T3. This can be affected by nutrition, other hormones, illness, and medications.

There are many medications that can affect thyroid function. Amiodarone is interesting in that it can cause both hypothyroidism and hyperthyroidism. The incidence of amiodarone-induced thyroid dysfunction is estimated to be around 14-18%. Studies have wide variations in the reports of thyroid dysfunction, which may be related to geographic differences in iodine deficiency. The incidence of amiodarone-induced thyrotoxicosis (AIT) has been reported to vary between 1% in some studies up to 23% in others. Similarly, the reported incidence of amiodarone-induced hypothyroidism (AIH) varies between 1% and 32%. Areas with a higher level of iodine deficiency have a higher incidence of AIT, while AIH is more common in areas without iodine deficiency.

The incidence of iodine deficiency in Australia differs by region. Tasmania has the highest proportion of people with urinary iodine levels below 50μg/L (denoting mild deficiency). This is thought to be due to lower levels in the soil and, therefore, lower levels in the foods produced locally.

Amiodarone

Amiodarone is a commonly used antiarrhythmic agent. It is indicated for the treatment of severe tachyarrythmias such as Wolff-Parkinson-White Syndrome; supraventricular, nodal and ventricular tachycardias; atrial flutter and fibrillation; and ventricular fibrillation.

The chemical structure of amiodarone and its main metabolite are also very similar to T3. Amiodarone and its metabolite demonstrate the ability to inhibit the transport of thyroid hormones across the plasma membrane, and the metabolite may also antagonise the effects of T3 at the molecular level.

Each molecule of amiodarone contains two iodine atoms, which accounts for around 37% of its molecular weight. A 200mg amiodarone tablet contains approximately 75mg of organic iodine. From this, around 6mg of free iodine is released following deiodination during drug metabolism. However, the recommended dietary intake for iodine is only 150 micrograms per day for adults. The amount of iodine released from a tablet also greatly exceeds the upper level of intake of 1,100 micrograms per day for adults.

When a normal thyroid gland is exposed to large quantities of iodine, the Wolff-Chaikoff effect is initiated. This autoregulatory phenomenon reduces thyroid activity in response to increased plasma iodide. This effect normally lasts for a few days before the normal synthesis of thyroid hormones resumes (referred to as escape from the Wolff-Chaikoff effect). However, in some patients, this escape from the Wolff-Chaikoff effect may not be achieved, and hypothyroidism results.

Alternatively, iodine overload can result in the Jod-Basedow phenomenon or iodine-induced thyrotoxicosis. This typically occurs in people with an underlying thyroid condition such as multinodular goitre or Graves’ disease and is more likely in areas of iodine deficiency. In these individuals, excess iodine from amiodarone therapy leads to uncontrolled overproduction of thyroid hormones.

Amiodarone can also cause thyroid dysfunction via mechanisms unrelated to iodine overload. Amiodarone causes inhibition of deiodinases, enzymes involved in the activation and inactivation of thyroid hormones. Amiodarone may also have a direct cytotoxic effect, resulting in apoptosis of thyroid cells.

Risk factors for amiodarone-induced thyroid dysfunction include advanced age, female sex, and a daily amiodarone dose exceeding 200mg.

Hypothyroidism

Amiodarone-induced hypothyroidism is more likely to arise in the first year of amiodarone treatment. The prevalence is thought to reduce after this time as the thyroid gland adapts to the increased thyroid intake.

Compared to AIT, this type of thyroid dysfunction is more likely to occur in:

• Areas with sufficient iodine intake;
• Women (ratio of women to men is 1.5:1);
• Patients that are older; and
• Earlier stages of therapy.

Amiodarone-induced hypothyroidism can affect patients with no previous history of thyroid dysfunction. However, the development of long-term AIH is more likely in patients with pre-existing thyroid disease and positive antithyroid antibodies.

Hyperthyroidism

Amiodarone-induced thyrotoxicosis is not as common as AIH. However, AIT can have serious complications for patients taking amiodarone due to worsening of their underlying cardiac condition. Patients with AIT have a significantly higher risk of experiencing major cardiovascular events, with one study demonstrating a 2.7-fold increased risk. The elderly and those with a left ventricular ejection fraction <45% are at particular risk.

Compared to AIH, this type of thyroid dysfunction is more likely to occur in:

• Areas of iodine deficiency;
• Men (male to female ratio of 3:1); and
• Later in therapy (typically between 4 months and 3 years after initiation of amiodarone).

There are two main types of AIT:  type 1 (related to the high iodine content of amiodarone) and type 2 (related to direct damage of thyroid cells). However, a mixed type has also been described in which both mechanisms are involved, and features of both may be present.

Type 1 AIT

This condition develops in patients with pre-existing thyroid disease. Increased intake of iodine in these patients is thought to promote the synthesis and release of increasing quantities of thyroid hormone to produce clinically evident hyperthyroidism.

Type 2 AIT

This condition is more likely to develop in a patient without pre-existing thyroid disease. Type 2 AIT is a destructive thyroiditis mediated by amiodarone and its metabolite. The resulting tissue damage leads to increased release of previously synthesised thyroid hormone.

The clinical presentation of AIT may include weight loss, reduced heat tolerance, fatigue, muscle weakness, increased frequency of bowel movements, oligomenorrhea, anxiety, depression, and palpitations. However, for some patients, the reappearance of anginal pain, atrial fibrillation or tachycardia may be the only indication.

Monitoring and treatment

Monitoring of thyroid function (ultrasensitive TSH assay) is recommended before starting amiodarone therapy, regularly during treatment, and for several months after discontinuation.

Identification of thyroid dysfunction in a patient taking amiodarone raises the question of whether the therapy should be continued. An individual assessment of the benefits and risks of continuing or ceasing therapy is required.

In many cases, amiodarone therapy can be continued for patients who have developed AIH. Hypothyroidism can be treated in these cases with levothyroxine, with the dose adjusted according to TSH levels.

Treatment decisions for AIT are more complex. This form of thyroid dysfunction may not respond to therapy discontinuation and can even develop after discontinuation of amiodarone. Type 1 AIT is treated with antithyroid therapy (e.g. carbimazole, propylthiouracil) and type 2 AIT is treated with high-dose glucocorticoids. Thyroidectomy may be required if no response is achieved after four to six weeks.

When considering discontinuation of amiodarone therapy, it is important to remember that amiodarone and its metabolite have long half-lives. With chronic dosing, the half-life of amiodarone may range from 14-110 days and 60-90 days for the metabolite. Therefore, the effects of ceasing amiodarone are gradual. In addition, discontinuing amiodarone in patients with AIT could actually exacerbate symptoms of thyrotoxicosis. This is due, in part, to the effects of amiodarone on blocking the peripheral conversion of T4 into the more active T3.