Amiodarone induced thyrotoxicosis

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Amiodarone induced thyrotoxicosis
Amiodarone structure.svg
Skeletal formula of amiodarone—a class III antiarrhythmic.
Specialty Endocrinology

Amiodarone induced thyrotoxicosis (AIT) is a form of hyperthyroidism due to treatment with antiarrhythmic drug, amiodarone.

Contents

Amiodarone induced thyroid dysfunction more commonly results in hypothyroidism, estimated to occur in 6-32% of patients, whereas hyperthyroidism from amiodarone use is estimated at 1-12%. [1] However, the prevalence of AIT varies based on geographical region, and is more common in areas with low dietary iodine intake, where it occurs in 10-12% of patients. In the United States, clinical manifestations of AIT occur in 3-5% of patients. [2]

AIT may present clinically early after initiation of amiodarone or can be delayed even up several years. [3] Symptoms associated with AIT are similar to those of other forms of hyperthyroidism, including new-onset or recurrence of arrhythmias, worsening of pre-existing heart conditions such as ischemic heart disease or heart failure, unattributed weight loss, and fever. [2] [3] Development of AIT is associated with an increased risk for major adverse cardiovascular events, and increased mortality specifically in patients with AIT and underlying heart failure. [3] [4]

Pathophysiology

Amiodarone has both direct and indirect effects on thyroid function. The most notable indirect thyroid altering property is that the drug is approximately one-third iodine by weight. As a result, amiodarone therapy elevates free circulating iodine levels up to 40 times greater than the iodine intake from the average American diet. [2] Iodine plays a role in thyroid production, and excess iodine levels within the body can result in overproduction of thyroid hormone. Initially, the thyroid reacts according to the auto-regulatory Wolff-Chaikoff effect to prevent an excess of thyroid hormone production. [5] Usually, the thyroid normalizes within 24-48 hours. In some cases, the thyroid responds with an alternative "escape" mechanism from the Wolff-Chaikoff auto-regulatory effect called the Jod-Basedow phenomenon. This usually occurs in response to exogenous iodine, and they develop hyperthyroidism instead. This Jod-Basedow phenomenon is considered one of the contributing factors for AIT. [3] [5] [6]

Amiodarone additionally alters the thyroid pathway through acting as a thyroid hormone analog and subsequently affecting the other enzymes involved in thyroid hormone production. [3] It also causes direct cytotoxicity and damages thyroid tissues. [6] [7] [8]

AIT often has a delayed clinical presentation, and studies have shown that the average delayed presentation is 2 years. [9] The pharmacology of the drug results in a prolonged half-life within the body as a result of its lipid solubility and distribution into tissues. This leads to a slow clearance of amiodarone from the body and a prolonged toxicity. [3] [8] Other factors affecting AIT include pre-existing heart conditions such as dilated cardiomyopathy and cardiac sarcoidosis, and both have been suggested to be predictive factors for developing AIT. [9]

Subtypes

AIT type 1 results from the Jod-Basedow phenomenon, in which the iodine contained in amiodarone is used by the thyroid gland for excess production of thyroid hormones. It primarily occurs in patients with pre-existing thyroid disease such as nodular goiter or latent autoimmune Graves' disease. [4] These pre-existing thyroid diseases involve thyroid tissue which have lost their auto-regulation and function independently in the presence of excess iodine from amiodarone. [8] AIT type 1 commonly occurs in iodine-deficient regions, and usually appears within weeks-months after patients start amiodarone.

AIT type 2 is a form of an immune system response to the cytotoxic properties of amiodarone and results in a destructive thyroiditis (inflammation in the thyroid). [7] [9] This causes pre-existing thyroid hormones to spill out from damaged cells into the circulation and a resultant immunologic reaction. AIT type 2 usually occurs in patients with a normal thyroid gland and could appear even several years after starting amiodarone.

Mixed/indefinite AIT (or AIT type 3) is used when subtype classification is unclear or when both AIT types occur at once.

Diagnosis

The effects of AIT as mentioned above can be especially dangerous for those with heart disease. Some cases can spontaneously improve, but AIT should generally be diagnosed and treated until normal levels of hormone have been reached, otherwise known as the euthyroid state.

Differentiating AIT sub-types can be difficult and multiple diagnostics are usually used including: thyroid hormone levels, radionucleotide scans such as radioactive iodine or sestamibi, [10] thyroid ultrasonography with color-flow-doppler and levels of circulating interleukin-6 or beta-glucoronidase, though none are considered the single gold-standard. [6] Imaging studies can demonstrate the presence of pre-existing thyroid disease and examine the activity levels of the thyroid gland. [4] [7]

Treatment

Due to the underlying differences in pathophysiology, there will be different treatment options according to the subtype of AIT.

AIT type 1 is initially treated with thionamides and sodium perchlorate to reduce production of thyroid hormones. Definitive treatment with radioiodine or thyroidectomy can be initiated after thyroid hormones levels are stabilized and returned to a euthyroid state. [6] [9]

AIT type 2 is treated with a different regime due to its immunologic pathophysiology. The thyrotoxic phase in AIT type 2 is usually self-limited but treatment with glucocorticoids can reduce its length through their anti-inflammatory and immunosuppressive effect. [1] [3]

AIT type 3 treatment usually combines both modalities with subsequent revaluation based on the response to treatment. [1] [7]

Persistent AIT that does not respond to treatment regardless of the subtype will likely have to consider alternatives such as plasmapheresis or surgery. [7] [8]

Monitoring is highly recommended for patients taking amiodarone, and thyroid function should be regularly evaluated during treatment and for at least one year following drug cessation. [2]

Related Research Articles

<span class="mw-page-title-main">Goitre</span> Medical condition

A goitre, or goiter, is a swelling in the neck resulting from an enlarged thyroid gland. A goitre can be associated with a thyroid that is not functioning properly.

<span class="mw-page-title-main">Hyperthyroidism</span> Thyroid gland disease that involves an overproduction of thyroid hormone

Hyperthyroidism is the condition that occurs due to excessive production of thyroid hormones by the thyroid gland. Thyrotoxicosis is the condition that occurs due to excessive thyroid hormone of any cause and therefore includes hyperthyroidism. Some, however, use the terms interchangeably. Signs and symptoms vary between people and may include irritability, muscle weakness, sleeping problems, a fast heartbeat, heat intolerance, diarrhea, enlargement of the thyroid, hand tremor, and weight loss. Symptoms are typically less severe in the elderly and during pregnancy. An uncommon but life-threatening complication is thyroid storm in which an event such as an infection results in worsening symptoms such as confusion and a high temperature; this often results in death. The opposite is hypothyroidism, when the thyroid gland does not make enough thyroid hormone.

<span class="mw-page-title-main">Graves' disease</span> Autoimmune endocrine disease

Graves' disease, also known as toxic diffuse goiter, is an autoimmune disease that affects the thyroid. It frequently results in and is the most common cause of hyperthyroidism. It also often results in an enlarged thyroid. Signs and symptoms of hyperthyroidism may include irritability, muscle weakness, sleeping problems, a fast heartbeat, poor tolerance of heat, diarrhea and unintentional weight loss. Other symptoms may include thickening of the skin on the shins, known as pretibial myxedema, and eye bulging, a condition caused by Graves' ophthalmopathy. About 25 to 30% of people with the condition develop eye problems.

<span class="mw-page-title-main">Hypothyroidism</span> Endocrine disease

Hypothyroidism is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormones. It can cause a number of symptoms, such as poor ability to tolerate cold, a feeling of tiredness, constipation, slow heart rate, depression, and weight gain. Occasionally there may be swelling of the front part of the neck due to goitre. Untreated cases of hypothyroidism during pregnancy can lead to delays in growth and intellectual development in the baby or congenital iodine deficiency syndrome.

Thyroid-stimulating hormone (also known as thyrotropin, thyrotropic hormone, or abbreviated TSH) is a pituitary hormone that stimulates the thyroid gland to produce thyroxine (T4), and then triiodothyronine (T3) which stimulates the metabolism of almost every tissue in the body. It is a glycoprotein hormone produced by thyrotrope cells in the anterior pituitary gland, which regulates the endocrine function of the thyroid.

<span class="mw-page-title-main">Amiodarone</span> Antiarrhythmic medication used for various types of irregular heartbeats

Amiodarone is an antiarrhythmic medication used to treat and prevent a number of types of cardiac dysrhythmias. This includes ventricular tachycardia (VT), ventricular fibrillation (VF), and wide complex tachycardia, as well as atrial fibrillation and paroxysmal supraventricular tachycardia. Evidence in cardiac arrest, however, is poor. It can be given by mouth, intravenously, or intraosseously. When used by mouth, it can take a few weeks for effects to begin.

<span class="mw-page-title-main">Hashimoto's thyroiditis</span> Autoimmune disease

Hashimoto's thyroiditis, also known as chronic lymphocytic thyroiditis and Hashimoto's disease, is an autoimmune disease in which the thyroid gland is gradually destroyed. A slightly broader term is autoimmune thyroiditis, identical other than that it is also used to describe a similar condition without a goitre.

Radiocontrast agents are substances used to enhance the visibility of internal structures in X-ray-based imaging techniques such as computed tomography, projectional radiography, and fluoroscopy. Radiocontrast agents are typically iodine, or more rarely barium sulfate. The contrast agents absorb external X-rays, resulting in decreased exposure on the X-ray detector. This is different from radiopharmaceuticals used in nuclear medicine which emit radiation.

<span class="mw-page-title-main">Potassium perchlorate</span> Chemical compound

Potassium perchlorate is the inorganic salt with the chemical formula KClO4. Like other perchlorates, this salt is a strong oxidizer although it usually reacts very slowly with organic substances. This, usually obtained as a colorless, crystalline solid, is a common oxidizer used in fireworks, ammunition percussion caps, explosive primers, and is used variously in propellants, flash compositions, stars, and sparklers. It has been used as a solid rocket propellant, although in that application it has mostly been replaced by the higher performance ammonium perchlorate.

<span class="mw-page-title-main">Wolff–Chaikoff effect</span> Effect of iodine on the thyroid

The Wolff–Chaikoff effect is a presumed reduction in thyroid hormone levels caused by ingestion of a large amount of iodine.

The Jod-Basedow effect is hyperthyroidism following administration of iodine or iodide, either as a dietary supplement, iodinated contrast medical imaging, or as a medication.

<span class="mw-page-title-main">Thyroid disease</span> Medical condition

Thyroid disease is a medical condition that affects the function of the thyroid gland. The thyroid gland is located at the front of the neck and produces thyroid hormones that travel through the blood to help regulate many other organs, meaning that it is an endocrine organ. These hormones normally act in the body to regulate energy use, infant development, and childhood development.

<span class="mw-page-title-main">Thyroiditis</span> Medical condition

Thyroiditis is the inflammation of the thyroid gland. The thyroid gland is located on the front of the neck below the laryngeal prominence, and makes hormones that control metabolism.

Thyroid storm is a rare but severe and life-threatening complication of hyperthyroidism. It occurs when overactive thyroid activity leads to hypermetabolism, the end result being death from cardiac arrest or multiple organ failure.

<span class="mw-page-title-main">Subacute thyroiditis</span> Medical condition

Subacute thyroiditis refers to a temporal classification of the different forms of thyroiditis based on onset of symptoms. The temporal classification of thyroiditis includes presentation of symptoms in an acute, subacute, or chronic manner. There are also other classification systems for thyroiditis based on factors such as clinical symptoms and underlying etiology.

Thyrotoxic myopathy (TM) is a neuromuscular disorder that develops due to the overproduction of the thyroid hormone thyroxine. Also known as hyperthyroid myopathy, TM is one of many myopathies that lead to muscle weakness and muscle tissue breakdown. Evidence indicates the onset may be caused by hyperthyroidism. Physical symptoms of TM may include muscle weakness, the breakdown of muscle tissue, fatigue, and heat intolerance. Physical acts such as lifting objects and climbing stairs may become increasingly difficult. If untreated, TM can be an extremely debilitating disorder that can, in extreme rare cases, lead to death. If diagnosed and treated properly the effects can be controlled and in most cases reversed leaving no lasting effects.

<span class="mw-page-title-main">Thyrotoxic periodic paralysis</span> Human disease

Thyrotoxic periodic paralysis (TPP) is a rare condition featuring attacks of muscle weakness in the presence of hyperthyroidism. Hypokalemia is usually present during attacks. The condition may be life-threatening if weakness of the breathing muscles leads to respiratory failure, or if the low potassium levels lead to abnormal heart rhythms. If untreated, it is typically recurrent in nature.

Thyroid disease in pregnancy can affect the health of the mother as well as the child before and after delivery. Thyroid disorders are prevalent in women of child-bearing age and for this reason commonly present as a pre-existing disease in pregnancy, or after childbirth. Uncorrected thyroid dysfunction in pregnancy has adverse effects on fetal and maternal well-being. The deleterious effects of thyroid dysfunction can also extend beyond pregnancy and delivery to affect neurointellectual development in the early life of the child. Due to an increase in thyroxine binding globulin, an increase in placental type 3 deioidinase and the placental transfer of maternal thyroxine to the fetus, the demand for thyroid hormones is increased during pregnancy. The necessary increase in thyroid hormone production is facilitated by high human chorionic gonadotropin (hCG) concentrations, which bind the TSH receptor and stimulate the maternal thyroid to increase maternal thyroid hormone concentrations by roughly 50%. If the necessary increase in thyroid function cannot be met, this may cause a previously unnoticed (mild) thyroid disorder to worsen and become evident as gestational thyroid disease. Currently, there is not enough evidence to suggest that screening for thyroid dysfunction is beneficial, especially since treatment thyroid hormone supplementation may come with a risk of overtreatment. After women give birth, about 5% develop postpartum thyroiditis which can occur up to nine months afterwards. This is characterized by a short period of hyperthyroidism followed by a period of hypothyroidism; 20–40% remain permanently hypothyroid.

The signs and symptoms of Graves' disease generally result from the direct and indirect effects of hyperthyroidism; sometimes they are caused by thyroidal conditions, such as Graves' ophthalmopathy, goitre and pretibial myxedema. These clinical manifestations can involve virtually every system in the body. The mechanisms that mediate these effects are not well understood. The severity of the signs and symptoms of hyperthyroidism is related to the duration of the disease, the magnitude of the thyroid hormone excess, and the patient's age. Although the vast majority of patients enjoy significant improvement and remission after proper medical care, health care providers should be aware of variability in the individual response to hyperthyroidism and individual sensitivity to thyroid hormone fluctuations generally. Graves' disease patients can also undergo periods of hypothyroidism, due to the challenges of finding the right dosage of thyroid hormone suppression and/or supplementation. The body's need for thyroid hormone can also change over time, such as in the first months after radioactive iodine treatment (RAI). Thyroid autoimmune diseases can also be volatile: hyperthyroidism can interchange with hypothyroidism and euthyroidism.

<span class="mw-page-title-main">Plummer effect</span>

The Plummer effect is one of several physiological feedforward mechanisms taking place in follicular cells of the healthy thyroid gland and preventing the development of thyrotoxicosis in situations of extremely high supply with iodine.

References

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