Drugs and environmental toxins take on the thyroid

Thyroid hormone metabolism

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The interactions between the thyroid and drugs and environmental toxins are many and varied. Herein, some of the drugs and environmental factors that can affect thyroid function and findings on thyroid function tests are highlighted.

Amiodarone

Approximately 30% of amiodarone is iodine. Approximately half of the 65 mg of iodine in a 200-mg amiodarone tablet is absorbed and delivered to the systemic circulation, whereas the daily recommended iodine intake is 0.15 to 0.30 mg.

Amiodarone is lipophilic and gradually deiodinated. Its elimination half-life is 40 to 100 days. Marius N. Stan, M.D., of the Division of Endocrinology, Diabetes, Metabolism, and Nutrition at Mayo Clinic in Rochester, Minnesota, says: "A major action of amiodarone regarding thyroid hormone metabolism is to inhibit the conversion of thyroxine (T4) to triiodothyronine (T3) in the peripheral tissues. It further blocks T4 entry into cells and intranuclear T3 receptor binding. Although most patients are able to compensate for these effects, hypothyroidism develops in about 10% of patients. At the other extreme, about 2% of amiodarone-treated patients have hyperthyroidism."

Amiodarone-induced thyrotoxicosis (AIT) has 2 types:

• Type I AIT usually occurs in patients with preexistent goiter, where amiodarone drives increased thyroid hormone production and is associated with increased or normal vascularity.
• Type II AIT usually occurs in patients with normal pretreatment thyroid examinations who have a destructive process with inflammation and decreased vascularity.

Dr. Stan continues: "Many patients with AIT have mixed features of both types. AIT has important clinical implications because these patients usually have underlying cardiomyopathy, and thyrotoxicosis increases the risk of arrhythmias and hemodynamic instability. In addition, the thyrotoxicosis is resistant to the usual therapies for hyperthyroidism.

"Typically, type I AIT is treated with methimazole and, in some cases, potassium perchlorate. In contrast, type II AIT is typically treated with corticosteroids. Combined treatment options should be considered when the first option is ineffective. Patients with hyperthyroidism that is unresponsive to combination pharmacotherapy should be referred early for thyroidectomy."

Tyrosine kinase inhibitors

Sunitinib and sorafenib can cause transient thyrotropin (TSH) suppression, which is followed by hypothyroidism in patients with an intact thyroid gland.

Hypothyroidism develops in approximately 40% of patients treated with sunitinib and 18% of those treated with sorafenib. At least 3 hypotheses have been suggested to explain sunitinib-induced hypothyroidism:

• Destructive thyroiditis
• Inhibition of thyroid peroxidase activity
• Decreased thyroid vascularity due to vasoconstriction and vascular endothelial growth factor downregulation

Dr. Stan explains: "Thyroid function tests should be monitored on days 1 and 28 of the treatment cycles. If the thyroid function tests continue to show reference levels after 3 cycles, then the frequency of monitoring should be decreased to every 3 cycles. If overt hypothyroidism develops or if the serum TSH concentration is increased at the beginning of the cycle, T4 replacement therapy should be initiated."

Interferon-a

Interferon-a can cause autoimmunity induction resulting in either hypothyroidism (usually subclinical) or Graves' disease. It can also cause a destructive thyroiditis. Dr. Stan highlights: "Risks of thyroid dysfunction in patients treated with interferon-a include positivity for thyroid peroxidase antibodies, female sex, and extended duration of therapy."

Lithium

Lithium is used to treat manic-depressive disorder. When given in high doses it is a goitrogen by blocking thyroid hormone secretion. Dr. Stan notes: "Approximately 50% of patients treated with lithium have a goiter. Lithium treatment can also trigger painless thyroiditis or Graves' disease and thus cause hyperthyroidism."

Drugs that affect thyroid

Hormone replacement therapy
Treatment with estrogen and selective estrogen receptor modulators can increase thyroxine-binding globulin. Antacids and calcium and mineral supplements can decrease the absorption of ingested T4. Treatment with phenobarbital or phenytoin can increase the clearance of administered T4. Therefore all of these drugs, along with the tyrosine kinase inhibitors motesanib and imatinib, usually result in a need to increase the T4 dosage in patients taking thyroid hormone replacement.

Environmental toxins

Dr. Stan highlights: "Many environmental factors have the potential to impact thyroid function." Some of these factors include:

• Potassium perchlorate, which inhibits iodine uptake by the thyroid, is used in rocket propellant, fireworks, and automobile airbags. Potassium perchlorate is stable in the environment and contaminates water throughout the United States. Newborns and infants are most susceptible to this inhibitory effect on iodine transport. The thiocyanates in cigarette smoke can have effects similar to potassium perchlorate.
• Isoflavones (phytoestrogens), found in soy proteins, are thyroid peroxidase inhibitors.
• Pesticides induce glucuronidation of T4 and reduce T4 half-life.
• Polychlorinated biphenyls are industrial chemicals that were banned in 1975 but still are routinely detected in the environment. They have been shown to reduce T4 levels in animals and are neurotoxic. Their effect varies because of partial agonist effect at the thyroid hormone receptor and their varied chemical structure.
• Bisphenol A—used in plastics, as resins for coating food cans, and as dental sealants—antagonizes T3 activation of the thyroid hormone b-receptor in rats, causing a thyroid hormone resistance–like syndrome.