Etiology
Globally, iodine deficiency is the most common cause of primary hypothyroidism.[8] Autoimmune thyroiditis (Hashimoto disease) is the most common cause of primary hypothyroidism in iodine-sufficient areas.[1] It affects women 8 to 9 times as often as men and has a peak incidence between the ages of 30 to 50 years.[14]
Less commonly, primary hypothyroidism can be caused by damage or destruction of the thyroid gland from other conditions such as thyroidectomy, radioactive iodine therapy for Graves disease or nodular goiter, or radiation therapy for head and neck cancer.[1][15] Infiltrative diseases such as sarcoidosis and hemochromatosis can rarely cause primary hypothyroidism.[1] Subacute granulomatous (De Quervain's) thyroiditis usually causes transient primary hypothyroidism.
Drugs that can cause hypothyroidism include lithium, amiodarone, aminoglutethimide, interferon alpha, thalidomide, stavudine, tyrosine kinase inhibitors, alemtuzumab, and immune checkpoint inhibitors (e.g., nivolumab, pembrolizumab, ipilimumab).[1][5][16][17]
Eight percent of postpartum women develop lymphocytic thyroiditis, which causes transient primary hypothyroidism.[18]
Pathophysiology
Thyroxine (T4) is the main hormone produced by the thyroid gland. It is converted to triiodothyronine (T3) in target tissues. T3 mediates the main actions of thyroid hormone, which include stimulation of cellular oxygen consumption and energy generation, by binding to nuclear receptors and modulating gene expression.[1] Through a negative feedback mechanism, failure of the thyroid to produce its hormones stimulates the pituitary to increase production of thyroid-stimulating hormone.
Iodine is an essential component of thyroid hormone.[1] Severe iodine deficiency causes hypothyroidism, despite an increase in thyroid activity and size (goiter), as iodine concentrations are not high enough to maintain thyroid hormone production.[19][20]
In autoimmune thyroiditis (the most common form of primary hypothyroidism in iodine-sufficient regions), the thyroid is diffusely infiltrated with lymphocytes.[1] A majority of patients have antithyroid peroxidase or antithyroglobulin antibodies.[1] The prevalence is higher in populations with high dietary iodine, which is thought to make the thyroid more antigenic.[21][22] Affected individuals have an increased risk for other autoimmune disorders such as vitiligo and Sjogren syndrome.[15]
Autoimmune thyroiditis may be part of a polyglandular autoimmune syndrome, which can include adrenal failure, hypoparathyroidism, type 1 diabetes mellitus, hypogonadism, and hypopituitarism.[15][23]
Drugs can cause hypothyroidism through a variety of mechanisms. Amiodarone contains a high iodine load, which can interfere with thyroid hormone synthesis.[1][24] Lithium interferes with thyroid hormone synthesis and release.[1] The hypothyroidism is usually reversible upon discontinuation of the offending drugs.[16]
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