Hypothyroidism: Overview and Treatment Options Authors: Laura P. Stegall, Pharm.D. , Harrison School of Pharmacy, Auburn University; Mary Cathryn Holladay, Pharm.D., Harrison School of Pharmacy, Auburn University; Amr M. Abdelrehiem, Pharm.D., Harrison School of Pharmacy, Auburn University; Bernie R. Olin, Pharm.D., Associate Clinical Professor and Director Drug Information Center, Harrison School of Pharmacy, Auburn University Universal Activity #: 0178-0000-14-105-H01-P | 1.25 contact hours (.125 CEUs) Initial Release Date: November 25, 2014 | Expires May. 1, 2016 Alabama Pharmacy Association | 334.271.4222 | www.aparx.org | [email protected] WINTER 2014: CONTINUING EDUCATION | WWW.APARX.ORG 1 Educational OBJECTIVES After the completion of this activity pharmacists will be able to: • List risk factors for the development of hypothyroidism. • Describe the pathophysiology of hypothyroidism. • Discuss treatment options for hypothyroidism. Introduction hypothyroidism; however, in a clinical trial, age of the pregnant Hypothyroidism is defined as an endocrinologic disorder woman did not increase risk.5 resulting from decreased thyroid hormone production and affects A patient is considered at high risk for the development of an estimated 1.5% to 2% of women and 0.2% of men worldwide.1 hypothyroidism if he/she is a postpartum woman; has a family It is categorized into either overt hypothyroidism or subclinical history of autoimmune disorders; has an autoimmune endocrine hypothyroidism based on the level of dysfunction. In the Third condition such as diabetes mellitus type I, adrenal insufficiency, National Health and Nutrition Examination Survey, 16,533 people Addison’s disease, or ovarian failure; has had previous head, neck, representing the geographic and ethnic distribution of the United or thyroid irradiation or surgery; has a non-endocrine autoimmune States population with no prior history of thyroid disorder had disorder such as celiac disease, rheumatoid arthritis, pernicious their levels of serum thyroid-stimulating hormone (TSH) and anemia, Sjögren’s syndrome, or multiple sclerosis; has primary 1,4 total thyroxine (T4) measured. As a result of this survey, 0.3% pulmonary hypertension; or has Down or Turner syndrome. of the study population was found to have overt hypothyroidism Although diabetes mellitus type II is not currently a risk factor for and 4.3% of the study population was found to have subclinical hypothyroidism, some studies have concluded that in some ethnic hypothyroidism.2 Hypothyroidism incidence increases with age groups, such as Saudi Arabians, type II diabetes does increase the risk and is three to four times more prevalent in females than males; for hypothyroidism.6 Caucasian and Mexican-Americans are also more likely to have Certain genetic factors, specifically polymorphisms with the hypothyroidism than African-Americans.1,2 HLA-DR gene can increase the risk for Hashimoto’s thyroiditis.7 Hypothyroidism is classified into either primary or secondary Other risk factors for overt hypothyroidism include iodine deficiency hypothyroidism. Causes of primary hypothyroidism include often associated with endemic goiter and cretinism, the presence of Hashimoto’s thyroiditis, iatrogenic hypothyroidism, iodine subclinical hypothyroidism, and the presence of infiltrative disorders deficiency, enzyme defects, thyroid hypoplasia, and goitrogens, such as hemochromatosis, sarcoidosis, amyloidosis, scleroderma, while causes of secondary hypothyroidism include pituitary and cystinosis, and Riedel’s thyroiditis. hypothalamic disease.1 Hypothyroidism can also be congenital, with the incidence of congenital hypothyroidism increasing by PathophYsioloGY 3% per year in the United States.3 The most common cause of In order to understand the pathophysiology of hypothyroidism, hypothyroidism worldwide is iodine deficiency; however in iodine one must first understand normal thyroid hormone physiology, sufficient countries, such as the United States, the most common including normal thyroid hormone synthesis. cause of hypothyroidism is Hashimoto’s thyroiditis, a chronic Thyroglobulin, a large glycoprotein synthesized within the autoimmune disease, accounting for 60% of all hypothyroidism thyroid cells, provides tyrosine for iodination to form active thyroid cases.1,2,4 Untreated hypothyroidism can lead to detrimental hormones. This process begins when ingested iodine converts to consequences, but often can go untreated for many years due to non- iodide and is actively transported into a thyroid follicular cell via a specific symptoms.1 sodium/iodide symporter. Iodination of tyrosine on thyroglobulin by thyroid peroxidase creates monoiodotyrosine (MIT) and RISK Factors diiodotyrosine (DIT). Sequentially, thyroid peroxidase combines Women are more likely to be diagnosed with hypothyroidism either two molecules of DIT to form thyroxine (T4) or one molecule than men; specifically autoimmune thyroid diseases are of MIT with one molecule of DIT to form triiodothyronine (T3). approximately five to ten times more common in females than In the case of iodine deficiency, an increased ratio of MIT to DIT 4 males. Although being a woman is a risk factor for hypothyroidism, occurs to increase production of T3 since it is four times more risk increases in both men and women with advancing age. potent than T4. However, T4 is solely formed within the thyroid Being a pregnant woman is also a risk factor for development of gland whereas only 20% of T3 is formed there. The majority of T3 Table 1. T3 Production 5’-monodeiodinase Tissue location Preferred substrate Role Type I Thyroid, liver, kidney rT3>T4>T3 Extracellular T3 production for peripheral tissues Type II Pituitary, thyroid, central nervous T4>T3 Intracellular T3 production system (CNS), brown adipose tissue Type III Placenta, developing brain, skin T3>T4 Inactivation of both thyroid hormones Adapted from DiPiro JT, et al, eds. Pharmacotherapy: A Pathophysiologic Approach, 20111 2 ALABAMA PHARMACY ASSOCIATION | WINTER 2014: CONTINUING EDUCATION is created by breakdown of T4 in peripheral tissue. Breakdown of the thyroid gland; thyroid hypoplasia; uncommon infection from T4 is catalyzed by three types of 5’-monodeiodinases listed in Table Pneumocystitis jiroveci; and maternal ingestion of goitrogens, such 1,9,10 1 and can breakdown T4 to T3 or to reverse T3 (rT3) which has no as rutabagas, turnips, and cabbage, during fetal development. significant biologic activity.1,8 Goitrogens interfere with iodine uptake and may therefore suppress Once in the bloodstream, over 99% of thyroid hormones are the function of the thyroid gland.1 Secondary hypothyroidism can transported by thyroxine-binding globulin (TBG), transthyretin be due to pituitary or hypothalamic inflammatory or infiltrative (TTR), and albumin. Thyroid hormones are highly protein bound diseases, tumors, surgical or radiation therapy, postpartum to assure minimal urinary loss of iodide, provide uniform tissue hemorrhagic necrosis known as Sheehan’s syndrome, trauma, distribution, and transport hormones into the central nervous histiocytosis, tuberculosis, and autoimmune mechanisms.1,4 Other system (CNS). The unbound T4 (0.03%) and T3 (0.3%) are able than primary and secondary hypothyroidism, there is also transient to diffuse into a cell and elicit a biological effect as well as elicit a hypothyroidism. Transient hypothyroidism can occur in severely response from the pituitary gland to release thyroid-stimulating ill patients or after excess exposure to iodine, referred to as the hormone (TSH, also known as thyrotropin).1,8,9 The hypothalamus Wolff-Chaikoff effect. Adaptation to the Wolff-Chaikoff effect releases TSH releasing hormone (TRH) stimulating release of typically occurs two days after iodine exposure.10 Although rare, TSH from the anterior pituitary gland when free thyroid hormone consumptive hypothyroidism is due to excessive type III deiodinase 8,9 10 levels are low. Therefore, the production of thyroid hormones are resulting in rT3 and T3. Drugs can also cause hypothyroidism in based on a negative feedback mechanism as well as extrathyroidal persons with pre-existing thyroid abnormalities (see Table 3).1,4,9,10 deiodination of T4 and T3 dependent on nutrition, other hormones, drugs, and illness.1 When there is a dysfunction in thyroid DIAGNOSIS production, hypothyroidism can occur. Normal levels for TSH, free Hypothyroidism has a wide range of signs and symptoms but T , total T , and total T are listed in Table 2. 4 4 3 it is straightforward to diagnose with the proper thyroid function Hypothyroidism is more commonly due to thyroid gland tests. While signs and symptoms are no longer used exclusively failure (primary hypothyroidism) versus pituitary or hypothalamus for diagnosis, it is important to recognize these symptoms in failure (secondary hypothyroidism). Primary hypothyroidism is most commonly caused by iodine deficiency on a worldwide basis. However in areas where iodine sufficiency exists, Table 2. Normal Thyroid Hormone Levels chronic autoimmune thyroiditis is the most common cause of TSH 0.5-4.7 mIU/L hypothyroidism.4 Chronic autoimmune thyroiditis, also known as Hashimoto’s disease, results from dysfunctional T-lymphocytes Free T4 0.8-2.7 ng/dL and excessive production of thyroid antibodies by differentiated Total T 4.5-10.9 mcg/dL B-lymphocytes that destroy thyroid cells and produce an underlying 4 defect of organobinding iodide to tyrosine. This results in Total T3 60-181 ng/dL 4 insufficient amount of