Hyperthyroidism: Exploring Treatment Strategies

Release Date: June 1, 2010

Expiration Date: June 30, 2012

FACULTY:

Arpit Mehta, PharmD Candidate
Jestine Voigt, PharmD Candidate
Deepak Pahuja, MD, FACP

Sachin S. Devi, PhD

Director, Laboratory of Experimental and Clinical Toxicology;
Assistant Professor, Department of Pharmaceutical Sciences, School of Pharmacy
Lake Erie College of Osteopathic Medicine
Erie, Pennsylvania

FACULTY DISCLOSURE STATEMENTS:

The authors have no actual or potential conflicts of interest in relation to this activity.

U.S. Pharmacist does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

ACCREDITATION STATEMENT:

Pharmacy
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UAN: 0430-0000-10-019-H01-P; 0430-0000-10-019-H01-T
Credits: 2.0 hours (0.20 ceu)
Type of Activity: Knowledge

TARGET AUDIENCE:

This accredited activity is targeted to pharmacists and pharmacy technicians. Estimated time to complete this activity is 120 minutes.

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DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

GOAL:

To discuss the etiology, diagnosis, and treatment of hyperthyroidism.

OBJECTIVES:

After completing this activity, the participant should be able to:

  1. Explain the biosynthesis, transport, and control of thyroid hormones.*
  2. Discuss the etiology and diagnosis of hyperthyroidism.*
  3. Review treatment options for hyperthyroidism.*
  4. Develop an individualized pharmacotherapy and monitoring plan for the management of hyperthyroidism.

*Also applies to pharmacy technicians.


The thyroid gland is one of the largest glands of the endocrine system. It is a butterfly-shaped gland located in the anterior portion of the lower neck, just below the voice box (larynx). The cells of the thyroid gland are the only cells in the body that are capable of iodine absorption. The thyroid gland secretes two hormones essential for energy metabolism and normal growth and development. These hormones are 3,5,3'-triiodothyronine (T3) and thyroxine (T4). In addition to being the body’s main metabolic regulator, both hormones play a vital role in the normal neuronal growth and development of the central nervous system (CNS) of humans and animals.

Biogenesis, Transport, and Control of Thyroid Hormones

The epithelial cells of the thyroid gland (thyrocytes) produce thyroglobulin, a tyrosine-containing molecule used in the production of T3 and T4. There are about 300 carbohydrate and 5,500 amino acid residues that comprise the 660 kDa of thyroglobulin.1

Iodine plays an essential role in thyroid hormone production. The normal blood level of iodine is very low (~15-30 nm or 0.2-0.4 µg/dL).2 The thyroid-stimulating hormone (TSH) or thyrotropin in the anterior pituitary gland stimulates the sodium-iodide symporter (NIS), a specific membrane-bound protein, to transport iodine from the blood circulation to the thyroid follicles (FIGURE 1). While in the thyroid follicle, iodine is oxidized to iodide by thyroid peroxidase, a heme-containing enzyme that utilizes hydrogen peroxide (H2O2). The oxidation process results in the formation of monoiodotyrosyl and diiodotyrosyl residues in thyroglobulin molecules. Coupling of one monoiodotyrosyl and one diiodotyrosyl residue in thyroglobulin molecule results in formation of 3,5,3'-triiodothyronine, hence the abbreviation T3 (total three residues). On the other hand, coupling of two diiodotyrosyl residues in the thyroglobulin molecule results in the formation of thyroxin, hence the abbreviation T4 (total four residues).

fig1

Thyroxine is primarily synthesized near the N-terminus (amino-terminus) of the thyroglobulin protein chain while the formation of triiodothyronine takes places near the C-terminus (carboxy-terminus). Since thyroid hormones are stored within thyroglobulin, directed degradation of thyroglobulin (proteolysis) by protease plays a vital role in the T3 and T4 secretory process. It is important to note that TSH enhances proteolysis of thyroglobulin by increasing the activity of endopeptidases, the proteolytic enzymes present in the lysosomes of the thyroid epithelial cells. This results in the cleaving of the thyroglobulin. The cleaved protein yields hormonecontaining intermediates (T4 and T3), which are eventually processed by exopeptidases that catalyze the removal of amino acids. Thyroid hormones then exit the basal membrane of the cell and are distributed in the body via the systemic circulation.

Hyperthyroidism

Hyperthyroidism is a clinical condition characterized by the overproduction of the thyroid hormones (T3 and T4) by the thyroid gland. People who have hyperthyroidism are said to have an “overactive thyroid.” The National Health and Nutrition Examination Survey III (NHANES III) assessed thyroid hormone levels in a randomly selected group of people in the United States.3 It reported that hyperthyroidism was prevalent in 1.2% of the selected group. Interestingly, 0.7% of hyperthyroid subjects were found to have subclinical hyperthyroidism or no clinical manifestation of the disease.3

The signs and symptoms of hyperthyroidism are dependent on age, duration of illness, extent of the overproduction of thyroid hormones, and existence of a disease condition not related to hyperthyroidism.4 TABLE 1 lists clinical manifestations of hyperthyroidism.4,5

tbl1

Etiology of Hyperthyroidism

Different causes of hyperthyroidism are described in TABLE 2, and are also discussed in this section.

tbl2

Graves’ Disease: Graves’ disease is the most common cause of hyperthyroidism. It accounts for 60% to 80% of the total reported cases of hyperthyroidism in the U.S.6 Women have a higher reported incidence of Graves’ disease than men, with a female to male incidence ratio of approximately 7:1 to 10:1.7 Graves’ disease is an autoimmune disorder where antibodies mistakenly attack the thyroid gland, particularly the TSH receptor sites. The attack stimulates the gland to synthesize and overproduce thyroid hormone.

Toxic Multinodular Goiter and Toxic Adenomas: Toxic multinodular goiter (TMNG), also known as toxic nodular struma, Parry’s disease, or Plummer’s disease, is a condition in which the thyroid gland contains multiple nodules or lumps that are hyperfunctional, causing an overproduction of thyroid hormones. TMNG usually occurs in patients who are more than 40 years old and accounts for 5% of the total cases of hyperthyroidism in the U.S. The incidence of TMNG is increased in iodine-deficient regions.8

Toxic adenomas are independently functioning thyroid nodules that produce excessive amounts of thyroid hormones. Toxic adenomas are most commonly found in younger patients who live in iodine-deficient regions.9

Thyroiditis: Thyroiditis is a condition where the thyroid gland becomes inflamed. Inflammation of thyroid causes excess thyroid hormone stored in the gland to leak into the systemic circulation. Subacute thyroiditis is the inflammation of the thyroid gland following a viral infection of the upper respiratory tract. It is a self-limiting inflammation of the thyroid characterized by an abrupt inception of thyrotoxic signs and symptoms that are usually resolved within 8 months. Despite being a rare condition, subacute thyroiditis can also be recurrent.9 Lymphocytic thyroiditis is the inflammation of the thyroid gland caused by the infiltration of lymphocytes. On the other hand, postpartum thyroiditis, also known as subacute lymphocytic thyroiditis, is the inflammation of the thyroid gland that occurs in the first 3 to 6 months after delivery in 5% to 10% of women.10

Tumors: Tumors are one of the rare causes of hyperthyroidism. Some of the tumors that can lead to a thyrotoxic state are struma ovarii (goiter of the ovary where predominantly or entirely existing thyroid cells in the ovary produce thyroid hormones), human chorionic gonadotropin (hCG)-producing and TSH receptor-activating trophoblastic tumors, and TSH-secreting adenomas.11

Treatment-Induced Hyperthyroidism: Iodine is vital to human life, as it is needed in the synthesis of thyroid hormones that regulate the physiologic and metabolic processes of the body. However, an excess of iodine in the diet can also have a devastating effect on human health, as it can cause excessive production of thyroid hormones leading to hyperthyroidism, especially in older patients with pre-existing multinodular goiter. Other iodine-related contributing factors include medications and radiographic contrast media exposure.12

Because of its high iodine content, amiodarone (Cordarone), a drug used for the treatment of arrhythmias, is known to disrupt normal thyroid functions in 14% to 18% of patients receiving the drug.5 Both hyperthyroidism and hypothyroidism (decreased production of thyroid hormones) can develop anytime during amiodarone treatment, irrespective of the normal or abnormal nature of the thyroid. It is therefore recommended that thyroid hormones and TSH levels of all patients subjected to amiodarone therapy should be continuously monitored every 6 months during treatment.5

Amiodarone-induced hyperthyroidism is classified in two different types. Type 1 amiodarone-induced hyperthyroidism is similar to iodine-induced hyperthyroidism and is manifested with a low level of TSH and high levels of T3 and T4. It is caused by uncontrolled excessive production of T3 and T4 by the solitarily functioning thyroid in response to iodine (Jod-Basedow phenomenon). As in Graves’ disease, there is also increased vascularity of the thyroid tissue in type 1 amiodarone-induced hyperthyroidism that is visible through color flow Doppler ultrasonography. Interestingly, the use of antithyroid drugs to treat type 1 amiodarone-induced hyperthyroidism has shown minimal success. Therefore, discontinuing of amiodarone therapy is highly recommended. It may take months before the thyroid returns to its euthyroid state after amiodarone therapy is discontinued.5

Type 2 amiodarone-induced hyperthyroidism is the destructive inflammation of the thyroid (thyroiditis). Laboratory findings (T3, T4, and radioiodine uptake tests) in type 2 amiodarone-induced hyperthyroidism are similar to type 1 amiodarone-induced hyperthyroidism. The only difference is that Doppler ultrasonography in type 2 amiodarone-induced hyperthyroidism shows decreased vascularity of the gland.13 Corticosteroids are the drug of choice for type 2 amiodarone-induced hyperthyroidism. In severe cases, surgical removal of the thyroid is recommended.

Factitious hyperthyroidism is characterized by higher than normal thyroid hormone levels brought about by taking too many thyroid hormone medications for hypothyroidism. Another cause of factitious hyperthyroidism is intentional intake of thyroid hormone preparation for weight loss.4

Diagnosis of Hyperthyroidism:
Diagnostic Tests

Three major tests are conducted to diagnose hyperthyroidism: 1) measurement of serum hormonal levels; 2) assessment of TSH-receptor antibodies; and 3) imaging techniques.

Serum Hormonal Levels: The main tool for the diagnosis of hyperthyroidism is the measurement of the TSH level in the blood. In hyperthyroidism, serum TSH level is inversely proportional to the serum thyroid hormone levels (T3 and T4). Overproduction of T3 and T4 is immediately compensated by diminished levels of TSH to regulate the excess in thyroid hormones, resulting in an abnormally low or undetectable serum TSH level.

Diagnostic findings show that 95% of patients with hyperthyroidism have a combination of suppressed serum TSH levels of <0.05 mIU/L and an elevated serum free T4 level.6 For routine screening of asymptomatic patients, measurement of the TSH level alone is good enough. However, if thyrotoxicosis is suspected, additional tests to measure the free serum T3 and T4 levels are warranted. When subclinical hyperthyroidism is suspected, the initial diagnostic step is to measure the TSH level. If the initial TSH measurement is below normal, the levels of T3 and T4 should subsequently be assessed.14 In patients who have hyperactive thyroid states secondary to recent treatment for hypothyroidism or thyroid hormone replacement therapy, the assessment of the serum thyroxine is a more accurate indicator of the thyroid status than serum TSH level measurement. For suspected noncompliant elderly patients and patients who have chronic or severe thyrotoxicosis and/or hypothyroidism, close monitoring of both TSH and T4 levels for 1 year is recommended until their condition is stabilized.5

Protein can bind with thyroid hormones, which in turn can interfere with and alter the accurate total T3 and T4 measurements. T4-binding globulin is especially elevated in pregnant women, in patients with infective hepatitis, and in those who are taking opiates and estrogens. Drugs like heparin, phenytoin, and diazepam, as well as nonsteroidal anti-inflammatory drugs (NSAIDs), diuretics (furosemide), salicylates, and carbamazepine, can also interfere with protein binding.15 Therefore, measurement of free hormone concentrations is preferred in diagnosing hyperthyroidism over the assessment of total serum thyroid hormonal levels.16

TSH Receptor Antibodies: TSH-receptor antibodies (TRAb) measurements are more useful in the diagnosis of postpartum Graves’ disease and neonatal hyperthyroidism.7 TSHbinding inhibitor immunoglobulin (TBII) assay is used to detect TRAb. TBII is not specific for antibodies that only stimulate the thyroid; rather, it measures all antibodies against the TSH receptors.

Imaging Tests: In addition to clinical evaluation and blood tests, imaging techniques are used to confirm diagnosis of hyperthyroidism.

The thyroid radioactive iodine uptake test with scanning is a key diagnostic tool in the evaluation of hyperthyroidism. It uses a small dose of radioactive isotope of 11.11 MBq of 123Iodine (300 µCi) or 0.19 MBq of 131Iodine (5 µCi) in liquid or capsule form that is taken orally. Over time (6-24 hours after) the ingested radioactive iodine is accumulated in the thyroid gland. The iodine concentration in the thyroid is visible through external scintigraphic imaging of the thyroid gland as the radioactive iodine collected by the thyroid emits gamma radiation. The average 6-hour radioiodine uptake reference range is 5% to 15%, whereas the normal 24-hour uptake ranges from 5% to 25%.17,18

Another useful and efficient radioactive agent used to determine thyroid hyperactivity is Technetium-99m (Tc-99m). Like iodide, Tc-99m is also actively collected by the follicular cells of the thyroid gland. This type of scanning is particularly useful in the differentiation of the numerous etiologic factors that cause hypermetabolic high-uptake states like Graves’ disease and nodular disease or low-uptake states like thyroiditis. Another advantage of Tc-99m is rapid study result. It takes only 20 to 30 minutes to complete the study versus 6 to 24 hours to complete the thyroid radioactive iodine uptake test. Because the thyroid cannot retain Tc-99m for longer periods of time, Tc-99m is not useful in the detection of defects in the synthesis of T3 and T4.19

Differential Diagnosis of Hyperthyroidism

Graves’ ophthalmopathy (thyroid eye disease) can easily be diagnosed because of the evident ocular signs and symptoms. However, old age can make the diagnosis of Graves’ disease more difficult. In general, in the elderly population the signs and symptoms of hyperthyroidism are manifested only with cardiac problems or weight loss. There are cases wherein some patients have elevated levels of free thyroid hormones (T3 and T4) despite a normal-sized thyroid gland. There are also circumstances wherein patients would only develop T3 toxicosis, as manifested by sole elevation of triiodothyronine hormone levels. Sensitive assay testing reveals depressed levels of TSH in Graves’ disease, whereas radioactive scans reveal diffused uptake of radioactive isotopes and, in some cases, a pyramidal lobe.5

Thyroid adenoma (toxic adenoma), also known as hot nodule, is manifested by suppressed levels of TSH, with or without elevated levels of free thyroid hormones. Thyroid scanning reveals a normally functioning thyroid nodule and decreased iodine uptake in the surrounding extranodular and contralateral thyroid tissue. The same is true of toxic multinodular goiter, wherein similar diagnostic findings and characteristics are manifested. However, unlike toxic adenoma, the thyroid gland in toxic multinodular goiter is variably enlarged and the growth is composed of multiple nodules. In spite of the increased ability to uptake iodine, iodine levels in toxic adenoma and toxic multinodular goiter may still remain in the normal range.5

Subacute thyroiditis, silent thyroiditis, iodine-induced thyrotoxicosis, and factitious thyroxine-induced thyrotoxicosis are characterized by a low radioiodine uptake and poor thyroid gland imaging in scintigraphic scan. In addition, as shown in radio-immunoassay tests, these conditions are often accompanied by increased levels of thyroid hormones during the hyperactive thyroid state.5

Classic subacute thyroiditis is a thyroid condition that is manifested by painful inflammation of the thyroid gland accompanied by fever. It has a triphasic clinical pathway consisting of: 1) the hyperthyroid phase, due to the release of accumulated preformed thyroid hormones from the inflamed gland; 2) the hypothyroid phase, secondary to the depletion of thyroid hormones, which lasts for about 2 to 3 months; and 3) the resolution phase, wherein the thyroid returns to its normal function.5 Silent thyroiditis is an autoimmune disorder characterized by painless inflammation of the thyroid gland. It has a clinical course similar to that of classic subacute thyroiditis. Women, especially during the postpartum period, are more commonly affected with this condition than men. Iodine-induced thyrotoxicosis more often affects elderly patients. It can also be seen in patients with pre-existing autonomously functioning thyroid nodules. Factors that can contribute to iodine-induced thyrotoxicosis include oral ingestion of iodine-containing medications and supplements and IV administration of iodine-based contrast media. Factitious thyrotoxicosis has the same clinical presentation as iodine-induced thyrotoxicosis. In contrast to all types of thyroiditis, in this condition the thyroglobulin level is very low and sometimes nonexistent.

Elevated levels of serum T3 and T4 and depressed TSH levels are not always associated with hyperthyroidism. Other etiologic factors can also contribute to altered thyroid hormone and TSH levels. For example, estrogen administration and pregnancy are known to increase thyroxin-binding globulin levels, resulting in high total thyroid hormone levels. However, it should be noted that in this situation, free thyroid hormone levels and TSH levels can be within normal range. Euthyroid hyperthyroxinemia is a condition in which serum total T4 concentration is increased without any clinical evidence of thyroid disease. This can also be attributed to abnormalities in other binding protein, including prealbumin and albumin. Corticosteroid administration, severe illness, and dysfunction of the pituitary gland may cause suppressed TSH levels in the absence of thyrotoxicosis.5

Treatment of Hyperthyroidism

Treatment of hyperthyroidism is based on its specific etiology. Antithyroid drugs that have numerous effects on the synthesis and release of thyroid hormones are used to treat hyperthyroidism caused by thyroid autonomy. Beta-adrenergic receptor blockers are useful and relieve many cardiovascular symptoms associated with hyperthyroidism.1

Antithyroid Medications: Thionamides are the drug of choice to treat an overactive thyroid. They are divided into two classes: 1) imidazoles, comprised of methimazole and carbimazole, and 2) thiouracils, consisting of propylthiouracil (TABLE 3). Thionamides block the synthesis of thyroid hormone by the thyroid gland by inhibiting thyroid peroxidase-mediated oxidation of iodine, coupling of iodine and tyrosine, and iodine organification (FIGURE 1). They also interfere in the last step of thyroid hormone synthesis by inhibiting the coupling of two iodotyrosine residues. Additionally, propylthiouracil acts by blocking the conversion of T4 to T3 in the peripheral tissues. Carbimazole, available only in Europe, is immediately metabolized to methimazole following ingestion.14

tbl3

The use of combination therapy with thionamides and thyroid hormone replacement therapy is currently not recommended for the treatment of hyperthyroidism.7 The choice of antithyroid agent is somewhat selective since methimazole and propylthiouracil exhibit different pharmacologic properties. Methimazole has a serum half-life of 6 to 8 hours, whereas the serum half-life of propylthiouracil is only 1 to 2 hours.7 Therefore, pharmacologic properties of both drugs should be taken into consideration when choosing thionamides as the preferred treatment for hyperthyroidism. Several studies confirm that efficacy of methimazole is higher at a once-daily dose.20-22 In contrast, propylthiouracil has shown to not be effective at a oncedaily dose.23 Additionally, it has been found that patient compliance can be improved significantly with methimazole given once daily. One study conducted on 22 selected hyperthyroid patients reported an 83.3% compliance in patients receiving a daily dose of 30-mg methimazole. On the other hand, patients receiving 100 mg propylthiouracil every 8 hours exhibited only 53.3% compliance.21However, this study has many limitations, including a small number of subjects.

Methimazole is often the drug of choice for the treatment of hyperthyroidism. In the treatment of nonlifethreatening thyrotoxicosis, methimazole is initially started at a single dose of 15 to 30 mg/day, whereas propylthiouracil is started at an initial dose of 100 mg three times a day.7 Thyrotoxic symptoms usually begin to improve within 6 to 12 weeks of treatment. However, antithyroid drugs should be taken at least a year or longer before they are discontinued. While some patients fully recover from hyperthyroidism, there are others who may experience a relapse.

Some of the common side effects of antithyroid drugs, which occur in about 1% to 5% of cases, include allergic reactions like urticaria, pruritus, abnormal sense of taste, and arthralgias.24 Antihistamine therapy may eliminate cutaneous reactions and permit continued treatment with antithyroid drugs. An alternative is to switch to another thionamide if allergic reactions continue. Up to 50% of patients who are taking methimazole or carbimazole and propylthiouracil develop cross-reactivity with the drugs.7 Therefore, in this scenario, it is recommended that thionamide therapy be discontinued and replaced with a more definitive treatment with radioactive iodine. Agents such as lithium, inorganic iodine, and potassium perchlorate are used as an ablative therapy. A potential rare but fatal complication of thionamide therapy that occurs within the first 3 months of therapy is agranulocytosis.25 Hepatotoxicity is another serious yet rare (0.1%-0.2% of treated patients) adverse effect of antithyroid drug therapy.26

Radioactive Iodine: Radioactive iodine ablation therapy is the most common treatment for hyperthyroidism in adults diagnosed with Graves’ disease or toxic multinodular goiter in the U.S. Ablative therapy with lithium, inorganic iodine, and potassium perchlorate eliminates the disturbing side effects associated with thionamide treatment, such as agranulocytosis, hepatotoxicity, and vasculitis. Long-term use of radioactive iodine treatment may lead to permanent hypothyroidism. An attempt to put the thyroid back to its euthyroid state by giving lower doses of radioactive iodine may fail to permanently cure the thyrotoxicosis, thereby requiring repeated treatments.27-29

Since desired outcomes are not seen immediately in radioactive iodine therapy, endocrinologists often require patients to continue antithyroid drug treatment until positive results are established. Often patients start to manifest signs and symptoms of hypothyroidism within 2 to 3 months of ablative radioactive iodine therapy. If complete ablation is not achieved 6 months after the radioactive iodine therapy, repeated treatment is recommended.30

Surgical Intervention: Thyroidectomy is reserved for special circumstances such as intolerance to antithyroid drugs or patient refusal to undergo radioactive iodine therapy. Other candidates for thyroidectomy are pregnant women with hyperactive thyroid who cannot tolerate antithyroid drugs, pediatric patients with severe hyperthyroidism, patients with overly large nodular goiters, and patients who require immediate normalization of their thyroid functions. However, unless a coexisting thyroid cancer is suspected, thyroidectomy is rarely performed to treat Graves’ disease in the U.S. Some of the risks and potential complications involved in thyroidectomy include damage to the parathyroid glands and vocal cords. Additionally, thyroidectomy necessitates lifelong treatment with levothyroxine to supply the body with normal levels of thyroid hormones. If the parathyroid glands are removed during total thyroidectomy, additional medications are necessary to maintain normal calcium level.31

System of Care

The goal of the diagnosis and treatment of Graves’ disease is to include the patient in the decision-making pertaining to care and treatment modalities. Soon after being diagnosed with hyperthyroidism, the patient should be thoroughly informed of the nature of the disease and possible options for treatment. A signed consent should be established if the patient opts to undergo radioactive iodine therapy. After the treatment, the patient should be made aware of the importance of follow-up disease management and be given instructions that delineate appropriate precautions. Radioactive iodine update testing should be performed prior to the radioiodine therapy to establish an accurate and adequate uptake. Additionally, this test helps to determine the dose of radioactive iodine and to rule out iodine contamination and the presence of variant thyroiditis. Toxic nodular goiter and toxic adenomas associated with Graves’ disease are easily distinguished through thyroid scans. A higher dose of radioactive iodine is needed in the treatment of toxic nodular goiter because of the goiter’s high resistance to radioactive iodine.7

Since patients with hyperactive thyroid are relatively resistant to the effects of beta-adrenergic blocking agents, larger and more frequent doses of this medication may be given before radioactive iodine treatment to provide relief from the cardiac symptoms associated with Graves’ disease. Once the patient no longer exhibits signs and symptoms of hyperthyroidism, the dose of this medication can be decreased and discontinued. Adjuvant treatment with organic or inorganic iodide and antithyroid medications is given to patients after radioactive therapy, especially if they have severe thyrotoxicosis.5

Follow-up examination at 4- to 6-week intervals is advised for patients after the completion of radioactive iodine therapy. These checkups should be continued until patients return to their euthyroid state and their condition stabilizes. Since the adverse effect of radioactive iodine therapy is permanent hypothyroidism, patients may require lifelong thyroid hormone replacement therapy. Even though signs and symptoms of hypothyroidism begin to appear 3 months after the initiation of radioactive iodine therapy, thyroid hormone replacements of levothyroxine should be initiated in the second month of radioactive iodine therapy. The decision to initiate hormonal replacement should be based on clinical evaluation and laboratory testing. This is because during the second month of radioactive therapy, the thyroid gland quickly changes from a euthyroid to a hypothyroid state. At this stage, the TSH level is not a good tool to use in determining hypothyroidism, as it takes about 2 weeks to several months to recover and increase TSH concentration in response to hypothyroidism. During this period, free thyroid hormone estimates are more accurate than TSH values. Once the patient’s condition stabilizes, the frequency of clinic visits can be decreased and intervals of examination can be extended and modified per the physician’s judgment. Usually, the follow-up consultations are conducted every 3 months, 6 months, and yearly.31,32

Management of Hyperthyroidism in Pregnancy

Hyperthyroidism during pregnancy can be fatal to both the fetus and the mother. Fatal effects and complications of hyperthyroidism to the fetus include prematurity, stillbirth, intrauterine growth retardation, low birth weight, and neonatal hyperthyroidism. Eclampsia, miscarriage, placenta abruptio, congestive heart failure, and thyroid storm are some of the obstetric complications that a hyperthyroid mother may experience.33 Therefore, hyperactive thyroid in pregnancy is best managed by both an endocrinologist and an obstetrician.

Past or present history of maternal Graves’ disease poses a threat to both mother and fetus. Patients with evident hyperthyroidism related to Graves’ disease or toxic thyroid nodules are treated with antithyroid drugs as initial treatment. For patients with history of maternal Graves’ disease, doses of antithyroid medication should be adjusted according to the severity of their thyroid state. The goal of antithyroid drug therapy is to maintain maternal free-thyroxin serum level in the upper nonpregnant range. The U.S. Preventive Service Task Force (USPSTF) recommendation level is A, evidence is good.34 Maintaining the maternal free-thyroxin serum level at the upper limit of the nonpregnant thyroxin range helps protect the fetus from possible hypothyroidism due to antithyroid medication.35 Since available evidence suggests that methimazole may cause congenital anomalies, propylthiouracil is the drug of choice for hyperthyroidism in pregnancy.36,37 It should be given during the first trimester of pregnancy. In the event that propylthiouracil is not available or if the patient cannot tolerate the effects of this drug, methimazole is given instead (the USPSTF recommendation level is B, evidence is fair). 131 Iodine should not be given to a woman who is or may be pregnant. If the patient has been treated with 131Iodine, then she should be informed about the dangers of radiation therapy to the fetus (USPSTF recommendation level is A, evidence is good).

Passage of TRAb through the placenta can cause fetal hyperthyroidism.38,39 During the end of the second trimester of pregnancy, these antibodies should be measured in pregnant women with Graves’ disease or with a history of the disease, treatment with 131Iodine, thyroidectomy, or a previous hyperthyroid. Fetal ultrasound is recommended for women who are taking antithyroid medications or have elevated TRAb. The ultrasound will determine and show evidence of fetal thyroid dysfunction such as hydrops, growth retardation, presence of goiter, or cardiac failure. Women who are not taking antithyroid medications and are negative for TRAb are at low risk to develop fetal thyroid dysfunction (USPSTF recommendation level is B, evidence is fair). Newborn babies of hyperthyroid mothers should be evaluated for thyroid dysfunction and treated if necessary (USPSTF recommendation level is B, evidence is fair).

Subclinical hyperthyroidism, commonly found in this setting, does not warrant any treatment, because that may lead to fetal hypothyroidism.40

Subclinical Hyperthyroidism

A serum TSH level of <0.1 mIU/L and normal estimates of free T3 and T4 are characteristics of subclinical hyperthyroidism.41 The below-normal TSH level can be the result of exogenous TSH suppression or endogenous production of T3 and T4 that is sufficient to suppress the production and secretion of TSH and keep the thyroid hormone levels within normal range. Studies have shown that subclinical hyperthyroidism is prevalent at the rate of <2% in the adult or elderly population.42 Subclinical hyperthyroidism is associated with three major risk factors: 1) progression to overt hyperthyroidism, 2) cardiovascular effects that can cause a wide spectrum of cardiovascular changes, and 3) skeletal effects affecting bone structure and metabolism. For this reason, maintenance of serum TSH levels between 0.3 and 3.0 mIU/L is very critical in patients receiving levothyroxine as hormone replacement therapy.5 However, this rule does not apply to patients who have undergone thyroidectomy for differentiated thyroid cancer. A moderately suppressed level of TSH is more appropriate in this case. Sufficient doses of levothyroxine are also given to patients with hypofunctional thyroid nodules to intentionally suppress their TSH level.

Patients with subclinical hyperthyroidism resulting from nodular thyroid disease are subjected to treatment because of the high incidence of conversion to clinical hyperthyroidism. Recent studies have shown that chronic subclinical hyperthyroidism decreases bone mineral density.43 These studies led investigators to conclude that subclinical hyperthyroidism should be considered as a risk factor in postmenopausal women. Interestingly, bone loss is minimal in men and in women at the premenopausal stage. The exact reason for less susceptibility of men and premenopausal women to bone mass in subclinical hyperthyroidism is unknown. In elderly populations with subclinical hyperthyroidism, relative risk for atrial fibrillation is increased by threefold. Subclinical hyperthyroidism can also cause cardiac effects such as impaired ventricular ejection fraction and impaired left ventricular diastolic filling. Despite the wide spectrum of effects of subclinical hyperthyroidism, no consensus exists about the management of subclinical hyperthyroidism. Generally, subclinical hyperthyroidism does not warrant any treatment. However, it is recommended that thyroid function be assessed regularly. The American Association of Endocrinologists also recommends periodic clinical and laboratory assessment of all patients with subclinical hyperthyroidism to determine therapeutic treatment options.5

Conclusion

Hyperthyroidism is a chronic health condition that affects a large segment of the American population. However, with quick diagnosis and correct treatment options such as antithyroid medications, radioactive iodine, or surgical intervention it can be effectively controlled. Measuring TSH and T4 levels on a regular basis is a highly recommended method of diagnosis for hyperthyroidism, especially in the population diagnosed with subclinical hyperthyroidism. Among the antithyroid medications, methimazole is considered the drug of choice because of its high patient compliance rate. If patients do not respond to the medications, radioactive iodine therapy and surgical intervention are other treatment options.

Pharmacists provide a significant contribution in the treatment of patients with hyperthyroidism. Educating patients about their medical condition and the various treatment options available is one of the most important services that pharmacists can provide. Pharmacists can also counsel patients on proper use of antithyroid medications, and by constantly monitoring the side effects of the current treatment, they can recommend other medications for optimal comfort. Pharmacists can monitor for other drug interactions that may be the cause of uneasiness in patients’ lives, and recommend changes accordingly. Overall, pharmacists can significantly contribute to the quality of life of the patient suffering from hyperthyroidism.

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