CONTINUING EDUCATION

Wyeth
TRENDS IN PHARMACY AND PHARMACEUTICAL CARE

An ongoing CE program of The University of Florida College of Pharmacy and DRUG TOPICS

The University of Florida College of Pharmacy is accredited by the American Council on Pharmaceutical Education as a provider of continuing pharmaceutical education. Accredited in every state requiring CE.® ACPE # 012-999-04-077-H01

This lesson is no longer valid for CE credit after 04/30/06.

CREDIT:

This lesson provides two hours of CE credit and requires a passing grade of 70%.*

OBJECTIVES:

Upon completion of this article, the pharmacist should be able to:

• State the causes and symptoms of hyperthyroidism
• Relate the incidence of thyroid cancer
• Describe the actions of thyroid hormones
• Develop a plan of treatment for a patient with hypothyroidism
• Counsel patients who have thyroid disorders

*To receive credit you must complete the evaluation. Upon successful completion, the University of Florida College of Pharmacy will mail Statements of Credit for written quizzes within 10 working days. Participants completing the program on-line may print a Statement of Credit after successfully completing the program.

GOAL:

To provide pharmacists with an understanding of thyroid disorders and the pharmacotherapies to treat these disorders

An update on the treatment of thyroid disease

By Veronika Butterweck, Ph.D., Associate Professor, Department of Pharmaceutics, University of Florida College of Pharmacy, Gainesville, Fla.

Disorders of the thyroid are common, disruptive, expensive, and treatable. Many are also preventable. Numerous studies support these descriptions:

1. Common—about 200 million people in the world have some form of thyroid disease. In the United States 5%-20% of the population have some thyroid abnormality; depending on the indicator chosen, this fraction increases in certain subpopulations (e.g., autoimmune disease in older women).

2. Disruptive—both hypothyroidism and hyperthyroidism impair physical and mental performance, produce morbidity, and pose special risks for pregnancy and the developing fetus and neonate.

3. Expensive—T₄ is among the most commonly prescribed medications in the United States. Testing of thyroid function is a routine laboratory procedure costing millions of dollars annually; the effects of iodine deficiency on the thyroid alone cost one country (Germany) an estimated annual $1 billion.

4. Treatable—highly satisfactory therapies exist for all the com-mon problems: hyperthyroidism, hypothyroidism, nodules, cancer, and iodine deficiency. The treatment in general is extremely satisfying, as most patients can be either cured or have their diseases controlled.

5. Preventable—the consequences of iodine deficiency are readily avoided by optimal iodine nutrition; appropriate diagnosis and treatment can keep at bay the effects of hypothyroidism on human development. Avoidance of excess iodine can prevent many of its complications, including goiter, hypothyroidism, hyperthyroidism, and autoimmune disease.

In 2002, the American Association of Clinical Endocrinologists (AACE) published medical guidelines for the assessment and treatment of patients with thyroid disorders. Based on these up-to-date guidelines, this article will briefly summarize the complexity of thyroid diseases and describe diagnostic and therapeutic strategies in various settings in greater detail.

Thyroid hormone regulation—the chain of command

The thyroid gland is made up of multiple follicles that consist of a single layer of epithelial cells surrounding a lumen filled with colloid (thyroglobulin), the storage form of thyroid hormone. Thyroid function is controlled by a tropic hormone, thyrotropin-stimulating hormone (TSH, thyrotropin), a glycoprotein synthesized by the anterior pituitary. TSH is secreted in a pulsatile manner and circadian pattern, its levels in the circulation being highest during sleep at night. The secretion of TSH is controlled by the hypothalamic peptide thyrotropin-releasing hormone (TRH). TRH is a tripeptide with both terminal amino and carboxyl groups blocked (L-pyroglutamyl-L-histidyl-L-proline amide).

TRH is synthesized by the hypothalamus and released into the hypophysioportal circulation, where it is brought into contact with TRH receptors on thyrotropes. The binding of TRH to its receptor, a G-protein-coupled receptor, elicits stimulation of the hydrolysis of polyphosphatidylinositols and activation of protein kinase C. Ultimately, TRH stimulates the synthesis and release of TSH by the thyrotroph, which, in turn, increases the production of the thyroid hormones thyroxine (T₄) and triiodothyronine (T₃).

Thyroid hormone synthesis and transport

The synthesis of the thyroid hormones is unique, complex, and seemingly grossly inefficient. The thyroid hormones are synthesized and stored as amino acid residues of thyroglobulin, a protein constituting the vast majority of the thyroid follicular colloid. The thyroid gland is unique in storing great quantities of potential hormone in this way, and extracellular thyroglobulin can represent a large portion of the mass of the gland. Thyroglobulin is a complex glycoprotein made up of two apparently identical subunits, each with a molecular mass of 330,000 daltons.

The major steps in the synthesis, storage, release, and interconversion of thyroid hormones are the following: 1) the uptake of iodide ion by the gland, 2) the synthesis of thyroglobulin from amino acids (tyrosine), 3) the oxidation of iodide and the iodination of tyrosyl groups of thyroglobulin, 4) the condensation of iodotyrosine residues by ether linkage to generate the iodothyronines, and 5) the proteolysis of thyroglobulin and the release of T₃ and T₄ into the blood. T₄ is converted to T₃ in peripheral tissues as well as in the thyroid.

The thyroid hormones are transported in the blood in strong but noncovalent association with certain plasma proteins. Thyroxine-binding globulin (TBG) is the major carrier of thyroid hormones. Binding of thyroid hormones to plasma proteins protects the hormones from metabolism and excretion, resulting in their long half-lives in the circulation.

The normal daily production of T₄ has been estimated to range between 70 mcg and 90 mcg, while T₃ is between 15 mcg and 30 mcg. Under normal conditions, about 41% of T₄ is converted to T₃, about 38% is converted to reverse T₃ (rT₃), and about 21% is metabolized via other pathways, such as conjugation in the liver and excretion in the bile. Normal circulating concentrations of T₄ in plasma range from 4.5 mcg to 11.0 mcg/dl, while those of T₃ are about 100-fold less (60 to 180 ng/dl).

Actions of thyroid hormones

T₃ is the more physiologically active hormone, approximately four times more potent than T₄. Whereas the precise biochemical mechanisms through which thyroid hormones exert their developmental and tissue-specific effects are only beginning to be understood, the concept that most of the actions of thyroid hormones are mediated by nuclear receptors has been well accepted since the mid-1980s. In this model, T₃ binds to high-affinity nuclear receptors, which then bind to a specific DNA sequence in the promoter/regulatory region of specific genes. In this fashion, T₃ modulates gene transcription and, ultimately, protein synthesis. T₄ also binds to these receptors, but it does so with a much lower affinity than T₃. Despite its ability to bind to nuclear receptors, T₄ has not been shown to alter gene transcription. Thus, it is likely that thyroxine serves principally as a "pro-hormone," with essentially all actions of thyroid hormone at the transcriptional level being caused by triiodothyronine.

Thyroid hormone regulates energy and heat production; facilitates healthy development of the central nervous system, somatic growth, and puberty; and regulates synthesis of proteins important in hepatic, cardiac, neurological, and muscular functions. A summary of thyroid hormone actions is given in Table 1.

Table 1 Actions of thyroid hormones
Effect on metabolic rate	Effect on growth	Effect on specific body mechanisms
basal metabolic rate	body growth and development	carbohydrate metabolism
protein synthesis		Rapid uptake of glucose by cells
cellular enzyme activity
in number and size of mitochondria resulting in
ATP production		gluconeogenesis
active transport of ions across cell membranes, most notably the sodium-potassium pump		absorption from the gastrointestinal tract
		insulin secretion
		fat metabolism Influences need for vitamins Influences body weight Affects: - cardiac output - rate of respiration - gastrointestinal motility - mood, sleep, cognitive functioning - muscle tone and strength - hormone secretion, sexual and menstrual function

Thyroid dysfunction

The two main problems seen with a dysfunctional thyroid gland are overactive hyperthyroidism and underactive hypothyroidism. Disorders of thyroid function are also classified as primary, secondary, or tertiary, depending upon which portion of the hypothalamic-pituitary-thyroid (HPT) axis is dysfunctional. Primary thyroid dysfunction occurs at the thyroid, secondary dysfunction results from problems with the pituitary, and tertiary dysfunction results from problems at the level of the hypothalamus.

Most commonly, thyroid dysfunction occurs as a result of autoimmune problems at the level of the thyroid gland and results in primary thyroid disease. Autoimmune dysfunction leads to Graves' disease, hyperthyroidism, or Hashimoto's thyroiditis. Other causes of thyroid dysfunction are listed in Table 2 but will not be discussed because they are rare and generally display the same signs, symptoms, and major concerns as the autoimmune etiologies. Table 3 lists the signs and symptoms associated with thyroid dysfunction.

Hypothyroidism

Hypothyroidism results from an undersecretion of thyroid hormone from the thyroid gland. Worldwide, hypothyroidism is most often the result of iodine deficiency. In nonendemic areas (e.g., the United States), where iodine is sufficient, chronic autoimmune thyroiditis (Hashimoto's thyroiditis) accounts for the majority of cases. This disorder is characterized by high levels of circulating antibodies directed against thyroid peroxidase and, less commonly, thyroglobulin. Other causes of hypothyroidism are surgical removal of the thyroid gland, thyroid gland ablation with radioactive iodine, external irradiation, a biosynthetic defect in iodine organification, replacement of the thyroid gland by tumor (lymphoma), and drugs such as lithium or interferon. Secondary causes of hypothyroidism include pituitary and hypothalamic disease. Patients should undergo assessment for the cause of their hypothyroidism.

• Diagnosis

Appropriate evaluation is critical to establishing the diagnosis and cause of hypothyroidism in the most cost-effective way. The most valuable test is a sensitive measurement of TSH levels. A TSH assay should always be used as the primary test to establish the diagnosis of primary hypothyroidism. Additional tests may include the following:

- free T₄ estimates

- thyroid autoantibodies, antithyroid peroxidase, and antithyroglobulin autoantibodies

- thyroid scan, ultrasonography, or both

• Treatment and management

With the exception of certain conditions that lead to self-limited hypothyroidism, treatment of hypothyroidism will be lifelong. The synthetic preparations of the sodium salts of the natural isomers of the thyroid hormones are available for the treatment of hypothyroidism. Levothyroxine sodium (L-T₄, Synthroid, Levoxyl, Levothyroid, others) is available in tablets and as a lyophilized powder for injection. Liothyronine sodium (L-T₃) is the salt of triiodothyronine and is available in tablets (Cytomel, Jones Pharma) and in an injectable form (Triostat, Jones Pharma). Desiccated thyroid preparations, derived from whole animal thyroids, contain both thyroxine and triiodothyronine and have highly variable biologic activity, making these preparations less desirable.

Levothyroxine is the drug of choice, because its conversion to L-triiodothyronine will be appropriately regulated by the tissues. AACE recommends the use of a high-quality brand preparation of levothyroxine. Bioequivalence is based on total T₄ measurement; therefore, bioequivalence is not the same as therapeutic equivalence. Furthermore, various brands of levothyroxine are not compared against a levothyroxine standard. Preferably, the patient should receive the same brand of levothyroxine throughout treatment. In general, desiccated thyroid hormone, combinations of thyroid hormones, or triiodothyronine should not be used as replacement therapy.

The mean replacement dosage of levothyroxine is 1.6 mcg/kg of body weight per day, although the appropriate dosage may vary among patients. The initial levothyroxine dosage may range from 12.5 mcg daily to a full replacement dose based on the age, weight, and cardiac status of the patient and the severity and duration of the hypothyroidism. Because of the prolonged half-life of thyroxine (seven days), new steady-state concentrations of the hormone will not be achieved until four to six weeks after a change in dose. Thus, reevaluation with determination of serum TSH concentration need not be performed at intervals of less than four to six weeks. The goal of thyroxine replacement therapy is to achieve a TSH value in the normal range. Once this goal is achieved, the frequency of visits can be decreased. Although each patient's care must be individualized, a follow-up visit in six months and then annually is a common schedule.

In noncompliant young patients, the cumulative weekly doses of levothyroxine may be given as a single weekly dose, which is safe, effective, and well tolerated. In individuals over the age of 60, institution of therapy at a lower daily dose of levothyroxine sodium (25 mcg per day) is indicated to avoid exacerbation of underlying and undiagnosed cardiac disease. Death due to arrhythmias has been reported during the initiation of thyroid hormone replacement therapy in hypothyroid patients. The dose can be increased at a rate of 25 mcg per day every few months until the TSH is normalized.

Thyroid hormone absorption can be affected by malabsorptive states and patient age. Because levothyroxine has a narrow therapeutic range, small differences in absorption can result in subclinical or clinical hypothyroidism or hyperthyroidism. Ideally, levothyroxine should be taken on awakening at least 30 minutes before eating, because some fiber or bran product may impair absorption.

Drug interactions also present a problem. Certain drugs—such as cholestyramine, ferrous sulfate, sucralfate, calcium, and some antacids containing aluminum hydroxide—interfere with levothyroxine absorption. Other drugs such as anticonvulsants affect thyroid hormone binding, whereas others such as rifampin and sertraline hydrochloride may accelerate levothyroxine metabolism and necessitate a higher replacement dose. The physician must make the appropriate adjustments in levothyroxine dosage in face of absorption variability and drug interactions. Overtreatment must be avoided, because thyroid hormone excess may lead to a decrease in bone mineral density in postmenopausal women and to adverse cardiac consequences.

Subclinical hypothyroidism is an asymptomatic state characterized by elevated serum TSH concentrations and serum T₄ and T₃ concentrations in the normal range. It is a common disorder, the prevalence ranging from 1% to 10% of the adult population, with increasing frequency in women, in patients with advanced age, and in those with greater dietary iodine intake. Usually, subclinical hypothyroidism is asymptomatic and is discovered on routine screening of TSH levels. Potential risks associated with this condition include progression to overt hypothyroidism, cardiovascular effects, hyperlipidemia, and neuropsychiatric effects.

Treatment of subclinical hypothyroidism remains controversial, and recent arguments for and against treatment have been proposed. According to AACE, treatment is indicated in patients with TSH levels > 10 mcU/ml or in patients with TSH levels between 5 and 10 mcU/ml in conjunction with goiter or positive antithyroid peroxidase antibodies (or both). An initial dosage of levothyroxine of 25 mcg to 50 mcg/day can be used. The serum TSH level should be measured in six to eight weeks, and the levothyroxine dose should be adjusted as necessary. The target TSH level should be between 0.3 and 3.0 mcU/ml. Once stable TSH levels are achieved, annual examination is appropriate.

Hypothyroidism during pregnancy: Untreated overt hypothyroidism during pregnancy may increase the incidence of maternal hypertension, preeclampsia, anemia, postpartum hemorrhage, cardiac ventricular dysfunction, spontaneous abortion, fetal death or stillbirth, low birth weight, and, possibly, abnormal brain development. Evidence from a population-based study suggests that even mild, asymptomatic, untreated maternal hypothyroidism during pregnancy may have an adverse effect on cognitive function of the offspring and that this outcome can be prevented by thyroid hormone replacement therapy. Because levothyroxine treatment is safe during pregnancy, thyroid hormone replacement treatment seems advisable for all pregnant women with hypothyroidism, even if it is mild. The dose of levothyroxine during pregnancy often needs to be increased, perhaps due to the increased serum concentrations of thyroxine-binding globulin induced by estrogen. As a further recommendation, TSH measurement should be routine before pregnancy or during first trimester screening for thyroid dysfunction.

Hyperthyroidism

Hyperthyroidism is the consequence of excessive thyroid hormone action. Causes of hyperthyroidism are various, including Graves' disease, thyroid autonomy (toxic nodule and multinodular goiter), autosomal dominant and non-autoimmune hyperthyroidism, thyroiditis, and TSH-producing pituitary adenomas. The iodine intake level of a population is a major determinant of the epidemiology of thyroid disorders. The total incidence of hyperthyroidism is significantly higher in iodine-deficient areas than in high iodine intake areas, due to a much higher incidence of multinodular toxic goiter and single toxic adenoma. In high iodine intake areas, Graves' disease is by far the most common form of hyperthyroidism.

• Diagnosis

To diagnose hyperthyroidism, a comprehensive history should be elicited, and a thorough physical examination should be performed, including the following: weight and blood pressure, pulse rate and cardiac rhythm, thyroid palpation and auscultation, neuromuscular examination, eye examination, dermatologic examination, cardiovascular examination, and lymphatic examination.

The development of sensitive TSH assays has considerably facilitated the diagnosis of hyperthyroidism. Hyperthyroidism of any cause results in a lower than normal TSH level. Other laboratory and isotope tests may include the following:

- T₄ or free T₄

- T₃ or free T₃

- thyroid autoantibodies, including TSH receptor antibodies

- radioactive iodine uptake

- thyroid scan—with either ¹²³I (preferably) or ^99mTC

• Treatment and management

Three types of therapy are available for hyperthyroidism: (1) surgical intervention, (2) antithyroid drugs, and (3) radioactive iodine.

(1) Surgical intervention: Although thyroidectomy was frequently used in the past, it is now uncommonly performed in the United States unless coexistent thyroid cancer is suspected. Pregnant patients with hyperthyroidism who are intolerant of antithyroid drugs, or nonpregnant patients desiring definitive therapy but who refuse radioactive iodine treatment, are candidates for surgical intervention. Some physicians prefer surgical treatment of pediatric patients with Graves' disease or patients with very large or nodular goiters. Potential complications associated with surgical management of hyperthyroidism include hypoparathyroidism and vocal cord paralysis in a small proportion of patients.

(2) Antithyroid drugs: Antithyroid drugs inhibit the formation of thyroid hormones by interfering with the incorporation of iodine into tyrosyl residues of thyroglobulin; they also inhibit the coupling of these iodotyrosyl residues to form iodothyronines. It is proposed that the drugs inhibit the peroxidase enzyme, thereby preventing oxidation of iodide or iodotyroxyl groups to the required active state. The antithyroid compounds currently used in the United States are propylthiouracil and methimazole (Tapazole, Jones Pharma). In Great Britain and Europe, carbimazole, a carbethoxy derivative of methimazole, is available, and its antithyroid action is due to its conversion to methimazole after absorption.

Some pharmacokinetic features of propylthiouracil and methimazole are shown in Table 4. Methimazole is used in preference to propylthiouracil, because it has a longer inhibitory effect on glandular hormone synthesis and can therefore be taken as a single daily dose, improving compliance. Moreover, in doses up to 30 mg/d, methimazole may carry a lower risk of agranulocytosis. Treatment is usually initiated with 30 mg of methimazole daily or 100 mg of propyl- thiouracil three times daily. The patient should be alerted to the major, albeit rare (< 1%), adverse effects of these drugs, including agranulocytosis, liver disease, and a lupus-like syndrome that tend to occur within the first several months of therapy. The patient should be instructed to notify the physician immediately if symptoms suggesting one of these adverse reactions appear.

After treatment has been initiated, the patient should be followed up at approximately monthly intervals and the antithyroid drug dose reduced to a maintenance dose until a euthyroid state is approached.

Nonselective beta-adrenoceptor antagonistic drugs (e.g., propranolol) should be administered as adjunctive agents in patients with moderate or severe hyperthyroidism. The applied doses for propranolol vary from 40 mg/d to 320 mg/d. Propranolol does not affect synthesis and secretion of thyroid hormones but inhibits the peripheral monodeiodination of thyroxine to triiodothyronine. Beta-blockers ameliorate the features of adrenergic hyperstimulation, such as tremor, anxiety, heat intolerance, and tachycardia. If beta-blockers are contraindicated, calcium-channel-blocking drugs (e.g., diltiazem, 60 to 120 mg four times daily) should be administered.

Long-term antithyroid drug therapy is appropriate only for Graves' disease, since this disorder has the potential to enter a spontaneous remission. It is generally considered the treatment of choice for young patients with a small goiter or patients with active ophthalmopathy. Antithyroid drugs are not indicated as long-term therapy in toxic nodular goiter, since hyperthyroidism does not remit. The likelihood of a long-term remission is positively influenced by the duration of antithyroid drug therapy, and a duration of one to two years is recommended, with reported remission rates ranging from 37% to 70%.

(3) Radioactive iodine

¹³¹I is the treatment of choice for patients with Graves' hyperthyroidism who relapse after long-term antithyroid drug therapy, patients with severe thyrocardiac disease, for most patients with toxic multinodular or uninodular goiter, and patients with major adverse reaction to antithyroid drugs. ¹³¹I is absolutely contraindicated during pregnancy because it may ablate the thyroid in the fetus. Furthermore, ¹³¹I should not be given to women who are breastfeeding, because it appears in the breast milk.

The dose of ¹³¹I used to treat Graves' hyperthyroidism ranges from 185 to 555 Mbq (5-15 mCi), depending on the size of the goiter and the magnitude of uptake of an antecedent tracer dose of ¹³¹I. With toxic nodular goiter, larger doses are required to achieve a euthyroid state. In more than 80% of patients, hyperthyroidism will be cured and the goiter will decrease with a single dose of ¹³¹I. Since it may take several months for euthyroidism to be restored, patients with severe hyperthyroidism may require treatment with an antithyroid drug or a beta-adrenergic receptor-blocking agent during this interim period. Women of childbearing age should be advised to postpone conception for at least six months after treatment with ¹³¹I.

Permanent hypothyroidism is the major complication of ¹³¹I therapy; its prevalence at one year is determined by the dose given. Thereafter, the prevalence rises at a rate of 2% to 3% per year. Accordingly, the patient should be followed up at monthly intervals initially and at increasing intervals once euthyroidism is restored. Transient hypothyroidism may occur during the first six months after ¹³¹I therapy. When hypothyroidism emerges or persists for more than six months after ¹³¹I therapy, it is likely to be permanent, and levothyroxine treatment should be instituted. Other adverse effects of therapeutic doses of ¹³¹I for hyperthyroidism are minimal.

Subclinical hyperthyroidism is characterized by a serum TSH level < 0.1 mcU/ml and normal free T₄ and T₃ estimates. The low TSH levels result from either exogenous TSH suppression or endogenous production of thyroid hormones that, presumably, is sufficient to keep free T₄ and free T₃ levels normal but suppress pituitary TSH production and secretion. The clinical significance of subclinical hyperthyroidism is related to three risk factors: (1) progression to overt hyperthyroidism, (2) cardiac effects, and (3) skeletal effects.

No consensus exists about the management of subclinical hyperthyroidism. AACE recommends that all patients with subclinical hyperthyroidism undergo periodic clinical and laboratory assessment to determine individual therapeutic options.

Hyperthyroidism during pregnancy presents special concerns. Use of radioactive iodine is contraindicated during pregnancy because it crosses the placenta. Antithyroid drugs are the treatment of choice for hyperthyroidism during pregnancy, and propyl-thiouracil is clearly preferred to methimazole. Antithyroid drugs also cross the placenta, and overtreatment with them may adversely affect the fetus. Therefore, the lowest possible dose of antithyroid drug should be used to maintain the mother's thyroid function at the upper limit of normal. Because pregnancy itself has an ameliorative effect on Graves' disease, the dose of antithyroid drug required usually decreases as the pregnancy progresses. Often the antithyroid drug can be discontinued before delivery. If surgical treatment does become necessary, it is best done during the second trimester of pregnancy.

Patients taking amiodarone

This very effective antiarrhythmic agent contains approximately 37% iodine by weight. Thus, a 200-mg tablet will deliver 75 mg of iodine/day, some 40 times the normal recommended intake of the element. The drug has effects on thyroid hormone synthesis as well as on thyroid hormone metabolism. In patients receiving amiodarone, either hypothyroidism (which is treated with levothyroxine replacement) or hyperthyroidism may develop. Amiodarone-induced hyperthyroidism is of two types: Type 1 is similar to iodine-induced hyperthyroidism (Jod-Basedow phenomenon) and manifests with a low TSH level, a high free T₄ or T₃ estimate, and a low radioiodine uptake. Doppler ultrasonography shows increased vascularity of thyroid tissue, similar to that in Graves' disease. Because of low radioiodine uptake, ¹³¹I treatment cannot be used, and use of antithyroid drugs has yielded only varied success. Treatment of type 1 includes withdrawal of the drug, if possible; administration of antithyroid drugs, including potassium perchlorate, if necessary; and the use of prednisone.

Type 2 amiodarone-induced hyperthyroidism resembles a destructive thyroiditis. Laboratory values and radioiodine uptake are similar to the findings in type 1. Corticosteroid treatment is recommended, and patients sometimes require surgical removal of the thyroid.

However, clinical features of amiodarone-induced hyperthyroidism can be masked by alpha- and beta-blocking properties of the drug.

Thyroid cancer

The incidence of thyroid cancer is low in most countries and varies between 1 and 4/100,000/year. Although the overall incidence of thyroid cancer does not vary, the ambient iodine concentration influences significantly the distribution of different histological types (papillary, follicular, anaplastic). In iodine-sufficient areas, the most common type is papillary; in iodine-deficient areas, the follicular type prevails. Overall, the vast majority of patients with thyroid cancer will not die of their disease.

Papillary cancer is not an aggressive tumor. It metastasizes locally and has a 10-year survival time of greater than 90%. Lymph node metastases at the time of diagnosis do little to alter the prognosis. Follicular cancer is more aggressive and can metastasize via the bloodstream. Still, prognosis is fair, and long-term survival is common. Treatment of differentiated thyroid cancer usually involves surgical resection of the tumor followed in many cases by radiotherapy. The measurement of serum thyroglobulin is used routinely as a tumor marker in the follow-up of these patients.

Conclusion

Treatments for patients with thyroid diseases have not changed over half a century and are aimed to support, inhibit, destroy, or remove the thyroid gland. Current research is directed toward genetic and molecular approaches to finding the causes of autoimmune thyroid diseases and should ultimately produce targeted treatments that will cure these diseases noninvasively, without toxicity, and without permanent damage to the thyroid gland.

References are available upon request.

TEST QUESTIONS

Write your answers on the answer form below (photocopies of the answer form are acceptable) or on a separate sheet of paper. Mark the most appropriate answer.

1. Symptoms of hyperthyroidism include all of the following except:

a. Tachycardia
b. Nervousness
c. Poor resistance to cold
d. Decreased body weight
e. Tremor

2. Which of the following best describes the effect of propyl-thiouracil on thyroid hormone production?

a. It blocks the release of thyrotropin-releasing hormone.
b. It inhibits uptake of iodide by thyroid cells.
c. It prevents the release of thyroid hormone from thyroglobulin.
d. It blocks iodination and coupling of tyrosines in thyroglobulin to form thyroid hormones.
e. It blocks the release of hormones from the thyroid gland.

3. Hyperthyroidism can be treated by all but which of the following?

a. T₃
b. Surgical removal of the gland
c. Iodide
d. Propylthiouracil

4. The incidence of thyroid cancer in most countries varies between:

a. 3 and 6/10,000/year
b. 1 and 4/100,000/year
c. 1 and 2/5,000/year
d. 2 and 5/50,000/year
e. 10 and 15/1,000,000/year

5. Which of the following statements is correct?

a. In amiodarone-induced hyperthyroidism, clinical features may be masked by the alpha- and beta-blocking properties.
b. Amiodarone-induced thyrotoxicosis is common in iodine-replete areas.
c. Amiodarone-induced hypothyroidism is common in iodine-replete areas.
d. The destructive thyroiditis caused by amiodarone is usually treated with antithyroid drugs.

6. Which of the following statements is false?

a. Untreated overt hypothyroidism during pregnancy may increase the incidence of low birth weight and abnormal brain development.
b. The drug of choice for treatment of hyperthyroidism in pregnancy is methimazole.
c. Levothyroxine treatment is safe during pregnancy and seems advisable for all pregnant women with hypothyroidism.
d. In Graves' disease, the dose of antithyroid drug required usually decreases as the pregnancy progresses.

7. All of the following statements about radioactive iodine are true except:

a. Permanent hypothyroidism is the major complication of ¹³¹I therapy.
b. The dose of ¹³¹I used to treat Graves' hyperthyroidism ranges from 185 to 555 Mbq.
c. Women of childbearing age should be advised to postpone conception for at least six months after treatment with ¹³¹I.
d. Persisting hypothyroidism for more than six months after ¹³¹I therapy is normal and there is no need for further treatment.

8. Which of the following statements is correct?

a. TSH is synthesized in the hypothalamus and secreted in a pulsatile manner.
b. TRH is a tripeptide with both terminal amino and carboxyl groups blocked.
c. TRH increases the production of the thyroid hormones thyroxine (T₄) and triiodothyronine (T₃).
d. T₃ has a strong stimulatory effect on TRH secretion.

9. Which one of the following actions of thyroid hormones is false?

a. Increased cellular enzyme activity
b. Increased insulin secretion
c. Decreased development
d. Increased protein synthesis

10. The normal daily production of T₄ has been estimated to range between:

a. 30 and 50 mcg
b. 70 and 90 mcg
c. 50 and 70 mcg
d. 40 and 60 mcg

11. Under normal conditions, about

a. 21% of T₄ is converted to T₃
b. 31% of T₄ is converted to T₃
c. 41% of T₄ is converted to T₃
d. 51% of T₄ is converted to T₃

12. Disorders of thyroid function are also classified as:

a. Primary
b. Secondary
c. Tertiary
d. All of the above

13. Which of the following statements is true?

a. Only selective beta₁-adrenoceptor antagonistic drugs should be administered as adjunctive agents in patients with moderate or severe hyperthyroidism.
b. Propranolol inhibits iodination.
c. Beta-blockers ameliorate the features of adrenergic hyperstimulation, such as tremor, anxiety, heat intolerance, and tachycardia.
d. Calcium-channel-blocking drugs are contraindicated in hyperthyreosis.

14. The plasma half-life of methimazole is:

a. Four to six minutes
b. Four to six days
c. Four to six hours
d. 40–60 minutes

15. Subclinical hyperthyroidism is characterized by:

a. A serum TSH level < 0.1 mcU/ml and normal free T₄ and T₃ estimates
b. A serum TSH level of > 0.1 mcU/ml and normal free T₄ and T₃ estimates
c. A serum TSH level < 0.1 mcU/ml and increased free T₄ and T₃ estimates
d. A serum TSH level < 0.1 mcU/ml and decreased free T₄ and T₃ estimates

16. Which of the following statements is true?

a. Levothyroxine should be taken on awakening at least 30 minutes after eating.
b. Rifampin accelerates levothyroxine metabolism.
c. Small differences in absorption do not result in subclinical or clinical hypothyroidism or hyperthyroidism.
d. Anticonvulsants do not affect thyroid hormone binding.

17. Subclinical hypothyroidism is an asymptomatic state characterized by:

a. Decreased serum TSH concentrations and serum T₄ and T₃ concentrations in the normal range
b. Elevated serum TSH concentrations and increased serum T₄ and T₃ levels
c. Elevated serum TSH concentrations and decreased serum T₄ and T₃ levels
d. Elevated serum TSH concentrations and serum T₄ and T₃ concentrations in the normal range

18. Causes of hyperthyroidism are various except:

a. Graves' disease
b. TSH-producing pituitary adenomas
c. Hashimoto's thyroiditis
d. Excessive iodine intake

19. The mean replacement dosage of levothyroxine in hypothyroidism is:

a. 1.6 ng/kg of body weight per day
b. 1.6 mcg/kg of body weight per week
c. 1.6 mcg/kg of body weight per day
d. 1.6 mg/kg of body weight per day

20. Which of the following best describes pharmacokinetic features of propylthiouracil (PTU)?

a. PTU has a plasma protein binding of ~ 75%.
b. The metabolism of PTU in patients with severe kidney disease is decreased.
c. The distribution volume of PTU is ~ 10l.
d. The plasma half-life time of PTU is ~ 4-6h.

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