Introduction

Background
Thyrotoxicosis is the hypermetabolic condition associated with elevated levels of free thyroxine (FT4) and/or free triiodothyronine (FT3). Hyperthyroidism includes diseases that are a subset of thyrotoxicosis, that are caused by excess synthesis and secretion of thyroid hormone by the thyroid; they are not associated with exogenous thyroid hormone intake and subacute thyroiditis. Most clinicians, exclusive of endocrinologists, use the terms hyperthyroidism and thyrotoxicosis interchangeably. This article discusses the causes of thyrotoxicosis associated with hyperthyroidism (excess synthesis and release of thyroid hormone) and surreptitious use of thyroid hormone. Subacute thyroiditis is discussed in the article Subacute Thyroiditis. The most common forms of hyperthyroidism include diffuse toxic goiter (Graves disease), toxic multinodular goiter (Plummer disease), and toxic adenoma. Together with subacute thyroiditis, these conditions constitute 85-90% of all causes of thyrotoxicosis. Table 1 contains a list of hyperthyroid conditions associated with thyrotoxicosis. Table 1. Common, Less Common, and Uncommon Forms of Thyrotoxicosis and Hyperthyroidism Open table in new window [ CLOSE WINDOW ]
Table

Common Forms (85-90% of cases) Diffuse toxic goiter (Graves disease) Toxic multinodular goiter (Plummer disease) Thyrotoxic phase of subacute thyroiditis Toxic adenoma Less Common Forms Iodide-induced thyrotoxicosis Thyrotoxicosis factitia Uncommon Forms Pituitary tumors producing thyroid-stimulating hormone Excess human chorionic gonadotropin (molar pregnancy/choriocarcinoma) Pituitary resistance to thyroid hormone Metastatic thyroid carcinoma Struma ovarii with thyrotoxicosis Common Forms (85-90% of cases) Diffuse toxic goiter (Graves disease)

Radioactive iodine uptake over neck Increased Increased Decreased Increased Variable Decreased Increased Increased Increased Decreased Decreased Radioactive iodine uptake over neck Increased

Toxic multinodular goiter (Plummer disease) Thyrotoxic phase of subacute thyroiditis Toxic adenoma Less Common Forms Iodide-induced thyrotoxicosis Thyrotoxicosis factitia Uncommon Forms Pituitary tumors producing thyroid-stimulating hormone Excess human chorionic gonadotropin (molar pregnancy/choriocarcinoma) Pituitary resistance to thyroid hormone Metastatic thyroid carcinoma Struma ovarii with thyrotoxicosis

Increased Decreased Increased Variable Decreased Increased Increased Increased Decreased Decreased

Pathophysiology
The hypermetabolic effect of thyrotoxicosis affects every organ system. The pituitary gland stimulates the thyroid to make thyroid hormone, which is released into the circulation to reach every cell in the body. Thyroid hormone is necessary for normal growth and development, and it regulates cellular metabolism. Excess thyroid hormone causes an increase in the metabolic rate that is associated with increased total body heat production and cardiovascular activity (increased heart contractility, heart rate, vasodilation). Graves disease The most common cause of thyrotoxicosis is Graves disease (50-60%). Graves disease is an organ-specific autoimmune disorder characterized by a variety of circulating antibodies, including common autoimmune antibodies, as well as anti-thyroid peroxidase (anti-TPO) and antithyroglobulin (anti-TG) antibodies. The most important autoantibody is thyroidstimulating immunoglobulin (TSI). TSI is directed toward epitopes of the thyroid-stimulating hormone (TSH) receptor and acts as a TSH-receptor agonist. Similar to TSH, TSI binds to the TSH receptor on the thyroid follicular cells to activate thyroid hormone synthesis and release and thyroid growth (hypertrophy). This results in the characteristic picture of Graves thyrotoxicosis, with a diffusely enlarged thyroid, very high radioactive iodine uptake, and excessive thyroid hormone levels compared with a healthy thyroid. See the images below.

Iodine 123 (123I) nuclear scintigraphy: 123I scans of a normal thyroid gland (A) and common hyperthyroid conditions with elevated radioiodine uptake, including Graves disease (B), toxic multinodular goiter (C), and toxic adenoma (D). [ CLOSE WINDOW ]

Iodine 123 (123I) nuclear scintigraphy: 123I scans of a normal thyroid gland (A) and common hyperthyroid conditions with elevated radioiodine uptake, including Graves disease (B), toxic multinodular goiter (C), and toxic adenoma (D).

Color flow ultrasonogram in a patient with Graves disease. Generalized hypervascularity is visible throughout the gland, which often can be heard as a hum or bruit with a stethoscope. [ CLOSE WINDOW ]

Color flow ultrasonogram in a patient with Graves disease. Generalized hypervascularity is visible throughout the gland, which often can be heard as a hum or bruit with a stethoscope. Thyroid hormone levels can be extremely elevated in this condition. Clinical findings specific to Graves disease include thyroid ophthalmopathy (periorbital edema, chemosis [conjunctival edema], injection, proptosis) and, rarely, dermopathy over the lower extremities. This autoimmune condition may be associated with other autoimmune diseases, such as pernicious anemia, myasthenia gravis, vitiligo, adrenal insufficiency, and type 1 diabetes mellitus. Subacute thyroiditis The next most common cause of thyrotoxicosis is subacute thyroiditis (approximately 1520%), a destructive release of preformed thyroid hormone. A typical nuclear scintigraphy scan shows no radioactive iodine uptake in the thyrotoxic phase of the disease. (See images below.) Thyroid hormone levels can be extremely elevated in this condition. This topic is discussed and a typical nuclear scintigraphy scan is shown in the article Subacute Thyroiditis.

Absence of iodine 123 (123I) radioactive iodine uptake in a patient with thyrotoxicosis and subacute painless or lymphocytic thyroiditis. Laboratory studies at the time of the scan demonstrated the following: thyroid-stimulating hormone (TSH), less than 0.06 mIU/mL; total thyroxine (T4), 21.2 mcg/dL (reference range, 4.5-11); total triiodothyronine (T3), 213 ng/dL (reference range, 90-180); T3-to-T4 ratio, 10; and erythrocyte sedimentation rate (ESR), 10 mm/h. The absence of thyroid uptake, the low T3-to-T4 ratio, and the low ESR confirm the diagnosis of subacute painless thyroiditis. [ CLOSE WINDOW ]

Absence of iodine 123 (123I) radioactive iodine uptake in a patient with thyrotoxicosis and subacute painless or lymphocytic thyroiditis. Laboratory studies at the time of the scan demonstrated the following: thyroid-stimulating hormone (TSH), less than 0.06 mIU/mL; total thyroxine (T4), 21.2 mcg/dL (reference range, 4.5-11); total triiodothyronine (T3), 213 ng/dL (reference range, 90-180); T3-to-T4 ratio, 10; and erythrocyte sedimentation rate (ESR), 10 mm/h. The absence of thyroid uptake, the low T3-to-T4 ratio, and the low ESR confirm the diagnosis of subacute painless thyroiditis.

Three multinuclear giant cell granulomas observed in a fine-needle aspiration biopsy of the thyroid from a patient with thyrotoxicosis from subacute painful or granulomatous thyroiditis. [ CLOSE WINDOW ]

Three multinuclear giant cell granulomas observed in a fine-needle aspiration biopsy of the thyroid from a patient with thyrotoxicosis from subacute painful or granulomatous thyroiditis. Toxic multinodular goiter Toxic multinodular goiter (Plummer disease) occurs in 15-20% of patients with thyrotoxicosis. It occurs more commonly in elderly individuals, especially in patients with a long-standing goiter. Thyroid hormone excess develops very slowly over time and often is only mildly elevated at the time of diagnosis. As discussed below, very high thyroid hormone levels may occur in this condition after high iodine intake, ie, with contrast or amiodarone

exposure. Symptoms of thyrotoxicosis are mild, often because only a slight elevation of thyroid hormone levels is present, and the signs and symptoms of thyrotoxicosis often are blunted (apathetic hyperthyroidism) in older patients. A typical nuclear scintigraphy scan of a toxic multinodular goiter is shown in the first image above and demonstrates an enlarged thyroid gland with areas of increased and decreased activity. See also the image below.

Scan in a patient with a toxic multinodular goiter. The 5-hour iodine uptake was elevated at 28%. Note the multiple foci of variably increased tracer uptake. [ CLOSE WINDOW ]

Scan in a patient with a toxic multinodular goiter. The 5-hour iodine uptake was elevated at 28%. Note the multiple foci of variably increased tracer uptake. Toxic adenoma Toxic adenoma is caused by a single hyperfunctioning follicular thyroid adenoma. Patients with a toxic thyroid adenoma comprise approximately 3-5% of patients who are thyrotoxic. The excess secretion of thyroid hormone occurs from a benign monoclonal tumor that usually is larger than 2.5 cm in diameter. The excess thyroid hormone suppresses TSH levels. Radioactive iodine uptake usually is normal, and the radioactive iodine scan shows only the hot nodule, with the remainder of the normal thyroid gland suppressed because the TSH level

is low. See the first image above. Other causes of thyrotoxicosis Several rare causes of thyrotoxicosis exist that deserve mention. Iodide-induced thyrotoxicosis (Jod-Basedow syndrome) occurs in patients with excessive iodine intake, such as after an iodinated radiocontrast study. It occurs in patients with areas of thyroid autonomy, such as a multinodular goiter or autonomous nodule. The thyrotoxicosis appears to be a result of loss of the normal adaptation of the thyroid to iodide excess. It is treated by cessation of the excess iodine intake and administration of antithyroid medication. Usually, after depletion of the excess iodine, thyroid functions return to preexposure levels. Struma ovarii is ectopic thyroid tissue associated with dermoid tumors or ovarian teratomas that can secrete excessive amounts of thyroid hormone and produce thyrotoxicosis. Metastatic follicular thyroid carcinoma maintains the ability to make thyroid hormone and can cause thyrotoxicosis in patients with bulky tumors. Patients with a molar hydatidiform pregnancy or choriocarcinoma have extremely high levels of beta human chorionic gonadotropin (HCG) that can weakly activate the TSH receptor. At very high levels of HCG, activation of the TSH receptor occurs that is sufficient to cause thyrotoxicosis. Physiologic maximum elevation of HCG at the end of the first trimester of pregnancy is associated with a mirror-image temporary reduction in TSH. Despite the reduction in TSH, the FT4 levels usually remain normal or only slightly above the reference range. As the pregnancy progresses and the HCG plateaus at a lower level, TSH levels decrease back to normal levels.

Frequency
United States Graves disease is the most common form of hyperthyroidism. Approximately 60-80% of cases of thyrotoxicosis are due to Graves disease. The annual incidence of the disease is 0.5 cases per 1000 persons during a 20-year period, with the peak occurrence in people aged 2040 years. Toxic multinodular goiter (15-20% of thyrotoxicosis) occurs more frequently in regions of iodine deficiency. Most persons in the United States receive sufficient iodine, and the incidence of toxic multinodular goiter is less than the incidence in areas of the world with iodine deficiency. Toxic adenoma is the cause of 3-5% of cases of thyrotoxicosis. International The incidences of Graves disease and toxic multinodular goiter change with iodine intake. Compared with regions of the world with less iodine intake, the United States has more cases of Graves disease and fewer cases of toxic multinodular goiters.

Mortality/Morbidity
The clinical manifestations of thyrotoxicosis can be divided into those associated with any form of thyrotoxicosis and those associated specifically with Graves disease.

Nonspecific changes due to excessive thyroid hormone include weight loss, nervousness, fatigue, heat intolerance, and rapid heartbeat or palpitations sometimes associated with atrial fibrillation and high-output congestive heart failure (CHF).1 An increase in the rate of bone resorption occurs, but bone loss measured by bone mineral densitometry has been convincingly shown to occur only in postmenopausal women with hyperthyroidism. Thyroid hormone excess causes left ventricular thickening, which is associated with an increased risk of CHF. Thyrotoxicosis has been associated with dilated cardiomyopathy, right heart failure with pulmonary hypertension, and diastolic dysfunction.1 Ophthalmopathy and dermopathy specifically associated with Graves disease include periorbital edema, chemosis, and proptosis with extraocular muscle dysfunction and diplopia. The dermopathy, a painless swelling of the pretibial area, may occur in patients with severe ophthalmopathy.

Race
Autoimmune thyroid disease occurs with the same frequency in Caucasians, Hispanics, and Asians, and it occurs less frequently in the black population.

Sex
All thyroid diseases occur more frequently in women than in men. Graves autoimmune disease occurs in a male-to-female ratio of 1:5-10. The male-to-female ratio for toxic multinodular goiter and toxic adenomas is 1:2-4.

Age
Autoimmune thyroid diseases have a peak incidence in people aged 20-40 years. Toxic multinodular goiters occur in patients who usually have a long history of nontoxic goiter and who therefore typically present when they are older than 50 years. Patients with toxic adenomas present at a younger age than do patients with toxic multinodular goiter.

Clinical
History
The presentation of thyrotoxicosis is variable among patients. Thyrotoxicosis leads to an apparent increase in sympathetic nervous system symptoms. Younger patients tend to exhibit symptoms of more sympathetic activation, such as anxiety, hyperactivity, and tremor, while older patients have more cardiovascular symptoms, including dyspnea and atrial fibrillation with unexplained weight loss. The clinical manifestations of thyrotoxicosis do not always correlate with the extent of the biochemical abnormality.

Common symptoms of thyrotoxicosis include the following: o Nervousness

o

Anxiety

o o o o o o o

Increased perspiration Heat intolerance Tremor Hyperactivity Palpitations Weight loss despite increased appetite Reduction in menstrual flow or oligomenorrhea

Common signs of thyrotoxicosis include the following:

o o o o o o o o

Hyperactivity Tachycardia or atrial arrhythmia Systolic hypertension Warm, moist, and smooth skin Lid lag Stare Tremor Muscle weakness

Generally, a constellation of information, including extent and duration of symptoms, past medical history, social and family history, and physical examination, help guide the clinician to the appropriate diagnosis. Subclinical hyperthyroidism is associated with no clinical symptoms of thyrotoxicosis. However, certain conditions, such as atrial fibrillation, osteoporosis, or hypercalcemia, may suggest the possibility of thyrotoxicosis. In fact, subclinical hyperthyroidism may be associated with a 3-fold increase in the risk of atrial fibrillation. The prevalence of subclinical hyperthyroidism may be as high as 12% in the general population. A report from the Netherlands on 1426 patients whose TSH levels were in the normal range (0.4-4.0 mU/L), found evidence, after a median follow-up of 8 years, of an increased risk of atrial fibrillation even in persons with high-normal thyroid function.2

Radiation exposure, whether due to radiation therapy or to lower-level radiographic therapy, increases the risk of benign and malignant nodular thyroid diseases, with an observed increase in the incidence of autoimmune hyperthyroidism. The frequency and severity of symptoms of thyrotoxicosis vary from person to person. Graves disease is an autoimmune disease, and often, a strong family history or past medical history exists with autoimmune diseases such as with rheumatoid arthritis, vitiligo, or pernicious anemia.

The symptoms of Graves disease often are more marked, because thyroid hormone levels usually are the highest with this form of hyperthyroidism. Also consider the diagnosis of Graves disease if any evidence of thyroid eye disease exists, including periorbital edema, diplopia, or proptosis. Toxic multinodular goiters occur in patients who have had a known nontoxic goiter for many years or decades. Often, patients have emigrated from regions of the world with borderline low-iodine intake or have a strong family history of nontoxic goiter.

Recording a careful family history of autoimmune disease, thyroid disease, and emigration from iodine-deficient areas is important. Review a complete list of medications. A number of compoundsincluding expectorants, amiodarone, health food supplements containing seaweed, and iodinated contrast dyescontain large amounts of iodine that can induce thyrotoxicosis in a patient with thyroid autonomy. Rarely, iodine exposure can cause thyrotoxicosis in a patient with an apparently healthy thyroid.

Physical
Physical examination often can help the clinician determine the etiology of thyrotoxicosis.

Thyroid examination - The thyroid is located in the lower anterior neck. The isthmus of the butterfly-shaped gland generally is located just below the cricoid cartilage of the trachea, with the wings of the gland wrapping around the trachea. o Thyrotoxicosis due to Graves disease is associated with a diffusely enlarged and slightly firm thyroid gland. Sometimes, a thyroid bruit is audible using the bell of the stethoscope.
o

Toxic multinodular goiters occur when goiters generally are enlarged to at least 2 to 3 times normal size. The gland often is soft, but individual nodules occasionally can be palpated. A toxic adenoma generally does not cause thyrotoxicosis in a patient until it is at least 2.5 cm in diameter. If the thyroid is enlarged and painful, the diagnosis is likely subacute painful or granulomatous thyroiditis, but consider degeneration or hemorrhage into a nodule or suppurative thyroiditis.

Thyroid-specific physical examination - Graves thyrotoxicosis can be associated with mild thyroid ophthalmopathy in 50% of patients.
o

Often, it is manifested only by periorbital edema, but it also can include conjunctival edema (chemosis), injection, poor lid closure, extraocular muscle dysfunction (diplopia), and proptosis. Evidence of thyroid eye disease and high thyroid hormone levels confirms the diagnosis of autoimmune Graves disease.

Graves disease rarely can affect the skin by deposition of glycosaminoglycans in the dermis of the lower leg. This causes nonpitting edema, usually associated with erythema and thickening of the skin, without pain or pruritus.

Signs of thyrotoxicosis - Usually, signs upon physical examination include sinus tachycardia or atrial fibrillation, systolic hypertension, excessive perspiration, palmar erythema and sweating, lid lag, extension tremor, hyperkinesis, large-muscle weakness, and soft, smooth skin.

Causes
Genetics and iodine intake appear to influence the incidence of thyrotoxicosis.

Genetics - Autoimmune thyroid disease and Graves disease have a higher prevalence in patients with human leukocyte antigen (HLA)-DRw3 and HLA-B89. o Graves disease is felt to be an HLA-related, organ-specific defect in suppressor T-lymphocyte function.
o

Observing autoimmune thyroid disease, including Hashimoto hypothyroidism and Graves disease, in multiple members of a patient's family is common. Similarly, subacute painful or granulomatous thyroiditis occurs more frequently in patients with HLA-Bw35. Similar to other immune diseases, these thyroid conditions occur more frequently in women than in men.

Iodine intake - Clearly, patients in borderline iodine-deficient areas of the world develop nodular goiter, often with areas of autonomy. When this population is moved to areas of sufficient iodine intake, thyrotoxicosis occurs. Evidence that iodine can act as an immune stimulator exists, precipitating autoimmune thyroid disease and acting as a substrate for additional thyroid hormone synthesis.

Workup
Laboratory Studies

Laboratory evaluation of thyrotoxicosis: The most reliable screening measure of thyroid function is a TSH level. TSH levels usually are suppressed to immeasurable levels (<0.05 IU/mL) in thyrotoxicosis. Third-generation TSH assays are recommended for screening purposes. o The degree of thyrotoxicosis cannot be estimated easily by the TSH level and must be measured using an assay of thyroid hormone levels in the plasma. Thyroid hormone circulates as T3 and T4 with 99% bound to protein. Only the free unbound thyroid hormone is biologically active. T3 is 20-100 times more biologically active than T4. Of patients with thyrotoxicosis, 5% have only elevated T3 levels. Therefore, measuring free T4 (and T3 if T4 levels are normal) is recommended in patients with suspected thyrotoxicosis when TSH is low.

Many laboratories do not measure free T4 directly and use a calculation to estimate the FT4 levels. The free thyroxine index (FTI) is equal to total T4 multiplied by the correction for thyroid hormone binding, such as thyroid hormone-binding ratio [THBR] or triiodothyronine resin uptake [T3 RU]). A similar calculation can be used with total T3. Subclinical hyperthyroidism is defined as a suppressed TSH level (<0.5 U/mL in many laboratories) in combination with serum concentrations of T3 and T4 that are within the reference range. Thyroid autoantibodies - The most specific autoantibody for autoimmune thyroiditis is an enzyme-linked immunosorbent assay (ELISA) for anti-TPO antibody. The titers usually are significantly elevated in the most common type of hyperthyroidism, Graves thyrotoxicosis, and usually are low or absent in toxic multinodular goiter and toxic adenoma. A significant number of healthy people without active thyroid disease have mildly positive TPO antibodies; thus, the test should not be performed for screening purposes. TSI, if elevated, helps establish the diagnosis of Graves disease. A positive anti-TG antibody test does not predict the development of thyroid dysfunction and should not be measured.

Imaging Studies
Nuclear thyroid scintigraphy iodine 123 (123 I) uptake and scan - If the etiology of thyrotoxicosis is not clear after physical examination and other laboratory tests, it can be confirmed by an123 I uptake, as in the images below. Values are elevated in patients with Graves disease and toxic multinodular goiters.123 I and technetium-99m (99m Tc) can be used for thyroid scanning, which provides anatomic information on the type of goiter (eg, diffuse vs nodular). Scans essentially are pictures of the thyroid and do not necessarily confirm or refute the presence of hyperthyroidism per se; only123 I uptake provides information in this area.

Graves disease is associated with diffuse enlargement of both thyroid lobes, with an elevated uptake, as shown below.
o

Iodine 123 (123I) nuclear scintigraphy: 123I scans of a normal thyroid gland (A) and common hyperthyroid conditions with elevated

radioiodine uptake, including Graves disease (B), toxic multinodular goiter (C), and toxic adenoma (D). [ CLOSE WINDOW ]

Iodine 123 (123I) nuclear scintigraphy: 123I scans of a normal thyroid gland (A) and common hyperthyroid conditions with elevated radioiodine uptake, including Graves disease (B), toxic multinodular goiter (C), and toxic adenoma (D).

A toxic multinodular goiter demonstrates an enlarged thyroid with multiple nodules and areas of increased and decreased isotope uptake, as in the image above. Subacute thyroiditis usually demonstrates very low123 I isotope uptake. A toxic adenoma demonstrates a solitary hot nodule with suppression of function in the surrounding normal thyroid tissue, as shown above.

If a dominant nodule is found upon examination of a patient with thyrotoxicosis, obtain an123 I thyroid scan to assure that the dominant nodule is functioning. If the nodule is cold, perform a biopsy on the nodule by fine-needle aspiration to exclude concomitant malignancy.
o

Absence of iodine 123 (123I) radioactive iodine uptake in a patient with thyrotoxicosis and subacute painless or lymphocytic thyroiditis. Laboratory studies at the time of the scan demonstrated the following: thyroid-stimulating hormone (TSH), less than 0.06 mIU/mL; total thyroxine (T4), 21.2 mcg/dL (reference range, 4.5-11); total triiodothyronine (T3), 213 ng/dL (reference range, 90-180); T3-to-T4 ratio, 10; and erythrocyte sedimentation rate (ESR), 10 mm/h. The absence of thyroid uptake, the low T3-to-T4 ratio, and the low ESR confirm the diagnosis of subacute painless thyroiditis. [ CLOSE WINDOW ]

Absence of iodine 123 (123I) radioactive iodine uptake in a patient with thyrotoxicosis and subacute painless or lymphocytic thyroiditis. Laboratory studies at the time of the scan demonstrated the following: thyroid-stimulating hormone (TSH), less than 0.06 mIU/mL; total thyroxine (T4), 21.2 mcg/dL (reference range, 4.5-11); total triiodothyronine (T3), 213 ng/dL (reference range, 90-180); T3-to-T4 ratio, 10; and erythrocyte sedimentation rate (ESR), 10 mm/h. The absence of thyroid uptake, the low T3-to-T4 ratio, and the low ESR confirm the diagnosis of subacute painless thyroiditis.
o

Scan in a patient with a toxic multinodular goiter. The 5-hour iodine uptake was elevated at 28%. Note the multiple foci of variably increased tracer uptake. [ CLOSE WINDOW ]

Scan in a patient with a toxic multinodular goiter. The 5-hour iodine uptake was elevated at 28%. Note the multiple foci of variably increased tracer uptake.

Other Tests

Hyperthyroidism in older patients often presents with atrial arrhythmias or CHF. ECG is recommended if an irregular heart rate or CHF is noted upon examination.

Treatment
Medical Care
With the exception of low123 I uptake hyperthyroidism (eg, subacute thyroiditis; see the eMedicine topics Subacute Thyroiditis; Thyrotoxicosis), the treatment of hyperthyroidism includes symptom relief and therapy with antithyroid medications, therapy with radioactive iodine131 I, or thyroidectomy.

Symptom relief - Many of the neurologic and cardiovascular symptoms of thyrotoxicosis are relieved by beta-blocker therapy. Prior to therapy, examine the patient for signs and symptoms of dehydration that often occur with hyperthyroidism. After oral rehydration, beta-blocker therapy can be started. Do not administer betablocker therapy to a patient with a significant history of asthma. Calcium-channel blockers can be used for the same purposes when beta blockers are contraindicated or poorly tolerated. Antithyroid drugs - Antithyroid drugs (eg, methimazole, propylthiouracil) have been used for hyperthyroidism since their introduction in the 1940s. These drugs inhibit multiple steps in the synthesis of T4 and T3, leading to a gradual reduction in thyroid hormone levels over 2-8 weeks or longer. Titrate the antithyroid drug dose every 4 weeks until thyroid functions normalize. Some patients with Graves disease go into a remission after treatment for 12-18 months, and the drug can be discontinued. Notably, half the patients who go into remission have a recurrence of hyperthyroidism within the following year. Nodular forms of hyperthyroidism (toxic multinodular goiter and toxic adenoma) are permanent conditions and will not go into remission.
o

Antithyroid medications inhibit formation and coupling of iodotyrosines in thyroglobulin, which are necessary for thyroid hormone synthesis. A second therapeutic action of propylthiouracil, but not methimazole, is the inhibition of conversion of T4 to T3. T3 is a more biologically active form of thyroid hormone. A quick reduction in T3 is associated with a clinically significant improvement in thyrotoxic symptoms. The antithyroid medications are used for the long-term control of hyperthyroidism in children, adolescents, and pregnant women (propylthiouracil only for pregnancy). In women who are not pregnant, the medications are used to control hyperthyroidism prior to definitive therapy with radioactive iodine. In surveys of thyroid specialists in the United States, the preferred treatment of hyperthyroidism is radioactive iodine therapy. The choice between propylthiouracil and methimazole is somewhat arbitrary. Methimazole is a more potent and longer-acting drug. Often, patient compliance is better with methimazole taken once or twice daily than with propylthiouracil given 3 or 4 times daily. Propylthiouracil often is the drug of

choice in severe thyrotoxicosis because of the additional benefit of inhibition of T4 -to-T3 conversion. Administer propylthiouracil every 6-8 hours. The reduction in T3, which is 20-100 times more potent than T4, theoretically helps to reduce the thyrotoxic symptoms more quickly than does methimazole.
o

Adverse effects of antithyroid medications - The most common effects are allergic reactions of fever, rash, urticaria, and arthralgia, which occur in 1-5% of patients, usually within the first few weeks of treatment. Serious adverse effects include agranulocytosis, aplastic anemia, hepatitis, polyarthritis, and a lupuslike vasculitis. All of these adverse effects, except agranulocytosis, occur more frequently with propylthiouracil. Agranulocytosis occurs in 0.2-0.5% of patients, with an equal frequency for both drugs. Patients with agranulocytosis usually present with fever and pharyngitis. After the drug is stopped, granulocyte counts usually start to rise within several days but may not normalize for 10-14 days. Granulocyte colony-stimulating factor (G-CSF) appears to accelerate recovery in patients with a bone marrow aspiration showing a granulocyte-to-erythrocyte (G:E) ratio of 1:2 or greater than 0.5. The US Food and Drug Administration (FDA) added a boxed warning, the strongest warning issued by the FDA, to the prescribing information for propylthiouracil. The boxed warning emphasizes the risk for severe liver injury and acute liver failure, some of which have been fatal. The boxed warning also states that propylthiouracil should be reserved for use in patients who cannot tolerate other treatments, such as methimazole, radioactive iodine, or surgery. The decision to include a boxed warning was based on the FDA's review of postmarketing safety reports and on meetings held with the American Thyroid Association, the National Institute of Child Health and Human Development, and the pediatric endocrine clinical community. The FDA has identified 32 cases (22 adult and 10 pediatric) of serious liver injury associated with propylthiouracil. Of the adults, 12 deaths and 5 liver transplants occurred, and among the pediatric patients, 1 death and 6 liver transplants occurred. Propylthiouracil is indicated for hyperthyroidism due to Graves disease. These reports suggest an increased risk for liver toxicity with propylthiouracil compared with methimazole. Serious liver injury has been identified with methimazole in 5 cases (3 resulting in death).

Propylthiouracil is considered to be a second-line drug therapy, except in patients who are allergic to or intolerant of methimazole, or in women who are in the first trimester of pregnancy. Rare cases of embryopathy, including aplasia cutis, have been reported with methimazole during pregnancy. The FDA recommends the following criteria be considered for prescribing propylthiouracil (for more information, see the FDA Safety Alert)3 :

Reserve propylthiouracil use during first trimester of pregnancy or in patients who are allergic to or intolerant of methimazole

Closely monitor propylthiouracil therapy for signs and symptoms of liver injury, especially during the first 6 months after initiation of therapy For suspected liver injury, promptly discontinue propylthiouracil therapy, evaluate the patient for evidence of liver injury, and provide supportive care Propylthiouracil should not be used in pediatric patients unless the patient is allergic to or intolerant of methimazole and no other treatment options are available Counsel patients to promptly contact their health care provider for the following signs or symptoms: fatigue, weakness, vague abdominal pain, loss of appetite, itching, easy bruising, or yellowing of the eyes or skin.

Other drugs - In severe thyrotoxicosis from Graves disease or subacute thyroiditis, iodine or iodinated contrast agents have been administered to block T4 conversion to T3 and the release of thyroid hormone from the gland. This therapy is reserved for severe thyrotoxicosis, because its use prevents definitive therapy of Graves thyrotoxicosis with radioactive iodine for many weeks. Either a saturated solution of potassium iodide (SSKI) at 10 gtt twice daily or iopanoic acid/ipodate (1 g/d) can be administered with rapid reduction in T3 levels. Take care to not administer these drugs to patients with toxic multinodular goiter or toxic adenomas. The autonomous nature of these conditions can lead to worsening of the thyrotoxicosis in the presence of pharmacologic levels of iodide, a substrate in thyroid hormone synthesis. Radioactive iodine therapy4 - Radioactive iodine therapy is the most common treatment for hyperthyroidism in adults in the United States. Although the effect is less rapid than it is in antithyroid medication or thyroidectomy, it is effective and safe and does not require hospitalization. It is administered orally as a single dose, in capsule or liquid form. The radioactive iodine is quickly absorbed and taken up by the thyroid. No other tissue or organ in the body is capable of retaining the radioactive iodine and, therefore, very few adverse effects are associated with this therapy.
o

The treatment results in a thyroid-specific inflammatory response, causing fibrosis and destruction of the thyroid over weeks to many months. Generally, the dose of131 I administered is 75-200 Ci/g of estimated thyroid tissue divided by the percent of123 I uptake in 24 hours. This dose is intended to render the patient hypothyroid. Lithium used in the weeks following radioactive iodine therapy may extend the retention of radioactive iodine and result in increased efficacy. However, studies looking at this are inconsistent, and the benefits of lithium used with radioactive iodine must be weighed against the toxicities associated with lithium. Hypothyroidism is considered by many experts to be the expected goal of radioactive iodine therapy. In several large epidemiologic studies of radioactive iodine therapy in patients with Graves disease, no evidence indicated that radioactive iodine therapy caused the development of thyroid carcinoma. No evidence of increased mortality exists for any other form of

cancer, including leukemia, with radioactive iodine therapy of hyperthyroidism.

o

Long-term follow-up data of children and adolescents treated with radioactive iodine are lacking. Consequently, long-term antithyroid medications, rather than radioiodine therapy, usually are recommended in children. Radioactive iodine is never administered to pregnant or lactating women; it can cross the placenta and can be excreted into milk, which can ablate the infant's thyroid and result in hypothyroidism. Checking for pregnancy prior to radioactive iodine therapy and suggesting that the patient not become pregnant for at least 3-6 months after the treatment and until thyroid functions are normal are standard practice. Retrospective reviews have demonstrated no excess in fetal malformations or miscarriage rates in women previously treated with radioactive iodine for hyperthyroidism. Radioactive iodine usually is not administered to patients with severe ophthalmopathy, because clinical evidence suggests that usually mild, but occasionally severe, worsening of thyroid eye disease occurs after radioactive iodine therapy. The risk of ophthalmopathy is worse in patients who smoke cigarettes, but apparently it can be reduced by glucocorticoid therapy (prednisone 0.4 mg/kg for 1 mo with subsequent taper) after the radioactive iodine therapy.

Surgical Care
Subtotal thyroidectomy is the oldest form of treatment for hyperthyroidism. Total thyroidectomy and combinations of hemithyroidectomies and contralateral subtotal thyroidectomies also have been used.4,5

Because of excellent effectiveness in regulating thyroid function with antithyroid medications and radioactive iodine, thyroidectomy is reserved for special circumstances, including the following: o Severe hyperthyroidism in children
o o o o o

Pregnant women who are noncompliant or intolerant of antithyroid medication Patients with very large goiters or severe ophthalmopathy Patients who refuse radioactive iodine therapy Refractory amiodarone-induced hyperthyroidism Patients who require normalization of thyroid functions quickly, such as pregnant women, women who desire pregnancy in the next 6 months, or patients with unstable cardiac conditions

With current operative techniques, bilateral subtotal thyroidectomy should have a mortality rate approaching zero in patients who are properly prepared. Historically,

the most common cause of thyroid storm, a physiologic decompensation in patients who are severely thyrotoxic, with a mortality rate of 50-100%, is operative stress.

Preoperative preparation includes antithyroid medication, stable (cold) iodine treatment (to decrease gland vascularity), and beta-blocker therapy.5
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Generally, antithyroid drug therapy should be administered until thyroid functions normalize (4-8 wk). Titrate propranolol until the resting pulse rate is less than 80 bpm. Finally, administer iodide as SSKI (1-2 drops bid for 10-14 d) before surgery. An additional benefit from stable iodide therapy, besides the reduction in thyroid hormone excretion, is a demonstrated decrease in thyroid blood flow and possible reduction in blood loss during surgery.

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Adverse effects of therapy include recurrent laryngeal nerve damage and hypoparathyroidism due to damage of local structures during surgery. (A Swiss study indicated that a single dose of steroid administered prior to thyroidectomy can reduce nausea, pain, and vomiting associated with the procedure, as well as improve voice function.)6

Consultations

Generally, thyrotoxicosis should be evaluated and treated by an endocrinologist. Therapy including radioactive iodine and antithyroid medication requires careful follow-up, which is best performed by a specialist. Generally, after definitive therapy is completed with radioactive iodine or surgical thyroidectomy, the patient can be cared for by the primary care doctor (with thyroid hormone replacement therapy if necessary). Patients with Graves thyrotoxicosis should be examined by an ophthalmologist for thyroid eye disease, which occurs in some form in 50% of patients. Often, the eye disease is subclinical and remits with time. The eye disease usually occurs within 1 year before or after the diagnosis of hyperthyroidism, but new-onset has been detected decades later. Graves eye disease also can occur without the patient ever having developed hyperthyroidism.

Diet

No special diet must be followed by patients with thyroid disease. Notably, excess amounts of iodide found in some expectorants, radiographic contrast dyes, seaweed tablets, and health food supplements should be avoided, because the iodide interferes with or complicates the management of antithyroid and radioactive iodine therapies.

Activity

In otherwise healthy patients with hyperthyroidism, exercise tolerance often is not significantly affected. For these people, no reduction in physical activity is necessary. For elderly patients or for persons with cardiopulmonary comorbidities, a decrease in activity is prudent until hyperthyroidism is medically controlled. With severe thyrotoxicosis, systolic and diastolic cardiac dysfunction are often manifested by dyspnea upon exertion. In many cases, beta-blocker therapy greatly improves exercise tolerance until thyroid hormones levels are reduced by other therapies.