AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Thyrotoxicosis is the hypermetabolic condition associated with elevated levels of free thyroxine (FT₄), free triiodothyronine (FT₃), or both. Hyperthyroidism includes diseases that are a subset of thyrotoxicosis (excludes exogenous thyroid hormone intake and subacute thyroiditis) that is caused by excess synthesis and secretion of thyroid hormone by the thyroid. 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 Thyroiditis, Subacute.

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

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). 

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, antithyroperoxidase (anti-TPO), and antithyroglobulin (anti-TG) antibodies. The most important autoantibody is thyroid-stimulating 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 (see Image 1B) compared to a healthy thyroid (see Image 1A).

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, and 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.

The next most common cause of thyrotoxicosis is subacute thyroiditis (approximately 15-20%), a destructive release of preformed thyroid hormone. A typical nuclear scintigraphy scan shows no radioactive iodine uptake in the thyrotoxic phase of the disease. 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.

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 Image 1C and demonstrates an enlarged thyroid gland with areas of increased and decreased activity.

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 Image 1D).

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 (bHCG) that can weakly activate the TSH receptor. At very high levels of bHCG, activation of the TSH receptor occurs that is sufficient to cause thyrotoxicosis. Physiological maximum elevation of bHCG 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 bHCG 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 20-40 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 to 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 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). 



• 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.



• 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. Toxic multinodular goiter and toxic adenomas occur more frequently in women than in men, with a ratio of 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, therefore, usually present when they are older than 50 years. Patients with toxic adenomas present at a younger age than patients with toxic multinodular goiter.

CLINICAL

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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:
  
  
  • Nervousness
  
  
  
  • Anxiety
  
  
  
  • Increased perspiration
  
  
  
  • Heat intolerance
  
  
  
  • Tremor
  
  
  
  • Hyperactivity
  
  
  
  • Palpitations
  
  
  
  • Weight loss despite increased appetite
  
  
  
  • Reduction in menstrual flow or oligomenorrhea (in women)
     
• Common signs of thyrotoxicosis include the following:
  
  
  • 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 times increased risk of atrial fibrillation. The prevalence of subclinical hyperthyroidism may be as high as 12% in the general population.



• Radiation exposure, whether due to radiation therapy or lower-level x-ray 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 medications contain large amounts of iodine, including expectorants, amiodarone, health food supplements containing seaweed, and iodinated contrast dyes, 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.
  
  
  • 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.
  
  
  
  • Toxic multinodular goiters occur in goiters that 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.
  
  
  • 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, soft smooth skin, excessive perspiration, palmar erythema and sweating, lid lag, extension tremor, hyperkinesis, and large-muscle weakness.

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.
• • Graves disease is felt to be an HLA-related organ-specific defect in suppressor T-lymphocyte function.

  • 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.

DIFFERENTIALS

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Other Problems to be Considered

Thyrotoxicosis
Subclinical hyperthyroidism
Toxic thyroid adenoma
Toxic multinodular goiter

WORKUP

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Lab 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 µIU/mL) in thyrotoxicosis. Third-generation TSH assays are recommended for screening purposes.
  
  
  • 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 [T₃RU]). A similar calculation can be used with total T₃.
  
  
  
  • Subclinical hyperthyroidism is defined as a suppressed TSH level (<0.5 μU/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 (thyroperoxidase). 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 antithyroglobulin antibody test does not predict the development of thyroid dysfunction and should not be measured.

Imaging Studies

• Nuclear thyroid scintigraphy iodine 123 (I-123) uptake and scan: If the etiology is not clear after physical examination and other laboratory tests, the etiology of thyrotoxicosis can be confirmed by an I-123 uptake. Values are elevated in patients with Graves disease and toxic multinodular goiters. Both I-123 and technetium-99m 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; only I-123 uptake provides information in this area.
• • Graves disease is associated with diffuse enlargement of both thyroid lobes, with an elevated uptake (see Image 1B).
  
  
  
  • A toxic multinodular goiter demonstrates an enlarged thyroid with multiple nodules and areas of both increased and decreased isotope uptake (see Image 1C).
  
  
  
  • Subacute thyroiditis usually demonstrates very low I-123 isotope uptake.
  
  
  
  • A toxic adenoma demonstrates a solitary hot nodule with suppression of function in the surrounding normal thyroid tissue (see Image 1D).
  
  
  
  • If a dominant nodule is found upon examination of a patient with thyrotoxicosis, obtain an I-123 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.

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

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Medical Care

With the exception of low I-123 uptake hyperthyroidism (eg, subacute thyroiditis; see Thyrotoxicosis), the treatment of hyperthyroidism includes symptom relief and therapy with antithyroid medications, therapy with radioactive iodine 131 (I-131), or thyroidectomy.

• Symptom relief: Many of the neurological 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 beta-blocker 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 another 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.
  
  
  • 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 reduce the thyrotoxic symptoms more quickly that methimazole.
  
  
  
  • 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.
     
• 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 pharmacological levels of iodide, a substrate in thyroid hormone synthesis.



• Radioactive iodine therapy: Radioactive iodine therapy is the most common treatment of hyperthyroidism in adults in the United States. Although the effect is less rapid than antithyroid medication or thyroidectomy, it is effective, 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.
  
  
  • The treatment results in a thyroid-specific inflammatory response, causing fibrosis and destruction of the thyroid over weeks to many months.
  
  
  
  • Generally, the dose of I-131 administered is 75-200 µCi/g of estimated thyroid tissue divided by the percent of I-123 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 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 epidemiological 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.
  
  
  
  • Long-term follow-up data of children and adolescents treated with radioactive iodine are lacking. Because of this absence of data, long-term antithyroid medications usually are recommended in children rather than radioiodine therapy.
  
  
  
  • Radioactive iodine is never administered to pregnant or lactating women. Radioactive iodine can cross the placenta and 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 of hyperthyroidism. Total thyroidectomy and combinations of hemithyroidectomies and contralateral subtotal thyroidectomies also have been used.

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

  • 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 physiological decompensation in patients who are severely thyrotoxic with a mortality of 50-100%, is operative stress.

• Preoperative preparation includes antithyroid medication, stable (cold) iodine treatment (to decrease gland vascularity), and beta-blocker therapy.
• • 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.

• Adverse effects of therapy include recurrent laryngeal nerve damage and hypoparathyroidism due to damage of local structures during surgery.

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) of 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, x-ray contrast dyes, seaweed tablets, and health food supplements should be avoided because the iodide interferes with or complicates the management of both antithyroid and radioactive iodine therapies.

Activity

• Often, in otherwise healthy patients with hyperthyroidism, exercise tolerance is not affected significantly. For these people, no reduction in physical activity is necessary. For elderly patients or for those with cardiopulmonary comorbidities, a decrease in activity is prudent until hyperthyroidism is medically controlled.



• Often with severe thyrotoxicosis, systolic and diastolic cardiac dysfunction manifested by dyspnea upon exertion exists.



• Often, beta-blocker therapy greatly improves exercise tolerance until thyroid hormones levels are reduced by other therapies.

MEDICATION

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Drug therapy includes medications that reduce the symptoms of thyrotoxicosis and decrease the synthesis and release of thyroid hormone. In the United States, the most common definitive therapy of hyperthyroidism is ablation of the hyperactive thyroid with an oral dose of I-131. Sometimes, the patient is treated with antithyroid medication to return thyroid hormone levels to normal. When that is accomplished, some patients (eg, those with a toxic multinodular goiter or toxic adenoma) are treated immediately with radioactive iodine, while patients with autoimmune Graves disease may be treated for 12-18 months with antithyroid medications because of the possibility that the patient will go into remission.

Nevertheless, the most common treatment for these patients in the United States is to receive I-131 as their first and only medication. Patients with other forms of hyperthyroidism, including toxic multinodular goiter and toxic adenoma, continue indefinitely to be thyrotoxic, and remissions with antithyroid medications are not expected.

Drug Category: Antithyroid medications

Inhibit T₄ and T₃ synthesis.

Drug Category: Beta-adrenergic receptor blockers

Reduce many of the symptoms of thyrotoxicosis, including tachycardia, tremor, and anxiety. Usually propranolol is recommended because of CNS penetration, but some patients prefer longer-acting beta-blockers. Patients note an immediate improvement in tachycardia, anxiety, heat intolerance, and tremor. Calcium channel blockers for tachycardia sometimes are used when beta-blockers are contraindicated or not tolerated.

Drug Category: Inorganic iodide or iodinated radiographic contrast agents

High intrathyroidal iodine levels in Graves thyrotoxicosis leads to an inhibition of iodine transport and thyroid hormone synthesis (Wolff-Chaikoff effect) and blocks release of T₄ and T₃ from the thyroid. Excess iodide with toxic multinodular goiter or toxic adenoma may result in exacerbation of thyrotoxicosis. Administration of pharmacological doses of iodide prevents radioactive iodine therapy for many weeks. Many patients unexpectedly escape from the inhibitory effects of iodide. Therefore, it is not used in long-term maintenance therapy of Graves thyrotoxicosis.

FOLLOW-UP

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Further Outpatient Care

• Patients with normalization of thyroid functions after surgery require routine follow-up because they may develop hypothyroidism (from their chronic thyroiditis), recurrent hyperthyroidism, or thyroid eye disease sometime in the future.
• Care after initiation of antithyroid medications includes the following:
• • After 4-6 weeks, antithyroid medications usually must be reduced; otherwise, the patient becomes hypothyroid. Hypothyroidism causes the usual symptoms of fatigue and weight gain, but in patients with Graves disease, it has been anecdotally associated with worsening of thyroid ophthalmopathy.

  • Initially, the patient should have thyroid function tests performed every 4-6 weeks until thyroid levels are stabilized on a low dose of antithyroid medication. Perform follow-up tests of thyroid function at least every 3 months for the first year. After 12-18 months, stop antithyroid medication or decrease it in patients with Graves hyperthyroidism to determine if the patient has gone into remission.

  • Non–Graves hyperthyroidism rarely has remissions. Once a patient with Graves hyperthyroidism becomes euthyroid on oral antithyroid medication, consider other definitive treatment such as radioactive iodine therapy. A significant fraction of patients with Graves disease go into remission and most eventually, over many years, become hypothyroid from autoimmune destruction of the gland.

• Care after radioactive iodine ablation includes the following:
• • Ablation of the gland occurs over several (4-5) months after the therapy. Most patients become hypothyroid. Checking thyroid functions every 4-6 weeks until they stabilize is recommended.

  • Once the thyroid hormone levels start falling into the low normal range, stopping antithyroid medications and considering starting a low dose of thyroid hormone replacement before the patient becomes hypothyroid is reasonable; however, some prefer to document persistently elevated TSH values off antithyroid medication before starting thyroid hormone replacement. Starting with partial or low-dose thyroid hormone replacement is recommended (25-50 mcg/d and adjusted every 6-8 wk to normalize the TSH level). Starting with full replacement doses when TSH first becomes elevated after I-131 therapy leads to a higher incidence of hyperthyroidism due to overreplacement.

  • Rarely after I-131 therapy, patients can become thyrotoxic due to vigorous thyroid destruction and release of preformed hormone. Also, radioablation can cause the release of thyroid antigens and exacerbate the autoimmune thyroid disease process. When the former happens, it often is accompanied by a painful radiation-induced thyroiditis that can be treated with nonsteroidal anti-inflammatory medication or glucocorticoids.

• Care after subthyroidectomy or other thyroid surgery includes the following:
• • Most patients remain euthyroid after a lobectomy or lobectomy plus isthmusectomy. Obtain thyroid function tests 3-4 weeks postoperatively after a lobectomy to ensure normal thyroid function.

  • After subtotal thyroidectomy for hyperthyroidism and cessation of antithyroid therapy, most patients become hypothyroid, depending on how much functional tissue is left by the surgeon.

  • After a subtotal thyroidectomy, partial replacement (T₄ 50-75 mcg/d) is recommended, to begin shortly after surgery. Monitor thyroid function tests 4-8 weeks postoperatively, and adjust the T₄ dose to maintain a normal TSH level.

Complications

• Graves ophthalmopathy
  
  
  • Graves ophthalmopathy is more common in women than in men.
  
  
  
  • Although 50% of patients with Graves disease have clinical evidence of thyroid eye disease, only 5% develop severe ophthalmopathy, eg, diplopia, visual-field deficits, blurred vision, tearing, and photophobia. The less serious symptoms (photophobia, irritation, tearing) are treated with tight-fitting sunglasses that should be worn at all times when the patient is outside and saline eye drops that are taken as necessary for comfort.
  
  
  
  • The pathogenesis of Graves ophthalmopathy lies in the deposition of glycosaminoglycans (GAG) in the extraocular muscles and adipose and connective tissue of the retro-orbit, leading to T-cell activation. The TSH receptor antigen is thought to be a key mediator in the process of T-cell activation.
  
  
  
  • Patients should be monitored by an ophthalmologist if exposure keratitis is suspected. Exposure keratitis usually occurs when eyelid closure is incomplete and the cornea is exposed at night, when the patient does not blink. Characteristically, the patient complains of irritation and tearing upon awakening. This is treated with saline gel or drops and taping eyelids closed with paper tape prior to sleep. Some ophthalmologists are concerned about corneal abrasion from the tape and, instead, recommend wearing goggles at night to maintain a moist eye.
  
  
  
  • A medical emergency occurs when sufficient orbital edema exists to cause optic nerve compression with early loss of color vision and orbital pain. Without treatment, continued pressure of the optical nerve may cause permanent vision loss. High-dose glucocorticoids are administered with consideration for decompressive surgery and radiation therapy.
  
  
  
  • Cigarette smoking is also a significant risk factor, increasing the odds of ophthalmopathy approximately 7-fold. Patients who are treated with radioactive iodine are more likely to experience worsening of their ophthalmopathy than patients treated with antithyroid medications or surgery. 
     
• Dermopathy
  
  
  • This is an infiltrative dermopathy, usually over the lower extremities, that is characterized by an accumulation of glycosaminoglycans and inflammatory cells in the dermis. The skin changes usually include a nonpitting erythematous edema of the anterior shins.
  
  
  
  • Dermopathy can occur at other sites of repeat trauma. The dermopathy usually only occurs in the presence of significant ophthalmopathy. No effective treatment exists. Nightly occlusive wraps of the affected site are recommended with plastic wrap after application of a high-potency topical steroid cream.

Prognosis

• Hyperthyroidism from toxic multinodular goiter and toxic adenoma is permanent and usually occurs in adults. After normalization of thyroid functions with antithyroid medications, radioactive iodine ablation usually is recommended as the definitive therapy. Long-term high-dose antithyroid medication is not recommended. Both conditions probably will continue to grow slowly in size during antithyroid medication therapy. The prognosis is good after radioactive iodine therapy.
• • Generally, the thyrotoxic areas are ablated, and patients may remain euthyroid. Those who become hypothyroid after radioactive iodine therapy are easily maintained on thyroid hormone replacement therapy with T₄ taken once daily.

  • Patients with Graves disease often become hypothyroid in the natural course of their disease. Whether treatment is radioactive iodine or surgery, the outcome usually is hypothyroidism. The development of an eye disease can happen at a time distant from the initial diagnosis and therapy. Generally, the ophthalmopathy slowly improves over years after the diagnosis.

Patient Education

• For excellent patient education resources, visit eMedicine's Endocrine System Center. Also, see eMedicine's patient education article Thyroid Problems.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• If a physician treats enough patients who are hyperthyroid, eventually, the physician will encounter a patient who develops agranulocytosis or hepatitis from the antithyroid medications. Discussing these adverse effects with patients before starting therapy is important; give the patients written instructions or document verbal instructions to stop the medication and receive a blood count with differentials for a high fever (>100.5°F) or a severe sore throat.
• The use of radioisotopes to diagnose and treat thyroid disease exposes the practitioner to certain risks. Examples of potential problems include the administration of isotopes to patients who are pregnant or may become pregnant in the near future. The Nuclear Regulatory Commission and specific state agencies maintain specific regulations on the proper use of radioisotopes, and practitioner noncompliance may lead to fines and other disciplinary actions.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Iodine 123 nuclear scintigraphy: Iodine 123 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).
	View Full Size Image
Media type:  CT

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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• Bahn RS, Heufelder AE. Pathogenesis of Graves' ophthalmopathy. N Engl J Med. Nov 11 1993;329(20):1468-75. [Medline].
• Bal CS, Kumar A, Pandey RM. A randomized controlled trial to evaluate the adjuvant effect of lithium on radioiodine treatment of hyperthyroidism. Thyroid. May 2002;12(5):399-405. [Medline].
• Bartalena L, Marcocci C, Bogazzi F, et al. Relation between therapy for hyperthyroidism and the course of Graves' ophthalmopathy. N Engl J Med. Jan 8 1998;338(2):73-8. [Medline].
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• Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab. Feb 2002;87(2):489-99. [Medline].
• Leslie WD, Ward L, Salamon EA, et al. A randomized comparison of radioiodine doses in Graves' hyperthyroidism. J Clin Endocrinol Metab. Mar 2003;88(3):978-83. [Medline].
• Loh KC. Amiodarone-induced thyroid disorders: a clinical review. Postgrad Med J. Mar 2000;76(893):133-40. [Medline].
• Prummel MF, Wiersinga WM. Smoking and risk of Graves' disease. JAMA. Jan 27 1993;269(4):479-82. [Medline].
• Ringel MD. Management of hypothyroidism and hyperthyroidism in the intensive care unit. Crit Care Clin. Jan 2001;17(1):59-74. [Medline].
• Sawin CT, Geller A, Wolf PA, et al. Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med. Nov 10 1994;331(19):1249-52. [Medline].
• Siegel RD, Lee SL. Toxic nodular goiter. Toxic adenoma and toxic multinodular goiter. Endocrinol Metab Clin North Am. Mar 1998;27(1):151-68. [Medline].
• Weetman AP. Graves' disease. N Engl J Med. Oct 26 2000;343(17):1236-48. [Medline].

Article Last Updated: Jul 18, 2006