Hyperthyroidism is characterized by hypermetabolism and elevated serum levels of free thyroid hormones. Symptoms are many and include tachycardia, fatigue, weight loss, nervousness, and tremor. Diagnosis is clinical and with thyroid function tests. Treatment depends on cause.
Hyperthyroidism can be classified on the basis of thyroid radioactive iodine uptake and the presence or absence of circulating thyroid stimulators (see Table 1: Results of Thyroid Function Tests in Various Clinical Situations).
Hyperthyroidism may result from increased synthesis and secretion of thyroid hormones (thyroxine [T4] and triiodothyronine [T3]) from the thyroid, caused by thyroid stimulators in the blood or by autonomous thyroid hyperfunction. It can also result from excessive release of thyroid hormone from the thyroid without increased synthesis. Such release is commonly caused by the destructive changes of various types of thyroiditis. Various clinical syndromes also cause hyperthyroidism.
The most common causes overall include
Graves disease (toxic diffuse goiter), the most common cause of hyperthyroidism, is characterized by hyperthyroidism and one or more of the following:
Graves disease is caused by an autoantibody against the thyroid receptor for thyroid-stimulating hormone (TSH); unlike most autoantibodies, which are inhibitory, this autoantibody is stimulatory, thus causing continuous synthesis and secretion of excess T4 and T3. Graves disease (like Hashimoto thyroiditis) sometimes occurs with other autoimmune disorders, including type 1 diabetes mellitus, vitiligo, premature graying of hair, pernicious anemia, connective tissue disorders, and polyglandular deficiency syndrome. The pathogenesis of infiltrative ophthalmopathy (responsible for the exophthalmos in Graves disease) is poorly understood but may result from immunoglobulins directed to the TSH receptors in the orbital fibroblasts and fat that result in release of proinflammatory cytokines, inflammation, and accumulation of glycosaminoglycans. Ophthalmopathy may also occur before the onset of hyperthyroidism or as late as 20 yr afterward and frequently worsens or abates independently of the clinical course of hyperthyroidism. Typical ophthalmopathy in the presence of normal thyroid function is called euthyroid Graves disease.
Inappropriate TSH secretion is a rare cause. Patients with hyperthyroidism have essentially undetectable TSH except for those with a TSH-secreting anterior pituitary adenoma or pituitary resistance to thyroid hormone. TSH levels are high, and the TSH produced in both disorders is biologically more active than normal TSH. An increase in the α-subunit of TSH in the blood (helpful in differential diagnosis) occurs in patients with a TSH-secreting pituitary adenoma.
Molar pregnancy, choriocarcinoma, and hyperemesis gravidarum produce high levels of serum human chorionic gonadotropin (hCG), a weak thyroid stimulator. Levels of hCG are highest during the 1st trimester of pregnancy and result in the decrease in serum TSH and mild increase in serum free T4 sometimes observed at that time. The increased thyroid stimulation may be caused by increased levels of partially desialated hCG, an hCG variant that appears to be a more potent thyroid stimulator than more sialated hCG. Hyperthyroidism in molar pregnancy, choriocarcinoma, and hyperemesis gravidarum is transient; normal thyroid function resumes when the molar pregnancy is evacuated, the choriocarcinoma is appropriately treated, or the hyperemesis gravidarum abates.
Nonautoimmune autosomal dominant hyperthyroidism manifests during infancy. It results from mutations in the TSH receptor gene that produce continuous thyroid stimulation.
Toxic solitary or multinodular goiter (Plummer disease) sometimes results from TSH receptor gene mutations causing continuous thyroid activation. Patients with toxic nodular goiter have none of the autoimmune manifestations or circulating antibodies observed in patients with Graves disease. Also, in contrast to Graves disease, toxic solitary and multinodular goiters usually do not remit.
Inflammatory thyroid disease (thyroiditis) includes subacute granulomatous thyroiditis, Hashimoto thyroiditis, and silent lymphocytic thyroiditis, a variant of Hashimoto thyroiditis (see Silent Lymphocytic Thyroiditis). Hyperthyroidism results from destructive changes in the gland and release of stored hormone, not from increased synthesis. Hypothyroidism may follow.
Drug-induced hyperthyroidism can result from amiodarone and interferon-alfa, which may induce thyroiditis with hyperthyroidism and other thyroid disorders. Although more commonly causing hypothyroidism, lithium can rarely cause hyperthyroidism. Patients receiving these drugs should be closely monitored.
Thyrotoxicosis factitia is hyperthyroidism resulting from conscious or accidental overingestion of thyroid hormone.
Excess iodine ingestion causes hyperthyroidism with a low thyroid radioactive iodine uptake. It most often occurs in patients with underlying nontoxic nodular goiter (especially elderly patients) who are given drugs that contain iodine (eg, amiodarone, iodine-containing expectorants) or who undergo radiologic studies using iodine-rich contrast agents. The etiology may be that the excess iodine provides substrate for functionally autonomous (ie, not under TSH regulation) areas of the thyroid to produce hormone. Hyperthyroidism usually persists as long as excess iodine remains in the circulation.
Metastatic thyroid cancer is a possible cause. Overproduction of thyroid hormone occurs rarely from functioning metastatic follicular carcinoma, especially in pulmonary metastases.
Struma ovarii develops when ovarian teratomas contain enough thyroid tissue to cause true hyperthyroidism. Radioactive iodine uptake occurs in the pelvis, and uptake by the thyroid is usually suppressed.
In hyperthyroidism, serum T3 usually increases more than does T4, probably because of increased secretion of T3 as well as conversion of T4 to T3 in peripheral tissues. In some patients, only T3 is elevated (T3 toxicosis). T3 toxicosis may occur in any of the usual disorders that cause hyperthyroidism, including Graves disease, multinodular goiter, and the autonomously functioning solitary thyroid nodule. If T3 toxicosis is untreated, the patient usually also develops laboratory abnormalities typical of hyperthyroidism (ie, elevated T4 and 123I uptake). The various forms of thyroiditis commonly have a hyperthyroid phase followed by a hypothyroid phase.
Symptoms and Signs
Most symptoms and signs are the same regardless of the cause. Exceptions include infiltrative ophthalmopathy and dermopathy, which occur only in Graves disease.
The clinical presentation may be dramatic or subtle. A goiter or nodule may be present. Many common symptoms of hyperthyroidism are similar to those of adrenergic excess, such as nervousness, palpitations, hyperactivity, increased sweating, heat hypersensitivity, fatigue, increased appetite, weight loss, insomnia, weakness, and frequent bowel movements (occasionally diarrhea). Hypomenorrhea may be present. Signs may include warm, moist skin; tremor; tachycardia; widened pulse pressure; atrial fibrillation; and palpitations.
Elderly patients, particularly those with toxic nodular goiter, may present atypically (apathetic or masked hyperthyroidism) with symptoms more akin to depression or dementia. Most do not have exophthalmos or tremor. Atrial fibrillation, syncope, altered sensorium, heart failure, and weakness are more likely. Symptoms and signs may involve only a single organ system.
Eye signs include stare, eyelid lag, eyelid retraction, and mild conjunctival injection and are largely due to excessive adrenergic stimulation. They usually remit with successful treatment. Infiltrative ophthalmopathy, a more serious development, is specific to Graves disease and can occur years before or after hyperthyroidism. It is characterized by orbital pain, lacrimation, irritation, photophobia, increased retro-orbital tissue, exophthalmos, and lymphocytic infiltration of the extraocular muscles, causing ocular muscle weakness that frequently leads to double vision.
Infiltrative dermopathy, also called pretibial myxedema (a confusing term, because myxedema suggests hypothyroidism), is characterized by nonpitting infiltration by proteinaceous ground substance, usually in the pretibial area. It rarely occurs in the absence of Graves ophthalmopathy. The lesion is often pruritic and erythematous in its early stages and subsequently becomes brawny. Infiltrative dermopathy may appear years before or after hyperthyroidism.
Thyroid storm is an acute form of hyperthyroidism that results from untreated or inadequately treated severe hyperthyroidism. It is rare, occurring in patients with Graves disease or toxic multinodular goiter (a solitary toxic nodule is a less common cause and generally causes less severe manifestations). It may be precipitated by infection, trauma, surgery, embolism, diabetic ketoacidosis, or preeclampsia. Thyroid storm causes abrupt florid symptoms of hyperthyroidism with one or more of the following: fever, marked weakness and muscle wasting, extreme restlessness with wide emotional swings, confusion, psychosis, coma, nausea, vomiting, diarrhea, and hepatomegaly with mild jaundice. The patient may present with cardiovascular collapse and shock. Thyroid storm is a life-threatening emergency requiring prompt treatment.
Diagnosis is based on history, physical examination, and thyroid function tests. Serum TSH measurement is the best test because TSH is suppressed in hyperthyroid patients except in the rare instance when the etiology is a TSH-secreting pituitary adenoma or pituitary resistance to the normal inhibition by thyroid hormone. Screening selected populations for TSH level is warranted (see Laboratory Testing of Thyroid Function). Free T4 is increased in hyperthyroidism. However, T4 can be falsely normal in true hyperthyroidism in patients with a severe systemic illness (similar to the falsely low levels that occur in euthyroid sick syndrome) and in T3 toxicosis. If free T4 level is normal and TSH is low in a patient with subtle symptoms and signs of hyperthyroidism, then serum T3 should be measured to detect T3 toxicosis; an elevated level confirms that diagnosis.
The cause can often be diagnosed clinically (eg, exposure to a drug, the presence of signs specific to Graves disease). If not, radioactive iodine uptake by the thyroid may be measured by using 123I. When hyperthyroidism is due to hormone overproduction, radioactive iodine uptake by the thyroid is usually elevated. When hyperthyroidism is due to thyroiditis, iodine ingestion, or ectopic hormone production, radioactive iodine uptake is low.
TSH receptor antibodies can be measured to detect Graves disease, but measurement is rarely necessary except during the 3rd trimester of pregnancy to assess the risk of neonatal Graves disease; TSH receptor antibodies readily cross the placenta to stimulate the fetal thyroid. Most patients with Graves disease have circulating antithyroid peroxidase antibodies, and fewer have antithyroglobulin antibodies.
Inappropriate TSH secretion is uncommon. The diagnosis is confirmed when hyperthyroidism occurs with elevated circulating free T4 and T3 concentrations and normal or elevated serum TSH.
If thyrotoxicosis factitia is suspected, serum thyroglobulin can be measured; it is usually low or low-normal—unlike in all other causes of hyperthyroidism.
Treatment depends on cause but may include
Methimazole and propylthiouracil:
These antithyroid drugs block thyroid peroxidase, decreasing the organification of iodide, and impair the coupling reaction. Propylthiouracil in high doses also inhibits the peripheral conversion of T4 to T3. About 20 to 50% of patients with Graves disease remain in remission after a 1- to 2-yr course of either drug. The return to normal or a marked decrease in gland size, the restoration of a normal serum TSH level, and less severe hyperthyroidism before therapy are good prognostic signs of long-term remission. The concomitant use of antithyroid drug therapy and l-thyroxine does not improve the remission rate in patients with Graves disease. Because toxic nodular goiter rarely goes into remission, antithyroid drug therapy is given only in preparation for surgical treatment or 131I therapy.
Because of severe hepatic failure in some patients < 40, especially children, propylthiouracil is now recommended only in special situations (eg, in the 1st trimester of pregnancy, in thyroid storm). Methimazole is the preferred drug. The usual starting dosage of methimazole is 5 to 20 mg po tid and of propylthiouracil 100 to 150 mg po q 8 h. When T4 and T3 levels normalize, the dosage is decreased to the lowest effective amount, usually methimazole 5 to 15 mg once/day or propylthiouracil 50 mg tid. Usually, control is achieved in 2 to 3 mo. More rapid control can be achieved by increasing the dosage of propylthiouracil to 150 to 200 mg q 8 h. Such dosages or higher ones (up to 400 mg q 8 h) are generally reserved for severely ill patients, including those with thyroid storm, to block the conversion of T4 to T3. Maintenance doses of methimazole can be continued for one or many years depending on the clinical circumstances. Carbimazole, which is used widely in Europe, is rapidly converted to methimazole. The usual starting dose is similar to that of methimazole; maintenance dosage is 5 to 20 mg po once/day, 2.5 to 10 mg bid, or 1.7 to 6.7 mg tid.
Adverse effects include rash, allergic reactions, abnormal liver function (including hepatic failure with propylthiouracil), and, in about 0.1% of patients, reversible agranulocytosis. Patients allergic to one drug can be switched to the other, but cross-sensitivity may occur. If agranulocytosis occurs, the patient cannot be switched to the other drug; other therapy (eg, radioiodine, surgery) should be used.
Each drug has advantages and disadvantages. Methimazole need only be given once/day, which improves adherence. Furthermore, when methimazole is used in dosages of < 40 mg/day, agranulocytosis is less common; with propylthiouracil, agranulocytosis may occur at any dosage. Methimazole has been used successfully in pregnant and nursing women without fetal or infant complications, but rarely methimazole has been associated with scalp and GI defects in neonates and with a rare embryopathy. Because of these complications, propylthiouracil is used in the 1st trimester of pregnancy. Propylthiouracil is preferred for the treatment of thyroid storm, because the dosages used (800 to 1200 mg/day) partially block the peripheral conversion of T4 to T3.
The combination of high-dose propylthiouracil and dexamethasone, also a potent inhibitor of T4 to T3 conversion, can relieve symptoms of severe hyperthyroidism and restore the serum T3 level to normal within a week.
Symptoms and signs of hyperthyroidism due to adrenergic stimulation may respond to β-blockers; propranolol has had the greatest use, but atenolol or metoprolol may be preferable.
Other manifestations typically do not respond.
Propranolol is indicated in thyroid storm (see Table 2: Treatment of Thyroid Storm). It rapidly decreases heart rate, usually within 2 to 3 h when given orally and within minutes when given IV. Esmolol may be used in the ICU because it requires careful titration and monitoring. Propranolol is also indicated for tachycardia with hyperthyroidism, especially in elderly patients, because antithyroid drugs usually take several weeks to become fully effective. Ca channel blockers may control tachyarrhythmias in patients in whom β-blockers are contraindicated.
Iodine in pharmacologic doses inhibits the release of T3 and T4 within hours and inhibits the organification of iodine, a transitory effect lasting from a few days to a week, after which inhibition usually ceases. Iodine is used for emergency management of thyroid storm, for hyperthyroid patients undergoing emergency nonthyroid surgery, and (because it also decreases the vascularity of the thyroid) for preoperative preparation of hyperthyroid patients undergoing subtotal thyroidectomy. Iodine generally is not used for routine treatment of hyperthyroidism. The usual dosage is 2 to 3 drops (100 to 150 mg) of a saturated K iodide solution po tid or qid or 0.5 to 1 g Na iodide in 1 L 0.9% saline solution given IV slowly q 12 h.
Complications of iodine therapy include inflammation of the salivary glands, conjunctivitis, and rash.
Radioactive sodium iodine (131I, radioiodine):
In the US, 131I is the most common treatment for hyperthyroidism. Radioiodine is often recommended as the treatment of choice for Graves disease and toxic nodular goiter in all patients, including children. Dosage of 131I is difficult to adjust because the response of the gland cannot be predicted; some physicians give a standard dose of 8 to 15 mCi. Others adjust the dose based on estimated thyroid size and the 24-h uptake to provide a dose of 80 to 120 microCi/g thyroid tissue.
When sufficient 131I is given to cause euthyroidism, about 25 to 50% of patients become hypothyroid 1 yr later, and the incidence continues to increase yearly. Thus, most patients eventually become hypothyroid. However, if smaller doses are used, incidence of recurrence is higher. Larger doses, such as 10 to 15 mCi, often cause hypothyroidism within 6 mo.
Radioactive iodine is not used during lactation because it can enter breast milk and cause hypothyroidism in the infant. It is not used during pregnancy because it crosses the placenta and can cause severe fetal hypothyroidism. There is no proof that radioiodine increases the incidence of tumors, leukemia, thyroid cancer, or birth defects in children born to previously hyperthyroid women who become pregnant later in life.
Surgery is indicated for patients with Graves disease whose hyperthyroidism has recurred after courses of antithyroid drugs and who refuse 131I therapy, patients who cannot tolerate antithyroid drugs, patients with very large goiters, and in some younger patients with toxic adenoma and multinodular goiter. Surgery may be done in elderly patients with giant nodular goiters.
Surgery usually restores normal function. Postoperative recurrences vary between 2 and 16%; risk of hypothyroidism is directly related to the extent of surgery. Vocal cord paralysis and hypoparathyroidism are uncommon complications. Saturated solution of K iodide 3 drops (about 100 to 150 mg) po tid should be given for 10 days before surgery to reduce the vascularity of the gland. Methimazole must also be given, because the patient should be euthyroid before iodide is given. Dexamethasone can be added to rapidly restore euthyroidism. Surgical procedures are more difficult in patients who previously underwent thyroidectomy or radioiodine therapy.
Treatment of thyroid storm:
A treatment regimen for thyroid storm is shown in Table 2: Treatment of Thyroid Storm.
|Treatment of Thyroid Storm
Propylthiouracil: 600 mg po given before iodine, then 400 mg q 6 h
Iodine: 5 drops saturated solution of K iodide po tid
10 drops Lugol solution po tid
1g Na iodide slowly by IV drip over 24 h
Propranolol: 40 mg po qid
1 mg slowly IV q 4 h (not to exceed 1 mg/min) under close monitoring
A repeat 1-mg dose given after 2 min, if needed, or esmolol
IV dextrose solutions
Correction of dehydration and electrolyte imbalance
Cooling blanket for hyperthermia
Antiarrhythmics (eg, Ca channel blockers, adenosine, β-blockers) if necessary for atrial fibrillation
Treatment of underlying disorder, such as infection
Corticosteroids: Hydrocortisone 100 mg IV q 8 h
Dexamethasone 8 mg IV once/day
Definitive therapy after control of the crisis via ablation of the thyroid with 131I or surgical treatment
Treatment of infiltrative dermopathy and ophthalmopathy:
In infiltrative dermopathy (in Graves disease), topical corticosteroids or corticosteroid injections into the lesions may decrease the dermopathy. Dermopathy sometimes remits spontaneously after months or years. Ophthalmopathy should be treated jointly by the endocrinologist and ophthalmologist and may require selenium, corticosteroids, orbital radiation, and surgery.
Subclinical hyperthyroidism is low serum TSH in patients with normal serum free T4 and T3 and absent or minimal symptoms of hyperthyroidism.
Subclinical hyperthyroidism is far less common than subclinical hypothyroidism (see Subclinical Hypothyroidism). Patients with serum TSH < 0.1 mU/L have an increased incidence of atrial fibrillation (particularly elderly patients), reduced bone mineral density, increased fractures, and increased mortality. Patients with serum TSH that is only slightly below normal are less likely to have these features. Many patients with subclinical hyperthyroidism are taking L-thyroxine; in these patients, reduction of the dose is the most appropriate management unless therapy is aimed at maintaining a suppressed TSH in patients with thyroid cancer. The other causes of subclinical hyperthyroidism are the same as those for clinically apparent hyperthyroidism
Therapy is indicated for patients with endogenous subclinical hyperthyroidism (serum TSH < 0.1 mU/L), especially those with atrial fibrillation or reduced bone mineral density. The usual treatment is 131I. In patients with milder symptoms (eg, nervousness), a trial of antithyroid drug therapy is worthwhile.
Last full review/revision May 2014 by Jerome M. Hershman, MD
Content last modified May 2014