Thyrotoxicosis is the general term for the presence of increased levels of thyroxine (T₄), triiodothyronine (T₃), or both, from any cause. It does not imply that a patient is markedly symptomatic or “toxic.” Hyperthyroidism refers to causes of thyrotoxicosis in which the thyroid is actively overproducing thyroid hormone.

Thyroid autonomy refers to the spontaneous production and secretion of thyroid hormone, independent of thyroid-stimulating hormone (TSH).

Subclinical thyrotoxicosis is defined as a low serum TSH level with normal free T₄ and T₃. The low TSH concentration can result from either excessive ingestion of thyroid hormone or excessive release of endogenous thyroid hormone. The free T₄ or T₃ level is frequently in the high normal range in affected patients. Clinical symptoms and signs are generally absent or nonspecific.

Some studies have linked subclinical thyrotoxicosis to (1) progression to clinical thyrotoxicosis, (2) skeletal effects, including decreased bone mineral density, accelerated bone loss, and increased fracture risk, particularly in postmenopausal women, and (3) cardiac effects, such as a twofold to threefold higher risk of atrial fibrillation, impaired left ventricular diastolic filling, and impaired ventricular ejection fraction response to exercise. An extensive meta-analysis by Collet and colleagues (see Bibliography) found an increased rate of both cardiovascular and all-cause mortality in patients with subclinical hyperthyroidism. A TSH value below 0.1 mU/L is more likely to be associated with adverse consequences than a TSH value in the range 0.1 to 0.5 mU/L.

The 2011 American Thyroid Association (ATA)/American Association of Clinical Endocrinologists (AACE) hyperthyroidism management guidelines suggest that patients with TSH levels below 0.1 mU/L who are older than 65 years or who are younger but with symptomatic disease or comorbidities that may be aggravated by mild hyperthyroidism, such as coronary heart disease, should be actively treated. In patients with TSH values between 0.1 and 0.5 mU/L, therapy should at least be considered if they are older than 65 years or younger but with comorbidities as previously listed.

 Graves’ disease

 Toxic multinodular goiter (TMNG)

 Toxic adenomas or autonomously functioning thyroid nodules (AFTNs)

Graves’ disease is an autoimmune disorder in which activating autoantibodies directed against the TSH receptor result in continuous stimulation of thyroid hormone production and secretion as well as thyroid growth (goiter). Extrathyroidal manifestations of Graves’ disease include ophthalmopathy (proptosis, periorbital edema, extraocular muscle dysfunction, and optic neuropathy), dermopathy (pretibial myxedema), and thyroid acropachy (digital clubbing and edema).

TMNG generally arises in the setting of a long-standing multinodular goiter in which certain individual nodules have developed autonomous function and secrete thyroid hormone independent of stimulation by TSH.

AFTNs, or toxic adenomas, are benign tumors that have either constitutive activation of the TSH receptor or its signal-transduction apparatus. These tumors frequently produce subclinical thyrotoxicosis and have a predilection for spontaneous hemorrhage. AFTNs generally must be more than 3 cm in diameter before attaining sufficient secretory capacity to produce overt thyrotoxicosis. Often, inefficient iodine processing leads to an excess of T₃ relative to T₄ in AFTNs.

The Jod-Basedow phenomenon is iodine-induced thyrotoxicosis following exposure to large quantities of iodine (typically in iodinated radiographic contrast agents for computed tomography [CT] or angiography, but also with the antiarrhythmic drug amiodarone). It was first described following iodine supplementation in people living in regions of endemic iodine deficiency.

Rarer causes of hyperthyroidism include TSH-secreting pituitary adenomas; stimulation of TSH receptors by high levels of human chorionic gonadotropin (hCG), most often in choriocarcinomas in women or germ cell tumors in men; struma ovarii (ectopic thyroid hormone production in thyroid tissue–containing ovarian teratomas); and functional metastatic follicular or papillary thyroid carcinoma. Thyroiditis (postpartum, subacute, painless, radiation- or palpation-induced) and ingestion of excessive exogenous thyroid hormone (iatrogenic, inadvertent, or surreptitious) are causes of thyrotoxicosis but not hyperthyroidism (see question 1).

Common symptoms of thyrotoxicosis include palpitations, anxiety, agitation, restlessness, insomnia, impaired concentration/memory, irritability or emotional lability, weight loss, heat intolerance, exertional dyspnea, fatigue, hyperdefecation, amenorrhea, oligomenorrhea, hypomenorrhea, anovulation, and hair thinning. Occasionally patients may experience weight gain rather than loss during thyrotoxicosis, presumably owing to polyphagia.

Older patients with hyperthyroidism may lack typical symptoms and signs of sympathetic activation and may present instead with apathy or depression, weight loss, atrial fibrillation, worsening angina pectoris, or congestive heart failure.

Tremors, tachycardia, flow murmurs, systolic hypertension, warm and moist skin, hyperreflexia with rapid relaxation phases, lid lag/lid retraction, ophthalmopathy, pretibial myxedema, thyroid acropachy, and a goiter (with a bruit in patients with Graves’ disease) may be found in hyperthyroid patients. Eye findings in thyrotoxicosis are discussed in question 15.

Lid retraction and stare can be seen with any cause of thyrotoxicosis and are due to sympathetic/adrenergic overactivity. True ophthalmopathy or orbitopathy is unique to Graves’ disease and is thought to be caused by thyroid autoantibodies that cross-react with antigens in fibroblasts, preadipocytes, and adipocytes of the retroorbital tissues. Common manifestations of ophthalmopathy include proptosis (exophthalmos), diplopia, and inflammatory changes such as conjunctival injection and periorbital edema.

Measurement of serum TSH with a third-generation assay (with detection limits of 0.01 mU/L) is the most sensitive means of detecting thyrotoxicosis. Serum free T₄ and T₃ levels should be measured to determine the degree of biochemical thyrotoxicosis. Other associated laboratory findings include mild leukopenia, normochromic normocytic anemia, hepatic transaminitis, elevations of serum alkaline phosphatase and osteocalcin (increased bone turnover), mild hypercalcemia, hyperphosphatemia, and low serum levels of albumin and total cholesterol.

The cause of hyperthyroidism can usually be determined with history, physical examination, and radionuclide studies. Testing for TSH receptor antibodies can be used to diagnose Graves’ disease during pregnancy, when radionuclide imaging is contraindicated. Such testing is also useful in (1) pregnant women with current or previously treated Graves’ disease to determine the risk of fetal and neonatal thyroid dysfunction due to transplacental passage of stimulating or blocking antibodies, (2) biochemically euthyroid patients with ophthalmopathy, (3) patients with alternating periods of hyperthyroidism and hypothyroidism as a result of fluctuations in blocking and stimulating TSH receptor antibodies, and (4) atypical cases in which differentiation of Graves’ disease from toxic multinodular goiter is challenging and therapeutically essential.

A radioactive iodine uptake (RAIU) test uses radioactive iodine, either ¹³¹I or ¹²³I, to quantitatively assess the functional status of the thyroid gland. A small dose of radioisotope is given orally followed by measurement of radioactivity in the area of the thyroid in 4 to 24 hours. Often two measurements are taken, at 4 to 6 hours and at 24 hours. High radioiodine uptake confirms hyperthyroidism whereas low (nearly absent) uptake indicates either inflammation and destruction of thyroid tissue with release of preformed hormone into the circulation or an extrathyroidal source of thyroid hormone (Table 33-1). A thyroid scan provides a two-dimensional image showing the distribution of isotope trapping within the thyroid gland. Uniform distribution in a hyperthyroid patient suggests Graves’ disease, patchy distribution suggests TMNG, and unifocal activity corresponding to a nodule, with suppression of the rest of the thyroid, suggests a toxic adenoma.

The three main treatment options are antithyroid drugs (ATDs), radioiodine (¹³¹I) ablation, and surgery. ATDs available in the United States include methimazole and propylthiouracil. Methimazole is almost always the preferred agent. Owing to concerns about severe hepatotoxicity, propylthiouracil is recommended only in (1) the first trimester of pregnancy (methimazole has been linked to embryopathy when used during the first trimester), (2) thyroid storm therapy because of the ability of propylthiouracil to block T₄-to-T₃ conversion, and (3) patients with minor reactions to methimazole who refuse ¹³¹I ablation or surgery. Unless contraindicated, most patients should receive beta-blockers for heart rate control and symptomatic relief. Most thyroidologists in the United States prefer ¹³¹I ablation over surgery or prolonged courses of ATDs. Patients scheduled to undergo ¹³¹I ablation should be advised to avoid pregnancy for 4 to 6 months and should be cautioned that oral contraceptives may not be fully protective in the hyperthyroid state because of increased levels of sex hormone-binding globulin and higher clearance of the contraceptive.

Surgery is generally not the treatment of choice for hyperthyroidism. It is most often used in the following patients: (1) those with symptomatic compression or large goiters (> 80 g), which is less likely to respond to ATDs or ¹³¹I ablation, (2) those with relatively low RAIU values, (3) those in whom thyroid cancer is documented or suspected, (4) those with large nonfunctioning, photopenic, or hypofunctioning nodules, (5) pregnant patients who are allergic to or intolerant of ATDs (¹³¹I is contraindicated in pregnancy), (6) those with coexisting hyperparathyroidism requiring surgery, (7) women who plan a pregnancy in less than 4 to 6 months, especially if thyroid-stimulating immunoglobulin (TSH receptor [TSI]) antibody levels are high, and (8) patients who wish to avoid ¹³¹I exposure and the potential side effects of ATDs. Surgery may also be preferred when there is moderate to severe active Graves’ ophthalmopathy, because use of ¹³¹I has been linked to worsening eye disease in this situation. Patients should be euthyroid before surgery in order to decrease the risk of both arrhythmias during anesthesia induction and postoperative thyroid storm.

Inorganic iodine rapidly decreases the synthesis and release of T₄ and T₃. The transient inhibition of thyroid hormone synthesis by excess iodine is known as the Wolff-Chaikoff effect. However, because this effect generally lasts for about 10 to 14 days, iodine is usually used only after ATDs have been started, to prepare a patient rapidly for surgery, or as an adjunctive measure in patients with thyroid storm. Iodine is also used in some centers to decrease the vascularity of the thyroid prior to thyroidectomy for Graves’ disease. Typical doses are Lugol’s solution (6.5 mg iodide/drop) 10 drops three times daily or saturated solution of potassium iodide (SSKI, 50 mg iodide/drop) 1 to 2 drops three times daily mixed in water or juice for 10 days prior to surgery.

Yes. Two iodine-containing oral cholecystographic agents, ipodate and iopanoic acid, cause dramatic reductions in serum T₃ and T₄ through inhibition of T₄ 5′-monodeiodinase. Neither of these agents is currently available in the United States. Other agents occasionally used to treat hyperthyroidism include lithium, which decreases thyroid hormone release, and potassium perchlorate, which inhibits thyroid uptake of iodine. Additionally, cholestyramine 4 g four times daily given with methimazole lowers serum T₄ and T₃ more rapidly than methimazole alone.

Propylthiouracil, propranolol, glucocorticoids, iopanoic acid, and amiodarone inhibit the peripheral conversion of T₄ to T₃.

Ninety percent of patients taking ATDs become euthyroid without significant side effects. Approximately half of patients attain a remission from Graves’ disease after a treatment course of 12 to 18 months. However, only 30% maintain long-term remission; the remainder experience recurrence of Graves’ disease within 1 to 2 years after the drugs are withdrawn. TMNG and AFTNs are not autoimmune diseases; therefore, they do not go into remission. The role of ATDs in these two disorders is only to render a patient euthyroid before surgery or when pretreatment is necessary before ¹³¹I therapy (see question 27). The usual starting doses for moderate thyrotoxicosis are methimazole, 10 to 20 mg/day, or propylthiouracil, 50 to 150 mg 3 times/day. Methimazole is recommended for all patients who select ATD therapy for Graves’ disease, except in the clinical circumstances listed in question 19.

 Agranulocytosis is a rare but life-threatening complication of ATD therapy, occurring in approximately 1 in every 200 to 500 patients treated with ATDs. Patients should be instructed to promptly report fever, sore throat, or minor infections that do not resolve quickly. Agranulocytosis appears to be dose-related with methimazole but not with propylthiouracil. Patients experiencing agranulocytosis when taking one ATD should not be exposed to another.

 Hepatotoxicity with occasional progression to fulminant hepatic necrosis can occur with propylthiouracil; cholestatic jaundice has been reported with methimazole. Patients should report right upper quadrant pain, anorexia, nausea, and new pruritus.

 Rashes occur in approximately 2% of patients and can range from limited erythema to an exfoliative dermatitis. Dermatologic reactions to one ATD do not preclude the use of another, although cross-sensitivity occurs in approximately 50% of cases.

 Arthropathy and a lupus-like syndrome can rarely be seen with either propylthiouracil or methimazole.

 Antineutrophil cytoplasmic antibody (ANCA)–positive vasculitis has been associated with propylthiouracil use.

 Potential teratogenicity (so-called methimazole embryopathy) can be associated with methimazole; this includes rare fetal scalp defects (aplasia cutis), choanal atresia, and tracheoesophageal fistulas.

Serum free T₄ and T₃ levels should be remeasured about 4 weeks after initiation of an ATD, and the dose adjusted accordingly. Because TSH may remain suppressed for several months, free T₄ and T₃ levels are more reliable for assessing thyroid hormone status during this time. Thyroid parameters should be monitored every 4 to 8 weeks until euthyroidism is achieved, with a goal of using the lowest effective ATD dose. Routine monitoring of the white blood cell (WBC) count and liver function, though commonly done in clinical practice, has not been shown to prevent agranulocytosis or hepatotoxicity. A WBC count with differential should be assessed during any febrile illness and at the onset of sore throat/pharyngitis in all patients taking ATDs. Liver function tests should be ordered in patients who experience a pruritic rash, jaundice, light-colored stools or dark urine, arthralgias, abdominal pain or bloating, anorexia, nausea, or fatigue. The ATD should be discontinued if transaminase levels are elevated to two to three times the upper normal limit and fail to improve within 1 week. Liver function values should be monitored every week until resolution of transaminitis after discontinuation of the ATD.

Thyroid cells trap and concentrate iodine and use it to make thyroid hormone. ¹³¹I is utilized in the same manner as inorganic iodine. Because ¹³¹I emits locally destructive beta particles, extensive local thyrocyte damage and ablation of thyroid function occurs over a period of approximately 6 to 18 weeks after treatment. Dosages of ¹³¹I should be high enough to cause permanent hypothyroidism and are usually based on the size of the thyroid gland and the pretreatment RAIU value. A typical dose for Graves’ disease is 10 to 15 millicuries (mCi); for TMNG, higher doses, 25 to 30 mCi, are given. These doses are effective in 90% to 95% of patients.

The use of ATDs before and after radioactive iodine therapy may be considered in (1) patients who are extremely symptomatic or in whom free T₄ levels are three to four times the upper normal limit, (2) the elderly, and (3) those with substantial comorbidities, such as atrial fibrillation, heart failure, pulmonary hypertension, renal failure, infection, trauma, poorly controlled diabetes mellitus, and cerebrovascular or pulmonary disease. These patients should also be medically stable and treated with beta-adrenergic blocking drugs prior to ¹³¹I therapy.

Pretreatment with ATDs helps deplete the thyroid of preformed hormones and thereby to theoretically reduce the risk of radioactive iodine–induced thyroid storm. When pretreatment with ATDs is used, the drugs are generally discontinued 3 to 5 days before ¹³¹I is given. However, pretreatment with ATDs is associated with a rapid increase in thyroid hormone levels upon ATD discontinuation. Patients who are not pretreated usually experience a rapid decrease in thyroid hormone levels after ¹³¹I therapy. Therefore most patients do not require or benefit from ATD pretreatment.

Pregnancy should be deferred for at least 4 to 6 months after ¹³¹I ablation to ensure successfully cured hyperthyroidism and corrected hypothyroidism prior to conception. In addition, patients should be taking a stable dose of thyroid hormone replacement and be free of active ophthalmopathy. Breast milk radioactivity, measured in one study after an 8.3-mCi therapeutic dose of ¹³¹I, remained unacceptably high for 45 days, prohibiting resumption of breast-feeding after ¹³¹I therapy. If technetium ^99mTc or ¹²³I is used for diagnostic studies, breast-feeding may be resumed in 2 to 3 days, with pumping and disposal of breast milk in the interim.

The natural history of Graves’ disease is such that up to 25% of patients experience clinically apparent ophthalmopathy. The majority of cases arise in the period from 18 months before to 18 months after the onset of thyrotoxicosis. Thus a fair number of new cases can be expected to coincide with the timing of ¹³¹I ablation. However, three randomized clinical trials have shown that ¹³¹I therapy is more likely to be associated with new or worsened ophthalmopathy than either ATDs or thyroidectomy. ¹³¹I therapy results in a sustained increase in TSH receptor (TSI) antibodies that may be important in exacerbating ophthalmopathy. Patients with preexisting eye disease, those who smoke cigarettes, and those with higher levels of thyroid hormone and high titers of TSH receptor antibodies are more likely to experience worsening. It is therefore prudent to avoid use of ¹³¹I in patients with active moderate to severe Graves’ ophthalmopathy. In patients with initially mild eye involvement, oral glucocorticoids can be used concurrently to prevent an exacerbation during ¹³¹I therapy, particularly in the presence of risk factors for worsening ophthalmopathy.

Caution must be used in interpreting thyroid laboratory results during pregnancy, because low TSH values are not uncommon in the first trimester, and total T₄ and T₃ values are elevated by increased thyroxine-binding globulin (TBG) levels. Free T₄ levels, measured with the use of equilibrium dialysis or an assay with trimester-specific reference ranges, are the best indicator of thyroid function during pregnancy. Symptomatic women with marked elevation in trimester-specific free T₄ values or those with total T₄ and/or total T₃ above 1.5 times the upper normal limit should be considered for treatment. Pregnant women with subclinical hyperthyroidism (low TSH, normal free T₄) and asymptomatic or mild hyperthyroidism may be monitored without treatment by measurement of TSH and free T₄ every 4 to 6 weeks. Beta-blockers can be used cautiously and should be slowly tapered off once hyperthyroidism is controlled by ATDs, because of the risks of fetal growth restriction, hypoglycemia, respiratory depression, and bradycardia. Nuclear medicine testing with RAIU or thyroid scanning is contraindicated in pregnancy because of the risk of fetal exposure to isotopes. Because ¹³¹I therapy is also contraindicated during pregnancy, treatment options are limited to ATDs and surgery. The American Thyroid Association and the U.S. Food and Drug Administration (FDA) recommend that use of propylthiouracil be limited to the first trimester only, owing to the potentially serious teratogenic effects of methimazole during organogenesis of the first trimester (aplasia cutis, choanal atresia, esophogeal atresia, and tracheoesophageal fistulas). Treatment should be switched to methimazole at the beginning of the second trimester. A 300-mg daily dose of propylthiouracil is roughly equivalent to a 10- or 15-mg daily dose of methimazole. Thyroid function tests should be obtained 4 weeks after the switch to methimazole to ensure maintenance of euthyroidism. Pregnant patients with Graves’ disease require close follow-up to ensure adequate control and to prevent hypothyroidism, because Graves’ disease frequently remits during the course of pregnancy. TSH receptor antibodies, which are able to cross the placenta after 26 weeks, should be measured in the third trimester to assess the risk of neonatal thyroid dysfunction. Antepartum testing should include monitoring for fetal tachycardia in mothers with persistent elevations in TSH receptor antibodies, and fetal ultrasound to assess for evidence of fetal goiter or growth restriction.

Patients with Graves’ orbitopathy should be treated according to the severity of their eye disease. Those with only mild eye involvement may generally be treated with local measures alone, such as tinted lenses for photosensitivity, artificial tears, and raising the head of the bed to prevent worsening retroocular edema in the recumbent position overnight. Moderate eye involvement with lid erythema and edema and conjunctival erythema and edema (chemosis) generally requires glucocorticoid therapy. Severe ophthalmopathy, including advanced proptosis or extraocular muscle dysfunction, often requires initial immunomodulatory medication followed by surgical rehabilitative surgery. Sight-threatening ophthalmopathy is a medical emergency, occurring either as a result of optic nerve compression by enlarged extraocular muscles at the apex of the orbit or because of corneal ulceration. In the former case, pulse intravenous glucocorticoids should be given immediately and patients should be admitted to the hospital for possible urgent orbital decompression surgery.