Thyrotoxicosis …

Douglas S Ross MD

General Neurology

Updated 12.27.2023
Released 08.03.1994
Expires For CME 12.27.2026

Thyrotoxicosis

Author: Douglas S Ross MD

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Editor: Douglas J Lanska MD MS MSPH

Thyrotoxicosis

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Introduction

Overview

In this article, the author summarizes the clinical manifestations, causes, and treatment of thyrotoxicosis. Graves disease, toxic adenoma and toxic nodular goiter, and painless thyroiditis are the principal causes of thyrotoxicosis. Neurologists may encounter undiagnosed patients who present with a cerebrovascular accident due to atrial fibrillation complicating thyrotoxicosis, or they may see patients whose primary complaint is proximal muscle weakness or tremor. Subclinical hyperthyroidism has been associated with both subtle cognitive impairment and improvement in measures of mental health and mood. Initial evaluation and subsequent treatment of thyrotoxic patients is reviewed.

Key points

	• Tremor, proximal muscle weakness, and embolic stroke complicating atrial fibrillation are the most common neurologic manifestations of thyrotoxicosis.
	• Determining the etiology of hyperthyroidism (eg, Graves disease, toxic nodule or toxic nodular goiter, painless thyroiditis, and other disorders) is essential for selecting appropriate treatment.
	• Beta-adrenergic-blocking drugs, methimazole, radioiodine, and thyroidectomy, are common treatment modalities depending on the etiology and severity of the thyrotoxicosis.

Historical note and terminology

Thyrotoxicosis was appreciated in the Middle Ages when burnt sponge extract was used to treat exophthalmic goiter. In the mid-nineteenth century both Graves, an Irish physician, and Basedow, a German physician, described the most common etiology and presentation of thyrotoxicosis, which is referred to as Graves disease in English-speaking countries and as Basedow disease in many European countries. Plummer first described toxic multinodular goiter in the early twentieth century, and this entity is sometimes referred to as Plummer disease. Painless (lymphocytic) thyroiditis was not well-appreciated as a common cause of thyrotoxicosis until the 1980s; this entity is also referred to as silent thyroiditis, subacute lymphocytic thyroiditis, or lymphocytic thyroiditis with spontaneously resolving hyperthyroidism, and some view this as a variant presentation of Hashimoto thyroiditis.

Some reserve the term hyperthyroidism to refer to those etiologies of thyrotoxicosis that result from excess synthesis and release of thyroid hormone from the thyroid gland, whereas others use the terms hyperthyroidism and thyrotoxicosis interchangeably.

The degree of hyperthyroidism may be defined biochemically or clinically. Patients with “subclinical” hyperthyroidism have normal serum levels of thyroid hormone with subnormal or undetectable serum TSH concentrations, whereas those with “overt” hyperthyroidism have elevated serum thyroid hormone levels with suppressed serum TSH levels. Clinically severe hyperthyroidism, which is rare, is called “thyroid storm.”

Clinical manifestations

Presentation and course

Hyperthyroidism has protean effects on all organ systems. A typical patient with moderate hyperthyroidism will complain of palpitations, tremulousness, heat intolerance and excess sweating, increased appetite with weight loss, frequent bowel movements, fatigue, and excess anxiety and irritability. However, symptoms may be absent or few in the elderly (15). Patients with subclinical hyperthyroidism are usually asymptomatic, and those with mild hyperthyroidism may be asymptomatic or may notice only some of these symptoms.

Neurologic manifestations. Tremor and proximal muscle weakness are the two common neurologic manifestations of thyrotoxicosis. Tremor is seen in 70% of patients (67) and is best illustrated by extension of the arms or the tongue. Patients frequently note poor handwriting or difficulty with fine motor tasks. Proximal muscle weakness is occasionally the presenting symptom of hyperthyroidism, although in one series 67% of patients had muscle weakness, and it was a presenting symptom in 36% (32). Difficulty getting up from a chair or the toilet and difficulty climbing stairs are common complaints. Myalgias are not uncommon, although muscle atrophy (shoulders and pelvic girdle) is uncommon (53). Diaphragmatic muscle weakness is common and contributes to dyspnea (44). Flaccid quadriplegia has been described (24).

Headache may be a manifestation of thyrotoxicosis, especially in patients with underlying migraines (87). Rarely, a large goiter will cause headache by compressing the major vessels in the neck (33).

Embolic stroke occurs in 10% to 40% of patients when thyrotoxicosis is complicated by atrial fibrillation (11). Transesophageal echocardiogram demonstrates a thrombogenic milieu in 45% of patients and does not correlate with other clinical risk factors (29). The risk of ischemic stroke in a study of 3176 hyperthyroid patients younger than 45 years of age was 1.0%, compared to 0.6% in matched euthyroid controls (81). In a population based study, 20,733 anticoagulation naïve hyperthyroid patients with atrial fibrillation were propensity score matched 3 to 1 with non-hyperthyroid patients with atrial fibrillation (49). The hyperthyroid patients had a higher risk of ischemic stroke and thromboembolism: 1.83 versus 1.62 per 100,000 patient years; the risk was 36% higher during the first year. Intracranial arterial stenosis in Graves hyperthyroidism is more common in patients with elevated antithyroid peroxidase antibodies (100; 82). Graves hyperthyroidism has also been associated with Moyamoya disease (55). Central venous thrombosis also appears to be more common in thyrotoxicosis (93; 38).

Other neurologic manifestations of thyrotoxicosis are rare. Choreoathetosis has been described in a few patients and resolved after treatment (60); among 3382 hyperthyroid patients, only seven (0.2%) had a seizure without a prior history or other known cause (85). Similarly, a few patients have had seizures, which resolved after therapy (53). In a prospective study, evidence for a peripheral neuropathy was seen in four of 21 patients (32). The deep tendon reflexes have a shortened relaxation phase (72). An acute neuropathy (Basedow paraplegia) associated with paraplegia, severe muscle weakness, and areflexia has rarely been reported and resolves with treatment of the hyperthyroidism (68).

Agitation, irritability, emotional lability, anxiety, and difficulty focusing are common symptoms in moderate thyrotoxicosis (53). Hyperthyroid patients have higher scores on the Zung Self-Rating Anxiety Scale and have impaired executive function and decision making on the Stroop Color-Word Test and the Iowa Gambling Task (99). Parietooccipital white matter glutamine measured by proton magnetic resonance spectroscopy is reduced in thyrotoxicosis, correlates with attention and concentration cognitive scores, and may persist after treatment (27). In its most severe form, thyroid storm, delirium, psychosis, and encephalopathy are seen (16).

Subclinical hyperthyroidism has been associated with subtle cognitive impairment (19), whereas experimental subclinical hyperthyroidism has resulted in improved mood (Profile of Mood States (POMS)) and motor learning (79). Controversy remains as to whether these patients have an increased risk of dementia; the Framingham Study found an increased risk of Alzheimer disease in women with subclinical hyperthyroidism (89). A review of 23 studies and a meta-analysis confirmed the association of subclinical hyperthyroidism with cognitive impairment, but it found no mechanistic explanation or evidence that antithyroid treatment was useful (40; 73). However, another study found that serum tau protein levels, which are associated with Alzheimer disease, are increased in patients with hyperthyroidism (56). Another 9-year prospective study of 2558 individuals between 70 to 79 years of age found 22% developed dementia and 3% developed subclinical hyperthyroidism; the hazard ratio for dementia if one’s TSH was less than 0.1 mU/mL was 2.38 (95% CI 1.13-5.04) (05). However, in another analysis of individual participant data from eight cohorts, including 2033 participants with dementia and 44,573 controls, there was no association between subclinical hyperthyroidism and dementia (92). Patients with subclinical hyperthyroidism have an increased risk of functional disability after ischemic stroke (96).

Two important clinical syndromes are seen in association with thyrotoxic patients:

Thyrotoxic periodic paralysis. Thyrotoxic periodic paralysis is seen primarily in Asian males with an incidence of about 2% (52) and less commonly in Caucasians with an estimated incidence of 0.1% (48). In one study, only 24% of the patients were diagnosed with hyperthyroidism before the attack; most, but not all, patients had Graves disease (20). Exercise, upper respiratory infections, and ingestion of alcohol or carbohydrate-rich foods may precipitate an attack, which can last from minutes to days and is characterized by proximal muscle weakness that can progress to flaccid paralysis (52; 46; 20). Deep tendon reflexes are diminished or absent. Only rarely are bulbar or respiratory muscles involved. Hypokalemia is the characteristic laboratory finding, resulting from a shift of potassium into cells due to increased Na/K-ATPase activity. Up to 62% of patients have recurrent attacks (46). Attacks resolve after correction of the hyperthyroidism, and their frequency may be ameliorated with propranolol therapy (98). A video image of an attack is published (37). Patients with thyrotoxic periodic paralysis have a mutation in a gene with a thyroid hormone response element, which encodes the skeletal muscle-specific inward rectifying K+ channel Kir2.6 (78).

Myasthenia gravis. Myasthenia gravis and Graves hyperthyroidism may occur together. Of patients with myasthenia gravis, 3% to 17% have hyperthyroidism, although less than 1% of patients with Graves disease have myasthenia gravis (70; 53). In a series of 51 patients, 44 presented simultaneously with both disorders, or the hyperthyroidism started a few months before the myasthenia gravis (70). Hyperthyroidism may exacerbate the course of myasthenia gravis, and patients with myasthenia gravis and Graves disease may have a 2-fold higher rate of ocular involvement (57). The symptoms from the ophthalmopathy of Graves disease may overlap with symptoms from ocular myasthenia gravis; however, the syndromes are fairly distinct. Each disease is treated independently, although their course may run in parallel, and both may respond to immunosuppressive medication, consistent with their shared autoimmune pathogenesis and genetic susceptibility. Of note, thymic hyperplasia is not uncommon in young patients with Graves disease (25).

Cardiovascular manifestations. Heart rate is increased, pulse pressure is widened, systolic hypertension is common (47), and peripheral vascular resistance is reduced. Cardiac output is increased due to increased cardiac contractility and increased peripheral oxygen needs (50). Congestive heart failure, if present, will worsen; an occasional patient develops high output congestive heart failure. A paradoxic fall in left ventricular ejection fraction with exercise suggests a cardiomyopathy (36). Patients with coronary artery disease may have exacerbation of ischemia.

Atrial fibrillation is a common complication occurring in 15% of patients in the seventh decade (39). Left atrial enlargement is present in 90% of these patients, and 10% to 40% will have an embolic event; therefore, anticoagulation is indicated (11). However, 60% of patients will spontaneously convert to sinus rhythm within four months of becoming euthyroid (63). Once euthyroid, the recurrence rate after electrical cardioversion is lower than that of patients with atrial fibrillation unrelated to hyperthyroidism (84).

Hematologic manifestations and anticoagulation. There is evidence that hyperthyroidism may increase the risk of venous thrombosis, especially at cerebral sites (38). Hyperthyroidism also potentiates the effects of warfarin by increasing the clearance of vitamin K-dependent clotting factors (80), and it may increase the risk of hemorrhage in anticoagulated patients.

Pulmonary manifestations. Oxygen consumption and carbon dioxide production increase causing hypoxemia and hypercapnia, but respiratory muscle weakness may limit ventilation and is an important cause of dyspnea (44). Thyrotoxicosis may exacerbate asthma.

Gastrointestinal manifestations. Weight loss occurs because of the increase in metabolism; hyperdefecation and malabsorption occur due to increased gut motility. Appetite is stimulated. Paradoxically, young patients with mild hyperthyroidism may be so hungry they gain weight, whereas some elderly patients are anorectic (67).

Genitourinary manifestations. Urinary frequency, nocturia, and polydipsia are common. Enuresis occurs in children. Oligomenorrhea or amenorrhea is seen in women as thyrotoxicosis increases sex hormone-binding globulin and results in lower free estradiol concentrations (51). In men, gynecomastia and erectile dysfunction occur because of increased extragonadal conversion of testosterone to estradiol (17).

Skeletal manifestations. Thyroid hormone directly affects bone resorption, resulting in reduced bone density and increased fracture risk (74).

Ocular manifestations. All patients with thyrotoxicosis may exhibit stare and lid lag, hyperadrenergic signs. However, patients with Graves disease may also present with ophthalmopathy, resulting from the infiltration of periorbital fat and muscle with lymphocytes and the accumulation of glycosaminoglycans; this leads to proptosis, lid retraction, corneal exposure, impaired extraocular muscle function and diplopia, and, in the most severe cases, traction on, or compression of, the optic nerve with loss of vision (07).

Geriatric thyrotoxicosis. Some elderly patients with hyperthyroidism present with apathy rather than the typical signs of adrenergic stimulation. They may not have tachycardia due to coexistent conduction system disease. In these cases, weight loss may be the major finding (67).

Thyroid storm. This is a rare presentation of severe hyperthyroidism characterized by fever, tachycardia, congestive heart failure, diarrhea, possible vomiting, agitation or delirium, and, rarely, seizures or coma associated with as much as a 50% mortality (16). Neuropsychiatric manifestations are associated with a poor prognosis (88).

Prognosis and complications

The prognosis for most patients with thyrotoxicosis is excellent. Both proximal muscle weakness and cardiac myopathy are reversible, and thyrotoxic symptoms resolve. There may be a permanent reduction in bone density and an increased risk of osteoporotic fracture (74). Only the most severe degree of hyperthyroidism, thyroid storm, is associated with significant mortality.

Atrial fibrillation and other atrial arrhythmias are the most common serious complications of thyrotoxicosis. Atrial fibrillation may be associated with an embolic cerebrovascular accident. Thyrotoxicosis may also exacerbate underlying cardiac ischemia or congestive heart failure or may result in a cardiomyopathy with biventricular failure. Untreated hyperthyroidism results in osteoporosis and fractures.

Clinical vignette

A 72-year-old man presented to the emergency room with an acute cerebrovascular accident and was found to be in atrial fibrillation. He had lost 30 pounds in the past month and felt exhausted and short of breath. Physical examination was notable for a 2-fold enlarged non-tender, non-nodular thyroid. There was no proptosis. TSH was less than 0.01 mU/mL; free T4 was 3.2 ng/mL; and T3 was 280 ng/mL. A 24-hour radioiodine uptake was elevated at 38%, and the pattern of uptake was diffuse, consistent with Graves disease. He was started on atenolol 25 mg twice daily and methimazole 10 mg twice daily. During his rehabilitation hospitalization, he converted spontaneously to sinus rhythm. His neurologic deficits improved, and he was discharged home. In follow-up, thyroid tests were normal, and he was treated with radioiodine. Six months later he was on levothyroxine-replacement therapy, felt well, and had regained 30 pounds.

Biological basis

Etiology and pathogenesis

There are many causes of thyrotoxicosis. The 24-hour radioiodine uptake test can be used to distinguish those disorders that result in increased synthesis of thyroid hormone within the thyroid from those disorders where preformed hormone is leaking out of an inflamed gland or where the source of thyroid hormone is extrathyroidal. Most patients with thyrotoxicosis have Graves disease, toxic adenoma or toxic multinodular goiter, or painless (lymphocytic) thyroiditis.

Thyrotoxicosis with normal or elevated radioiodine uptake
	• Autoimmune
		- Graves disease - Hashitoxicosis
	• Thyroid autonomy (iodine-induced hyperthyroidism may be associated with a low uptake)
		- Toxic adenoma - Toxic multinodular goiter
	• Trophoblastic
		- Gestational hyperthyroidism - Molar pregnancy - Choriocarcinoma (also testicular choriocarcinomas)
	• TSH-producing pituitary adenomas
Thyrotoxicosis with nearly absent radioiodine uptake
	• Thyroiditis
		- Subacute (granulomatous) thyroiditis (de Quervain) - Painless (lymphocytic) thyroiditis
			Postpartum thyroiditis Lymphocytic thyroiditis associated with cytokine or lithium therapy
		- Palpation thyroiditis - Amiodarone-induced thyroiditis - Destructive thyroiditis caused by tyrosine kinase inhibitors or immune checkpoint inhibitors - Radiation thyroiditis
	• Ectopic thyrotoxicosis
		- Factitious ingestion of thyroid hormone - Struma ovarii - Metastatic follicular thyroid cancer

Autoimmunity. Autoimmune mechanisms are prominent in the pathogenesis of thyrotoxicosis. A spectrum of autoimmune mechanisms produces disease. Thyrotropin receptor antibodies (TRAb) occupy and stimulate the thyrotropin receptor, causing Graves hyperthyroidism (although some antibodies block the receptor and cause hypothyroidism) (71). Lymphocytes may infiltrate the thyroid gland and destroy thyroid follicular tissue, resulting in permanent hypothyroidism (Hashimoto, or chronic lymphocytic, thyroiditis). However, a subacute lymphocytic infiltration may disrupt thyroid follicles and cause release of preformed hormone into the circulatory system, resulting in transient hyperthyroidism, which is usually followed by transient hypothyroidism and recovery of thyroid function (painless lymphocytic thyroiditis) (64). This flare in autoimmunity is common postpartum (86), after cytokine therapy (18), or during therapy with lithium (61). Some of these patients (under 10%) do not recover thyroid function and appear to have Hashimoto thyroiditis following painless thyroiditis, whereas others (over 20%) develop permanent hypothyroidism after a decade or more (65). For this reason, some view painless thyroiditis as a variant presentation of Hashimoto thyroiditis. The term “Hashitoxicosis” has been used to describe patients in whom thyrotropin receptor antibodies stimulate the thyrotropin receptor simultaneous with lymphocytic destruction of the gland (35). Once sufficient thyroid tissue has been destroyed, the patient becomes hypothyroid despite persistent thyrotropin receptor antibodies. Patients may present with different autoimmune mechanisms over time, for example a patient with a prior history of Graves disease, in remission, may develop hyperthyroidism postpartum due to thyroiditis. Autoimmune thyroid disease is commonly familial and is associated with HLA-DR3 and DR5 (34).

Controversy continues regarding thyroid autoimmunity (especially Graves disease) induced or exacerbated by COVID vaccines (31). A population-based study of 2.3 million vaccine recipients failed to demonstrate vaccine-associated thyroid dysfunction (97).

Autonomy. The pathophysiology of autonomy is not well understood, although activating mutations in the thyrotropin receptor have been described in some toxic adenomas (45). The development of an autonomous nodule or multiple autonomous nodules or foci within an adenomatous goiter requires the unregulated replication of thyroid follicular cells that fail to respond to the normal negative feedback through pituitary thyrotropin. Goiter and autonomy develop with increasing age and are more common in areas of iodine deficiency.

Iodine-induced hyperthyroidism occurs when either an acute (eg, radiocontrast) or chronic (eg, amiodarone) iodine load is administered to a patient with underlying thyroid autonomy. Many of these patients have low or subnormal serum thyrotropin concentrations prior to the iodine exposure. In a metaanalysis, the risk of iodine-induced hyperthyroidism after radiocontrast at 30 days was only 0.2% (13).

Trophoblastic. Human chorionic gonadotrophin, which shares a common alpha subunit with thyrotropin, is a weak stimulator of the thyrotropin receptor. Up to 15% of women have minimal increases in free T4 (usually within the normal range) and subnormal serum thyrotropin concentrations in the first trimester (42). When HCG levels are very high patients may have hyperemesis gravidarum and mild overt hyperthyroidism (43). Even higher levels of HCG associated with neoplasms (molar pregnancy, choriocarcinoma) are a rare cause of hyperthyroidism.

Destructive thyroiditis due to viral or post-viral inflammation. Subacute thyroiditis (also known as granulomatous, painful, viral, or de Quervain thyroiditis) has been associated with mumps, coxsackie, and other viral infections in the past and follows the time course of other causes of destructive thyroiditis: transient hyperthyroidism, followed by hypothyroidism and recovery. It has been associated with COVID-19 infection (21). It is notable for thyroid pain frequently requiring corticosteroids for relief.

Other. Alemtuzumab treatment for multiple sclerosis has been associated with a 20% to 30% incidence of new-onset Graves disease (04; 26). Of the patients who developed Graves disease, 23% became spontaneous euthyroid and 15% hypothyroid (26). Some patients fluctuate between hyper- and hypothyroidism due to variable levels of thyrotropin-receptor stimulating and blocking antibodies (69). Painless thyroiditis developed in 4% of patients treated with alemtuzumab.

Amiodarone causes thyrotoxicosis in 2% of patients taking the drug. The most common mechanism is a destructive thyroiditis, but in patients with underlying goiter and autonomy, iodine-induced hyperthyroidism may occur (12). Sunitinib, another tyrosine kinase inhibitor used to treat renal cell and other carcinomas, may also be associated with a destructive thyroiditis (90). Immune checkpoint inhibitors also are associated with a destructive thyroiditis, and rarely, Graves disease (10).

Rare causes of thyrotoxicosis include thyrotropin-producing pituitary adenomas; palpation thyroiditis (eg, after parathyroid surgery); radiation thyroiditis; struma ovarii (hyperactive thyroid tissue in ovarian teratomas); large bony metastases of follicular thyroid cancer, which are rich in deiodinases that convert exogenous T4 to T3, resulting in T3 hyperthyroidism (62); and factitious ingestion of thyroid hormone.

Diagnostic workup

If thyrotoxicosis is suspected, a serum TSH is the recommended screening test. It is important to note that a subnormal or low TSH might indicate thyrotoxicosis, but it does not indicate the degree of thyrotoxicosis. Other causes of a low TSH include central hypothyroidism and severe nonthyroidal illness. Therefore, many laboratories utilize algorithms that automatically add serum-free T4 and T3 concentrations if the TSH is abnormally low, both to confirm the diagnosis and to assess the degree of hyperthyroidism. TSH-mediated hyperthyroidism is associated with normal or elevated serum TSH concentrations, but TSH-mediated hyperthyroidism is quite rare and is suspected if the normal or elevated TSH is “inappropriate” for the elevated levels of T4 and T3.

The revised American Thyroid Association guidelines for the management of hyperthyroidism suggest that if Graves disease is clinically suspected because of moderately severe hyperthyroidism, a large goiter, or simultaneous onset of orbitopathy, TRAb can be measured and, if elevated, further diagnostic evaluation is unnecessary (77). Third-generation TRAb assays are very sensitive and specific, but they may be normal in very mild or subclinical hyperthyroidism; in one real-world study, TRAb was diagnostic in only 79% of patients with documented Graves disease (Silva de Morias er al 2022). In the presence of thyroid nodularity, negative TRAb, or a clinical scenario suggestive of another etiology for thyrotoxicosis, a 24-hour radioiodine scan and uptake is indicated to complete the diagnostic workup. In Graves disease, the uptake is usually elevated, occasionally normal, and the pattern of uptake is diffuse. In a toxic nodule or toxic nodular goiter, the uptake is normal or elevated, and the pattern demonstrates focal increased uptake. In contrast, the uptake is less than 1% in painless thyroiditis or subacute thyroiditis. A radioiodine uptake may be the only way to distinguish painless thyroiditis from Graves disease in a patient with mild thyrotoxicosis, a modest goiter, and no other stigmata of Graves disease (64).

A radioiodine uptake may be contraindicated (eg, postpartum if the woman is still nursing) or of questionable utility (eg, shortly after an iodine load). Measurement of TRAb, the ratio of total T3/T4 as ng/dl/mcg/dl (greater than 20 in Graves disease; less than 20 in thyroiditis) (02), or color-flow Doppler (elevated in Graves disease) (54) may also be of utility.

Other forms of thyrotoxicosis are usually suspected based on the clinical setting (eg, pregnancy, amiodarone use, recent parathyroid surgery, radiation exposure, or known thyroid cancer), whereas the rare entities of struma ovarii and factitious ingestion of thyroid hormone can be diagnostic dilemmas. Struma ovarii demonstrates focal radioiodine uptake over the pelvis, whereas factitious thyrotoxicosis is associated with subnormal levels of serum thyroglobulin (58), a protein that is elevated in all other causes of thyrotoxicosis.

Biotin is a significant cause of a false positive diagnosis of thyrotoxicosis. Adequate intake of biotin is 30 mcg a day. Neurologists are prescribing doses as high as 100 mg three times daily for multiple sclerosis and ataxia due to multiple carboxylase deficiencies. Hairdressers are also recommending biotin in doses of 5 to 10 mg daily to improve hair. Patients taking these high doses of biotin have false results if their blood is analyzed in immunoassays that utilize biotin-avidin separation systems; immunometric (“sandwich”) assays such as those used for TSH measurement give falsely low values, whereas competitive-binding assays such as those used for T4, T3, or TRAb assays give falsely high values, thus mimicking Graves hyperthyroidism. Repeat measurements several days after stopping biotin are all normal in euthyroid patients (08).

Management

Beta-adrenergic-blocking drugs will ameliorate the adrenergic symptoms of thyrotoxicosis, especially tachycardia and tremor (41). They may also reduce the risk of atrial arrhythmia. Unless there is a specific contraindication, most thyrotoxic patients should be treated with beta-blockers. Beta1-selective agents such as atenolol allow for once-daily dosing.

The choice of therapy for hyperthyroidism depends on the etiology, and the values that both the physician and patient confer on the risks and benefits of the appropriate treatment options (77). For example, the management guidelines of the American Thyroid Association suggest that a trial of antithyroid drugs, radioiodine, or surgery are all reasonable options for the treatment of Graves hyperthyroidism.

Antithyroid drugs (thionamides) are indicated only for the treatment of hyperthyroidism when the mechanism of the hyperthyroidism involves de novo synthesis of thyroid hormone, ie, Graves disease and toxic nodular goiter, but not painless thyroiditis (23). These medications prevent the synthesis of new thyroid hormone by interfering with the organification of iodine to tyrosine residues on thyroglobulin. Because thyroid hormone is stored in the colloid space, and because thyroxine has a serum half-life of 7 days, it can take 3 to 6 weeks or longer for these medications to ameliorate biochemical hyperthyroidism.

Methimazole is the preferred thionamide in the Unites States except during the first trimester of pregnancy; carbimazole is a similar drug marketed in Europe. Propylthiouracil is an alternative thionamide that should only be used in patients who do not tolerate methimazole because of the rare risk of hepatocellular necrosis. Methimazole is more potent, has a longer duration of action, can be administered as a single daily dose, and has a lower incidence of side effects than propylthiouracil. Both drugs can cause birth defects, but the embryopathy associated with methimazole is more severe (03). Thionamides interfere with the radioiodine uptake; therefore, unless the diagnosis of Graves disease has been made by obtaining an elevated TRAb, and unless treatment is urgent, the radioiodine uptake should be obtained to ascertain both the cause of the hyperthyroidism and whether thionamide therapy is appropriate before starting treatment. Initial treatment is 10 to 30 mg of methimazole daily, depending on goiter size and the degree of hyperthyroidism, and is usually tapered to a maintenance dose of approximately 5 to 15 mg daily to maintain euthyroidism.

Thionamides are used in three ways: (1) to control hyperthyroid symptoms as quickly as possible before proceeding with definitive treatment with radioiodine or surgery, (2) in patients with Graves disease only, treatment to control the hyperthyroidism for one or more years may be associated with a remission of the disease in about 30% of patients, or (3) as long-term therapy in patients who prefer to avoid radioiodine or surgery. In a study from Iran, the long-term use of methimazole (approximately 10 years) was associated with remission four years after discontinuing methimazole in 84% of patients (06). TRAb titers during treatment help predict remission (09). Some studies suggest that almost all cases of agranulocytosis or liver failure from thionamide use usually occur within the first 120 to 180 days of treatment, respectively, suggesting that long-term use of methimazole is also a reasonable alternative (94).

Radioiodine ablation of the thyroid (75) and thyroid surgery are treatment options for Graves disease or toxic nodules. These definitive therapies cure the hyperthyroidism but result in permanent hypothyroidism requiring lifelong thyroid hormone replacement. Because it may take 10 to 12 weeks or longer for radioiodine to be effective, it may be used as primary therapy only in younger patients with mild hyperthyroidism who are tolerating symptoms well. Older patients or those with moderately severe symptoms and those patients who choose thyroid surgery are best pretreated with thionamides to attain a euthyroid state as quickly as possible (95). In a study of 1036 individuals over the age of 40, an increase in all causes of mortality was demonstrated during treatment with thionamides, and after radioiodine while still hyperthyroid, but not after levothyroxine treatment was started for post-radioiodine hypothyroidism (14). Although ideally patients should be euthyroid prior to thyroidectomy, when patient-related factors delay treatment, surgery while still thyrotoxic may reduce the risk of thyroid storm (76).

Corticosteroids are occasionally used in patients with painless thyroiditis who are not tolerating hyperthyroid symptoms, or who have complications from the hyperthyroidism. In a study, 50 mg prednisone daily, reduced by 10 mg each week, shortened the duration of the thyrotoxic phase (66).

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Douglas S Ross MD

Dr. Ross of Harvard Medical School has no relevant financial relationships to disclose.
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Editor

Douglas J Lanska MD MS MSPH

Dr. Lanska of the University of Wisconsin School of Medicine and Public Health and the Medical College of Wisconsin has no relevant financial relationships to disclose.
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Former Authors

Andrew F Stewart MD, Mary Kane-Brock MD (original authors), and Chadwick W Christine MD

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: female>male, 10:1
Heredity: heredity may be a factor
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-9: Toxic diffuse goiter without thyrotoxic crisis or storm: 242.00

Toxic uninodular goiter without thyrotoxic crisis or storm: 242.10

Toxic multinodular goiter without thyrotoxic crisis or storm: 242.20

Toxic nodular goiter unspecified type without thyrotoxic crisis or storm: 242.30

Thyrotoxicosis without goiter or other cause and without thyrotoxic crisis or storm: 242.90

Subacute thyroiditis: 245.1
ICD-10: Thyrotoxicosis with diffuse goitre: E05.0

Thyrotoxicosis with toxic single thyroid nodule: E05.1

Thyrotoxicosis with toxic multinodular goitre: E05.2

Thyrotoxicosis, unspecified: E05.9
OMIM: Graves disease (thyrotoxicosis): #275000

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Thyrotoxicosis

Associated Disorders

Amiodarone-induced hyperthyroidism
Factitious hyperthyroidism
Gestational hyperthyroidism
Graves disease
Hashimoto thyroiditis
- Hashitoxicosis
- Iodine-induced hyperthyroidism
- Lymphocytic thyroiditis
- Myasthenia gravis
- Painless thyroiditis
- Palpation thyroiditis
- Postpartum thyroiditis
- Radiation thyroiditis
- Silent thyroiditis
- Struma ovarii
- Subacute thyroiditis
- Thyrotoxic periodic paralysis
- Toxic adenoma
- Toxic multinodular goiter
- Trophoblastic hyperthyroidism
- TSH-producing pituitary adenomas

Differential Diagnosis

anxiety
panic disorder
other hyperadrenergic states (especially if associated with tachycardia)
occult malignancy
proximal muscle weakness
- depression, weight loss, and inactivity in the elderly

Also Relevant

Hypothyroidism
Myasthenia gravis
Myopathies associated with thyroid disease

Clinical Categories

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Tremor

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NIH: Thyrotoxicosis

Thyrotoxicosis …

Thyrotoxicosis

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

References

Contributors

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Patient Profile

ICD & OMIM codes

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Also in This Category

Brain death/death by neurologic criteria

Hepatic encephalopathy

Wilson disease

Bowel dysfunction in neurologic disorders

Coma due to primary brainstem and diencephalic lesions

Anti-LGI1 encephalitis

Transient visual loss

Fatal familial insomnia

Thyrotoxicosis

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Brain death/death by neurologic criteria

Hepatic encephalopathy

Wilson disease

Bowel dysfunction in neurologic disorders

Coma due to primary brainstem and diencephalic lesions

Anti-LGI1 encephalitis

Transient visual loss

Fatal familial insomnia

This is an article preview.
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