Thyrotoxicosis

Etiology

The etiology of thyrotoxicosis can be categorized into endogenous and exogenous sources of thyroid hormones.

Increased Endogenous Secretion of Thyroid Hormone

Graves disease: This condition is a form of autoimmune thyroid disease and is the leading cause of hyperthyroidism and thyrotoxicosis in the United States, accounting for 60% to 80% of cases. In this condition, thyroid-stimulating immunoglobulins bind to and activate the TSH receptor, resulting in excessive thyroid hormone production.[7] This continuous, inappropriate stimulation causes hyperplasia of thyroid follicular cells, leading to a diffuse goiter. While the exact cause of Graves disease remains unclear, genetic and environmental factors, including smoking, stress, and dietary iodine, contribute to its development.[8][9] Please see StatPearls' companion resource, "Graves Disease," for more information.

Toxic multinodular goiter: This condition is the second most common cause of thyrotoxicosis, especially in older adults and regions with iodine deficiency. Toxic multinodular goiter is characterized by multiple autonomously functioning thyroid nodules that produce excessive thyroid hormones independent of TSH regulation.[10][11] In rare cases, nontoxic adenomas or goiters may convert to toxic adenomas after exposure to iodinated contrast.[12] Please see StatPearls' companion resource, "Toxic Multinodular Goiter," for more information.

Toxic adenoma: A toxic adenoma, also referred to as a hyperfunctioning adenoma or a follicular adenoma (according to the recent World Health Organization [WHO] classification), is a single autonomously functioning nodule within the thyroid gland that secretes excessive thyroid hormone. Follicular adenomas are benign, encapsulated, noninvasive neoplasms that demonstrate thyroid follicular cell differentiation without the nuclear features of papillary thyroid cancer. Although these nodules are typically benign, they can lead to clinical thyrotoxicosis.[4][13]

Thyroid-stimulating hormone–producing adenoma or pituitary adenoma: TSH-producing adenoma, or pituitary adenoma, is a rare cause of thyrotoxicosis resulting from a TSH-producing pituitary tumor. Unlike most forms of hyperthyroidism, where TSH is suppressed, patients with a TSH-producing adenoma present with inappropriately normal or elevated TSH levels alongside high T₃ and T₄ levels.[14] TSH-producing adenomas account for less than 1% of all pituitary adenomas and are often detected incidentally.[15]

Human chorionic gonadotropin–mediated hyperthyroidism: Human chorionic gonadotropin (hCG)–mediated hyperthyroidism occurs when HCG, which is structurally similar to TSH, stimulates the TSH receptor, particularly during the first trimester of pregnancy or as a result of infertility treatments. This inappropriate stimulation can lead to hyperthyroidism, especially in conditions such as gestational trophoblastic disease or choriocarcinoma.[2][16]

Thyroiditis: Thyroiditis encompasses various forms, such as subacute (De Quervain) thyroiditis, painless thyroiditis, and postpartum thyroiditis, all of which can cause transient thyrotoxicosis due to the release of preformed thyroid hormones from damaged thyroid follicles. Reidel thyroiditis, a rare condition, is characterized by progressive fibrosis of the thyroid gland. Although the exact etiology of Reidel thyroiditis remains unclear, recent studies suggest it is closely associated with immunoglobulin G (IgG)-4–related sclerosing disease. In thyroiditis, a hypothyroid phase typically follows thyrotoxicosis, after which thyroid function usually normalizes.[4] Please see StatPearls' companion resource, "Thyroiditis," for more information.

Drug-induced thyrotoxicosis: This condition can be caused by certain medications, particularly amiodarone and iodinated contrast agents. Amiodarone, which contains a significant amount of iodine, can induce both type 1 (increased hormone synthesis in predisposed individuals) and type 2 (destructive thyroiditis) thyrotoxicosis. Iodinated contrast agents can lead to thyrotoxicosis, typically 2 to 12 weeks after exposure, through the increased substrate effect, known as the Jod-Basedow effect.[17] 

Immune checkpoint inhibitors, a newer class of medications, can cause thyrotoxicosis through both hyperthyroidism and thyroiditis. Thyrotoxicosis can typically occur within 1 to 2 months of initiating therapy, although it may present as late as 12 months following therapeutic initiation. The incidence of thyrotoxicosis is as high as 8% with combined PD-1 and anti-CTLA-4 treatment and lower with individual drug treatment. Please see StatPearls' companion resource, "Endocrine-Related Adverse Events from Immune Checkpoint Inhibitors," for more information.

Increased Exogenous Secretion of Thyroid Hormone

• Factitious hyperthyroidism
• Excessive levothyroxine replacement therapy (iatrogenic)

Graves disease is the most common cause of thyrotoxicosis, followed by toxic multinodular goiter and toxic adenoma.[4] Rare causes of thyrotoxicosis include TSH-producing adenomas, struma ovarii, gestational trophoblastic neoplasia, thyrotoxicosis factitia, activating mutations of the TSH receptor, and functional thyroid cancer metastases.[18] Struma ovarii, a type of ovarian teratoma, can produce functional thyroid hormone.[19] 

Another rare cause of thyrotoxicosis is contamination of ground meat by the thyroid gland of the animal, known as "hamburger thyrotoxicosis." This condition should be suspected in the context of community outbreaks or when meat is prepared by inexperienced butchers.[20] Factitious hyperthyroidism occurs when individuals ingest thyroid replacement medication without appropriate medical supervision, often with the goal of weight loss. This behavior is observed in a variety of populations, ranging from competitive athletes to patients with psychiatric disorders, such as Munchausen syndrome.[21][22] 

Epidemiology

The global prevalence of hyperthyroidism is estimated to be between 0.2% and 1.2%, while subclinical hyperthyroidism, characterized by suppressed TSH with normal T₃ and T₄ levels, affects approximately 0.7% to 1.4% of the population.[4] The incidence of thyrotoxicosis is highest between the ages of 20 and 50. Recent studies indicate a higher prevalence of subclinical thyrotoxicosis in older populations, attributed to more frequent screening, with rates increasing to 2% to 3% in individuals aged 65 or older. Women are disproportionately affected, with a female-to-male ratio of 7:1 to 10:1.[8]

Graves disease is the leading cause of thyrotoxicosis in iodine-replete countries, with an incidence of 20 to 50 cases per 100,000 individuals. This condition is followed by toxic multinodular goiter, with an incidence of 1.5 to 18 cases per 100,000, and toxic adenoma. Graves disease most commonly affects women aged 30 to 50, with a male-to-female ratio of 1:5, although it can occur at any age and in both genders.[14][23] 

Toxic nodular goiter is more prevalent with advancing age and in iodine-deficient regions. Thyroiditis accounts for approximately 10% of thyrotoxicosis cases. Although the incidence of thyroid storm—a life-threatening complication of thyrotoxicosis—remains low at less than 2%, recent studies emphasize the importance of early detection due to the high mortality rate associated with delayed treatment.[2][24] 

Globally, iodine intake significantly impacts the incidence of thyrotoxicosis. Graves disease is the predominant cause in iodine-sufficient regions, while toxic multinodular goiter and toxic adenoma are more common in iodine-deficient areas.[25]

Pathophysiology

Thyroid hormones affect almost every tissue and organ system by increasing basal metabolic rate and enhancing tissue thermogenesis through the upregulation of β-adrenergic receptors, which in turn increases sympathetic activity.[26] Symptoms can range from asymptomatic to life-threatening thyroid storm.

The cardiovascular system is particularly affected by thyroid hormones, which increase both inotropy and chronotropy and play a crucial role in conduction pathways. These hormones enhance the expression of myocardial sarcoplasmic reticulum calcium-dependent ATP, leading to an increased heart rate and myocardial contractility, ultimately resulting in a higher cardiac output. Decreased systemic vascular resistance (SVR) and afterload result from arterial smooth muscle relaxation caused by metabolic byproducts, such as lactic acid, generated during increased oxygen consumption. The reduction in SVR activates the renin-angiotensin system, promoting sodium reabsorption and blood volume expansion, which increases preload. If untreated, these changes can lead to left ventricular hypertrophy and congestive heart failure.[27][28][29]

Thyroid hormones are essential for the development of the central nervous system from embryonic stages through adulthood. They contribute to processes such as proliferation, differentiation, migration, synaptogenesis, and myelination. Additionally, thyroid hormones are vital for the development of visual and auditory structures and the cerebellar regulation of gait.[30]

The thyroid is a key regulator of metabolism, and some of the first signs of hypothyroidism are weight gain and cold intolerance. In thyrotoxicosis, metabolic needs may be increased by 50%, causing weight loss and hyperthermia, partially mediated through the sympathetic nervous system. Thyrotropin-releasing hormone production is stimulated by caloric intake, while reduced intake can lead to central hypothyroidism.[30][31]

Thyroid hormones affect both skeletal muscle differentiation and functional regulation via type-2 (DIO2) and type-3 (DIO3) iodothyronine deiodinases. These hormones are essential for glucose uptake, influence fiber type changes, regulate satellite cells, and stimulate muscle growth. Proximal muscle weakness is a hallmark of thyrotoxicosis.[32][33]

TSH also regulates bone development, with low or low-normal TSH levels linked to decreased bone mass, increased osteoporosis, and a higher risk of bone fractures. These findings appear to be independent of thyroid hormone levels.[34] In addition, thyroid hormones (T₃/T₄) activate the bone morphogenetic protein pathway, enhancing osteoblast activity and promoting bone resorption.[35] Children with thyrotoxicosis may experience premature closure of the growth plates and skull sutures, resulting in short stature and craniosynostosis. Some of these bone morphology changes are mediated through interactions between thyroid hormones, insulin-like growth factor-1 (IGF1), fibroblast growth factor, Indian hedgehog, and Wnt signaling pathways.[36]

Thyrotoxicosis can also have significant psychiatric manifestations, especially in individuals aged 65 or older. A large study found higher rates of dementia and mild cognitive impairment in patients with low TSH levels, whether from endogenous or exogenous sources. This is particularly concerning, as thyroid replacement therapy is commonly prescribed to patients aged 65 and older.[6] Other psychiatric symptoms may include anxiety, insomnia, paranoia, and, in severe cases, psychosis. While the exact pathophysiology remains unclear, it may be linked to hypermetabolism or increased sympathetic nervous system activity.[37][38]

The association between the eyes and hyperthyroidism has been recognized for over a millennium. Despite this long history, much remains unknown about thyroid eye disease. The condition is believed to involve a complex immune-mediated cycle that includes orbital fibroblasts, adipocytes, and lymphocytes. Please see StatPearls' companion resource, "Thyroid Eye Disease," for more information.

Histopathology

Toxic multinodular goiter and toxic adenoma are types of follicular adenomas, which are usually characterized by a non-malignant proliferation of thyroid follicles enclosed in a fibrous capsule. Generally, these are benign, nonfunctional adenomas that do not secrete thyroid hormones.[2]

Follicular Hyperplasia

In thyrotoxicosis, especially in Graves disease, histological examination typically shows follicular hyperplasia. This is characterized by an increase in the number of follicular cells and a reduction in colloids within the follicles, indicating increased thyroid hormone synthesis. A key diagnostic challenge is differentiating benign adenomas from papillary carcinoma, as some cases may exhibit papillary hyperplasia of the follicular epithelium, which can resemble papillary carcinoma. Histopathological features may include nuclear enlargement, cellular atypia, increased mitotic activity, pseudonuclear bodies, Psammoma bodies, and nuclear pleomorphism in follicular cells.[39] 

Graves Disease

This disease is associated with lymphocytic infiltration and follicular hyperplasia. Thyroglobulin and myeloperoxidase antibodies are associated with lymphocytic infiltration, while thyroid receptor antibodies are linked to follicular hyperplasia. Research has demonstrated that the degree of lymphocytic infiltration correlates with the severity of symptoms and the likelihood of remission after treatment.[40] 

Thyroiditis

In cases of thyroiditis leading to thyrotoxicosis, such as subacute thyroiditis, histopathological examination typically reveals the destruction of thyroid follicles accompanied by lymphocytic infiltration. Thyroglobulin and myeloperoxidase antibodies are often positive, indicating a distinct mechanism of thyrotoxicosis compared to autoimmune conditions.[40]

Toxicokinetics

Key Aspects of Toxicokinetics in Thyrotoxicosis

Absorption: Thyroid hormones, primarily T₄ and T₃, are absorbed through the gastrointestinal tract. Their bioavailability can be affected by dietary factors, the presence of certain medications, and the formulation of thyroid medications, such as levothyroxine.[16] 

Distribution: After absorption, thyroid hormones circulate in the bloodstream, primarily bound to plasma proteins such as thyroxine-binding globulin, albumin, and transthyretin. The unbound (free) hormones are biologically active and can enter cells, where they influence metabolic processes.

Metabolism: Thyroid hormones are primarily metabolized in the liver and other tissues. They can be converted from T₄ to T₃, which is the more active form. This metabolic conversion is critical in determining the physiological effects of thyroid hormones on various organs. Their metabolism can be influenced by factors such as liver function and genetic polymorphisms in enzymes responsible for hormone metabolism.

Elimination: Thyroid hormones are primarily eliminated through the kidneys. T₄ has a half-life of approximately 7 days, while T₃ has a shorter half-life of about 1 day. This difference is important when assessing the duration of action and the potential for toxicity in cases of thyrotoxicosis.

History and Physical

Patients with thyrotoxicosis most commonly present with signs and symptoms related to excess thyroid hormone, which affect the systems mentioned below.[4][11]

• Cardiovascular: Palpitations, tachycardia, atrial fibrillation, dyspnea, orthopnea, and edema (in the case of congestive heart failure).[5]
• Neurological: Proximal muscle weakness, brisk deep tendon reflexes with a rapid relaxation phase, and tremors.[11]
• Gastrointestinal or metabolic: Weight loss, increased appetite, diarrhea, and hyperdefecation.[41]
• Psychiatric: Anxiety, insomnia, cognitive impairment, and psychosis.[6][37][38]
• Adrenergic stimulation: Heat intolerance, hyperthermia, and increased sweating.[11]
• Dermatological: Onycholysis, vitiligo, pretibial myxedema, and thyroid acropachy (clubbing of the fingers and toes with swelling of the hands and feet).[42][43]
• Ocular: Exophthalmos, increased lacrimation, blurry vision, diplopia, photophobia, decreased color vision, and periorbital edema.[11] Please see StatPearls' companion resource, "Thyroid Eye Disease," for more information.
• Reproductive: Amenorrhea, oligomenorrhea, and gynecomastia.[15]

Compressive symptoms, including hoarseness, dysphagia, and orthopnea, may arise if the thyroid becomes significantly enlarged.[4][11] Dermatological and ophthalmic manifestations often occur together.[43]

Sinus tachycardia is the most common cardiac rhythm disturbance in thyrotoxicosis; however, atrial fibrillation can also occur, particularly in older patients or those with valvular disease and coronary artery disease. Older individuals often exhibit fewer typical clinical signs and may instead present with cardiac symptoms such as heart failure and arrhythmias, as well as hypercalcemia, depression, fatigue, and weight loss. This presentation is referred to as "apathetic hyperthyroidism" and may be mistaken for age-related conditions.[8]

On physical examination, patients with thyrotoxicosis often appear cachectic, hyperthermic, diaphoretic, and anxious. Common findings include:

• Goiter
• Palpable nodules
• Tachycardia or atrial fibrillation
• Systolic hypertension
• Dyspnea
• Abdominal tenderness
• Hyperreflexia
• Proximal muscle weakness
• Tremor
• Gynecomastia
• Short stature in affected children
• Stare
• Lid lag [2][4][11][44]

In rare cases, patients may present with thyroid storm, characterized by tachycardia, fever, altered mental status, agitation, signs of cardiac failure, and impaired liver function. Although rare, thyroid storm carries a mortality rate of up to 25%, making urgent recognition and treatment critical. Hyperthermia, which is characterized by body temperatures ranging between 104 °F and 106 °F (40 °C to 41 °C), is a key finding. Please see StatPearls' companion resource, "Thyroid Storm," for more information.

Findings specific to Graves disease include ophthalmopathy, which can lead to proptosis, chemosis, conjunctival injection, lid lag, exposure keratitis, and extraocular muscle dysfunction. Other manifestations include pretibial myxedema and thyroid acropachy (clubbing of the nails, fingers, and toes). Clinically significant Graves orbitopathy occurs in 25% of patients with Graves disease. Thyroid dermopathy, a rare condition affecting 1% to 4% of individuals with Graves disease, is a distinct sign of thyroid autoimmunity and is almost always associated with Graves orbitopathy.[44]

In subacute thyroiditis, patients may report a recent upper respiratory illness and typically present with fever, neck pain, and swelling, along with a firm and tender thyroid gland. Painless thyroiditis often occurs in the postpartum period, with patients frequently having a personal or family history of autoimmune or thyroid disorders. Suppurative thyroiditis presents with a tender, erythematous mass in the anterior neck, and patients often experience fever, dysphagia, and dysphonia. Drug-induced thyroiditis may be associated with a history of medications such as amiodarone, lithium, iodinated contrast, or immune checkpoint inhibitors.[44]

Neonatal thyrotoxicosis, caused by maternal autoimmune hyperthyroidism, may present with tachycardia, irritability with tremors, poor feeding, sweating, difficulty sleeping, emaciation, proptosis, and goiter. Severe cases can lead to craniosynostosis and microcephaly. Rare signs, such as thrombocytopenia, may mimic infection or sepsis.[45] Occasionally, patients may present with acute muscle paralysis and severe hypokalemia, a condition known as thyrotoxic periodic paralysis. In the rare case of a TSH-secreting pituitary adenoma, a visual field defect may also be present.[11]

Evaluation

Low serum TSH (<0.01 mU/L) levels demonstrate high sensitivity and specificity for the diagnosis of thyroid disorders. When TSH is low, elevated serum free T₄ (fT₄) and T₃ levels can differentiate overt hyperthyroidism from subclinical hyperthyroidism, with T₃ often rising before T₄. Variations in a patient's specific baseline TSH and T₄ levels may correlate more closely with clinical symptoms than standard reference ranges.[46]

Pituitary-dependent causes of hyperthyroidism may present with normal or elevated TSH levels, along with increased T₄ and T₃ levels and a rise in free alpha-subunit concentrations. Serum levels of antibodies to the TSH receptor are diagnostic for Graves disease, with a sensitivity of 98% and a specificity of 99%. In contrast, thyroid peroxidase antibodies are found in approximately 75% of Graves disease cases.[23]

Radioactive iodine uptake studies or thyroid scans can help differentiate between causes of thyrotoxicosis other than Graves disease. These tests are recommended for all thyrotoxic patients who do not present with the clinical features of Graves disease. In Graves disease, radioactive iodine uptake is typically diffuse unless nodules or fibrosis are present. A single toxic adenoma will show focal uptake in the adenoma, with suppressed uptake in the surrounding thyroid tissue. In toxic multinodular goiter, multiple areas of focal increased uptake are observed, with suppressed uptake in the surrounding tissue.

Radioactive iodine uptake is near zero in patients with painless, postpartum, or subacute thyroiditis, as well as those with thyroid hormone ingestion or recent excessive iodine exposure. While both thyroid ultrasound and radioactive iodine uptake are equally sensitive for diagnosing Graves disease, ultrasound offers advantages such as the absence of radiation exposure, improved nodule detection, and lower cost.[27] Thyroid scintigraphy is recommended if thyroid nodules are present or the etiology of thyrotoxicosis is unclear.[4] In subacute thyroiditis, inflammatory markers such as erythrocyte sedimentation rate and C-reactive protein are frequently elevated. A T₃:T₄ ratio of less than 20 also suggests thyroiditis, as it reflects the ratio of stored thyroid hormones.[4]

Gestational transient thyrotoxicosis is characterized by suppressed TSH and elevated T₄ levels in early pregnancy, which is caused by high serum hCG levels.[47][48] During pregnancy, the diagnosis should include serum TSH levels along with either free T₃ (fT₃) and T₄ or the total T₃ and T₄, using an adjusted reference range 1.5 times the nonpregnant range. In the first half of pregnancy, serum TSH levels may be lower than the nonpregnant reference range; however, fT₄ values should be normal.[2][8][49]

Thyroid storm is diagnosed by low or undetectable TSH levels (<0.01 mU/L), elevated fT₄ and fT₃, or positive thyroid receptor antibodies. Due to its high mortality rate, clinicians should maintain a high index of suspicion in patients presenting with classic symptoms or relevant risk factors.[50]

Factitious thyrotoxicosis, caused by the intentional ingestion of thyroid supplements, will typically present with increased T₃/T₄ levels, depending on the supplement, along with low TSH. A radioactive iodine uptake scan will show decreased uptake, and thyroglobulin levels will also be low. Additionally, Doppler ultrasound may reveal reduced vascularization.[22]

Treatment / Management

The recommended treatment of thyrotoxicosis depends on its underlying cause. Beta-blockers, such as propranolol, are used to alleviate adrenergic symptoms such as sweating, anxiety, and tachycardia. Theoretically, propranolol inhibits 5′-monodeiodinase, thus blocking the peripheral conversion of T₄ to T₃. Propranolol also blocks both β1- and β2 receptors, making it a first-line agent. However, it should generally be avoided in patients with asthma.[11] The 3 mainstays of treatment include thionamide drugs, radioiodine therapy, and thyroid surgery.

Thionamide Drugs

Thionamide drugs, including propylthiouracil (PTU) and methimazole, reduce the production of thyroid hormone by acting as preferential substrates for thyroid peroxidase. At high doses, PTU also inhibits the peripheral conversion of T₄ to T₃.

Methimazole is administered at a dosage of 15 to 30 mg/d for 4 to 8 weeks in the treatment of Graves disease, during which most patients achieve a euthyroid state. Once euthyroidism is established, treatment can proceed with 1 of 2 approaches. In the block-replace method, the same dose of thionamide is continued to inhibit thyroid hormone production, while levothyroxine is added to maintain euthyroidism. Alternatively, the thionamide dose can be gradually reduced to allow endogenous thyroid hormone synthesis, thereby sustaining a euthyroid state. Please see StatPearls' companion resource, "Methimazole," for more information. In Graves disease, long-term remission is achieved in about 50% of patients treated with thionamide drugs. However, a drawback of thionamides is the uncertainty of relapse after discontinuation. Prolonged treatment beyond 18 months has not been shown to improve remission rates. Methimazole is more effective and has a longer half-life than PTU, allowing for once-daily dosing.

Additionally, PTU carries a higher risk of hepatotoxicity. Agranulocytosis occurs in approximately 1 in 300 patients treated with thionamides and typically presents with symptoms such as sore throat, mouth ulcers, and high fever. A differential white blood cell count is recommended for all patients on thionamides experiencing febrile illness or pharyngitis. Minor adverse effects of thionamides include pruritus, arthralgia, and gastrointestinal upset. If patients continue to have anti-TSH receptor antibodies or signs of hyperthyroidism after 18 months of treatment, options such as radioiodine therapy or surgery should be considered.[23]

The IGF1 receptor (IGF1R) is required as a co-signal for certain pathways stimulated by TSH. Increased IGF1R expression has been observed in orbital fibroblasts of patients with thyroid eye disease, as well as in B- and T-cells of patients with Graves disease. Teprotumumab, an IGF1R blocker, is approved by the Food and Drug Administration (FDA) for the treatment of Graves orbitopathy. Teprotumumab also shows potential for treating Graves disease and other forms of thyrotoxicosis.[23][41][51]

Radioiodine Therapy

Radioiodine therapy is the most common treatment for adults with Graves disease in the United States. This therapy is also effective for treating follicular nodules and toxic multinodular goiter. Radioactive iodine is administered as a single oral dose. This is absorbed by the thyroid gland, causing tissue-specific inflammation that leads to thyroid fibrosis and a gradual destruction of thyroid tissue over the following months. Hypothyroidism typically develops within 6 to 12 months, necessitating lifelong levothyroxine therapy for most patients. Patients with large goiters, severe thyrotoxicosis, ischemic heart disease, heart failure, or arrhythmia are advised to undergo thionamide pretreatment until achieving a euthyroid state before receiving radioiodine therapy.

Notably, radiation therapy is contraindicated during pregnancy and lactation, and conception should be avoided for 6 to 12 months for both males and females. A small risk of thyrotoxicosis exacerbation exists in the first month after treatment due to the release of preformed thyroid hormones. Additionally, radioiodine therapy is a definitive risk factor for developing Graves orbitopathy.[23][41][52] Please see StatPearls' companion resource, "Radioactive Iodine Therapy," for more information.

The treatment of thyroiditis differs because antithyroid drugs are ineffective, as patients typically have reduced production of new thyroid hormones. Thyroiditis is usually transient, and the treatment is focused on symptom control using beta-blockers. In cases of subacute thyroiditis, nonsteroidal anti-inflammatory drugs (NSAIDs) and, occasionally, systemic glucocorticoids may be prescribed to manage pain and inflammation. Beta-blockers are recommended for older patients with symptomatic thyrotoxicosis and also for any thyrotoxic patient with a resting heart rate exceeding 90 bpm or with underlying cardiovascular disease.

Children with thyrotoxicosis may be treated with methimazole, radioiodine therapy, or thyroidectomy. Methimazole is the first-line therapy for Graves disease in children, typically administered for 1 to 2 years, as some children may achieve remission. Radioiodine therapy is not recommended for children aged 5 or younger. Additionally, PTU should be avoided in children due to its risk of hepatotoxicity.

Pregnancy: Radioiodine therapy, as mentioned above, is contraindicated during pregnancy; however, antithyroid drugs may be used, and thyroidectomy may be considered for severe hyperthyroidism.[47] During pregnancy, thionamide drugs should be administered in a titrated dose regimen. PTU is preferred during the first trimester of pregnancy due to the teratogenic risks associated with methimazole, such as aplasia cutis and choanal or esophageal atresia. Maternal TSH receptor antibodies can be measured to help assess the risk of fetal hyperthyroidism.[2][52][53](B3)

Gestational transient thyrotoxicosis typically resolves naturally as hCG levels decline around 10 to 12 weeks of gestation and is not associated with adverse pregnancy outcomes. Treatment focuses on supportive care for nausea, vomiting, and electrolyte imbalances, particularly in cases of hyperemesis gravidarum, without the need for antithyroid drugs.[47] Please see StatPearls' companion resource, "Hyperthyroidism in Pregnancy," for more information. 

Thyroid Surgery

Thyroidectomy, whether total or partial, provides a rapid and effective treatment for thyrotoxicosis. However, it is invasive and expensive and also results in permanent hypothyroidism, necessitating lifelong levothyroxine therapy. Pretreatment to achieve euthyroidism is recommended before surgery to minimize the risk of exacerbating thyrotoxicosis or triggering a thyroid storm. Surgery is indicated for cases of hyperthyroidism resistant to medical therapy, significant thyroid enlargement causing compressive symptoms, or when thyroid cancer is suspected. The surgical procedure usually involves either a total thyroidectomy, where the entire thyroid gland is removed, or a thyroid lobectomy, which involves removing one lobe of the thyroid (right or left). Most patients can resume normal activities within a few days. Common complications include transient hypocalcemia due to temporary hypoparathyroidism and vocal cord paresis caused by injury to the recurrent laryngeal nerve. Please see StatPearls' companion resource, "Thyroidectomy," for more information. 

Differential Diagnosis

Thyrotoxicosis is typically diagnosed through basic laboratory testing; however, several conditions can clinically resemble it. Some of these conditions include disorders that stimulate the sympathetic nervous system, such as pheochromocytoma or drug ingestions (such as beta-agonists, excessive caffeine, illicit drugs, or supplements). Primary cardiac conditions, such as atrial fibrillation or congestive heart failure, may also mimic thyrotoxicosis symptoms. Hypoglycemia can lead to palpitations, tremors, and sweating, while diabetes may present with weight loss and fatigue. Cushing syndrome can cause proximal muscle weakness and hypertension. Additionally, underlying malignancy can lead to weight loss and fatigue.

Surgical Oncology

‌The British Association of Endocrine and Thyroid Surgeons (BAETS) supports several key trials, as listed below.

• A study in the United Kingdom compares hemithyroidectomy and total thyroidectomy for low-risk thyroid cancer, focusing on cost-effectiveness and recurrence rates.
• The RABBIT Trial compares radiofrequency ablation (RFA) with open surgery for benign thyroid nodules, involving surgeons and endocrinologists throughout the United Kingdom.
• The CoNCent Study assesses the advantages of central neck dissection with completion thyroidectomy for incidental N1a thyroid cancer discovered during hemithyroidectomy.
• The Thy3000 Study is a national observational study on the epidemiology and management of thyroid nodules in the United Kingdom.
• The NIFTy Trial explores the use of near-infrared fluorescent imaging in thyroid surgery to decrease postsurgical hyperparathyroidism.

(Active Trials: British Association of Endocrine and Thyroid Surgeons (BAETS); 2024. Retrieved from Baets.org.uk.)

Pertinent Studies and Ongoing Trials

• The Mayo Clinic is currently conducting several trials related to thyroid disorders, including thyrotoxicosis. These studies focus on various aspects of thyroid disease, such as the use of teprotumumab for thyroid eye disease, the evaluation of different treatment approaches for hyperthyroidism, the investigation of immune checkpoint inhibitor-related thyroid disease, and the development of new clinical tools to support shared decision-making.

• New therapeutics on the horizon include biologics, small molecule peptides, immunomodulators, and antibodies targeting IGF1R.[41]

• Traditional Chinese medicine has also been studied for treating thyrotoxicosis, particularly Graves disease. Diosgenin, found in fenugreek, has been shown to decrease thyroid proliferation in mice. Resveratrol, produced by injured plants, helps reduce oxidative stress. Icariin, derived from the plant Epimedium brevicornum, has demonstrated a reduction in Graves orbitopathy in mouse models. Several other plant-derived molecules used in traditional Chinese medicine have also been studied and shown effectiveness in animal models.[41][54]

Prognosis

The prognosis of thyrotoxicosis depends mainly on its underlying cause. Thyroiditis typically resolves on its own within a few weeks. Symptoms of Graves disease often improve over time. In contrast, follicular and pituitary adenomas generally require treatment, as they can worsen without intervention.

Complications

Untreated or undiagnosed thyrotoxicosis can progress to thyroid storm. Patients typically present with tachycardia, fever, altered mental status, agitation, signs of cardiac failure, and impaired liver function. A thorough history is crucial to identify precipitating factors such as major stress, illness, or recent injury.

Thyrotoxicosis treatment involves the administration of thionamides, such as methimazole or PTU, to inhibit the synthesis of new thyroid hormones, along with iodine to block the release of preformed hormones. Supportive care, including the use of beta-blockers (preferably propranolol) and fluid resuscitation, is commonly provided in a critical care setting.