Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + Download Section PDF Listen ++ For further information, see CMDT Part 26-09: Hyperthyroidism (Thyrotoxicosis) + Key Features Download Section PDF Listen +++ +++ Essentials of Diagnosis ++ Sweating, weight loss or gain, anxiety, palpitations, loose stools, heat intolerance, menstrual irregularity Tachycardia; warm, moist skin; stare; tremor Graves disease Most common cause of hyperthyroidism Most patients have a palpable goiter (sometimes with bruit); ophthalmopathy Suppressed TSH in primary hyperthyroidism; usually increased T4, FT4, T3, FT3 +++ General Considerations ++ Causes Graves disease (most common) Can be precipitated by chemotherapy with immune checkpoint inhibitors (such as ipilimumab, pembrolizumab, tremelimumab, and atezolizumab) and alemtuzumab (for multiple sclerosis) Must be distinguished from hyperthyroidism due to destructive autoimmune thyroiditis (silent thyroiditis) that can be caused by these same medications Autonomous toxic adenomas, single or multiple Jod-Basedow disease, or iodine-induced hyperthyroidism, may occur with multinodular goiters after significant iodine intake, radiographic contrast, or drugs, eg, amiodarone Subacute de Quervain thyroiditis: hyperthyroidism followed by hypothyroidism Autoimmune (Hashimoto) thyroiditis may cause transient hyperthyroidism during initial phase and may occur postpartum Silent thyroiditis Also known as subacute lymphocytic thyroiditis or "hashitoxicosis" Can be caused by chemotherapeutic agents (such as tyrosine kinase inhibitors, denileukin diftitox, alemtuzumab, interferon-alpha, interleukin-2), immune checkpoint inhibitors as well as lithium and amiodarone Amiodarone-induced thyrotoxicosis Diagnosed when serum TSH levels are suppressed and serum T3 or FT3 levels are high or high-normal Categorized as type 1, type 2, or mixed (27%) Type 1 is caused by the active production of excessive thyroid hormone Type 2 is caused by thyroiditis with the passive release of stored thyroid hormone Thyrotoxicosis factitia: excessive exogenous thyroid hormone High serum human chorionic gonadotropin levels in first 4 months of pregnancy, molar pregnancy, choriocarcinoma, and testicular malignancies may cause hyperthyroidism + Clinical Findings Download Section PDF Listen +++ +++ Symptoms and Signs ++ Heat intolerance, sweating Palpitations Pruritus Frequent bowel movements Weight loss (or gain) Menstrual irregularities Nervousness, fine resting tremor Fatigue Muscle weakness, muscle cramps, hyperreflexia Tetany (rare) Thyroid Goiter (often with a bruit) in Graves disease Moderately enlarged, tender thyroid in subacute thyroiditis Eye Upper eyelid retraction Stare and lid lag with downward gaze Thyroid associated ophthalmopathy (exophthalmos) in 20–40% of patients with Graves disease Diplopia may be due to coexistent myasthenia gravis Skin Moist warm skin Fine hair Onycholysis Dermopathy (myxedema) in 3% of patients with Graves disease Heart Palpitations or angina pectoris Arrhythmias Sinus tachycardia Premature atrial contractions Atrial fibrillation or atrial tachycardia (can precipitate heart failure) Thyrotoxic cardiomyopathy due to thyrotoxicosis Thyrotoxic crisis or "storm" Hypokalemic paralysis (Asian or Native-American men) Subclinical hyperthyroidism (suppressed serum TSH with normal FT4) may increase the risk of nonvertebral fractures Clubbing and swelling of the fingers (acropachy) develop rarely +++ Differential Diagnosis ++ General anxiety, panic disorder, mania Other hypermetabolic state, eg, cancer, pheochromocytoma Exophthalmos due to other cause, eg, orbital tumor Atrial fibrillation due to other cause Acute psychiatric disorders (may falsely increase serum thyroxine) High estrogen states, eg, pregnancy Hypopituitarism Subclinical hyperthyroidism Diabetes mellitus and Addison disease may coexist with thyrotoxicosis and can aggravate the weight loss, fatigue, and muscle weakness seen with hyperthyroidism + Diagnosis Download Section PDF Listen +++ +++ Laboratory Tests ++ Serum TSH is suppressed in hyperthyroidism Serum FT4, T3, FT3, T4, thyroid resin uptake and FT4 index all usually increased FT4 sometimes normal but serum T3 elevated Serum FT3 (rather than T3) in women, pregnant or taking oral estrogen Hypercalcemia Increased liver enzymes and alkaline phosphatase Anemia Neutropenia Increased urinary magnesium excretion Hypokalemia and hypophosphatemia occur in thyrotoxic periodic paralysis Antibodies increased in most patients with Graves disease include Thyroid stimulating immunoglobulin (TSI), also known as serum TSH receptor antibody (TSHrAb) Antinuclear antibody (ANA) Thyroperoxidase or thyroglobulin antibodies Erythrocyte sedimentation rate often elevated in subacute thyroiditis TSH elevated or normal despite thyrotoxicosis in TSH-secreting pituitary tumor In type 1 amiodarone-induced thyrotoxicosis, the presence of proptosis, thyroid-stimulating immunoglobulin (TSI) is diagnostic In type 2 amiodarone-induced thyrotoxicosis, serum levels of interleukin-6 (IL-6) are usually quite elevated +++ Imaging Studies ++ Radioiodine scan Usually indicated for hyperthyroidism High 123I uptake in Graves disease and toxic nodular goiter Scan can detect toxic nodule or multinodular goiter Low uptake characteristic of subacute thyroiditis and amiodarone-induced hyperthyroidism Do not perform in pregnant women Technetium (Tc- 99m) pertechnetate Patients with Graves disease have increased or normal uptake Patients with thyrotoxicosis from thyroiditis (silent, subacute, postpartum) have reduced uptake Mimics radioiodine scanning but is more convenient, costs less, and confers less radiation exposure Thyroid ultrasound Can be helpful in patients with hyperthyroidism, particularly in patients with palpable thyroid nodules Color flow Doppler sonography helps distinguish type 1 from type 2 amiodarone-induced thyrotoxicosis MRI of the orbits is method of choice to visualize Graves ophthalmopathy affecting the extraocular muscles Imaging is required only in severe or unilateral cases or in euthyroid exophthalmos that must be distinguished from orbital pseudotumor, tumors, and other lesions + Treatment Download Section PDF Listen +++ +++ Medications +++ Graves disease ++ Propranolol Extended-release formulation 60 mg orally once or twice daily, with dosage increases every 2–3 days to a maximum daily dose of 320 mg Long-acting formulation Initially given every 12 hours for patients with severe hyperthyroidism, due to accelerated metabolism of the propranolol May be given once daily as hyperthyroidism improves Thioureas (methimazole or propylthiouracil [PTU]) Generally used for Young adults Those with mild thyrotoxicosis, small goiters, or fear of radioiodine Preparing patients for surgery and elderly patients for 131I treatment Methimazole Initial dose: 30–60 mg once daily orally Some patients with very mild hyperthyroidism may respond well to smaller initial doses: 10–20 mg daily May also be administered twice daily to reduce the likelihood of gastrointestinal upset Preferred over PTU (rarely causes fulminant hepatic necrosis) Reduce dosage as manifestations of hyperthyroidism resolve and as FT4 level falls toward normal If used during pregnancy or breastfeeding, the dose should not exceed 20 mg daily Propylthiouracil Dosage for nonpregnant women: 300–600 mg orally daily in four divided doses Reduce dose and frequency as symptoms of hyperthyroidism resolve and the FT4 level approaches normal Preferred over methimazole for pregnant women in first trimester of pregnancy Rare complications include arthritis, systemic lupus erythematosus, aplastic anemia, thrombocytopenia, and hypoprothrombinemia Acute hepatitis occurs rarely and is treated with prednisone Acute liver failure occurs in about 1 in 1000 patients Onset of severe liver toxicity varies from 3 days to 12 months after starting PTU Iodinated contrast agents (iopanoic acid [Telepaque] or ipodate sodium [Bilivist, Gastrografin, Oragrafin]) 500 mg twice daily orally for 3 days, then 500 mg once daily orally Begin after methimazole or PTU is started Lithium carbonate An effective substitute in cases of methimazole or PTU-induced hepatic toxicity or leukopenia Dosage: 500–750 mg/day orally in divided doses Should not be used during pregnancy Most patients require concurrent treatment with propranolol and sometimes prednisone +++ Autoimmune (Hashimoto) thyroiditis during the hyperthyroid phase ++ Propranolol ER 60–80 mg twice daily and increased every 3 days until the heart rate is < 90 beats per minute Ipodate sodium or iopanoic acid, 500 mg orally daily, promptly corrects elevated T3 levels and is continued for 15–60 days until the serum FT4 level normalizes With subacute thyroiditis, pain can usually be managed with nonsteroidal anti-inflammatory drugs, but opioid analgesics are sometimes required +++ Amiodarone-induced thyrotoxicosis ++ Propranolol ER, methimazole, iopanoic acid, prednisone +++ Hypokalemic thyrotoxic paralysis ++ Oral propranolol, 3 mg/kg, normalizes the serum potassium and phosphate levels and reverses the paralysis within 2–3 hours Continued propranolol, 60–80 mg every 8 hours (or sustained-action propranolol ER daily at equivalent daily dosage), along with methimazole or PTU Intravenous potassium or phosphate is not usually required +++ Graves ophthalmopathy ++ For mild cases, selenium 100 mcg orally twice daily slows progression of the disease For acute, progressive exophthalmos, Methylprednisolone is given intravenously, 500 mg weekly for 6 weeks, then 250 mg weekly for 6 weeks If oral prednisone is chosen for treatment, it must be given promptly in daily doses of 40–60 mg/day orally, with dosage reduction over several weeks Higher initial prednisone doses of 80–120 mg/day are used when there is optic nerve compression For corticosteroid-resistant acute Graves ophthalmopathy Teprotumumab or tocilizumab are administered intravenously, whereas rituximab may be given by retro-orbital injections Teprotumumab An experimental monoclonal antibody inhibitor of IGF-IR Produced responses in 69% of patients with Graves ophthalmopathy when given intravenous every 3 weeks for eight infusions Dosage: 10 mg/kg for the first infusion, followed by 20 mg/kg for the remaining seven infusions Tocilizumab Binds to IL-6 receptors Dosage: 8 mg/kg intravenously every 4 weeks Rituximab recommended dosing: 10 mg by retro-orbital injection into the affected eye weekly for 1 month, followed by a 1-month break, then another series of four weekly injections Avoid smoking and thiazolidinediones +++ Atrial fibrillation ++ Digoxin and beta-blockers to control rate Warfarin Cardioversion unsuccessful until hyperthyroidism controlled +++ Thyrotoxic heart failure ++ Aggressively control hyperthyroidism Use digoxin, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, diuretics +++ Surgery ++ Treat preoperatively with methimazole Six hours later, give ipodate sodium or iopanoic acid (500 mg twice daily orally) to accelerate euthyroidism and reduce thyroid vascularity Iodine (eg, Lugol solution, 2–3 gtts daily orally for several days) also reduces vascularity Give propranolol preoperatively until serum T3 or free T3 is normal For thyrotoxic patients undergoing surgery, larger doses of propranolol are required perioperatively to reduce possibility of thyroid crisis +++ Graves disease ++ Thyroidectomy preferred over radioiodine for Patients who do not wish to have radioiodine therapy Patients with an intolerance to thioureas Women planning pregnancy in the near future Patients with Graves ophthalmopathy Hartley-Dunhill operation Procedure of choice Total resection of one lobe and a subtotal resection of the other lobe, leaving about 4 g of thyroid tissue +++ Toxic solitary thyroid nodules ++ Partial thyroidectomy for patients aged < 40 131I for those aged > 40 years +++ Therapeutic Procedures +++ Graves disease, toxic multinodular goiter ++ Radioactive iodine (131I) therapy Patients usually only take propranolol However, those with coronary disease, aged > 65 years, or severe hyperthyroidism are usually first rendered euthyroid with methimazole Contraindicated in pregnancy Discontinue methimazole 4 days before 131I treatment Methimazole or PTU given after 131I for symptomatic hyperthyroidism until euthyroid Total or near-total thyroidectomy is recommended, since surgical pathology reveals unsuspected differentiated thyroid cancer in 18.3% of cases + Outcome Download Section PDF Listen +++ +++ Follow-Up ++ In patients taking methimazole or PTU, check WBC periodically to exclude agranulocytosis, particularly in those with sore throat or febrile illness Obtain free T4 levels every 2–3 weeks during initial treatment Hypothyroidism is common months to years after 131I therapy or subtotal thyroidectomy Lifelong clinical follow-up, with TSH and free T4 measurements, indicated in all patients +++ Complications ++ Osteoporosis, hypercalcemia Temporary decreased libido, diminished sperm motility, gynecomastia Cardiac arrhythmias and heart failure Thyroid crisis ("storm") Ophthalmopathy Dermopathy Thyrotoxic hypokalemic periodic paralysis +++ Prognosis ++ Posttreatment hypothyroidism common, especially with 131I therapy or surgery Recurrence of hyperthyroidism occurs most commonly after methimazole or PTU (~50%) Subacute thyroiditis usually subsides spontaneously in weeks to months Graves disease usually progresses, but may rarely subside spontaneously or even result in hypothyroidism Despite subtotal thyroidectomy of both lobes, recurrence of hyperthyroidism occurs in 9% Despite treatment, there is an increased risk of death from cardiovascular disease, stroke, and femur fracture in women Mortality of thyrotoxic crisis is high Subclinical hyperthyroidism: good prognosis; most patients do not have accelerated bone loss +++ When to Admit ++ Thyroid storm Hyperthyroidism-induced atrial fibrillation with severe tachycardia Thyroidectomy + References Download Section PDF Listen +++ + +Biondi B et al. Subclinical hyperthyroidism. N Engl J Med. 2018 Jun 21;378(25):2411–9. [PubMed: 29924956] + +Bourcier S et al. Thyroid storm in the ICU: a retrospective multicenter study. Crit Care Med. 2020 Jan;48(1):83–90. [PubMed: 31714398] + +Corvilain B et al. Treatment of adult Graves' disease. Ann Endocrinol (Paris). 2018 Dec;79(6):618–35. [PubMed: 30193753] + +Gronich N et al. Cancer risk after radioactive iodine treatment for hyperthyroidism: a cohort study. Thyroid. 2020 Feb;30(2):243–50. [PubMed: 31880205] + +Illouz F et al. Graves' disease and pregnancy. Ann Endocrinol (Paris). 2018 Dec;79(6):636–46. [PubMed: 30224035] + +Kitahara CM et al. Association of radioactive iodine treatment with cancer mortality in patients with hyperthyroidism. JAMA Intern Med. 2019 Jul 1;179(8):1034–42. [PubMed: 31260066] + +Ono Y et al. Factors associated with mortality of thyroid storm: analysis using a national inpatient database in Japan. Medicine (Baltimore). 2016 Feb;97(7):e2848. [PubMed: 26886648] + +Ross DS et al. 2016 American Thyroid Association guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis. Thyroid. 2016 Oct;26(10):1343–421. [PubMed: 27521067] + +Simsir IY et al. Therapeutic plasmapheresis in thyrotoxic patients. Endocrine. 2018 Oct;62(1):144–8. [PubMed: 2996824] + +Yu W et al. Side effects of PTU and MMI in the treatment of hyperthyroidism: a systematic review and meta-analysis. Endocr Pract. 2020 Feb;26(2):207–17. [PubMed: 31652102]