Hyperthyroidism: Diagnosis and Treatment

IGOR KRAVETS

IGOR KRAVETS, MD

Am Fam Physician. 2016;93(5):363-370

Patient information: See related handout on overactive thyroid gland (hyperthyroidism), written by the author of this article.

Author disclosure: No relevant financial affiliations.

Hyperthyroidism is an excessive concentration of thyroid hormones in tissues caused by increased synthesis of thyroid hormones, excessive release of preformed thyroid hormones, or an endogenous or exogenous extrathyroidal source. The most common causes of an excessive production of thyroid hormones are Graves disease, toxic multinodular goiter, and toxic adenoma. The most common cause of an excessive passive release of thyroid hormones is painless (silent) thyroiditis, although its clinical presentation is the same as with other causes. Hyperthyroidism caused by overproduction of thyroid hormones can be treated with antithyroid medications (methimazole and propylthiouracil), radioactive iodine ablation of the thyroid gland, or surgical thyroidectomy. Radioactive iodine ablation is the most widely used treatment in the United States. The choice of treatment depends on the underlying diagnosis, the presence of contraindications to a particular treatment modality, the severity of hyperthyroidism, and the patient's preference.

Hyperthyroidism is an excessive concentration of thyroid hormones in tissues causing a characteristic clinical state. In the United States, the overall prevalence of hyperthyroidism is 1.2%, and the prevalences of overt hyperthyroidism and subclinical hyperthyroidism are 0.5% and 0.7%, respectively.¹

Clinical recommendation	Evidence rating	References
The choice of treatment modality for hyperthyroidism caused by overproduction of thyroid hormones depends on the patient's age, symptoms, comorbidities, and preference.	C	²⁵, ²⁶
The diagnostic workup for hyperthyroidism includes measuring thyroid-stimulating hormone, free thyroxine (T₄), and total triiodothyronine (T₃) levels to determine the presence and severity of the condition, as well as radioactive iodine uptake and scan of the thyroid gland to determine the cause.	C	²⁰, ²¹
Methimazole (Tapazole) is the preferred antithyroid medication except in the first trimester of pregnancy and in patients with an adverse reaction to the medication.	B	²⁶

Recommendation	Sponsoring organization
Do not order multiple tests in the initial evaluation of a patient with suspected thyroid disease. Order TSH, and if abnormal, follow up with additional evaluation or treatment depending on the findings.	American Society for Clinical Pathology
Do not routinely order a thyroid ultrasound in patients with abnormal thyroid function tests if there is no palpable abnormality of the thyroid gland.	The Endocrine Society/American Association of Clinical Endocrinologists

Etiology and Pathogenesis

The common endogenous causes of hyperthyroidism are Graves disease, toxic multinodular goiter, toxic adenoma, and painless thyroiditis (Table 1).^1–9 Graves disease, the most common cause of hyperthyroidism in the United States,² is an autoimmune disorder in which thyroid-stimulating antibodies activate thyroid-stimulating hormone (TSH) receptors, triggering thyroid hormone synthesis. Risk factors for Graves disease include female sex and personal or family history of an autoimmune disorder.^2,3

Etiology	Mechanism
Most common causes
Graves disease	Autoimmune process in which antibodies stimulate the TSH receptor leading to overproduction of thyroid hormones
Painless or transient (silent) thyroiditis	Autoimmune destruction of thyroid tissue leading to a release of preformed thyroid hormones
Toxic adenoma (Plummer disease)	Somatic mutation in TSH receptor or Gs alpha gene in a thyroid nodule
Toxic multinodular goiter	Expansion of clonogenic cells with an activating TSH receptor mutation
Less common causes
Drug-induced thyroiditis	Overproduction of thyroid hormones (amiodarone-induced thyrotoxicosis type 1) or release of preformed thyroid hormones (amiodarone-induced thyrotoxicosis type 2, interferon alfa, interleukin-2, or lithium)
Hyperemesis gravidarum	High level of β-hCG stimulates TSH receptors
Postpartum thyroiditis	Variant of painless thyroiditis with the same mechanism, occurring after delivery
Subacute granulomatous (de Quervain) thyroiditis	Painful inflammation of the thyroid gland caused by viral infection, often with fever, triggering a release of preformed thyroid hormones
Rare causes
Factitious thyrotoxicosis	Surreptitious ingestion of thyroid hormones
Metastatic follicular thyroid cancer	Metastasis of functional follicular thyroid cancer
Struma ovarii	Ectopic thyroid tissue in ovarian dermoid tumor produces thyroid hormones
Trophoblastic tumor or a germ cell tumor	Tumor produces β-hCG, which stimulates thyroid TSH receptors
TSH-secreting pituitary adenoma	Tumor secreting large quantities of TSH, and not responding to thyroxine and triiodothyronine feedback

Toxic multinodular goiter is the second most common cause of hyperthyroidism in the United States and the most common cause in older persons living in iodine-deficient areas.² Over time, nodules arise from the frequent replication of clonogenic cells that leads to a somatic activating mutation of TSH receptors.⁴ A single nodule is called a toxic adenoma (Plummer disease).

In contrast with these three disorders, painless or transient (silent) thyroiditis causes a destruction of thyroid follicles via an autoimmune mechanism and a release of preformed thyroid hormones into the circulation.⁵ Its clinical presentation is the same as with other causes. In a Danish study, its prevalence among patients with thyrotoxicosis was 0.5%, as evaluated by scintigraphy.⁶ Painless thyroiditis can be triggered by childbirth (postpartum thyroiditis) or by use of medications such as lithium, interferon alfa, interleukin-2, and amiodarone.⁷

Gestational hyperthyroidism develops in the first trimester of pregnancy as a result of the stimulatory action of placental beta human chorionic gonadotropin (β-hCG), which shares structural features with TSH, on the thyroid gland.⁸ β-hCG-mediated hyperthyroidism can occasionally be caused by hyperemesis gravidarum and, rarely, by a gestational trophoblastic tumor.⁸

Other rare causes of hyperthyroidism are TSH-secreting pituitary adenoma, metastatic follicular thyroid cancer, and struma ovarii.⁹

Clinical Manifestations

The clinical presentation of hyperthyroidism ranges from asymptomatic to thyroid storm (Table 2).^10–18 Elevated thyroid hormone levels amplify catecholamine signaling through increased numbers of cell surface beta-adrenergic receptors. The resulting adrenergic symptoms (e.g., palpitations, heat intolerance, diaphoresis, tremor, stare [an appearance of a fixed look due to retraction of eyelids], lid lag, hyperdefecation) are the most common manifestations of hyperthyroidism.¹⁰ Hypermetabolism induces weight loss despite an increased appetite. Neuromuscular symptoms include weakness of proximal muscles.¹¹ Psychiatric symptoms range from anxiety to frank psychosis.¹² Patients with long-standing untreated hyperthyroidism may develop atrial fibrillation (10% to 15% of patients^13,14) or heart failure (5.8% of patients¹⁵).

Signs that are pathognomonic for Graves disease include orbitopathy, pretibial myxedema (thyroid dermopathy), and thyroid acropachy, which occur in 25%, 1.5%, and 0.3% of patients, respectively.¹⁶ Goiters that develop in Graves disease are usually smooth and may have a thrill on palpation or a bruit on auscultation. Single or multiple nodules on palpation raise suspicion for a toxic adenoma or a toxic multinodular goiter, although nonfunctioning thyroid nodules may coexist with a goiter in Graves disease.¹⁶

Graves orbitopathy manifests as exophthalmos or periorbital edema, and it can trigger photophobia, excessive lacrimation, increased eye sensitivity to wind or smoke, or a sensation of a foreign body in the eyes. In severe cases, blurred vision, diplopia, or reduced color perception may develop.¹⁶ Smoking increases the risk of developing Graves orbitopathy (odds ratio = 3.7).¹⁷

Pretibial myxedema, a less common finding, develops from fibroblast activation and manifests as swelling over the tibiae with the skin assuming a peau d'orange (orange peel) appearance.¹⁸ Thyroid acropachy, an uncommon sign, is the clubbing of fingers and toes with soft-tissue swelling of the hands and feet.¹⁹ Other skin manifestations of Graves disease include patchy hyperpigmentation and vitiligo.¹⁹

Laboratory and Radiographic Assessment

Clinical suspicion of hyperthyroidism should prompt laboratory testing (Figure 1^20–23 ). Some physicians first order a TSH test, which has the highest sensitivity and specificity for hyperthyroidism, and then subsequently obtain free thyroxine (T₄) and total triiodothyronine (T₃) levels (free T₃ assays are poorly validated¹) if the TSH level is low. Others prefer to order all three tests if hyperthyroidism is suspected to make the diagnosis more efficiently. Many laboratories perform reflex free T₄ testing if TSH is suppressed. Table 3 lists patterns of thyroid function tests in hyperthyroidism.^20,21 The serum level of thyroid-stimulating immunoglobulins or TSH-receptor antibodies helps distinguish Graves disease from other causes of hyperthyroidism in patients who lack signs pathognomonic of Graves disease and have a contraindication to radioactive iodine uptake and scan.

THYROID FUNCTION TEST RESULTS SIMULATING HYPERTHYROIDISM

Excess estrogen from pregnancy or estrogen therapy leads to elevated levels of thyroxine-binding globulin, which manifests as elevated total T₄ and T₃ levels while TSH and free T₄ levels remain normal (Table 3).^20,21 These findings do not indicate hyperthyroidism and require no treatment.²¹

Condition	TSH	Total T₄	Free T₄	Total T₃
Overt hyperthyroidism	Suppressed	Elevated	Elevated	Elevated
Subclinical hyperthyroidism*	Suppressed or low	Normal	Normal	Normal
TSH-secreting pituitary adenoma	Normal or elevated	Elevated	Elevated	Elevated
Estrogen excess	Normal	Elevated	Normal	Elevated
Nonthyroidal illness syndrome	Low	Normal or mildly decreased	Normal	Low (and reverse T₃ is elevated)
Glucocorticoid and/or dopamine therapy	Low	Normal	Normal	Normal

Patients with critical or acute illness often develop the nonthyroidal illness syndrome manifesting as mildly decreased TSH levels (0.1 to 0.4 mIU per mL) and normal or mildly decreased T₄ levels. In contrast to subclinical hyperthyroidism, the T₃ level is usually low and the reverse T₃ level is elevated. This condition resolves spontaneously when the patient recovers from the acute illness.²¹

Exogenous glucocorticoids or dopamine may cause a mild decrease of TSH levels, a situation often occurring in the intensive care unit. Total T₄, total T₃, and free T₄ levels remain normal. TSH levels return to normal after these medications are discontinued.²¹

RADIOACTIVE IODINE UPTAKE AND THYROID SCAN

A radioactive iodine uptake test and thyroid scan help determine the cause of hyperthyroidism (Table 4). Uptake is the percentage of an iodine 123 (I-123) tracer dose taken up by the thyroid gland, ranging from 15% to 25% at 24 hours. The uptake is very low (0% to 2%) in patients with thyroiditis and high in patients with Graves disease, a toxic adenoma, or a toxic multinodular goiter.^23,24

Condition	Radioactive iodine uptake (normal = 15% to 25%)	Radiotracer distribution in the thyroid gland
Graves disease	High	Homogeneous
Toxic adenoma	High	Iodine 123 is concentrated in one spot
Toxic multinodular goiter	High	Iodine 123 is concentrated in multiple spots
Thyroiditis	Low	Not applicable

The thyroid scan shows the distribution of radiotracer in the gland. A homogeneous distribution indicates Graves disease, but accumulation of I-123 in one area points to a toxic adenoma (Figure 2) or in multiple areas to a toxic multinodular goiter.^23,24

Ultrasonography is sometimes used as a cost-effective and safe alternative to radioactive iodine uptake and scan. It is the primary imaging modality used during pregnancy, lactation, and in amiodarone-induced thyrotoxicosis.²⁴

Treatment

Regardless of the cause of hyperthyroidism, the adrenergic symptoms are controlled by beta blockers (Table 5).^25–28 Propranolol has the theoretical advantage of also inhibiting 5′-monodeiodinase, thus blocking peripheral conversion of T₄ to T₃.²⁵ The choice of treatment modality for hyperthyroidism caused by overproduction of thyroid hormones depends on the patient's age, symptoms, comorbidities, and preference.^25,26

First-line agents	Dosage	Adverse effects	Comments	Cost*
Beta blockers
Atenolol	25 to 100 mg orally once per day	Exacerbation of congestive heart failure	Selective beta₁ blocker; safer than propranolol in asthma or chronic obstructive pulmonary disease; once-daily dosing improves compliance	$5
Propranolol	Immediate release: 10 to 40 mg orally every eight hours Extended release: 80 to 160 mg orally once per day	Exacerbation of congestive heart failure or asthma	Decreases T₄ to T₃ conversion; nonselective beta blocker	$20 to $84 for immediate release $76 to $152 for extended release
Antithyroid medications
Methimazole (Tapazole)	5 to 120 mg orally per day (can be given in divided doses)	Dose-related agranulocytosis	Contraindicated in the first trimester of pregnancy	$20 to $100 ($45 to $900)
Propylthiouracil	50 to 300 mg orally every eight hours	Agranulocytosis not related to dose; liver dysfunction; rash, including ANCA-associated vasculitis	Drug of choice in the first trimester of pregnancy; carries a higher risk of liver failure than methimazole	$60 to $400
Radioactive iodine	Usually 10 to 30 millicurie, depending on uptake and the size of the thyroid gland	May aggravate hyperthyroidism in the early posttreatment period Causes hypothyroidism three to six months after treatment	Contraindicated in severe Graves orbitopathy and in patients who are pregnant or nursing	—
Ancillary agents
Cholestyramine	1 to 2 g orally twice per day	Constipation or diarrhea; bloating	Binds thyroid hormones in the intestine and thus increases fecal excretion	$50
Glucocorticoids	Prednisone: 20 to 40 mg orally per day for up to four weeks Hydrocortisone: 100 mg intravenously every eight hours with subsequent taper	Hyperglycemia in patients with diabetes mellitus, otherwise few short-term adverse effects	Used in severe hyperthyroidism or thyroid storm to reduce T₄ to T₃ conversion; also used in severe subacute thyroiditis	Prednisone: $20 Hydrocortisone: NA
Nonsteroidal anti-inflammatory drugs	Depends on the specific agent	Nephrotoxicity; gastrointestinal bleeding	Treats pain in subacute thyroiditis	—
Supersaturated potassium iodide	5 drops orally every eight hours	May aggravate hyperthyroidism if given before an antithyroid agent	Give at least one hour after methimazole or propylthiouracil Do not give before radioactive iodine treatment	—

GRAVES DISEASE

Graves disease requires one of the three treatment options: an antithyroid medication (methimazole [Tapazole] or propylthiouracil), radioactive iodine (I-131) ablation of the thyroid gland, or surgical thyroidectomy. The choice of treatment depends on the benefits vs. risks in a specific clinical situation and on the patient's preference²⁵ (eTable A).

Treatment options	Benefits	Risks
Antithyroid medication (methimazole [Tapazole] or propylthiouracil)	No exposure to radiation or to surgical risks No permanent hypothyroidism Propylthiouracil is safe for the fetus in the first trimester of pregnancy	Agranulocytosis, hepatotoxicity (especially with propylthiouracil), rash Methimazole can cause aplasia cutis and other birth defects in the first trimester of pregnancy
Radioactive iodine ablation	No exposure to potential adverse effects of an antithyroid medication or to surgical risks Treatment of choice in the United States	Aggravation of Graves orbitopathy, especially in smokers Permanent hypothyroidism (occurs in most patients) Radiation exposure Failure to cure hyperthyroidism if the radioactive iodine dose is insufficient Risk of Graves disease recurrence even after successful treatment Contraindicated in pregnancy
Thyroidectomy	No exposure to adverse effects of an antithyroid medication or to radiation Little chance of Graves disease recurrence	Risk of general anesthesia Risk of damaging recurrent laryngeal nerve leading to hoarse voice (if damage is unilateral) or of respiratory distress (if damage is bilateral) Risk of inadvertent damage or removal of parathyroid glands leading to permanent hypoparathyroidism

Antithyroid Medications. Antithyroid medications are thionamides; they inhibit thyroid peroxidase, blocking the synthesis of T₃ and T₄. Thionamides can serve as a long-term therapy or as a bridge to I-131 ablation or thyroidectomy, with the goal of normalizing thyroid function and preventing exacerbation of hyperthyroidism after I-131 ablation or avoiding surgical risks associated with uncontrolled hyperthyroidism. Because Graves disease remits in up to 30% of patients treated with thionamides, these medications can be used as the initial treatment, with ablation or thyroidectomy performed if remission does not occur.^25,26 Once medical therapy is discontinued, relapse occurs in 30% to 70% of patients, mostly within the first year.²⁷ After discontinuation, thyroid function should be monitored every one to three months for six to 12 months, and the patient should be instructed to contact the physician if symptoms recur.

Because use of propylthiouracil has a higher risk of causing severe liver injury, as highlighted in the U.S. Food and Drug Administration's boxed warning, methimazole is preferred except during the first trimester of pregnancy (can cause birth defects) and in patients with an adverse reaction to methimazole.^28,29 For patients using methimazole, the prevalence of agranulocytosis is 0.17%, the incidence of hepatitis is 3.17 per 1,000 person-years, and the incidence of acute hepatic failure is 0.32 per 1,000 person-years.^30,31 Patients should be instructed to discontinue medication use and contact their physician if they develop jaundice, acholic stools, dark urine, arthralgias, abdominal pain, nausea, vomiting, fever, or sore throat. A baseline complete blood count (CBC) with differential and a hepatic panel should be obtained before initiating an antithyroid medication. Subsequent routine monitoring of CBC is unnecessary, but CBC with differential should be obtained if fever and/or pharyngitis develop.

Free T₄ and total T₃ should be obtained four weeks after starting a thionamide and every four to eight weeks thereafter with the dosage adjusted based on results. Once free T₄ and total T₃ levels normalize, they should be monitored every three months. Serum TSH is of limited value early in the treatment course because levels may remain suppressed for several months after treatment is started. An antithyroid medication should be continued for 12 to 18 months, then tapered or discontinued if the TSH level is normal at the time. Elevated or above-normal TSH levels (greater than 4.0 mIU per mL) at antithyroid drug discontinuation is associated with an increased likelihood of permanent remission.²⁷

Radioactive Iodine Ablation. Radioactive iodine ablation of the thyroid gland is the most common treatment of Graves disease in the United States. It is contraindicated in pregnancy. Moderate to severe Graves orbitopathy is a relative contraindication, especially in patients who smoke, because radioactive iodine may exacerbate the eye disease.^32,33 In mild cases of Graves orbitopathy, radioactive iodine ablation can be performed with concomitant glucocorticoid therapy. Nonradioactive iodine impedes radioactive iodine uptake by iodide transporter; therefore, exposure to large amounts of nonradioactive iodine (e.g., iodinated contrast, amiodarone) should be avoided within three months before radioactive iodine ablation. Pregnancy should be ruled out within 48 hours before radioactive iodine ablation and avoided for six months thereafter.¹ A thionamide should be discontinued at least five days before the treatment but can be restarted three to five days after to maintain control of thyroid function, because it may take up to 12 weeks to achieve the full effect of radioactive iodine.

Most patients develop permanent hypothyroidism between two and six months after radioactive iodine ablation and require thyroid hormone supplementation.^1,33 Free T₄ and total T₃ should be measured four to eight weeks after ablation; if hyperthyroidism persists, these indices should be monitored every four to six weeks and thyroid hormone replacement started in the early stages of hypothyroidism.¹

Thyroidectomy. This treatment option is preferred in patients with goiter-induced compressive symptoms and in patients with contraindications to radioactive iodine ablation or thionamides. Besides general anesthesia risk, thyroidectomy carries a risk of inadvertently injuring parathyroid glands and recurrent laryngeal nerves.³⁴

TOXIC ADENOMA OR TOXIC MULTINODULAR GOITER

Antithyroid medications can control hyperthyroidism, but do not induce remission of hyperthyroidism associated with toxic adenoma or toxic multinodular goiter. Therefore, radioactive iodine ablation and thyroidectomy are the main treatment options for these conditions. Thyroidectomy is favored if a nodule or goiter causes compressive symptoms. Antithyroid medications may be used for long-term treatment in select patients who refuse ablation or who have a contraindication to thyroidectomy.^35,36

THYROIDITIS

Painless thyroiditis and subacute thyroiditis are self-limiting conditions that usually resolve spontaneously within six months. There is no role for antithyroid medications or radioactive iodine ablation in the treatment of thyroiditis. Beta blockers may be used if needed to control adrenergic symptoms. Pain associated with subacute thyroiditis may be relieved with a nonsteroidal anti-inflammatory drug.⁵

THYROID STORM

Graves disease, toxic adenoma, and toxic multinodular goiter can sometimes cause severe hyperthyroidism, which is termed a thyroid storm. The Burch-Wartofsky score is a helpful tool for diagnosing thyroid storm³⁷ (eTable B). Treatment of thyroid storm is summarized in eTable C.

Criteria		Score
Thermoregulatory dysfunction
Temperature (°F)
	99 to 99.9	5
	100 to 100.9	10
	101 to 101.9	15
	102 to 102.9	20
	103 to 103.9	25
	≥ 104	30
Central nervous system effects
Absent		0
Mild		10
	Agitation
Moderate		20
	Delirium
	Psychosis
	Extreme lethargy
Severe		30
	Seizure
	Coma
Gastrointestinal-hepatic dysfunction
Absent		0
Moderate		10
	Diarrhea
	Nausea/vomiting
	Abdominal pain
Severe		20
	Unexplained jaundice
Cardiovascular dysfunction
Tachycardia (bpm)
	90 to 109	5
	110 to 119	10
	120 to 129	15
	130 to 139	20
	≥ 140	25
Congestive heart failure
Absent		0
Mild		5
	Pedal edema
Moderate		10
	Bibasilar rales
Severe		15
	Pulmonary edema
Atrial fibrillation
	Absent	0
	Present	10
Precipitant history
Negative		0
Positive		10

DRUG-ASSOCIATED HYPERTHYROIDISM

Amiodarone-induced thyrotoxicosis can be classified as type 1 (thyroid hormone overproduction, treated with antithyroid medications) or type 2 (thyroid tissue destruction, treated with steroids). Amiodarone should not be discontinued unless it can be stopped safely, without triggering cardiac complications.^38,39

Hyperthyroidism associated with use of other medications (e.g., lithium, interferon alfa, tyrosine kinase inhibitors, highly active antiretroviral therapy) is usually self-limited. The physician should determine whether the medication may be discontinued safely or replaced with a different medication.

Data Sources: A PubMed search was performed in Clinical Queries using the key terms hyperthyroidism, thyrotoxicosis, Graves disease, toxic multinodular goiter, toxic adenoma, and thyroiditis. The search included meta-analyses, randomized controlled trials, clinical trials, and reviews. Also searched were Essential Evidence Plus, the Cochrane database, the National Guideline Clearinghouse database, and UpToDate. Search dates: December 26, 2014, and August 24, 2015.

The author thanks Dr. Harold E. Carlson and Dr. Marie C. Gelato for reviewing this manuscript.

Bahn Chair RS, Burch HB, Cooper DS, et al. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists [published corrections appear in Thyroid. 2011;21(10):1169, and Thyroid. 2012;22(11):1195]. Thyroid. 2011;21(6):593-646.

Vanderpump MP. The epidemiology of thyroid disease. Br Med Bull. 2011;99:39-51.

Villanueva R, Greenberg DA, Davies TF, Tomer Y. Sibling recurrence risk in autoimmune thyroid disease. Thyroid. 2003;13(8):761-764.

Gozu HI, Lublinghoff J, Bircan R, Paschke R. Genetics and phenomics of inherited and sporadic non-autoimmune hyperthyroidism. Mol Cell Endocrinol. 2010;322(1–2):125-134.

Pearce EN, Farwell AP, Braverman LE. Thyroiditis [published correction appears in N Engl J Med. 2003;349(6):620]. N Engl J Med. 2003;348(26):2646-2655.

Schwartz F, Bergmann N, Zerahn B, Faber J. Incidence rate of symptomatic painless thyroiditis presenting with thyrotoxicosis in Denmark as evaluated by consecutive thyroid scintigraphies. Scand J Clin Lab Invest. 2013;73(3):240-244.

Sweeney LB, Stewart C, Gaitonde DY. Thyroiditis: an integrated approach. Am Fam Physician. 2014;90(6):389-396.

Carney LA, Quinlan JD, West JM. Thyroid disease in pregnancy [published correction appears in Am Fam Physician. 2014;90(1):8]. Am Fam Physician. 2014;89(4):273-278.

Usui T, Izawa S, Sano T, et al. Clinical and molecular features of a TSH-secreting pituitary microadenoma. Pituitary. 2005;8(2):127-134.

Silva JE, Bianco SD. Thyroid-adrenergic interactions: physiological and clinical implications. Thyroid. 2008;18(2):157-165.

Duyff RF, Van den Bosch J, Laman DM, van Loon BJ, Linssen WH. Neuromuscular findings in thyroid dysfunction: a prospective clinical and electrodiagnostic study. J Neurol Neurosurg Psychiatry. 2000;68(6):750-755.

Gulseren S, Gulseren L, Hekimsoy Z, Cetinay P, Ozen C, Tokatlioglu B. Depression, anxiety, health-related quality of life, and disability in patients with overt and subclinical thyroid dysfunction. Arch Med Res. 2006;37(1):133-139.

Selmer C, Olesen JB, Hansen ML, et al. The spectrum of thyroid disease and risk of new onset atrial fibrillation: a large population cohort study. BMJ. 2012;345:e7895.

J N, Francis J. Atrial fibrillation and hyperthyroidism. Indian Pacing Electrophysiol J. 2005;5(4):305-311.

Siu CW, Yeung CY, Lau CP, Kung AW, Tse HF. Incidence, clinical characteristics and outcome of congestive heart failure as the initial presentation in patients with primary hyperthyroidism. Heart. 2007;93(4):483-487.

Bartalena L, Fatourechi V. Extrathyroidal manifestations of Graves' disease: a 2014 update. J Endocrinol Invest. 2014;37(8):691-700.

Hegediüs L, Brix TH, Vestergaard P. Relationship between cigarette smoking and Graves' ophthalmopathy. J Endocrinol Invest. 2004;27(3):265-271.

Fatourechi V. Pretibial myxedema: pathophysiology and treatment options. Am J Clin Dermatol. 2005;6(5):295-309.

Fatourechi V. Thyroid dermopathy and acropachy. Best Pract Res Clin Endocrinol Metab. 2012;26(4):553-565.

van Deventer HE, Mendu DR, Remaley AT, Soldin SJ. Inverse log-linear relationship between thyroid-stimulating hormone and free thyroxine measured by direct analog immunoassay and tandem mass spectrometry. Clin Chem. 2011;57(1):122-127.

Dufour DR. Laboratory tests of thyroid function: uses and limitations. Endocrinol Metab Clin North Am. 2007;36(3):579-594.

Beck-Peccoz P, Persani L. TSH-induced hyperthyroidism caused by a pituitary tumor. Nat Clin Pract Endocrinol Metab. 2006;2(9):524-528.

Werner SC, Ingbar SH, Braverman LE, Utiger RD. Werner & Ingbar's The Thyroid: A Fundamental and Clinical Text. 9th ed. Philadelphia, Pa.: Lippincott Williams & Wilkins; 2005.

Cappelli C, Pirola I, De Martino E, et al. The role of imaging in Graves' disease: a cost-effectiveness analysis. Eur J Radiol. 2008;65(1):99-103.

Abraham P, Avenell A, Park CM, Watson WA, Bevan JS. A systematic review of drug therapy for Graves' hyperthyroidism. Eur J Endocrinol. 2005;153(4):489-498.

Abraham P, Avenell A, McGeoch SC, Clark LF, Bevan JS. Antithyroid drug regimen for treating Graves' hyperthyroidism. Cochrane Database Syst Rev. 2010;1:CD003420.

Liu X, Qiang W, Liu X, et al. A second course of antithyroid drug therapy for recurrent Graves' disease: an experience in endocrine practice. Eur J Endocrinol. 2015;172(3):321-326.

Bartalena L. Diagnosis and management of Graves disease: a global overview. Nat Rev Endocrinol. 2013;9(12):724-734.

Nakamura H, Noh JY, Itoh K, Fukata S, Miyauchi A, Hamada N. Comparison of methimazole and propylthiouracil in patients with hyperthyroidism caused by Graves' disease. J Clin Endocrinol Metab. 2007;92(6):2157-2162.

Huang CH, Li KL, Wu JH, Wang PN, Juang JH. Antithyroid drug-induced agranulocytosis: report of 13 cases. Chang Gung Med J. 2007;30(3):242-248.

Wang MT, Lee WJ, Huang TY, Chu CL, Hsieh CH. Antithyroid drug-related hepatotoxicity in hyperthyroidism patients: a population-based cohort study. Br J Clin Pharmacol. 2014;78(3):619-629.

Weetman AP. Radioiodine treatment for benign thyroid diseases. Clin Endocrinol (Oxf). 2007;66(6):757-764.

Acharya SH, Avenell A, Philip S, Burr J, Bevan JS, Abraham P. Radioiodine therapy (RAI) for Graves' disease (GD) and the effect on ophthalmopathy: a systematic review. Clin Endocrinol (Oxf). 2008;69(6):943-950.

Randolph GW, Shin JJ, Grillo HC, et al. The surgical management of goiter: Part II. Surgical treatment and results. Laryngoscope. 2011;121(1):68-76.

Vidal-Trecan GM, Stahl JE, Eckman MH. Radioiodine or surgery for toxic thyroid adenoma: dissecting an important decision. A cost-effectiveness analysis. Thyroid. 2004;14(11):933-945.

Ceccarelli C, Bencivelli W, Vitti P, Grasso L, Pinchera A. Outcome of radioiodine-131 therapy in hyperfunctioning thyroid nodules: a 20 years' retrospective study. Clin Endocrinol (Oxf). 2005;62(3):331-335.

Burch HB, Wartofsky L. Life-threatening thyrotoxicosis. Thyroid storm. Endocrinol Metab Clin North Am. 1993;22(2):263-277.

Eskes SA, Endert E, Fliers E, et al. Treatment of amiodarone-induced thyrotoxicosis type 2: a randomized clinical trial. J Clin Endocrinol Metab. 2012;97(2):499-506.

Basaria S, Cooper DS. Amiodarone and the thyroid. Am J Med. 2005;118(7):706-714.

Supportive treatment
	Airway maintenance
	Oxygen
	IV fluids
	Cooling blanket (do not use salicylate to treat fever because salicylates increase free T₄ and free T₃ levels)
Inhibit T₄ and T₃ synthesis
	Methimazole (Tapazole) orally, rectally, via nasogastric tube, or IV, 20 to 40 mg every eight hours
	Propylthiouracil orally, rectally, or via nasogastric tube, 200 to 400 mg every eight hours
Inhibit T₄ and T₃ release
	Saturated solution of potassium iodide, five drops orally every six hours to be started at least one hour after administration of an antithyroid agent
Heart rate control
	Esmolol (Brevibloc) IV, 50 to 100 mcg per kg per minute
	Propranolol, 60 to 80 mg orally every four hours
	Metoprolol IV, 5 to 10 mg every two to four hours
	If beta-blockade is contraindicated, use diltiazem IV, 0.25 mg per kg over two minutes, then 10 mg per hour IV infusion or 60 to 90 mg orally every six to eight hours
Inhibit T₄ to T₃ conversion
	Hydrocortisone 100 mg IV every eight hours (also suppresses autoimmune process in Graves disease)
Treat precipitating cause