Thyrotoxicosis and Hyperthyroidism

How to Cite This Chapter: Brito JP, Jarząb B, Płaczkiewicz-Jankowska E. Thyrotoxicosis and Hyperthyroidism. McMaster Textbook of Internal Medicine. Kraków: Medycyna Praktyczna. Accessed January 18, 2021.
Last Updated: June 17, 2019
Last Reviewed: June 17, 2019
Chapter Information

Definition, Etiology, PathogenesisTop

Subclinical (occult) thyrotoxicosis is a usually asymptomatic mild elevation in tissue levels of thyroid hormones with low or suppressed thyroid-stimulating hormone (TSH) levels and free thyroxine (FT4) and free triiodothyronine (FT3) levels within normal limits.

Clinically overt thyrotoxicosis refers to suppressed TSH with high FT4 and FT3 levels.

Thyrotoxicosis is a clinical state that results from any condition leading to high thyroid hormone action in tissues.

Hyperthyroidism is a form of thyrotoxicosis caused by high synthesis and secretion of thyroid hormone by the thyroid gland.

Thyrotoxic crisis (thyroid storm) is a life-threatening, sudden, and rapid collapse of homeostasis, developing as a result of undiagnosed or inadequately treated hyperthyroidism and involving altered mental status that may progress to coma, multiorgan failure, shock, and death. Causes of thyrotoxicosis: Figure 5.6-2.

Clinical Features and Natural HistoryTop

Thyrotoxicosis usually develops over the course of several months. It may also appear suddenly (eg, when associated with exposure to iodinated contrast media), develop over several years (autonomously functioning nodule, toxic multinodular goiter), or be transient and resolve spontaneously (subacute or postpartum thyroiditis). Various causes of thyrotoxicosis coexist rarely; for instance, a hyperfunctioning thyroid nodule in a patient with Graves disease may produce an unusual clinical course without periods of remission typical of Graves disease.

Subclinical Thyrotoxicosis

Subclinical thyrotoxicosis is the asymptomatic or occult phase of thyrotoxicosis regardless of its cause. In ~50% of cases serum TSH levels spontaneously normalize and the estimated risk of progression to overt thyrotoxicosis is ~5% per year (the progression may be triggered by exposure to iodine). Subclinical thyrotoxicosis may include subtle signs and symptoms of hypersecretion of thyroid hormones such as tachycardia, supraventricular arrhythmias (atrial fibrillation, premature supraventricular contraction), and (rarely) ventricular arrhythmias. If long-standing and untreated, subclinical thyrotoxicosis leads to decreased bone mineral density, and in elderly patients with TSH levels <0.1 mIU/L it may be associated with elevated risk of cardiovascular complications.

Overt Thyrotoxicosis

1. General symptoms: Loss of weight despite normal or good appetite (elderly people may present with weight loss and low appetite), weakness, and heat intolerance.

2. Neuropsychiatric symptoms: Anxiety, irritability, hyperactivity (hyperkinetic behavior), concentration problems, insomnia; rarely psychotic symptoms (suggestive of schizophrenia or bipolar disorder); fine tremor and hyperreflexia.

3. Ocular symptoms:

1) Eyelid retraction (staring appearance) resulting from sympathetic overactivity.

2) Graefe sign (more sclera exposed over the upper border of the iris when the patient looks downward [upper lid lag over the globe]).

3) Kocher sign (a similar sign observed in a patient looking up).

4) Möbius sign (deviation of one eye on convergent gaze).

5) Stellwag sign (infrequent blinking).

6) Signs and symptoms of Graves orbitopathy: Eye pain, tearing, diplopia, periorbital edema, and conjunctival injection.

4. Cutaneous symptoms: Hyperhidrosis and skin hyperemia (warm, pink, moist, and excessively smooth skin); rarely hyperpigmentation (not including mucosal surfaces) or urticaria; hair loss, thinning, and breaking; thin and fragile nails, which may separate from nail beds (onycholysis); thyroid dermopathy (pretibial myxedema) (Figure 5.6-3) and acropachy (Figure 5.6-4) may be present in Graves disease.

5. Musculoskeletal symptoms: Decrease of muscle mass and strength (in more severe thyrotoxicosis); in severe cases, thyrotoxic myopathy involving muscles of the face and distal limbs. Involvement of extraocular muscles may mimic myasthenia gravis.

6. Abnormalities of the neck: In some patients increased neck circumference and sensation of pressure are observed. On physical examination the thyroid gland is of normal size or, more frequently, enlarged (in overt thyrotoxicosis this is indicative of a toxic goiter). Finding a thrill or bruit on physical examination of the thyroid gland is indicative of a vascular goiter (typical of Graves disease) and if ≥1 nodule is present, it is necessary to consider toxic nodular goiter in the differential diagnosis (the presence of nodules does not exclude Graves disease).

7. Respiratory symptoms: Dyspnea caused by tracheal compression due to an enlarged thyroid gland is rare.

8. Cardiovascular symptoms: Palpitations, hyperkinetic circulation (tachycardia, systolic hypertension, widened pulse pressure, loud heart sounds); frequently arrhythmia with premature ventricular contractions or atrial fibrillation, systolic murmurs (due to mitral prolapse or regurgitation), sometimes end-diastolic murmurs; symptoms of heart failure, particularly in patients with preexisting heart disease.

9. Gastrointestinal symptoms: Increased stool frequency or diarrhea. In severe thyrotoxicosis hepatomegaly and jaundice may develop due to liver damage.

10. Abnormalities of the reproductive system and breast: Sometimes decreased libido, oligomenorrhea (generally with ovulation); in exceptional cases, amenorrhea, erectile dysfunction, or gynecomastia.

Thyrotoxic Crisis (Thyroid Storm)

Thyrotoxic crisis due to a sudden and large excess of thyroid hormones may develop in a patient with hyperthyroidism as a result of stress, infection, trauma, or other serious condition, or if the patient undergoes thyroid surgery without appropriate pretreatment with antithyroid drugs. In case of a sudden deterioration in the status of a patient with hyperthyroidism, always consider the possibility of impending or overt thyrotoxic crisis. The predominant signs and symptoms may be those related to the underlying disease that precipitated thyrotoxic crisis.

1. Precedent symptoms: Agitation, insomnia (hallucinations and other psychotic symptoms may occur at night), significant weight loss, worsening of tremor, fever, nausea, and vomiting.

2. Overt thyrotoxic crisis: Fever; extreme agitation and worsening of psychotic symptoms; sometimes somnolence, apathy, or even coma; in some cases status epilepticus; sudden worsening of cardiovascular symptoms (severe tachycardia, atrial fibrillation, symptoms of heart failure, sometimes shock) and gastrointestinal symptoms of thyrotoxicosis (nausea, diarrhea, and hepatic dysfunction); signs and symptoms of dehydration (often following a period of hyperhidrosis).


Always inquire about a family history of thyroid disorders, exposure to high doses of iodine (certain disinfecting agents [eg, iodine tincture] or expectorants; amiodarone; iodinated contrast media), and previous treatment of thyroid diseases and autoimmune diseases of other organs. Simultaneously assess thyroid function and morphology and aim at identifying the causative factors. Always make sure that serum TSH and free thyroid hormone levels are consistent and correspond with the presenting signs and symptoms. General diagnostic algorithm: Figure 5.6-5.

Diagnostic Tests

In patients suspected of thyrotoxicosis evaluate serum TSH levels and FT4 levels (in patients with low TSH and normal FT4 levels measure serum total T3 levels) and examine the thyroid gland for enlargement and presence of nodules in the parenchyma (palpable nodules or nodules detected on ultrasonography may fulfill the criteria for fine-needle biopsy [FNB]; see Nontoxic Multinodular Goiter). Antibodies to TSH receptors allow for a reliable differential diagnosis of autoimmune and nonautoimmune causes of thyrotoxicosis.

1. Hormone tests:

1) Serum TSH concentrations are the most sensitive marker of activity of thyroid hormones. They are decreased in primary thyrotoxicosis (both overt and subclinical) and increased in secondary thyrotoxicosis (very rare TSH-producing pituitary adenoma). Circadian fluctuations of serum TSH levels are of no significance for routine diagnostics.

2) Serum FT4 and FT3 concentrations are increased in overt thyrotoxicosis (more commonly FT4 or both FT4 and FT3 are affected; isolated FT3 elevation is rare but confirms thyrotoxicosis if TSH level is low and FT4 level is normal) and normal (often close to the upper limit of normal [ULN]) in subclinical thyrotoxicosis.

2. Other laboratory tests:

1) Serum antibodies to TSH receptor (TRAb): Measurement of TRAb antibodies is suggested to differentiate autoimmune causes of thyrotoxicosis (eg, Graves disease) from nonautoimmune causes.Evidence 1 Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to estimates of accuracy derived from studies at high risk of bias (selection bias and lack of blinding). Pedersen IB, Knudsen N, Perrild H, Ovesen L, Laurberg P. TSH-receptor antibody measurement for differentiation of hyperthyroidism into Graves' disease and multinodular toxic goitre: a comparison of two competitive binding assays. Clin Endocrinol (Oxf). 2001 Sep;55(3):381-90. PubMed PMID: 11589682.

2) Serum antibodies to thyroperoxidase (TPO Ab) and antibodies to thyroglobulin (Tg Ab) (least specific): Measurement of TPO Ab and Tg Ab is not suggested for the workup of patients with low TSH values,Evidence 2 Weak recommendation (downsides likely outweigh benefits, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the unclear accuracy of those tests to indicate the etiology of low thyroid-stimulating hormone. Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab. 2002 Feb;87(2):489-99. PubMed PMID: 11836274. as they do not definitely indicate etiology (may also be present in healthy individuals and patients with nonautoimmune thyroid diseases, most frequently in subacute thyroiditis) and can lead to unnecessary tests.

3) Serum Tg levels are useful only for excluding thyrotoxicosis caused by exogenous thyroid hormone excess (low levels of Tg).

3. Imaging studies: Ultrasonography of the thyroid gland is used to measure thyroid size and diagnose goiter, visualize thyroid nodules, select areas for biopsy, and monitor the position of the needle during FNB. Ultrasonography of the thyroid gland can be used in patients with suppressed TSH and palpable thyroid nodules but it is usually not helpful in the differential diagnosis of thyrotoxicosis. In thyroid radionuclide scintigraphy technetium scans are used to differentiate an autonomously functioning thyroid gland or nodules (hot) from subacute thyroiditis (cold); radioiodine scans are used to estimate iodine uptake when planning radioiodine treatment for hyperthyroidism. To prepare a patient for scintigraphy, discontinue all antithyroid drugs ≥5 days before the study. Inquire about any iodine-containing drugs, as they reduce iodine uptake by the thyroid gland. For radioiodine scans the patient should be fasting. Radiographs of the chest or neck are used to assess tracheal compression and/or dislocation by a large nodular goiter or to diagnose a retrosternal goiter. Computed tomography (CT) or magnetic resonance imaging (MRI) of the neck and chest is used to assess the size of retrosternal goiter. Orbital CT or MRI is used in patients with Graves orbitopathy to diagnose involvement of extraocular muscles.

4. Cytology is used to classify thyroid nodules as malignant (thyroid cancer), suspicious, or nonmalignant in order to determine indications for surgery. For hyperfunctioning nodules observed in scintigraphy, FNB is not suggestedEvidence 3 Weak recommendation (downsides likely outweigh benefits, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the high risk of bias (indirectness and lack of control). Michigishi T, Mizukami Y, Shuke N, et al. An autonomously functioning thyroid carcinoma associated with euthyroid Graves' disease. J Nucl Med. 1992 Nov;33(11):2024-6. PubMed PMID: 1432166. due to the low risk of malignancy and increased risk of indeterminate results.

Diagnostic Criteria

1. Subclinical thyrotoxicosis is diagnosed on the basis of hormone tests: low serum TSH concentrations (<0.1 mIU/L; in mild hyperthyroidism TSH levels may be in the range of 0.1-0.4 mIU/L) accompanied by normal (sometimes close to the ULN) serum concentrations of free thyroid hormones in patients in whom other causes of low serum TSH levels (eg, treatment with glucocorticoids or dopamine, first trimester of pregnancy) have been excluded and who are asymptomatic or present with minor symptoms only. If TSH levels are persistently low, differential diagnosis must be performed to determine the cause of excessive thyroid hormone levels (serum antibodies to TSH-R and thyroid radionuclide scintigraphy).

2. Overt thyrotoxicosis:

1) Primary: Low serum TSH concentrations (<0.05 mIU/L) and elevated (above the ULN) serum concentrations of free thyroid hormones (FT4; FT4 and FT3; or rarely FT3 alone) accompanied by typical clinical manifestations or atypical signs and symptoms (thyrocardiac disease: thyrotoxicosis presenting mainly with atrial fibrillation, symptomatic coronary heart disease, or heart failure; very rarely apathetic thyrotoxicosis in the elderly, with dominant fatigue, apathy, depression, or even confusion).

2) Secondary: Elevated serum FT4 and FT3 concentrations with normal or elevated serum TSH levels.

3. Thyrotoxic crisis (thyroid storm) should be suspected in every case of sudden deterioration in a patient with known thyrotoxicosis (serum TSH levels <0.05 mIU/L; FT4 and FT3 levels may not be markedly elevated). Assess the risk of thyrotoxic crisis using the Burch-Wartofsky criteria:

1) Temperature:

a) 38 to 38.5 degrees Celsius: 5 points.

b) 38.6 to 39 degrees Celsius: 10 points.

c) 39.1 to 39.5 degrees Celsius: 15 points.

d) 39.6 to 40 degrees Celsius: 20 points.

e) 40.1 to 40.6 degrees Celsius: 25 points.

f) >40.6 degrees Celsius: 30 points.

2) Central nervous system disturbance:

a) Absent: 0 points.

b) Mild (agitation): 10 points.

c) Moderate (delirium, psychosis, extreme lethargy): 20 points.

d) Severe (seizure, coma): 30 points.

3) Gastrointestinal-hepatic dysfunction:

a) Absent: 0 points.

b) Moderate (diarrhea, abdominal pain, nausea/vomiting): 10 points.

c) Severe (jaundice): 20 points.

4) Cardiovascular dysfunction:

a) Tachycardia (beats/min):

– <90/minute: 0 points.

– 90 to 109/minute: 5 points.

– 110 to 119/minute: 10 points.

– 120 to 129/minute: 15 points.

– 130 to 139/minute: 20 points.

– ≥140/minute: 25 points.

b) Congestive heart failure:

– Absent: 0 points.

– Mild (pedal edema): 5 points.

– Moderate (bibasilar rales): 10 points.

– Severe (pulmonary edema): 15 points.

c) Atrial fibrillation:

– Absent: 0 points.

– Present: 10 points.

5) A precipitating event in patients with untreated or inappropriately treated hyperthyroidism: acute infection, trauma, surgery, childbirth, ketoacidosis, myocardial infarction, stroke or transient ischemic attack, radioiodine treatment (rarely), or administration of iodinated contrast media:

a) Absent: 0 points.

b) Present: 10 points.

Score interpretation: Less than 25 points, unlikely to represent thyrotoxic crisis; 25 to 44 points, suggestive of impending crisis; ≥45 points, highly suggestive of thyrotoxic crisis.

Differential Diagnosis

Thyroid function disturbances are differentiated on the basis of serum TSH and FT4 levels (Figure 5.6-6) and other test results (Table 5.6-5). Note other causes of thyrotoxicosis: hashitoxicosis, subacute thyroiditis or postpartum thyroiditis, trophoblastic disease, TSH-secreting pituitary adenoma, iodine-induced or amiodarone-induced hyperthyroidism (see Other Types of Chronic Thyroiditis; see Table 5.6-4), levothyroxine (L-T4) overdose, functioning metastases of thyroid cancer, struma ovarii. In the differential diagnosis of TSH-secreting pituitary adenoma, consider conditions associated with elevated serum FT4 levels: high T4 syndrome and thyroid hormone resistance syndrome.


General Principles of Hyperthyroidism Treatment

The choice of treatment depends on the causes of thyrotoxicosis (see Table 5.6-6; see Graves Disease; see Nontoxic Multinodular Goiter; see Toxic Thyroid Nodule), its course, and the patient’s decisions.

In subclinical thyrotoxicosis with serum TSH levels <0.1 mIU/L, treatment is unequivocally indicated in patients >65 years of age and in younger individuals with coexisting comorbidities (cardiovascular disease, osteoporosis, postmenopause) and/or symptoms of thyrotoxicosis; in the remaining cases, watchful waiting is acceptable. Treatment may sometimes be considered in mild subclinical hyperthyroidism with TSH levels 0.4 to 0.1 mIU/L in patients >65 years of age, and in younger individuals only in the case of coexisting serious heart disease or symptomatic hyperthyroidism.

Management of L-T4–induced subclinical thyrotoxicosis depends on indications for the use of this drug. In patients with thyroid cancer on TSH suppression therapy, consider L-T4 dose reduction. In subclinical thyrotoxicosis in a patient treated for hypothyroidism or a nontoxic goiter, reduce the dose of L-T4 immediately.

Treatment Options


Pharmacotherapy can be used as the primary treatment of hyperthyroidism or as pretreatment before radical therapy (radioiodine or surgery).

1. Antithyroid drugs: Thionamides: The effects develop after 1 to 3 weeks of treatment (these agents inhibit synthesis of thyroid hormones but do not inhibit secretion of hormones that were synthesized earlier). Minor granulocytopenia may be a result of hyperthyroidism and is not a contraindication to the use of thionamides. If the patient has a history of agranulocytosis or liver disease, thionamides are contraindicated.

1) Methimazole (INN thiamazole): The drug of choice. Initially administer 20 to 40 mg/d orally (in 2 divided doses); the dose should be reduced, usually after 3 to 6 weeks (euthyroidism is achieved in up to 6 weeks). The maintenance dose is 2.5 to 10 mg/d orally and is usually administered once daily. In severe hyperthyroidism use up to 60 mg/d orally in 2 to 3 divided doses (in outpatient setting), and in impending thyrotoxic crisis, up to 120 mg/d orally or IV (in hospitalized patients). Currently methimazole is recommended instead of propylthiouracil in the second and third trimester of pregnancy due to the lower risk of adverse effects (initial dose 10-15 mg/d orally; the drug crosses the placenta, so the lowest effective doses should be used).

2) Propylthiouracil is a second-line drug (it should be used only in exceptional cases due to reports of serious liver injury and deaths); some authors consider it the drug of choice in the first trimester of pregnancy. It is also used in exceptional cases of patients allergic to methimazole in whom antithyroid treatment is required (in 50% of cases there is no cross-reactivity). The initial dose is 100 to 150 mg every 8 hours (in pregnant women 100 mg/d); the dose should be reduced after 4 to 8 weeks (euthyroidism is achieved after a longer time than with methimazole, in up to 10-17 weeks), and the maintenance dose is 50 to 150 mg/d. In pregnant women the dose should be reduced as soon as FT4 approaches the ULN (eg, 10% above the ULN). When switching antithyroid medications, 100 to 150 mg of propylthiouracil is equivalent to 10 mg of methimazole.

Monitoring treatment:

1) Evaluate improvement in clinical manifestations of hyperthyroidism. A rapid improvement may indicate a need for earlier reduction of doses of the antithyroid drug.

2) Measure serum TSH and FT4 concentrations at 3 to 6 weeks of treatment; if symptoms of thyrotoxicosis have improved and serum FT4 levels are in the lower range or below the normal limit, reduce the dose of the antithyroid drug (serum TSH levels may still be low). Normalization of serum TSH levels indicates a need for a rapid dose reduction.

3) The subsequent follow-up studies should be performed after another 3 to 6 weeks. If hyperthyroidism was not long-standing, only TSH concentrations should be measured; in patients in whom the blockade of TSH secretion was longer, this test may not be useful and management should be guided by FT4 levels.

No regular monitoring of white blood cell (WBC) differential counts is recommended during antithyroid treatment; however, it is necessary in patients with suspected granulocytopenia or agranulocytosis. If granulocyte counts during treatment are 1500 to 1000 cells/microL, more frequent follow-up is necessary and reduction of antithyroid drug dose should be considered. If granulocyte counts are 1000 to 500/microL, the dose of antithyroid drugs should be reduced and their discontinuation considered. If granulocyte counts are <500/microL, discontinuation of the antithyroid drug is mandatory (treatment with granulocyte colony-stimulating factor may be effective). Inform the patient about the possible adverse effects of treatment; if fever and sore throat appear (usually the first symptoms of agranulocytosis), the patient should discontinue the thionamide and promptly seek medical attention. Check WBC and differential counts.

Adverse effects:

1) Rare but warranting discontinuation of thionamide treatment: Agranulocytosis, aplastic anemia; acute hepatitis (propylthiouracil), obstructive jaundice (methimazole); vasculitis with antineutrophil cytoplasmic antibodies, lupus-like syndrome.

2) Not requiring immediate discontinuation of thionamides: Pruritus, rash, urticaria, sometimes very intense skin symptoms (administer antihistamines, reduce thionamide dose, or switch to another thionamide); muscle or joint pain (in case of arthritis consider discontinuation of the antithyroid drug); fever (do not use salicylates; advise the patient to seek prompt medical attention and obtain a complete blood count [CBC] in every case of fever with sore throat; if the WBC count is normal, antithyroid treatment may be continued); taste disturbances, nausea and vomiting (reduce thionamide dose and administer the drug in divided doses); minor increases in serum aminotransferase levels (use the lowest effective dose and schedule follow-up tests; discontinue the drug if alanine aminotransferase [ALT] levels increase to >3 × ULN); transient granulocytopenia or thrombocytopenia (reduce thionamide dose and schedule follow-up studies).

2. Other drugs lowering thyroid hormone levels should not be routinely administered due to adverse effects. They should only be used for limited periods of time and in specific situations: in patients with contraindications to thionamides (eg, due to agranulocytosis); for treatment of thyrotoxic crisis (see below); in cases when rapid control of hyperthyroidism is required.

1) Iodine (inorganic) in the form of potassium iodide administered as Lugol solution (1 drop contains 8 mg of iodine) or saturated solution of potassium iodide (SSKI) (1 drop contains 50 mg of iodine). Potassium iodide inhibits the synthesis and secretion of thyroid hormones; it is used in treatment of thyrotoxic crisis and sometimes in the preoperative treatment of patients with Graves disease, a coexisting vascular goiter, and no thyroid nodules. It is contraindicated in iodine-induced hyperthyroidism and in patients in whom radioiodine treatment is planned (it causes reduced iodine uptake for ≥6 months). A longer use (eg, >6 weeks) of iodine for treatment of thyrotoxicosis could lead to a paradoxical increase in the synthesis and secretion of thyroid hormones.

2) Iodinated contrast media (organic iodine; IV iohexol and oral sodium ipodate) inhibit T4 to T3 conversion and the inorganic iodine they release inhibits the synthesis and secretion of thyroid hormones; they are rarely used in treatment of thyrotoxic crisis.

3) Lithium carbonate has questionable efficacy. It decreases the secretion of thyroid hormones by inhibiting proteolysis of Tg. Oral lithium carbonate may be used in doses of 750 to 900 mg/d in treatment of thyrotoxic crisis or sometimes in severe hyperthyroidism (particularly in patients with contraindications to thionamides), although the drug is only approved for use in psychiatric indications. Monitoring of serum drug levels is required.

4) Sodium perchlorate or potassium perchlorate inhibits transport of iodine to the thyroid gland and may be used in treatment of iodine-induced hyperthyroidism. It should be used for a limited period only (<4 weeks) due to adverse effects (the most serious adverse effect is bone marrow suppression) at a dose ≤1 g/d.

5) Glucocorticoids have questionable efficacy. They inhibit the conversion of T4 to T3. For instance, oral dexamethasone 8 mg/d can be used in 2 to 3 divided doses in patients in whom rapid correction of thyroid hormone levels is required (when used in combination with thionamide and inorganic iodine glucocorticoids allow for significant reduction or normalization of FT3 levels within 24-48 hours).

3. Beta-blockers: Indications include tachycardia and supraventricular arrhythmias, eyelid retraction, tremor, and hyperhidrosis. If antithyroid drugs alone are effective, beta-blockers are not required. Usually oral propranolol is used at doses of 10 to 40 mg tid; larger doses may be used in treatment of thyrotoxic crisis. Less frequently beta1-selective drugs are used: atenolol, metoprolol, or bisoprolol.

Radioiodine (131I) Treatment

1. Effects and risks: Radioiodine (radioactive iodine, 131I) emits radiation limited to the thyroid gland. A portion of the administered 131I that has not been taken up by the thyroid gland is rapidly excreted with urine. Radiation exposure of sensitive organs (bone marrow, gonads) is low.

2. Contraindications: Pregnancy and breastfeeding; confirmed or suspected thyroid malignancy in a patient with hyperthyroidism; patients unable to follow the recommended safety precautions, including contraception.

3. Safety precautions: Before starting treatment, make sure that female patients are not pregnant; because of radiation emitted by 131I taken up by the thyroid gland, the patient must avoid any contact with young children and pregnant women for 1 to 2 weeks, depending on the dose given, to avoid causing their exposure to ionizing radiation. After completing the treatment, female patients should not become pregnant for 6 months (4-6 months according to the American Thyroid Association); the recommended 6-month contraception also applies to male patients treated with 131I. There is no risk of permanent fertility impairment or congenital malformations in children; therefore, reproductive age is not a contraindication to radioiodine treatment. If radioiodine treatment is used in patients with active thyroid-associated orbitopathy, concomitant prophylactic glucocorticoid therapy should be used (see below).

4. Preparation for radioiodine treatment:

1) Discontinue methimazole or propylthiouracil 5 to 7 days before planned radioiodine treatment.

2) Check iodine uptake (to plan required 131I activity; thyroid radiation sensitivity differs in patients with Graves disease and other types of hyperthyroidism).

3) Exclude pregnancy immediately before the administration of 131I (a negative pregnancy test result).

4) Advise the patient on the requirement of overnight fasting before the administration of radioiodine (131I is administered orally) and on subsequent management (including precautions and other radiation safety measures).

5. Management after radioiodine therapy: Euthyroidism is achieved within 6 weeks to 6 months after 131I administration. Some patients require continued antithyroid treatment throughout this time.

6. Indications for repeated radioiodine therapy: Persistent hyperthyroidism 6 months after therapy or recurrence of hyperthyroidism. A final evaluation of treatment efficacy is performed at 1 year.

7. Monitoring of thyroid function is required for early detection and treatment of hypothyroidism (which may develop as a consequence of radioiodine therapy; the risk is lowest in Graves disease and highest in solitary autonomously functioning nodules). Measure serum TSH concentrations at 6 weeks; at 3, 6, and 12 months; and then every year. Prevention of overt hypothyroidism with early detection can avoid or decrease symptoms of Graves ophthalmopathy.

Surgical Treatment (Thyroidectomy)

1. Indications:

1) Absolute: Confirmed or suspected thyroid cancer in a patient with hyperthyroidism.

2) Relative: An alternative to radioiodine therapy (surgery is indicated in patients with large nodular goiters causing compression of adjacent structures, large nonfunctioning nodules, or retrosternal goiters).

2. Preparation for surgery:

1) Elective surgery: In patients with previously untreated hyperthyroidism, administer methimazole at full doses for ≥4 to 6 weeks to achieve clinical remission of thyrotoxicosis and normalization of serum free thyroid hormone concentrations. Elevated serum TSH levels are not a contraindication to surgery (they result from previous potent inhibition of pituitary function by excess thyroid hormones). In patients with vascular goiters administration of Lugol solution may facilitate surgery by reducing goiter size and vascularity: give 3 to 7 drops of Lugol solution tid for 7 to 10 days before surgery. In patients with large goiters titrate the dose up to 10 to 15 drops tid; 1 to 2 drops of SSKI tid can be given instead of Lugol solution.

2) Urgent surgery may require administration of high doses of iodine and glucocorticoids, as in treatment of thyrotoxic crisis (see below).

3. Extent of surgery: Near-total thyroidectomy (leaving <1 mL of thyroid parenchyma) or total thyroidectomy are recommended for patients with Graves disease who opted for surgical options.Evidence 4 Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of intervention). Guo Z, Yu P, Liu Z, Si Y, Jin M. Total thyroidectomy vs bilateral subtotal thyroidectomy in patients with Graves' diseases: a meta-analysis of randomized clinical trials. Clin Endocrinol (Oxf). 2013 Nov;79(5):739-46. doi: 10.1111/cen.12209. Epub 2013 Apr 19. PubMed PMID: 23521078. Less extensive procedures carry a high risk of recurrence.

4. Complications following surgery: Permanent complications (lasting >12 months) are rare (they are more frequently associated with total or repeated thyroidectomy). Temporary complications, usually lasting several weeks to months, are more common and include hypoparathyroidism (see Hypoparathyroidism) and iatrogenic injury of the recurrent laryngeal nerve with resulting vocal cord paralysis (most commonly unilateral and causing hoarseness; very rarely bilateral paralysis with serious respiratory compromise, which may require emergency tracheotomy).

5. Postoperative L-T4 replacement therapy should be started immediately after surgery (calculated dose 1.6 microg/kg/d). Start from a low dose of L-T4, for instance, 50 microg/d, or 25 microg/d in the elderly (in the initial period of treatment patients may have increased sensitivity to thyroxine), and titrate up slowly based on TSH values.

Treatment of Thyrotoxic Crisis (Thyroid Storm)

Start treatment immediately, without waiting for confirmation by laboratory tests. Continue treatment at an intensive care unit.

1. Drugs:

1) To reduce serum thyroid hormone levels:

a) Methimazole 20 to 30 mg orally qid or propylthiouracil (PTU) 200 mg orally every 4 to 6 hours (PTU for acute phase only; either drug via a nasogastric tube if needed). Both drugs may be specially prepared for rectal or IV use.

b) Give iodine as soon as possible (unless thyrotoxic crisis is induced by iodine exposure) but ≥1 hour after the first dose of methimazole (to avoid utilization of iodine for synthesis of new thyroid hormones): oral SSKI 800 to 1000 mg/d in 4 divided doses (4-5 drops qid) or Lugol solution (10-30 drops bid to qid). Alternatively use IV iohexol 0.6 g (2 mL) bid.

2) Beta-blockers, for instance, IV propranolol 2 mg over 2 minutes (the dose may be repeated after a few minutes), then 2 mg every 4 hours; alternatively 40 to 80 mg orally tid to qid (this also causes minor inhibition of T4 to T3 conversion).

3) Hydrocortisone 50 to 100 mg IV qid (it has an antishock effect and inhibits T4 to T3 conversion).

4) Antibiotics if there is a suspicion of infection (continue empiric antibiotic therapy until culture and sensitivity results are available).

5) Sedative or anticonvulsive drugs if necessary.

2. Administer oxygen 2 L/min via a nasal tube. Increase oxygen flow if necessary.

3. Correct water-electrolyte disturbances while monitoring volume status and assess serum electrolyte levels every 12 hours.

4. Treat hyperthermia: Use noninvasive external cooling and acetaminophen (INN paracetamol) or, less preferably, nonsteroidal anti-inflammatory drugs (salicylates are contraindicated because they block binding of T4 to its carrier protein: thyroxine-binding globulin).

5. Aggressively treat the precipitating condition, such as infection, ketoacidosis, pulmonary embolism, or other conditions.

6. Use thromboprophylaxis (see Primary Prevention of Venous Thromboembolism) if indicated, for instance, in atrial fibrillation, severe heart failure, or immobilization.

7. Plasmapheresis may be considered if there is no effect of treatment after 24 to 48 hours.

Mortality rates in thyrotoxic crisis are 30% to 50%. Therefore, efforts should be made to prevent it with early and effective therapy of thyrotoxicosis.


Indirect (eg, stroke in a patient with atrial fibrillation caused by hyperthyroidism) or direct and acute (thyrotoxic crisis—a life-threatening complication) or chronic (atrial fibrillation, osteoporotic fractures) consequences of the excess of thyroid hormones. The risk of persistent atrial fibrillation in hyperthyroidism is increased ~3-fold and attempts to restore normal sinus rhythm are unsuccessful until the resolution of thyrotoxicosis is achieved. Increased cardiovascular morbidity and mortality results from elevated risk of arrhythmias, thromboembolic complications associated with atrial fibrillation, and worsening of coronary heart disease or heart failure.

Tables and FiguresTop

Table 5.6-5. Differential diagnosis of autoimmune and nonautoimmune hyperthyroidism


Graves disease

Nonautoimmune hyperthyroidism (toxic MNG, solitary autonomously functioning nodule)


Recurrent hyperthyroidism; family history of autoimmune thyroid disease or other autoimmune diseases

Previous nontoxic MNG

Signs and symptoms of thyrotoxicosis

No differential features


Features of vascular goiterb

MNG or solitary nodule

Ocular signs and symptoms

Features of orbitopathy (immunologic inflammation), overt orbitopathy in 20%-30% of patients, severe form of progressive ophthalmopathy with infiltrates and edema in 2%-3% of patients

Ocular signs and symptoms of sympathetic hyperactivity (eg, Graefe sign) do not preclude the diagnosis

Pretibial myxedema

1%-3% of patients


Laboratory thyroid function tests

↓ TSH and ↑ FT4 (less commonly ↑ FT3), no differential features


95% of patients


↑ Anti-TPOc

70% of patients

15% of patients (elderly)

Thyroid ultrasonography

Diffuse hypoechogenicity of thyroid parenchymab


Thyroid radionuclide scintigraphy

No evident nodules, frequently slightly heterogeneous marker uptake

Autonomously functioning nodules and nonfunctioning areas

a Lack of goiter is not a differential feature.

b Nodules may be present in one-fourth of patients.

↑, increased level; ↓, decreased level; anti-TPO, anti-thyroperoxidase; FT3, free triiodothyronine; FT4, free thyroxine; MNG, multinodular goiter; TRAb, thyroid-stimulating hormone receptor antibody; TSH, thyroid-stimulating hormone.

Table 5.6-4. Differential diagnosis and treatmenta of type I and type II amiodarone-induced thyrotoxicosis

Type I

Type II

Previous history of thyroid disease

Multinodular goiter or Graves disease (usually undiagnosed)



Excess iodine causing increased synthesis of thyroid hormones

Toxic effect of amiodarone (inflammation) causing damage of thyroid cells and release of thyroid hormones

Iodine uptake



Thyroid ultrasonography + Doppler

Thyroid gland frequently enlarged, nodules may be present; increased blood flow

Normal appearance of thyroid gland; decreased blood flow


Increased in Graves disease


Pharmacologic treatmenta

Eg, methimazole 40-60 mg/d + sodium perchlorate (<4 weeks) 200-250 mg qid (inhibits iodine accumulation in thyroid gland); consider radical treatment

For instance, prednisone 40-60 mg/d for 1-3 months, then taper off the dose over another 2 months

a When differential diagnosis of these types is impossible and thyroid status from before amiodarone use is unknown, combined treatment can be used: start with methimazole and sodium perchlorate; add glucocorticoids if there is no improvement.

qid, 4 times a day; TRAb, thyroid-stimulating hormone receptor antibody.

Table 5.6-6. Methods of treatment of thyrotoxicosis

Cause of thyrotoxicosis





Graves disease

First episode


Overt thyroid-associated orbitopathy


Severe thyroid-associated orbitopathy (progressive ophthalmopathy with infiltrates and edema)

Plus confirmed or suspected malignant nodule


Recurrence of Graves disease after surgery

Toxic multinodular goiter

Small goiter without airway compression, nonmalignant

Large goiter, previous biopsy of nodules: nonmalignant

Goiter with confirmed or suspected malignant nodule


Solitary autonomously functioning nodule

FNB: nonmalignant nodule or suspected follicular thyroid cancer with no evidence of clinical and ultrasound risk factors of malignancy


Confirmed thyroid cancer (very rare)


Iodine-induced hyperthyroidism

Amiodarone-induced hyperthyroidism


Other cases



Silent or postpartum

Early Hashimoto thyroiditis

Thyrotoxicosis in pregnancye


Subclinical thyrotoxicosis


      No indication            Optional method           Method in use            Preferred method            Contraindicated method

a Oral glucocorticoids are administered to prevent exacerbation of orbitopathy.
b After surgical treatment of cancer radioiodine treatment is usually necessary.
c Radioiodine treatment is also acceptable in patients with suspected follicular thyroid cancer based on FNB results if no clinical features suggestive of malignancy are present. The risk of cancer in a true solitary autonomously functioning nodule is 2% (it should be differentiated from an isolated autonomously hyperfunctioning area in toxic MNG).
d Depending on type. In type I sodium perchlorate is often indicated. In type II glucocorticoids are preferred.
e Differentiate from thyrotoxicosis of pregnancy, which rarely requires any treatment.
f At markedly lower doses; in the first trimester of pregnancy propylthiouracil can be used.
g Only if the indications for surgery are clinical symptoms of compression or malignancy.

BB, beta-blocker; FNB, fine-needle biopsy; 131I, radioiodine therapy; MNG, multinodular goiter; Op, surgery; T, thionamides (methimazole is the drug of choice).

Figure 5.6-2. Causes of thyrotoxicosis.

Figure 5.6-3. Thyroid dermopathy (pretibial myxedema) in Graves disease.

Figure 5.6-4. Thyroid acropachy.

Figure 5.6-5. General diagnostic algorithm for disorders of the thyroid gland.

Figure 5.6-6. Differential diagnosis of thyroid disorders based on serum TSH and FT4 concentrations.

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