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Hyperthyroidism and thyrotoxicosis

Last updated: April 28, 2021

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Thyrotoxicosis refers to the symptoms caused by the excessive circulation of thyroid hormones. It is typically caused by thyroid gland hyperactivity (i.e., hyperthyroidism), the most common causes of which are Graves disease (most common), toxic multinodular goiter (MNG), and toxic adenoma. It may also be caused by the inappropriate release of thyroid hormone from a damaged or inflamed thyroid gland (e.g., thyroiditis). In rare cases, thyrotoxicosis is caused by TSH-producing pituitary tumors (central hyperthyroidism), excessive production of β-hCG (gestational trophoblastic disease), or oral intake of thyroid hormones (exogenous hyperthyroidism). The most common symptoms of thyrotoxicosis include fatigue, anxiety, heat intolerance, increased perspiration, palpitations, and significant weight loss despite increased appetite. Serological thyroid hormone assay confirms thyrotoxicosis, while the measurement of antithyroid antibodies, thyroid ultrasonography, and radioactive iodine uptake tests help to identify the etiology. Management of any form of thyrotoxicosis involves the initial control of symptoms with beta blockers and antithyroid drugs, often followed by definitive therapy with either radioactive iodine ablation (RAIA) of the thyroid gland or surgery. An acute exacerbation of thyrotoxicosis can lead to a life-threatening hypermetabolic state known as thyroid storm, which is diagnosed clinically along with thyroid function tests. Patients with thyroid storm require urgent stabilization in critical care settings with fluids, beta blockers, antithyroid medications (propylthiouracil, potassium iodide, and parenteral glucocorticoids), active cooling, and management of tachyarrhythmias. Definitive therapy with RAIA or surgery is considered once they are stable.

While thyrotoxicosis and hyperthyroidism are often used interchangeably, the two terms are not synonymous. [1]

  • Thyrotoxicosis: a hypermetabolic condition caused by an inappropriately high level of circulating thyroid hormones irrespective of the source.
  • Hyperthyroidism: a condition characterized by the overproduction of thyroid hormones by the thyroid gland; can cause thyrotoxicosis
    • Overt hyperthyroidism
    • Subclinical hyperthyroidism
      • ↓ Serum TSH levels with normal serum free T4 and T3 levels
      • Patients are normally asymptomatic or mildly symptomatic.
      • May progress to overt hyperthyroidism

Overview of common etiologies in hyperthyroidism and thyrotoxicosis [2][3][4][5][6][7][8]

Graves disease Toxic MNG Subacute granulomatous thyroiditis (de Quervain thyroiditis) Subacute lymphocytic thyroiditis (silent thyroiditis) Iodine-induced hyperthyroidism
Thyroid status
Epidemiology
  • More common in iodine-deficient regions
Causes
  • Viral and mycobacterial infections causing damage to follicular cells
Goiter Consistency
  • Diffuse and smooth
  • Multinodular
  • Diffuse and firm
  • Depends on underlying thyroid disorder
Pain
  • Painless
  • Painless
  • Painful
  • Painless
  • Painless
Other findings
  • Nonspecific
  • Nonspecific
Thyroid function tests
  • ↓/Undetectable TSH
  • ↑ T3/T4
  • TSH
  • ↑ T3/T4
  • Thyrotoxic phase: TSH, ↑ T3/T4, and thyroglobulin
  • Hypothyroid phase: TSH and ↓ T3/T4
  • TSH
  • ↑ T3/T4
Antibodies
  • Absent
Iodine uptake on scintigraphy
  • Diffuse
  • Multiple focal areas of increased uptake
  • Reduced
  • Reduced
Pathologic findings
  • Patches of enlarged follicular cells distended with colloid and flattened epithelium
  • Depends on underlying thyroid disorder

References:[10][11][12][13]

Epidemiological data refers to the US, unless otherwise specified.

References:[2][12][14]

Hypothalamic-pituitary-thyroid axis

The hypothalamus, anterior pituitary gland, and thyroid gland, together with their respective hormones, make up a self-regulating circuit known as the hypothalamic-pituitary-thyroid axis.

Effects of thyrotoxicosis

Approach

Initial evaluation [17][18]

Interpretation of elevated thyroid hormones [17][18]
Condition TSH level Free T4 Total T3
Overt hyperthyroidism and thyrotoxic-phase thyroiditis ↑ In 90% of cases
Subclinical hyperthyroidism Normal Normal
Early pregnancy Normal Normal
Exogenous thyrotoxicosis or hyperthyroidism in older adults/comorbid illness Normal or ↑
Thyrotropic adenoma Normal or ↑

Subsequent evaluation

Indicated if the diagnosis remains uncertain after clinical assessment and initial evaluation. The choice and priority of studies depends on the clinical picture, patient characteristics and test availability.

TSH receptor antibody (TRAb)

  • Indication: if Graves disease is suspected but classic clinical features are absent [17]
  • Interpretation
    • Positive: Diagnosis of Graves disease is established.
    • Negative: Further investigation is necessary.

Nuclear medicine thyroid scan and radioactive iodine uptake measurement [19]

Characteristic findings of nuclear medicine thyroid scan and RAIU measurement [19]
Appearance of thyroid RAIU measurement
Normal thyroid tissue
  • Normal-sized gland with evenly distributed activity
  • Normal
Graves disease
  • Diffusely enlarged gland with increased activity
Toxic MNG
  • Heterogeneous appearance
    • Several hyperfunctioning (hot) nodules
    • Suppression of the rest of the gland
  • Normal or ↑ (mild)
Toxic adenoma
  • One or two hot nodules
  • Suppression of the rest of the gland
  • ↑ (Mild to moderate)
Subacute thyroiditis (de Quervain thyroiditis)
  • No or minimal activity throughout the gland
Exogenous thyrotoxicosis
  • Overall decreased activity
Thyrotropic adenoma
  • Enlarged gland with increased activity

Thyroid ultrasound with Doppler

Further evaluation

These additional tests are not routinely required but may be performed depending on the suspected underlying etiology.

The symptoms of thyrotoxicosis are nonspecific and overlap significantly with other common conditions. If there is any clinical uncertainty, TSH should be assessed.

References:[2][4][5][6][7][8][14]

The differential diagnoses listed here are not exhaustive.

Approach [17][18]

Symptomatic therapy for thyrotoxicosis [17]

The treatment of hyperadrenergic symptoms is important for decreasing the risk of cardiac complications in thyrotoxicosis, such as atrial fibrillation and heart failure.

Definitive therapy for hyperthyroidism and thyrotoxicosis [17][23]

Antithyroid drugs for thyrotoxicosis

Antithyroid drugs can effectively render a patient euthyroid. 20–75% of patients with Graves disease achieve permanent remission after 1–2 years of treatment; however, some patient groups have a higher likelihood of remission than others.

Radioactive iodine ablation (RAIA) [26]

Thyroid surgery [30]

The efficacy of antithyroid drugs and RAIA has reduced the need for thyroid surgery.

Hyperthyroidism in pregnancy

Suspect a molar pregnancy or choriocarcinoma if severe hyperthyroidism manifests during pregnancy!

Neonatal hyperthyroidism

Exogenous thyrotoxicosis

References:[33][34][35]

Definition [17]

Etiology [17]

Clinical features [17]

Diagnostics [17]

Burch-Wartofsky Point Scale for the diagnosis of thyroid storm (BWPS) [17]
Criteria Points
Temperature 37.2–37.7°C (99.0–99.9°F) 5
37.8–38.2°C (100–100.9°F) 10
38.3–38.8°C (101–101.9°F) 15
38.9–39.4°C (102–102.9°F) 20
39.4–39.9°C (103–103.9°F) 25
≥ 40°C (≥ 104°F) 30
Tachycardia 100–109/minute 5
110–119/minute 10
120–129/minute 15
130–139/minute 20
≥ 140/minute 25
Atrial fibrillation Absent 0
Present 10
Congestive heart failure Absent 0
Mild 5
Moderate 10
Severe 20
Gastrointestinal-hepatic dysfunction Absent 0
Moderate (e.g., diarrhea, abdominal pain, nausea/vomiting) 10
Severe (jaundice) 20
Central nervous system disturbance Absent 0
Mild (agitation) 10
Moderate (e.g., delirium, psychosis, extreme lethargy) 20
Severe (e.g., seizure, coma) 30
Identified precipitant Yes 0
No 10

Interpretation

Treatment of thyroid storm [17][36]

Thyroid storm has a high mortality rate and patients should receive aggressive treatment to manage complications and restore normal thyroid function.

Approach

Symptomatic treatment

If thyroid storm has led to congestive heart failure, esmolol is the preferred beta blocker. All patients receiving beta blockers should be monitored carefully for signs of heart failure.

Antithyroid drugs in thyroid storm [17][18][22]

Treat thyroid storm with PROverbial PROficiency and POetic GLUttony: PROpranolol, PROpylthiouracil, POtassium iodide, and GLUcocorticoids.

Acute management checklist for thyroid storm

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