What is the appropriate workup for a patient with suspected hyperthyroidism?

Workup for Suspected Hyperthyroidism

Begin with serum TSH measurement—if suppressed, confirm with free T4 and free T3 to distinguish overt from subclinical hyperthyroidism, then determine the underlying cause with TSH-receptor antibodies and thyroid imaging.

Initial Biochemical Confirmation

Measure serum TSH as the first test when hyperthyroidism is suspected. 1, 2

• If TSH is suppressed (<0.1 mIU/L): Proceed to measure free T4 (FT4) and free T3 (FT3) 1, 2

  • Overt hyperthyroidism: Suppressed TSH with elevated FT4 and/or FT3 1, 2
  • Subclinical hyperthyroidism: Suppressed TSH with normal FT4 and FT3 2

• If TSH is normal or elevated: Hyperthyroidism is effectively ruled out 1, 3

The combination of suppressed TSH with elevated thyroid hormones confirms biochemical hyperthyroidism and warrants immediate investigation of the underlying cause. 1

Determining the Etiology

Once biochemical hyperthyroidism is confirmed, the next critical step is nosological diagnosis to identify which disease is causing the condition. 1

Essential Diagnostic Tests

Measure TSH-receptor antibodies (TRAb or TBII) to identify Graves' disease, which accounts for 70% of hyperthyroidism cases. 1, 2

• Positive TSH-receptor antibodies: Diagnostic of Graves' disease 1, 2
• Negative TSH-receptor antibodies: Consider other etiologies 1

Measure thyroid peroxidase (TPO) antibodies to help identify autoimmune thyroid disease, though these are less specific than TRAb for Graves' disease. 1

Obtain thyroid ultrasonography to evaluate for:

• Diffuse thyroid enlargement (suggests Graves' disease) 1
• Thyroid nodules (suggests toxic nodular goiter or toxic adenoma) 1, 2
• Signs of thyroiditis 1

When Thyroid Scintigraphy Is Needed

Perform radionuclide thyroid scintigraphy when:

• Thyroid nodules are present on examination or ultrasound 2
• The etiology remains unclear after initial testing 2
• TSH-receptor antibodies are negative and clinical presentation is atypical 3

Scintigraphy patterns distinguish between causes:

• Diffusely increased uptake: Graves' disease 3, 4
• Focal increased uptake: Toxic adenoma or toxic multinodular goiter 3, 4
• Decreased or absent uptake: Thyroiditis (subacute, silent, or drug-induced) 1, 3

Radioiodine uptake helps differentiate true hyperthyroidism (increased synthesis and secretion) from destructive thyroiditis (release of preformed hormone without increased synthesis). 3, 5

Clinical Assessment Details

Key History Elements

Look specifically for:

• Symptoms of thyrotoxicosis: Anxiety, insomnia, palpitations, unintentional weight loss, diarrhea, heat intolerance 2
• Medication history: Amiodarone, tyrosine kinase inhibitors, immune checkpoint inhibitors (account for 9% of hyperthyroidism) 1
• Recent viral illness or neck pain: Suggests subacute thyroiditis 1
• Pregnancy status or recent pregnancy: Critical for treatment planning 3, 4

Physical Examination Findings

Examine for specific signs that narrow the differential:

• Diffusely enlarged thyroid gland, stare, or exophthalmos: Diagnostic of Graves' disease 2
• Ophthalmopathy or thyroid bruit: Diagnostic of Graves' disease and should prompt early endocrine referral 6
• Palpable thyroid nodules with compressive symptoms (dysphagia, orthopnea, voice changes): Suggests toxic nodular goiter 2
• Tender thyroid gland: Suggests subacute thyroiditis 1

Common Causes and Their Frequencies

Understanding the relative frequencies helps prioritize your differential:

• Graves' disease: 70% of hyperthyroidism cases 1
• Toxic nodular goiter: 16% of cases 1
• Drug-induced: 9% of cases 1
• Subacute granulomatous thyroiditis: 3% of cases 1

Critical Pitfalls to Avoid

Do not rely on TSH alone—always measure free T4 and free T3 when TSH is suppressed to distinguish overt from subclinical hyperthyroidism, as management differs significantly. 1, 2

Do not skip TSH-receptor antibody testing—this single test can establish the diagnosis of Graves' disease without requiring scintigraphy in most cases. 1, 2

Do not order thyroid scintigraphy as a first-line test—it is only needed when nodules are present or the etiology remains unclear after antibody testing. 2

Do not miss drug-induced hyperthyroidism—specifically ask about amiodarone, immune checkpoint inhibitors, and tyrosine kinase inhibitors, as these require different management approaches. 1

Do not overlook thyroiditis—decreased radioiodine uptake on scintigraphy distinguishes destructive thyroiditis from true hyperthyroidism, fundamentally changing management from observation to definitive treatment. 1, 3, 5