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

Diagnostic Workup for Suspected Hyperthyroidism

Begin with serum TSH measurement as the first-line screening test, followed by free T4 and free T3 if TSH is suppressed, then determine the underlying etiology using TSH-receptor antibodies and thyroid imaging.

Initial Biochemical Testing

• Measure serum TSH first as the primary screening test, which has sensitivity above 98% and specificity greater than 92% for detecting thyroid dysfunction 1, 2
• If TSH is suppressed (typically <0.1 mIU/L), proceed immediately to measure free thyroxine (FT4) and free triiodothyronine (FT3) to distinguish overt from subclinical hyperthyroidism 1, 3, 2
• Overt hyperthyroidism is defined as suppressed TSH with elevated FT4 and/or FT3, affecting approximately 0.2-1.4% of people worldwide 1
• Subclinical hyperthyroidism is defined as suppressed TSH with normal FT4 and FT3, affecting approximately 0.7-1.4% of people worldwide 1

Etiological Diagnosis After Biochemical Confirmation

Once hyperthyroidism is biochemically confirmed, the next critical step is determining which disease is causing it:

TSH-Receptor Antibody Testing

• Measure TSH-receptor antibodies (TRAb) to identify Graves disease, which is the most common cause of hyperthyroidism with a global prevalence of 2% in women and 0.5% in men 1, 2
• Positive TRAb confirms Graves disease as the etiology in approximately 70% of hyperthyroidism cases 2
• Also measure thyroid peroxidase antibodies (TPO antibodies) as part of the autoimmune workup 2

Thyroid Imaging

• Perform thyroid ultrasonography as first-line imaging to determine thyroid size, vascularity, and to identify nodules (location, size, number, and characteristics) 2, 4
• Thyroid scintigraphy with radioiodine (I-123 preferred over I-131) or 99mTc-pertechnetate is recommended if thyroid nodules are present or the etiology remains unclear after initial testing 5, 2, 4

The scintigraphic patterns distinguish:

• Graves disease: Diffusely increased uptake throughout the gland 4
• Toxic multinodular goiter (TMNG): Multiple areas of increased uptake with suppressed background (16% of hyperthyroidism cases) 2, 4
• Toxic adenoma (TA): Single area of increased uptake with suppressed background 4
• Destructive thyroiditis: Decreased or absent uptake (3% of cases from subacute granulomatous thyroiditis) 2, 4

Radioiodine Uptake Test

• Perform radioiodine uptake measurement when planning radioiodine therapy, as it provides essential dosimetric information 5, 4
• The uptake test confirms that tissue is functioning thyroid and helps differentiate hyperthyroidism (increased uptake) from thyroiditis (decreased uptake) 5

Special Imaging Considerations

When Goiter is Present

• US confirms that the neck mass arises from the thyroid and characterizes goiter size and morphology 5
• If obstructive symptoms are present (dysphagia, orthopnea, voice changes), imaging quantifies tracheal compression 5, 1
• CT neck is superior to US for evaluating substernal extension and retropharyngeal space involvement, though iodinated contrast is not necessary unless infiltrative neoplasm is suspected 5

Doppler Ultrasound

• Doppler US may serve as an alternative to nuclear medicine for distinguishing overactive thyroid (Graves disease, toxic adenoma) from destructive causes (thyroiditis) 5
• Overactive thyroid shows increased blood flow, while destructive thyroiditis shows decreased flow 5
• However, radionuclide uptake study remains preferred because it directly measures thyroid activity rather than inferring it from blood flow 5

Drug-Induced Hyperthyroidism

• For amiodarone-induced thyrotoxicosis, 99mTc-sestamibi scintigraphy differentiates type 1 (iodine-induced, shows uptake) from type 2 (destructive, no uptake) 4
• US can also distinguish: Type I shows enlarged or nodular thyroid, while Type II shows normal or small diffuse goiter 5

Clinical Presentation Clues

• Graves disease patients typically present with diffusely enlarged thyroid, stare, or exophthalmos on examination 1
• Toxic nodular disease patients may have symptoms from local neck compression (dysphagia, orthopnea, voice changes) 1
• Common thyrotoxicosis symptoms include anxiety, insomnia, palpitations, unintentional weight loss, diarrhea, and heat intolerance 1

Less Common Etiologies to Consider

• Drug-induced hyperthyroidism accounts for 9% of cases (amiodarone, tyrosine kinase inhibitors, immune checkpoint inhibitors) 2
• Factitious hyperthyroidism from exogenous thyroid hormone ingestion 4
• Trophoblastic disease, thyroid hormone resistance, struma ovarii (rare causes) 5

Critical Pitfalls to Avoid

• Never skip TSH-receptor antibody testing when trying to distinguish Graves disease from toxic nodular disease, as this avoids unnecessary imaging 2
• Do not order FDG-PET/CT as initial imaging for goiter or hyperthyroidism evaluation—it is not recommended 5
• Avoid performing CT or MRI with IV contrast for simple goiter evaluation unless infiltrative neoplasm is suspected 5
• In multinodular goiter, compare the radionuclide scan to US to identify hypofunctioning or isofunctioning nodules that require biopsy to exclude malignancy 5
• Recognize that thyroiditis causes thyrotoxicosis without hyperthyroidism—these patients have decreased radioiodine uptake and require different management (symptomatic care or glucocorticoids, not antithyroid drugs) 3, 4