What laboratory tests should be ordered to diagnose hyperthyroidism?

Laboratory Testing for Hyperthyroidism

Order TSH first, followed by free T4 and free T3 if TSH is suppressed, then add TSH receptor antibodies (TRAb) to establish the etiology. 1, 2

Initial Screening Approach

Start with serum TSH as the primary screening test for suspected hyperthyroidism, as it has sensitivity above 98% and specificity greater than 92%. 3 A suppressed or low TSH confirms biochemical hyperthyroidism and triggers the need for additional testing. 1

Confirmatory Hormone Testing

Once TSH is low, measure:

• Free T4 (FT4) to quantify the degree of thyroid hormone excess 1, 2
• Free T3 (FT3) because some patients have isolated T3 toxicosis where FT4 may be normal but FT3 is elevated 1, 2
• Free thyroid hormones are superior to total hormones because they are not influenced by binding protein abnormalities that can give misleading results 4

In suspected hyperthyroidism, FT3 measurement is particularly important since it may be the only elevated hormone in early or mild cases, and FT4 can occasionally be elevated in euthyroid patients on certain medications like amiodarone. 4

Etiologic Testing

After confirming biochemical hyperthyroidism (low TSH with elevated FT4 and/or FT3), measure TSH receptor antibodies (TRAb) to diagnose Graves' disease, which accounts for 70% of hyperthyroidism cases. 1, 2

• Both American and European Thyroid Associations strongly recommend TRAb measurement for accurate diagnosis and management of Graves' disease 2
• Binding assays for TRAb have clinical sensitivity of 97.4% and specificity of 99.2%, making them the best first-line test 2
• If TRAb is negative, proceed to radioiodine uptake scan to differentiate toxic nodular goiter (16% of cases) from other causes 1, 2

Additional Antibody Testing

• Thyroid peroxidase antibodies (TPO) can help identify autoimmune thyroid disease, though they are less specific for Graves' disease than TRAb 1
• Consider anti-thyroglobulin antibodies in selected cases, though these are less diagnostically useful for hyperthyroidism specifically 2

Imaging Studies

Thyroid ultrasonography helps evaluate nodular disease and goiter size, which has prognostic implications for treatment response. 1

Radioiodine scintigraphy is indicated when:

• TRAb is negative, to distinguish toxic nodular goiter from destructive thyroiditis 1, 2
• There is diagnostic uncertainty about the etiology 2
• Diffuse increased uptake confirms Graves' disease; focal uptake indicates toxic nodular disease; low/absent uptake suggests destructive thyroiditis 1

Common Pitfalls to Avoid

• Do not rely on total T4 or T3 alone, as these are affected by binding protein abnormalities (TBG excess/deficiency, familial dysalbuminemic hyperthyroxinemia) that can falsely suggest thyroid dysfunction in euthyroid patients 4
• Do not skip FT3 measurement when FT4 is normal but TSH is suppressed, as isolated T3 toxicosis occurs in a significant proportion of hyperthyroid patients 4, 5
• Do not order TRH stimulation tests in the modern era, as sensitive TSH assays have made this obsolete for hyperthyroidism diagnosis 5
• In elderly patients, recognize that low TSH is often not associated with true hyperthyroidism, requiring careful clinical correlation 5

Special Clinical Contexts

For patients on antithyroid drugs being monitored, TSH may remain suppressed for months after achieving euthyroidism, while FT3 is a better indicator of current thyroid status. 5 In these cases, total T3 or FT3 may remain elevated even when FT4 drops, indicating persistent hyperthyroidism despite a normalizing FT4. 5

For pregnant patients or those with suspected complications (atrial fibrillation, thyroid storm), the same initial testing algorithm applies, but results should prompt urgent specialist consultation. 1