When to Order TSH‑Receptor Antibody (TRAb) and Thyroid‑Peroxidase Antibody (TPO‑Ab) Tests
Order TRAb When You Need to Diagnose or Manage Graves' Disease
Order TRAb to confirm Graves' disease in any patient with biochemical hyperthyroidism (suppressed TSH with elevated free T4/T3), as a positive result establishes the diagnosis while a negative result points toward other etiologies. 1, 2
Specific Clinical Scenarios Requiring TRAb Testing
Differential diagnosis of thyrotoxicosis: Order TRAb when TSH is suppressed and free T4/T3 are elevated to distinguish Graves' disease from toxic nodular goiter, thyroiditis, or exogenous thyroid hormone excess 1, 2
Predicting remission in Graves' disease: Measure TRAb at diagnosis and again at the time of antithyroid drug withdrawal—persistently elevated levels identify patients unlikely to achieve remission and may guide decisions toward definitive therapy (radioiodine or surgery) 1, 2
Pregnancy with current or past Graves' disease: Order TRAb in any pregnant woman with active Graves' disease or a history of Graves' disease (even if previously treated with radioiodine or thyroidectomy) to assess risk of fetal and neonatal thyroid dysfunction—this should be done in early pregnancy and repeated in the third trimester 1, 2
Graves' orbitopathy in euthyroid or hypothyroid patients: When a patient presents with orbital signs (proptosis, diplopia, periorbital edema) but has normal or low thyroid function, TRAb can confirm the diagnosis of Graves' orbitopathy even without concurrent hyperthyroidism 1, 2
Understanding TRAb Assay Types
Two classes of TRAb assays exist: binding immunoassays (which detect antibody binding to TSH receptor) and bioassays (which measure functional stimulating or blocking activity)—bioassays provide more clinically useful information about antibody potency and functional activity 2, 3
Ordering both TRAb and TSI (thyroid stimulating immunoglobulin) on the same encounter is redundant in most scenarios, as they show good clinical agreement—choose one test rather than paired orders to avoid unnecessary costs (31-325% increase) and potential discordant results 3
Order TPO‑Ab to Identify Autoimmune Thyroid Disease and Predict Progression to Hypothyroidism
Order TPO‑Ab when TSH is elevated (even with normal free T4) to confirm autoimmune etiology, as positive antibodies identify patients at 4.3% annual risk of developing overt hypothyroidism versus 2.6% in antibody-negative individuals. 4, 5, 6
Specific Clinical Scenarios Requiring TPO‑Ab Testing
Subclinical hypothyroidism (TSH 4.5-10 mIU/L with normal free T4): Measure TPO‑Ab to stratify progression risk and guide treatment decisions—positive antibodies support earlier intervention, especially in symptomatic patients or those planning pregnancy 5, 6
Newly diagnosed type 1 diabetes: Check TPO‑Ab (and anti-thyroglobulin antibodies) soon after diagnosis, as 25% of children with type 1 diabetes have thyroid autoantibodies at diagnosis, and their presence predicts future thyroid dysfunction 4
Suspected Hashimoto's thyroiditis: Order TPO‑Ab when clinical features suggest autoimmune hypothyroidism (goiter, family history, other autoimmune conditions)—99.3% of Hashimoto's patients are TPO‑Ab positive 7, 6
Monitoring thyroid cancer patients: When measuring thyroglobulin for differentiated thyroid cancer surveillance, always order anti-thyroglobulin antibodies (TgAb) simultaneously, as their presence interferes with thyroglobulin assays and can mask true levels—a negative TgAb reduces but does not exclude interference 5, 1
Unexplained symptoms with borderline thyroid function: In patients with fatigue, weight changes, or other hypothyroid symptoms but TSH in the 2.5-4.5 mIU/L range, TPO‑Ab positivity confirms thyroid autoimmunity and may justify closer monitoring or a therapeutic trial 5, 6
Interpreting TPO‑Ab Results
TPO‑Ab cannot differentiate between Graves' disease and Hashimoto's thyroiditis—74% of Graves' patients and 99.3% of Hashimoto's patients are TPO‑Ab positive, so thyroid function tests (TSH, free T4) determine which condition is present 5, 6
TPO‑Ab is more predictive than anti-thyroglobulin antibodies for progression to hypothyroidism in multivariate analysis, making it the preferred antibody test for risk stratification 4, 5
TPO‑Ab levels typically decline with levothyroxine treatment in hypothyroid patients, but only 16% achieve complete antibody normalization—the primary treatment goal is maintaining euthyroidism, not antibody suppression 5
Common Pitfalls to Avoid
Do not order thyroid antibodies during acute metabolic stress (hyperglycemia, ketosis, severe illness)—thyroid function tests may be misleading due to euthyroid sick syndrome, and antibody testing should wait until metabolic stability is achieved 4
Do not assume negative TPO‑Ab excludes autoimmune thyroid disease—approximately 8% of normal controls have detectable TPO‑Ab, and some patients with autoimmune thyroiditis may be antibody-negative, particularly early in disease 7
Avoid ordering both TRAb and TSI simultaneously—this paired testing is redundant in 14-17% of orders and leads to discordant results in 6-13% of cases without improving diagnostic accuracy 3
Do not use TPO‑Ab levels to guide levothyroxine dosing—antibody titers do not correlate reliably with thyroid function or treatment requirements; dose adjustments should be based on TSH and free T4 5
Screening for Associated Autoimmune Conditions When Antibodies Are Positive
When TPO‑Ab is positive, consider screening for other autoimmune conditions including type 1 diabetes (fasting glucose, HbA1c), celiac disease (IgA tissue transglutaminase with total IgA), Addison's disease (21-hydroxylase antibodies, morning cortisol), and pernicious anemia (vitamin B12) 4, 5
Patients with positive thyroid antibodies and type 1 diabetes require TSH monitoring every 1-2 years or sooner if symptoms develop, as the combination carries particularly high risk of thyroid dysfunction 4