Antibodies to Order for New Overt Hyperthyroidism
For new overt hyperthyroidism, order TSH receptor antibodies (TRAb or TSI) as the primary antibody test to diagnose Graves' disease, and add thyroid peroxidase (TPO) antibodies to identify underlying autoimmune thyroid disease. 1, 2
Primary Antibody Testing Algorithm
First-Line: TSH Receptor Antibodies
- TSH receptor antibodies (TRAb) or thyroid stimulating immunoglobulin (TSI) are essential to distinguish Graves' disease from other causes of thyrotoxicosis. 1
- Graves' disease accounts for approximately 70% of hyperthyroidism cases, making TRAb/TSI the most clinically useful initial antibody test. 2
- These antibodies directly cause hyperthyroidism by stimulating the TSH receptor, unlike TPO antibodies which are markers of autoimmune activity but don't cause hyperthyroidism. 2
Second-Line: Thyroid Peroxidase Antibodies
- TPO antibodies should be measured when thyroiditis is suspected or to identify underlying autoimmune thyroid disease. 1
- TPO antibodies are present in more than 70% of patients with Graves' disease and almost all patients with Hashimoto's thyroiditis. 3
- The presence of TPO antibodies indicates lymphocytic infiltration of the thyroid gland and helps predict the natural history of disease progression. 3
Clinical Context for Antibody Selection
When Graves' Disease is Suspected
- Order TRAb/TSI when clinical features suggest Graves' disease: diffuse goiter, ophthalmopathy, or dermopathy. 2
- Positive TRAb/TSI confirms Graves' disease as the etiology and guides treatment decisions toward antithyroid drugs, radioactive iodine, or surgery. 2
- However, TRAb may be negative in subclinical or mild Graves' disease, so negative antibodies don't exclude the diagnosis. 4
When Thyroiditis is Suspected
- TPO antibodies help distinguish destructive thyroiditis (painless thyroiditis, postpartum thyroiditis, subacute thyroiditis) from Graves' disease. 1
- In thyroiditis, the thyrotoxic phase is self-limiting and typically leads to hypothyroidism after 1-2 months, requiring different management than Graves' disease. 1
- Thyroiditis accounts for approximately 3% of hyperthyroidism cases but is more common with immune checkpoint inhibitor therapy. 1, 2
Additional Diagnostic Tests Beyond Antibodies
Imaging Studies When Antibodies Are Equivocal
- Radioactive iodine uptake scan (RAIUS) or Technetium-99m thyroid scan should be obtained when antibody results are negative or equivocal. 1
- High uptake indicates Graves' disease or toxic nodular goiter (16% of hyperthyroidism cases), while low uptake suggests thyroiditis. 1, 2
- Recent iodinated contrast exposure requires Technetium-99m instead of radioactive iodine. 1
Thyroid Ultrasound
- Ultrasound helps identify toxic nodular goiter versus diffuse thyroid enlargement in Graves' disease. 2
- Ultrasound can detect nodules requiring further evaluation and assess thyroid vascularity. 2
Special Clinical Scenarios
Immune Checkpoint Inhibitor-Induced Thyrotoxicosis
- Thyroiditis is the most common cause of thyrotoxicosis with anti-PD1/PD-L1 drugs, while Graves' disease is rare but occurs more with anti-CTLA-4 agents. 1
- Order both TRAb/TSI and TPO antibodies to distinguish between these etiologies, as management differs significantly. 1
- Thyroid dysfunction occurs in 6-20% of patients on immune checkpoint inhibitors, requiring routine monitoring. 1
Postpartum Thyrotoxicosis
- TPO antibodies are particularly useful in postpartum women, as postpartum thyroiditis occurs with high frequency in TPO-positive women. 3
- The presence of TPO antibodies predicts transient thyroiditis rather than new-onset Graves' disease. 3
Critical Pitfalls to Avoid
Don't Rely Solely on Antibodies
- Negative TRAb/TSI doesn't exclude Graves' disease, especially in mild or subclinical hyperthyroidism. 4
- In one study, TRAb was positive in only 2 of 6 patients with subclinical Graves' disease, demonstrating the limitations of antibody testing alone. 4
- Always correlate antibody results with clinical presentation, thyroid hormone levels, and imaging studies. 1, 2
Don't Order Thyroglobulin Antibodies Routinely
- Anti-thyroglobulin antibodies are less predictive than TPO antibodies for autoimmune thyroid disease in multivariate analysis. 5
- Reserve anti-thyroglobulin testing for cases where TPO is negative but clinical suspicion for autoimmune disease remains high. 5
Timing of Antibody Testing
- Avoid antibody testing during acute illness, as thyroid function tests may be misleading due to non-thyroidal illness. 5
- Wait until the patient is clinically stable before ordering antibodies to confirm autoimmune etiology. 5
Prognostic Value of Antibodies
Predicting Disease Course
- TPO antibodies correlate with the degree of lymphocytic infiltration and predict progression from hyperthyroidism to hypothyroidism. 6, 3
- In Graves' disease, extensive thyroiditis can eventually cure hyperthyroidism, resulting in hypothyroidism—a natural progression more likely in TPO-positive patients. 6
- After radioactive iodine treatment, TPO positivity at diagnosis is associated with reduced relapse rates (13.9% vs 24.6%). 7