Recommended Antibody Testing for Low TSH
For patients with low TSH levels, thyroid stimulating hormone receptor antibody (TRAb) testing is the recommended antibody test, which can be measured as either thyroid stimulating antibody (TSAb) or TSH-binding inhibitor immunoglobulin (TBII). 1, 2
Diagnostic Approach for Low TSH
Initial Assessment
- Low TSH with elevated free T4 or T3 indicates thyrotoxicosis, which may be due to Graves' disease or thyroiditis 1
- Thyrotoxicosis (high free T4 or total T3 with low or normal TSH) can occur secondary to thyroiditis or Graves' disease 1
- Thyroiditis is more common with anti-PD1/PD-L1 drugs, while Graves' disease is rare and more common with anti-CTLA-4 drugs 1
Recommended Antibody Testing
- TRAb testing is the primary antibody test for patients with low TSH 2, 3
- TRAb can be measured in two ways:
- Both TSAb and TBII have high sensitivity and specificity for diagnosing Graves' disease 4, 3
Additional Testing When Thyroiditis is Suspected
- TRAb or TSI (thyroid stimulating immunoglobulin) to rule out Graves' disease 1
- TPO (thyroid peroxidase) antibody testing 1
- Imaging studies when feasible: radioactive iodine uptake scan (RAIUS) or Technetium-99m thyroid scan if recent iodinated contrast was used 1
Clinical Significance of Test Results
Graves' Disease
- Positive TRAb (TSAb and/or TBII) is the hallmark of Graves' disease 5, 2
- TRAb measured with 2nd and 3rd generation immunoassay methods have very high sensitivity (97-98%) and specificity (97-99%) in diagnosing Graves' disease 3
- The likelihood of a TRAb-positive individual having Graves' disease is 1367- to 3420-fold greater compared to a TRAb-negative person 3
Thyroiditis
- Typically TRAb negative 1
- Thyroiditis is a self-limiting process that often leads to permanent hypothyroidism after approximately 1 month following the thyrotoxic phase 1
- TPO antibodies may be positive 1
Management Implications
Graves' Disease
- Requires antithyroid medication (e.g., methimazole or propylthiouracil) 1
- May eventually need definitive therapy (radioactive iodine or surgery) 1
- TRAb levels can help predict clinical course and response to therapy 4
Thyroiditis
- Conservative management during thyrotoxic phase 1
- Non-selective beta blockers may be needed for symptomatic patients 1
- Monitor thyroid hormone levels every 2-3 weeks 1
- Thyroid hormone replacement may be needed when hypothyroidism develops 1
Clinical Pitfalls and Caveats
- Low TSH with low free T4 suggests central hypothyroidism, which requires evaluation for hypophysitis 1
- Clinical diagnosis alone compared to TRAb testing has a sensitivity of 88% but specificity of only 66%, indicating clinicians are liable to both over- and under-diagnose Graves' disease 6
- In patients receiving immunotherapy, thyroid dysfunction (including thyroiditis) is reported in 6-20% of patients 1
- When both adrenal insufficiency and hypothyroidism are present, steroids should always be started prior to thyroid hormone to avoid an adrenal crisis 1
- Endocrinology consultation is recommended in all cases of suspected or confirmed hyperthyroidism or thyroiditis 1