Can Thyroid-Stimulating Hormone (TSH) and free Thyroxine (T4) be normal in someone with elevated Thyroid Receptor Antibodies (TRAb)?

Can TSH and Free T4 Be Normal with Elevated TRAb?

Yes, TSH and free T4 can be completely normal in someone with elevated TRAb (thyroid receptor antibodies). This represents a recognized clinical scenario that occurs in several distinct contexts.

Clinical Scenarios Where This Occurs

Transient Thyrotoxicosis with Positive TRAb

• Patients with transient thyrotoxicosis can have mildly elevated TRAb (TSI or TBII) that resolve spontaneously without treatment, typically within 2-14 weeks, demonstrating that positive TRAb does not always indicate Graves' disease 1
• In these cases, TRAb levels are typically elevated less than twice the upper limit of the reference range, and patients achieve spontaneous resolution without thionamides or radioactive iodine 1
• For clinically stable patients presenting without pathognomonic evidence of Graves' disease, mildly elevated TRAb results require cautious interpretation, and alternative diagnostic testing or close monitoring should be considered 1

Post-Radioiodine Treatment

• Following 131I treatment for nontoxic goiter, patients can develop TRAb with initially normal thyroid function, though this may progress to hyperthyroidism in approximately 5% of cases within 3 months 2
• At the time of 131I treatment, all patients have serum TRAb values within the normal range, but TRAb can appear subsequently even in patients who remain euthyroid 2

Subclinical or Evolving Graves' Disease

• In early Graves' disease, TRAb may be present before overt thyroid dysfunction develops, as all 277 untreated Graves' patients in one study had positive TRAb (TSAb and/or TBII), but the timing of antibody appearance relative to thyroid dysfunction varies 3
• The presence of TRAb has high sensitivity and specificity for diagnosing Graves' disease (92% had both positive TSAb and positive TBII), but this does not mean thyroid function is always abnormal at the time of antibody detection 3

Immunotherapy-Related Thyroid Dysfunction

• Patients on immune checkpoint inhibitors can have thyroid antibodies (including anti-TSH receptor antibodies) with normal thyroid function, and even subclinical hypothyroidism should prompt consideration of thyroid hormone replacement if fatigue or other complaints are present 4
• Thyroid dysfunction occurs in 5-10% with anti-PD-1/PD-L1 therapy and 20% with combination immunotherapy, but routine monitoring includes TSH and FT4 before every infusion or monthly 4

Critical Management Considerations

When to Monitor vs. Treat

• For asymptomatic patients with elevated TRAb but normal TSH and free T4, close monitoring is appropriate rather than immediate treatment 1
• Repeat thyroid function tests in 3-6 months to assess for any changes in thyroid function, as progression to overt dysfunction may occur 5
• If thyroid function remains normal at 3-6 month follow-up, continue monitoring annually 5

Common Pitfalls to Avoid

• Do not initiate treatment based solely on the presence of thyroid antibodies without evidence of thyroid dysfunction, as many asymptomatic persons with thyroid autoantibodies may receive unnecessary treatment despite normal thyroid function 5
• Avoid relying on a single set of thyroid function tests—confirm abnormal results with repeat testing before making treatment decisions 5
• Consider that TRAb positivity in the context of normal thyroid function may represent transient thyroiditis, early autoimmune disease, or a false positive result requiring careful clinical correlation 1

Special Populations Requiring Different Approaches

• Patients with elevated anti-TPO antibodies pretreatment have a 51% complication frequency compared to 15% in those with normal anti-TPO levels, indicating that baseline autoimmune markers predict risk of developing thyroid dysfunction 2
• For patients on immunotherapy, continue monitoring TSH every cycle for the first 3 months, then every second cycle thereafter, as late endocrine dysfunction can occur 4

Diagnostic Algorithm

• Measure both TSH and free T4 to distinguish between euthyroid status, subclinical dysfunction, and overt dysfunction 5
• If TSH becomes abnormal on follow-up testing, obtain free T4 to differentiate between subclinical and overt thyroid dysfunction 5
• Consider measuring anti-TPO antibodies to identify autoimmune etiology, which predicts higher risk of progression (4.3% per year vs 2.6% in antibody-negative individuals) 6
• In patients with persistently elevated TRAb but normal thyroid function, consider thyroid ultrasound and clinical assessment for Graves' orbitopathy, as TRAb levels have been linked to orbital involvement 7