Significance of Thyroglobulin in Thyroid Function Tests
Thyroglobulin (Tg) has no role in the initial diagnosis of thyroid cancer or routine thyroid function testing, but it is essential as a tumor marker for post-treatment surveillance of differentiated thyroid carcinoma after total thyroidectomy. 1, 2
Role in Initial Diagnosis
- Tg measurement is not helpful for diagnosing thyroid cancer in patients presenting with thyroid nodules 1, 2
- Tg levels can be elevated in both benign thyroid diseases (multinodular goiter, thyroiditis, Graves' disease) and malignant conditions, making it non-specific for cancer detection 3, 4
- The diagnostic workup should focus on TSH levels, ultrasound characteristics, and fine needle aspiration cytology instead 1
Critical Role in Post-Treatment Surveillance
After total thyroidectomy for differentiated thyroid cancer, Tg becomes the most important tumor marker for detecting residual or recurrent disease. 1, 2
Surveillance Timeline and Interpretation:
At 2-3 months post-treatment:
- Measure TSH, FT3, and FT4 to verify adequate levothyroxine suppressive therapy 1, 2
- Do not rely on Tg at this early timepoint due to surgical trauma effects 5
At 6-12 months post-treatment (the critical assessment):
- Measure both basal Tg (on levothyroxine) and rhTSH-stimulated Tg with anti-thyroglobulin antibodies 1, 2
- Stimulated Tg <1.0 ng/mL with negative neck ultrasound indicates complete remission with <1% recurrence risk at 10 years 1, 2
- Stimulated Tg 0.1-2.0 ng/mL requires yearly rhTSH stimulation testing 1
- Stimulated Tg ≥2.0 ng/mL warrants imaging for disease localization 1
For long-term follow-up:
- Annual basal Tg measurement on levothyroxine therapy with neck ultrasound 1, 2
- Rising Tg trends indicate possible recurrent disease requiring further investigation 1, 6
Modern High-Sensitivity Assays
- Newer assays with functional sensitivity <0.1 ng/mL allow some patients to avoid rhTSH stimulation 1
- When basal Tg ≤0.1 ng/mL with unremarkable neck ultrasound, patients can be considered disease-free (NPV = 100%) 1
- However, basal Tg >0.1 but <1.0 ng/mL cannot reliably distinguish presence or absence of disease, requiring rhTSH stimulation 1
Critical Pitfalls to Avoid
Anti-thyroglobulin antibody interference:
- Always measure anti-Tg antibodies concurrently, as approximately 25% of patients have interfering antibodies 2, 5
- TgAbs cause false-negative results in immunometric assays and false-positive results in radioimmunoassay 5
- Interference can occur even when TgAbs are not detected by some assays 5
Assay-specific considerations:
- Despite international standardization, significant inter-assay variability exists 5
- Monitor patients with the same Tg assay throughout follow-up to avoid misinterpretation due to assay bias 5
TSH-dependent secretion:
- Tg secretion is TSH-dependent, making interpretation impossible without knowing concurrent TSH levels 5
- Suppressed TSH (on levothyroxine) yields lower Tg values than stimulated conditions 1
Timing after intervention:
- Surgical trauma, biopsy, or radioiodine treatment transiently elevates Tg levels 5
- Wait appropriate intervals (2-3 months minimum) before using Tg for surveillance decisions 1, 2
Alternative Clinical Uses
Beyond thyroid cancer surveillance, Tg measurement can help diagnose: