Thyroglobulin (Tg)

Thyroglobulin (Tg) Overview

Thyroglobulin (Tg) is a large glycoprotein produced exclusively by the follicular cells of the thyroid gland. It serves as the essential protein scaffold or substrate upon which thyroid hormones – thyroxine (T4) and triiodothyronine (T3) – are synthesized and stored within the thyroid follicles (colloid).

Small amounts of Tg normally leak into the bloodstream from the healthy thyroid gland. However, its primary clinical significance lies in its use as a highly specific tumor marker for monitoring patients with Differentiated Thyroid Cancer (DTC), specifically Papillary Thyroid Cancer (PTC) and Follicular Thyroid Cancer (FTC), after the thyroid gland has been surgically removed (thyroidectomy).

Tg Biology and Function

Tg is a large dimeric protein with a molecular mass of approximately 660 kDa. It is synthesized within the thyroid follicular cells and secreted into the follicular lumen (the colloid space), which constitutes the bulk of the thyroid gland's colloid.

Within the colloid, tyrosine residues on the Tg molecule are iodinated, and then coupled together to form T4 and T3, which remain stored as part of the Tg molecule until needed. When stimulated by Thyroid-Stimulating Hormone (TSH) from the pituitary gland, the follicular cells take up colloid, break down the Tg molecule via proteolysis, and release the active thyroid hormones (T4 and T3) into the bloodstream. A small amount of intact Tg also enters the circulation during this process.

Therefore, the presence of detectable Tg in the blood signifies the presence of either normal thyroid tissue or differentiated thyroid cancer tissue derived from follicular cells.

Clinical Indications for Tg Testing

Measuring serum Thyroglobulin (Tg) levels is indicated primarily for:

1. Monitoring Differentiated Thyroid Cancer (DTC) after Initial Treatment: This is the main application. After total thyroidectomy (surgical removal of the thyroid gland) and often radioactive iodine (RAI) ablation to destroy any remaining thyroid cells (normal or cancerous), Tg levels should ideally become undetectable or very low. Serial Tg measurements are used to:
   • Assess the effectiveness of initial therapy (surgery and RAI ablation).
   • Detect persistent or residual disease.
   • Monitor for recurrence (local or distant metastasis) during long-term follow-up. A rising Tg level is often the earliest sign of recurrence.
2. Assessment Before RAI Therapy: Pre-ablation Tg levels (usually measured after thyroidectomy while TSH is elevated) can help predict the likelihood of residual disease or metastases.
3. Differential Diagnosis of Congenital Hypothyroidism: In newborns with hypothyroidism, measuring Tg can help determine if the cause is thyroid agenesis (absent thyroid, resulting in undetectable Tg) or dyshormonogenesis (thyroid present but not making hormone properly, often associated with high Tg).
4. Evaluation of Thyrotoxicosis Factitia: Undetectable Tg levels in a patient with signs of hyperthyroidism (thyrotoxicosis) and suppressed TSH strongly suggests exogenous thyroid hormone intake (surreptitious use).
5. Assessing Iodine Status (Population Level): Tg levels can reflect iodine intake in populations (research context).
6. Monitoring Benign Thyroid Conditions (Limited Use): May sometimes be measured in patients with large goiters or thyroiditis, but levels are variable and less clinically useful than in the post-thyroidectomy cancer setting. Its use in monitoring individuals exposed to radiation for general thyroid disease risk is not standard practice; thyroid ultrasound and TSH are primary tools.

Tg testing is not useful for the initial diagnosis of thyroid cancer when the thyroid gland is still present, as levels can be elevated in many benign thyroid conditions (like goiter, nodules, Graves' disease, thyroiditis).

Interpretation of Tg Levels

Interpretation depends heavily on the clinical context, particularly whether the patient has had a total thyroidectomy and RAI ablation, and their current TSH level.

• Reference Range (Intact Thyroid): In individuals with a normal thyroid gland, serum Tg levels vary widely but are typically detectable, often ranging up to around 30-50 µg/L (ng/mL). The original text reference of < 50 µg/L reflects this broad normal range in the presence of a thyroid.
• Post-Thyroidectomy / Post-Ablation Goal: After successful total thyroidectomy and RAI ablation for DTC, the goal is usually an undetectable Tg level, especially when TSH is suppressed (by thyroid hormone replacement therapy). Modern sensitive assays may have undetectable limits < 0.1 or < 0.2 µg/L.
• Stimulated vs. Suppressed Tg: TSH stimulates Tg production by both normal and cancerous thyroid cells. Therefore, Tg levels are more sensitive for detecting residual/recurrent disease when TSH is elevated (either by withdrawing thyroid hormone medication or using recombinant human TSH - rhTSH).
  • TSH-Suppressed Tg: Measured while the patient is taking thyroid hormone replacement to keep TSH low. An undetectable suppressed Tg is reassuring.
  • TSH-Stimulated Tg: Measured after TSH becomes elevated. A detectable or rising stimulated Tg is more concerning for persistent or recurrent disease.
• Interpreting Detectable/Rising Levels Post-Treatment:
  • Any detectable Tg after total thyroidectomy/ablation may indicate residual thyroid tissue (benign remnant or cancer) or metastases.
  • A clear trend of rising Tg levels over time on serial measurements is highly suspicious for recurrent or progressive disease, even if the absolute levels are still low.
  • The magnitude of the Tg level can sometimes correlate with the burden of disease.

Anti-Thyroglobulin Antibodies (TgAb)

It is essential to measure Anti-Thyroglobulin Antibodies (TgAb) every time a serum Tg level is measured.

• Interference: TgAb are autoantibodies that bind to Tg. Their presence in the blood can interfere with most standard Tg immunoassays, typically causing a falsely low or undetectable Tg result, even if significant Tg protein is actually present.
• Prevalence: TgAb are present in about 10% of the general population and 20-25% of patients with DTC.
• Clinical Implication: If TgAb are positive, the measured serum Tg level is unreliable for monitoring DTC. In these TgAb-positive patients, serial monitoring of the TgAb level itself may serve as a surrogate marker for disease status, although this is less reliable than Tg in TgAb-negative patients. A rising TgAb titer may suggest recurrence, while a falling titer after treatment may suggest response.
• Assay Methods: Some newer Tg assays using mass spectrometry may be less prone to TgAb interference, but immunoassays remain standard.

Therefore, concurrent Tg and TgAb testing is mandatory for interpreting Tg results accurately in the context of DTC monitoring.

Other Factors Affecting Tg Levels

• TSH Levels: Higher TSH stimulates Tg production.
• Thyroid Mass: Larger thyroid glands or tumors generally produce more Tg.
• Thyroid Injury/Inflammation: Thyroiditis (Hashimoto's, subacute, postpartum) or thyroid manipulation (surgery, biopsy, palpation) can cause transient release of stored Tg, increasing serum levels.
• Benign Thyroid Conditions: Multinodular goiter, Graves' disease, adenomas can be associated with elevated Tg levels (when the thyroid is present).
• Kidney Failure: May slightly affect clearance, but generally not a major confounding factor.
• Assay Method: Different Tg assays can yield different results; consistency in the laboratory method is important for serial monitoring.

The Tg Blood Test Procedure

• Sample Type: Blood serum.
• Preparation: No fasting is usually required. The key factor is the patient's TSH status (suppressed on medication vs. stimulated after withdrawal or rhTSH injection), which should be known when interpreting results.
• Collection: Standard venipuncture (blood draw from a vein).
• Mandatory Co-Test: Anti-Thyroglobulin Antibodies (TgAb) must always be measured on the same sample.
• Analysis: Performed using sensitive immunoassays (e.g., IMA, ICMA, LC-MS/MS).

References

1. Haugen, B. R., Alexander, E. K., Bible, K. C., Doherty, G. M., Mandel, S. J., Nikiforov, Y. E., ... & American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer Task Force. (2016). 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer. *Thyroid*, 26(1), 1–133. https://doi.org/10.1089/thy.2015.0020
2. Spencer, C. A. (2011). Clinical review: Clinical utility of thyroglobulin antibody (TgAb) measurements for patients with differentiated thyroid cancers (DTC). *The Journal of Clinical Endocrinology & Metabolism*, 96(12), 3615–3627. https://doi.org/10.1210/jc.2011-1740
3. National Cancer Institute (NCI). (n.d.). Thyroid Cancer Treatment (PDQ®)–Health Professional Version. Retrieved from https://www.cancer.gov/types/thyroid/hp/thyroid-treatment-pdq
4. Mayo Clinic Laboratories. (n.d.). Test ID: TGMS - Thyroglobulin, Mass Spectrometry, Serum. Test Catalog. Retrieved from https://www.mayocliniclabs.com/test-catalog/Overview/62731 (Example of a specific Tg assay)
5. Lab Tests Online. (n.d.). Thyroglobulin and Thyroglobulin Antibody. Retrieved from https://labtestsonline.org/tests/thyroglobulin-and-thyroglobulin-antibody