What is a stimulated thyroglobulin (Tg) test?

What is a Stimulated Thyroglobulin Test?

A stimulated thyroglobulin (Tg) test is a blood test that measures thyroglobulin levels after deliberately raising thyroid-stimulating hormone (TSH) levels, either by withdrawing thyroid hormone medication or by administering recombinant human TSH (rhTSH), to detect residual or recurrent differentiated thyroid cancer after thyroidectomy. 1

Purpose and Clinical Context

The stimulated Tg test serves as the most sensitive marker for detecting persistent or recurrent well-differentiated thyroid cancer in patients who have undergone thyroidectomy with or without radioactive iodine ablation. 2, 3 Since thyroglobulin is produced by normal thyroid tissue and almost all non-medullary thyroid cancers, any detectable Tg after total thyroidectomy indicates either residual normal thyroid tissue or cancer. 4

Methods of TSH Stimulation

There are two approaches to achieve adequate TSH stimulation:

Thyroid Hormone Withdrawal

• Traditional method: Withdraw levothyroxine (T4) for 4-6 weeks or liothyronine (T3) for 2 weeks to allow endogenous TSH to rise. 1
• Shortened protocol: Some evidence supports T4 withdrawal for only 3 weeks as sufficient for TSH stimulation in low-risk patients, reducing hypothyroid morbidity. 5
• Target TSH level: Adequate stimulation typically requires TSH ≥25-30 mIU/L. 5

Recombinant Human TSH (rhTSH/THYROGEN)

• Dosing: 0.9 mg intramuscular injection to the buttock, followed by a second 0.9 mg injection 24 hours later. 3
• Timing of Tg measurement: Blood sample should be obtained 72 hours after the final rhTSH injection. 3
• Advantage: Avoids hypothyroid symptoms associated with hormone withdrawal. 1

Interpretation of Results

Post-Ablation Follow-up (6-12 months after initial treatment)

Excellent response indicators:

• Stimulated Tg <1 ng/mL with negative imaging indicates complete remission with recurrence rate <1% at 10 years. 1, 2, 6
• These patients do not require repeat stimulated Tg testing. 2

Biochemical incomplete response:

• Stimulated Tg 1-10 ng/mL warrants closer surveillance and consideration of additional imaging. 1
• Stimulated Tg >10 ng/mL suggests significant residual disease and may prompt radioiodine therapy. 1

High-Sensitivity Assays

Modern assays with functional sensitivity <0.2 ng/mL allow some patients to avoid TSH stimulation:

• Basal Tg <0.1 ng/mL with negative ultrasound has 100% negative predictive value for disease. 1
• Basal Tg 0.1-1.0 ng/mL remains indeterminate and may still benefit from stimulated testing. 1, 7

Critical Limitations and Pitfalls

Anti-thyroglobulin antibodies (TgAb) interference:

• TgAb must be measured with every Tg test, as these antibodies can cause false-negative or false-positive results. 2, 6, 3
• Even with negative or low stimulated Tg, patients with TgAb should be evaluated further as Tg levels may be uninterpretable. 3

Discordance with imaging:

• Stimulated Tg levels after rhTSH are generally lower than those after thyroid hormone withdrawal and do not directly correlate. 3
• Even with negative radioiodine scans, there remains risk of missing disease or underestimating extent. 3
• One study found 64% discordancy rate between positive whole-body scans and negative Tg levels. 8

Assay consistency:

• The same Tg assay should ideally be used throughout follow-up to minimize variability. 2, 6

Clinical Application Timeline

Initial assessment (2-3 months post-surgery):

• Measure basal Tg and TgAb on levothyroxine to establish baseline. 1, 2

Definitive evaluation (6-12 months post-surgery):

• Perform stimulated Tg test with neck ultrasound to classify treatment response. 1, 2, 6
• This determines subsequent surveillance intensity and TSH suppression targets. 1, 6

Higher-risk patients:

• Those with lymph node metastases (N1 disease) should undergo stimulated Tg testing even if basal Tg is undetectable. 1
• Concomitant radioiodine imaging may help determine if radioiodine therapy is indicated. 1