Thyroglobulin and Anti-Thyroglobulin Antibodies

Thyroglobulin (Tg) is a 660 kDa iodinated glycoprotein made only by thyroid follicular cells. It is the storage form of thyroid hormone and is present in small amounts in the blood of anyone with thyroid tissue. After total thyroidectomy and radioiodine ablation, no thyroid tissue should remain, so a measurable Tg indicates residual thyroid tissue or cancer. It is measured by immunoassay in serum, reported in microg/L (ng/mL), and always with a test for anti-thyroglobulin antibodies (TgAb), which interfere with it.

The test is the main tumour marker for differentiated thyroid cancer (papillary and follicular), used after treatment to judge cure and to detect recurrence. It has no value in diagnosing thyroid cancer in a nodule, since Tg is raised in most thyroid diseases. It also helps to explain thyrotoxicosis (factitious thyrotoxicosis has low Tg) and neonatal hypothyroidism (thyroid dysgenesis).

Differentiated thyroid cancer accounts for over 90% of thyroid cancers, and survival is over 95% at 10 years in low risk disease. Recurrence occurs in 10 to 30% of patients and can be decades later, so lifelong follow up with Tg is the rule. TgAb are present in about 20 to 25% of patients with thyroid cancer, twice the rate in the general population (about 10%).

Indications. Follow up after total or near total thyroidectomy with or without radioiodine for differentiated thyroid cancer, assessment of response to treatment, detection of recurrence, evaluation of thyrotoxicosis with low iodine uptake (to separate thyroiditis and factitious thyrotoxicosis), congenital hypothyroidism with absent uptake, and investigation of unexplained neck mass with a suspected thyroid origin.

Specimen. Serum, taken with simultaneous TgAb and TSH. Biotin supplements must be stopped for at least 48 hours (several days at high doses), because they interfere with most assays. Record whether the patient is on levothyroxine, and whether thyrotropin alfa has been given.

Reference range. In people with an intact thyroid: about 3 to 40 microg/L, assay specific, and related to gland volume and TSH. After thyroidectomy, the aim is an undetectable value, using a functional sensitivity of under 0.1 microg/L (high sensitivity assays) or under 0.2 to 1 microg/L.

Interpretation after treatment.

• Excellent response: Tg under 0.2 microg/L on levothyroxine (suppressed TSH), or under 1 microg/L after TSH stimulation, with negative imaging and negative TgAb. Recurrence risk is under 1 to 4%.
• Indeterminate response: Tg 0.2 to 1 microg/L on treatment, or 1 to 10 microg/L after stimulation, or stable low level TgAb. Close observation is usual.
• Biochemical incomplete response: Tg over 1 microg/L on treatment, or over 10 microg/L after stimulation, or rising TgAb, with negative imaging.
• Structural incomplete response: any Tg level with imaging showing disease.
• A rising trend in Tg on repeated measurement is more informative than a single value, and a doubling time under 1 year indicates aggressive disease.

Stimulated Tg. Measured after thyroid hormone withdrawal or after two intramuscular injections of recombinant TSH (thyrotropin alfa) 24 hours apart, with sampling on day 3 to 5. It is more sensitive than basal Tg, but with modern high sensitivity assays a basal value under 0.1 microg/L predicts a negative stimulated test in most patients.

Anti-thyroglobulin antibodies. Always tested on the same sample, since they falsely lower immunoassay Tg (and rarely raise it with radioimmunoassay). A persistent TgAb after thyroidectomy suggests residual thyroid tissue, and a falling trend is a sign of cure while a rising trend suggests recurrence. TgAb in the first year after surgery may be high and slowly fall over 1 to 3 years.

Other causes of raised Tg.

• Graves disease, toxic nodular goitre and thyroiditis (subacute and painless), with release of stored Tg.
• Benign goitre and nodules.
• Thyroid biopsy, surgery, palpation or radioiodine therapy (transient).
• Iodine deficiency, hypothyroidism from thyroid dysgenesis (high Tg with low uptake means a gland present but poorly functioning).
• Liquid state medicines such as lithium (rarely).

Low Tg in thyrotoxicosis. A low or undetectable Tg with raised thyroid hormone suggests exogenous thyroid hormone (factitious thyrotoxicosis), while a high Tg suggests thyroiditis or Graves disease.

Critical values and findings needing immediate action.

• A rising Tg or TgAb after treatment, or a Tg over 10 microg/L stimulated or over 1 microg/L basal: neck ultrasound and further imaging.
• A new neck mass, hoarseness, dyspnoea or bone pain in a thyroid cancer survivor with a raised Tg.
• Very high Tg (over 1000 microg/L) with a normal looking neck, which suggests distant metastases in lung or bone.
• A falsely undetectable Tg with a progressing mass (TgAb interference or loss of Tg production by dedifferentiated tumour).

Interferences and pitfalls.

• Tg without TgAb is uninterpretable. A negative Tg in a patient with TgAb has no value.
• The hook effect in very high Tg (over 1000 to 50 000 microg/L) can produce a falsely low result, and dilution is used when the clinical picture does not match.
• Heterophile antibodies cause false positives and false negatives.
• Biotin interferes, with false lowering in sandwich assays.
• Tg assays differ, and a change in method needs a new baseline. Results from different methods are not interchangeable.
• Remnant thyroid tissue after incomplete surgery raises Tg without cancer.
• Dedifferentiated tumours stop making Tg while remaining aggressive, and imaging is needed.
• The interval since treatment matters, and Tg may take several months to fall after surgery or radioiodine (half life about 65 hours).
• Tg testing is not used in medullary or anaplastic thyroid cancer.

Special groups.

• Children: differentiated thyroid cancer is more extensive at presentation, and Tg is followed lifelong.
• Pregnancy: Tg rises modestly, and follow up is adapted.
• Patients after lobectomy only: Tg has limited value, since the remaining lobe makes it, and trend and imaging are used.
• Patients with Hashimoto thyroiditis: TgAb are frequent, and Tg may be uninterpretable.
• Regions: iodine deficiency raises Tg in healthy people, and Tg screens iodine status in populations.

Follow up tests. TSH and free T4, TgAb trend, neck ultrasound with fine needle aspiration (Tg washout), whole body radioiodine scan, FDG PET-CT, CT of chest and neck (non-contrast, because of iodine), tumour molecular testing (BRAF, RAS, RET, TERT), and calcitonin when medullary carcinoma is considered.