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Thyroglobulin (Tg) is a large glycoprotein that is synthesized in thyroid follicles and serves as the precursor of thyroid hormone (T4). Small amounts of thyroglobulin are secreted into the serum of normal individuals. Serum levels are proportional to thyroid size. Destruction of thyroid follicles by inflammation or neoplasia results in an increase in serum Tg concentrations.

Tg is not recommended as a screening or diagnostic test for thyroid cancer because serum levels often overlap the concentration found in normal individuals or patients with benign thyroid diseases.

Measurement of serum Tg is primarily used to detect recurrence of follicular thyroid cancer following total thyroidectomy and radioactive iodine ablation. Serum concentration reflects the sum of Tg from normal thyroid tissue and residual or recurrent tumor. Follwing thyroidectomy for thyroid cancer, approximately 10% of patients have tumor recurrence within the first 10 years after surgery and an additional 5% have an even later recurrence.

A preoperative serum Tg level has no diagnostic or prognostic significance by itself, but does document that Tg can be followed postoperatively as a tumor marker for that patient. Preoperative specimens should either be drawn before fine needle aspirate (FNA) or more than 3 weeks following FNA. The sensitivity of postoperative serum Tg is highest when the tumor is relatively small (2 cm or less) and the preoperative serum Tg value is high. If the preoperative Tg level is within normal limits, an undetectable postoperative Tg value is less reassuring, because it is unclear whether the tumor originally secreted Tg.

Following thyroid surgery, serum Tg concentrations fall rapidly with a half-life of 2 to 4 days. Any Tg released from surgical margins should disappear within the first month after surgery. During this time TSH is the dominant influence on serum Tg level. If thyroid hormone therapy is initiated immediately before surgery to prevent the rise in TSH, serum Tg concentration will decline to a level that reflects the size of the normal thyroid remnant  plus any residual or metastatic tumor. Each gram of thyroid remnant contributes approximately 1 ng/mL (ng/mL = ug/L) to serum Tg in patients with a detectable TSH level and 0.5 ng/mL in those with suppressed TSH. Since the thyroid remnant left after near total thyroidectomy typically approximates 2 grams of tissue, a serum Tg concentration less than 2 ng/mL is expected when the patient has undergone successful near-total thyroidectomy and has serum TSH maintained below 0.1 mU/L. Tumor recurrence is usually associated with a progressive rise in serum Tg. Post-treatment levels above 5 ng/mL usually indicate recurrent cancer.

The value of Tg measurement for thyroid cancer follow-up is diminished in patients with more than a remnant of postsurgical thyroid tissue. Consequently, many physicians recommend postsurgical radioactive iodine (RAI) remnant ablation to enhance the ability of Tg to detect recurrence.

The success of RAI ablation has been traditionally assessed by diagnostic RAI scanning or by postablation stimulated Tg measurements, either after thyroid hormone withdrawal or, more commonly in recent years, after recombinant TSH (rhTSH) administration. However, neither of these approaches is ideal because thyroid withdrawal is unpleasant and rhTSH is costly.

Current guidelines recommend using functional sensitivity to define the sensitivity of Tg methods. Functional sensitivity is the lowest Tg concentration that can be measured with 20% coefficient of variation determined by multiple measurements over a period of 6 to 12 months. First generation Tg assays , such as radioimmunoassay and many immunometric assays, have a functional sensitivity of 0.5 to 1.0 ng/mL. First generation assays are too insensitive to detect tumor recurrence without TSH stimulation.  A Tg level above 2.0 ng/mL after a 72 hour rhTSH stimulation is considered to be a risk factor for recurrent tumor. However, this fixed cutoff point has been shown to have a low positive predictive value for disease of only 50%.

Newer second generation immunometric assays for Tg have a functional sensitivity of 0.05 to 0.1 ng/mL. These assays are sensitive enough to detect tumor recurrence and obviate the need for rhTSH stimulation as long as thyroglobulin antibody is not present. Unstimulated serum Tg levels <0.1 ng/mL during follow-up exclude thyroid cancer recurrence, except in patients with thyroglobulin antibodies and in very rare individuals with highly dedifferentiated tumors (J Clin Endocrinol Metab 2007;92:82-87).

Serum concentrations of Tg are highly specific for thyroid tissue in the body, but are not specific for malignancy. Elevated thyroglobulin serum levels may also be found in patients with endemic and multinodular goiter, Grave's disease, congenital TBG deficiency, benign adenomas, and acute thyroiditis.

A high dose hook effect can occur when using immumetric assays to measure very high concentrations of Tg. Very high concentrations overwhelm, the assays binding capacity and produce falsely low values. Hook effect should be considered when measuring Tg in saline wash-outs of biopsy needles, where Tg concentration may exceed 10,000 ng/mL.

Both thyroglobulin antibodies and human anti-mouse antibodies (HAMA) may interfere with Tg immunoassays. Tg antibodies can cause falsely low or undetectable Tg levels that may mask the presence of tumor recurrence.

HAMA bind to murine monoclonal antibody used in the Tg immunoassay and produce a false signal. Most immunometric Tg assays contain blocking reagents to minimize interference from HAMA. Very high concentrations of HAMA can overwhelm these blocking reagents and produce a falsely elevated Tg level that may lead to unnecessary imaging or radioiodine treatment. Physicians should suspect HAMA when the Tg concentration does not correlate with a patient’s clinical condition or when Tg concentration does not increase after TSH stimulation.

Tg can be reliably measured in patients with thyroglobulin antibodies using mass spectrometry.

Reference range for thyroglobulin is 0 – 35 ng/mL.


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