Clinical Information

Thyroglobulin (Tg) is a highly thyroid-specific large homodimeric glycoprotein (approximately 660 kDa). It contains 8% to 10% of carbohydrates and iodine. Thyroxine (T4) and triiodothyronine (T3) are synthesized on Tg within the lumen of thyroid follicles. For T4 and T3 release, Tg is reabsorbed into thyrocytes and proteolytically degraded, liberating T4 and T3 for secretion. Small amounts of intact Tg are secreted alongside T4 and T3 and are detectable in the serum of healthy individuals, with levels roughly paralleling thyroid size (0.5-1.0 ng/mL Tg per gram thyroid tissue, depending on thyrotropin [TSH] level). In situations of disordered thyroid growth (eg, goiter), increased thyroid activity (eg, Graves disease), or glandular destruction (eg, thyroiditis), larger amounts of Tg may be released into the circulation.

Clinically, the main use of serum Tg measurements is in the follow-up of differentiated follicular cell-derived thyroid carcinoma. Because Tg is highly organ-specific, serum Tg concentrations should be undetectable, or very low, after the thyroid gland is removed during primary treatment for thyroid cancer.

Current clinical guidelines consider a serum Tg of more than 1 ng/mL in an athyrotic individual as suspicious of possible residual or recurrent disease. To improve diagnostic accuracy, it is recommended this measurement be initially obtained after TSH stimulation, either following thyroid hormone withdrawal, or after injection of recombinant human TSH. Most patients will have a relatively low risk of recurrence and thereafter, will only require unstimulated Tg measurement.

If unstimulated (on thyroxine) serum Tg measurements are less than 0.1 to 0.2 ng/mL, the risk of disease is below 1%. Patients with higher Tg levels, who have no demonstrable remnant of thyroid tissue, might require additional testing, such as additional stimulated Tg measurements, neck ultrasound, or isotope imaging. A stimulated Tg above 2 ng/mL is considered suspicious.

There are 3 situations, when serum Tg measurement may be misleading:

1. Remnant thyroid tissue (see above, 0.5-1 ng/mL Tg per gram)

2. Antithyroglobulin autoantibodies (TgAb), which occur in 15% to 30% of thyroid cancer patients, can lead to false-low measurement in immunometric assays (most commonly used); in competitive assays they may cause false-high results.

3. Heterophile antibodies (HAb), which are antibodies that are capable of interacting with the antibodies used in immunoassays, usually resulting in false-high measurements. Depending on the assay and the patient population, this can lead to erroneously high results in 0.1% to 3.0% of patients.

Traditionally, there have been no reliable means to obtain accurate Tg measurements in patients with TgAb or HAb. However trypsin digestion of serum proteins, which cuts both antibodies and Tg into predictable fragments, has allowed accurate quantification of Tg in samples with antibody interferences through measurement of Tg-specific tryptic peptides by mass spectrometry.