Thyroglobulin (Tg) is a thyroid-specific glycoprotein (approximately 660 kDa) that serves as the source for thyroxine (T4) and triiodothyronine (T3) production 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 thyroid-stimulating hormone [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 thyroid-specific, serum Tg concentrations should be undetectable or very low after the thyroid gland is removed during treatment for thyroid cancer.
Current clinical guidelines consider a serum Tg concentrations above 1 ng/mL in an athyreotic 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 will thereafter 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 remnants of thyroid tissue might require additional testing, such as further stimulated Tg measurements, neck ultrasound, or isotope imaging. A stimulated Tg above 2 ng/mL is considered suspicious.
The presence of antithyroglobulin autoantibodies (TgAb), which occur in 15% to 30% of patients with thyroid cancer, could lead to misleading Tg results. In immunometric assays, the presence of TgAb can lead to falsely low results, whereas it might lead to falsely high results in competitive assays.
Traditionally, there have been no reliable means to obtain accurate Tg measurements in patients with TgAb. However, recently 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 by mass spectrometry. See TGMS / Thyroglobulin Mass Spectrometry, Serum for accurate analysis of patients who are known to be TgAb positive. If TgAb status is unknown, see HTGR / Thyroglobulin, Tumor Marker Reflex, Serum. When HTGR is ordered, TgAb testing is performed first. If TgAb is negative (<1.8 IU/mL), Tg is assayed by immunoassay (sensitive down to 0.1 ng/mL). If TgAb is positive, Tg is assayed by mass spectrometry (sensitive down to 0.2 ng/mL).
