Interpretation

Current guidelines recommend measurement of thyroglobulin (Tg) with a sensitive immunoassay limit of quantification below 1 ng/mL; for measurements of unstimulated Tg, the detection limit should be in the 0.1 to 0.2 ng/mL range.

In all cases, serum antithyroglobulin autoantibodies (TgAb) should also be measured, preferably with a method that allows detection of low concentrations of TgAb (≤20 kIU/L). If TgAb are detected, the laboratory report should alert the ordering provider to the possibility of false-low Tg results. If the apparent Tg concentration is below 1 ng/mL, the sample should be remeasured by mass spectrometry. This will allow confident detection of Tg in the presence of TgAb down to 0.2 ng/mL (risk of residual/recurrent disease <1-3%).

Samples from patients with Tg concentrations above 1 ng/mL (or 2 ng/mL; there is some discussion in the literature) might not require Tg measurement by mass spectrometry, because current guidelines suggest further work-up may be necessary above this threshold. However, the positive predictive value for residual/recurrent disease is modest at best when Tg is just above this threshold (3%-25%, rising in parallel with Tg concentrations up to 10 ng/mL) in athyrotic patients. Above 10 ng/mL, the risk of residual/recurrent disease is at least 25%, with many studies showing 60% to >90% risks. In selected patients, it might also be useful to test TgAb positive samples by mass spectrometry, even if the Tg concentration is above 1.0 ng/mL but has not yet passed the 10 ng/mL threshold. These considerations are even more relevant in patients with a known thyroid remnant of a few grams, who may always have serum Tg concentrations between 1.0 and 10 ng/mL, owing to remnant Tg secretion, regardless of the presence or absence of residual/recurrent cancer.

There are no routine tests that can detect heterophile antibodies in patient samples. An unexpected high result is usually the tip-off in this case and should prompt remeasurement by mass spectrometry, which will provide a reliable result.

It has been determined that the presence of TgAb in serum can lead to underestimation of Tg concentration by immunoassay methods. When antibodies are present in samples with detectable Tg, the Tg values may be underestimated by up to 60% in immunoassays. In addition, 20% of specimens containing antibodies that are negative for Tg by immunoassay tested positive by liquid chromatography tandem mass spectrometry (LC-MS/MS); no results over 3 ng/mL by LC-MS/MS were observed.

In rare cases, when Tg is measured in patients with an intact thyroid gland who do not have thyroid cancer, substantial elevations will primarily be observed in very large goiters, highly active Graves disease, and, most pronounced, in the early phase of acute thyroiditis when follicular destruction releases massive amounts of stored Tg into the circulation. Levels are often well above 100 ng/mL.