Thyroglobulin and thyroglobulin antibodies in differentiated thyroid cancer: interpretation, challenges, and future perspectives.

Thyroglobulin (Tg) is a thyroid-specific protein playing a key role in thyroid hormone production. For patients with differentiated thyroid carcinoma (DTC), Tg is the main biomarker during follow-up determining treatment response and risk of disease recurrence. Accurate Tg measurement is complicated by assay-specific performance and interference, most notably thyroglobulin autoantibodies (TgAbs). High-sensitivity Tg assays can detect very low Tg levels, eliminating the need for TSH-stimulated Tg measurements. Because of potential TgAb interference in Tg assays, TgAb measurement must always accompany Tg analysis. TgAbs are present in a minority of healthy individuals, but in up to one-third of patients with DTC. While low-level TgAbs are often clinically irrelevant, higher titres interfere with Tg immunoassays, possibly causing false-negative Tg results. Importantly, TgAb trends themselves provide prognostic information: declining concentrations support remission, whereas rising titres may indicate recurrence, offering a potential useful surrogate marker when Tg is unreliable. Alternative and complementary laboratory strategies are emerging. Novel proteomic approaches may allow isoform-specific Tg detection, potentially distinguishing tumour-derived Tg from normal Tg. In parallel, liquid biopsy technologies, particularly cell-free DNA, circulating tumour DNA, and microRNA assays, are being explored for non-invasive detection of minimal residual disease, although their role in DTC remains to be defined. In summary, Tg and TgAbs remain the mainstay of laboratory monitoring in DTC. Their interpretation demands awareness of assay limitations, appropriate cut-offs, and the clinical context. Future integration of advanced proteomic and genomic biomarkers holds promise for more specific, individualized surveillance strategies in thyroid cancer.