Thyroid Biomarkers: Thyroglobulin

Optimal Takeaways

Thyroglobulin is a precursor to thyroid hormones and a storage depot for iodine which is used in the production of T3 and T4. An increase in thyroid stimulating hormone increases thyroglobulin and will increase T3 and T4 when iodine is sufficient. However, persistently elevated thyroglobulin may reflect iodine insufficiency. Thyroglobulin may also be elevated with thyroid cancer, goiter, inflammation, thyroiditis, Hashimoto’s, Graves’ disease, and smoking. Low thyroglobulin can be observed with thyroidectomy, thyrotoxicosis, congenital hypothyroidism, and elevated Tg antibodies which can cause a falsely low Tg serum level.

Standard Range: 2.80 – 40.90 ng/mL (2.80 – 40.90 ug/L)  

The ODX Range: 5.00 – 14.00 ng/mL (5.00 – 14.00 ug/L)

Low levels of thyroglobulin are associated with thyroidectomy, elevated Tg autoantibodies, which can mask Tg levels with radioimmunoassay Tg testing (Indrasena 2017), thyrotoxicosis factitia (Cahoon 2013), and congenital hypothyroidism (Chanoine 2001).

High levels of thyroglobulin may be associated with iodine insufficiency, increasing TSH, untreated Graves’ disease, subacute thyroiditis, increasing thyroid gland volume, thyroid nodules (Cahoon 2013), Hashimoto’s (Pagana 2021), goiter (Ovadia 2014), thyroid cancer recurrence or metastasis, residual tissue following thyroid surgery (Indrasena 2017), and cigarette smoking (Belin 2004, Bertelsen 1994).          

Overview

Thyroglobulin (Tg) is a glycoprotein precursor to thyroid hormones T3 and T4, which have three or four iodine molecules attached to Tg, respectively. Under normal circumstances, thyroglobulin is produced exclusively by the follicular cells of the thyroid gland under the influence of thyroid-stimulating hormones. The level of Tg in the blood generally reflects the mass of the thyroid gland, i.e., 1 ng/mL per gram of thyroid tissue. A serum Tg of 20-25 ng/mL reflects a normal-sized thyroid gland of 20-25 grams. However, serum levels can be influenced by gender and iodine intake. Reference ranges may increase in the event of iodine deficiency, which stimulates TSH release and thyroglobulin production. However, Tg levels should be very low or near zero following total thyroidectomy. An increase over time may reflect residual thyroid tissue or metastases, which may be associated with Tg levels above 5,000 ng/mL (Indrasena 2017).

Additional Tg can leak into the bloodstream due to inflammation, Hashimoto’s, Graves, nodular goiter, or cancer and can trigger an immune antibody response. Thyroglobulin antibodies should be measured alongside TPO antibodies in the evaluation of autoimmune thyroid disease (Pagana 2021).

Mean thyroglobulin levels in healthy adults range from 5-14 ng/mL, while levels in those with endemic goiter have a mean level of 94-208 ng/mL (Ma 2014). Evaluation of thyroglobulin reference ranges in a cohort of 438 healthy non-smoking euthyroid subjects revealed an overall mean Tg level of 9.15 ng/mL and a median value of 7.5 ng/mL, with levels being lower in males than females. The National Academy of Clinical Biochemistry criteria that were used to establish a healthy population included non-smokers with a TSH range between 0.5-2.0 mIU/L, no history or physical evidence of thyroid disease, and no thyroid autoantibodies, i.e., TgAb or TPOAb (Giovanella 2012).

Thyroglobulin protein is a major storage site for iodine, and increasing thyroglobulin may serve as an indicator of iodine deficiency as thyroid volume increases (Cahoon 2013). Selenium availability also influences thyroglobulin levels, and supplementation reduced elevated thyroglobulin in children with congenital hypothyroidism. This effect may be due to enhanced conversion of T4 to T3 at the cellular level (Chanoine 2001).

NOTE regarding thyroglobulin levels

Thyroglobulin levels may be monitored in individuals with thyroid cancer who have had a thyroidectomy and ablation of the thyroid gland. The test is used to detect residual or recurrent thyroid cancer.

The standard thyroglobulin reference range for athyrotic individuals is very low and does not apply to those with an intact thyroid. Ranges also vary depending on the testing method, i.e., Immunoassay versus LC/MS/MS:

Immunoassay method:

• Thyroglobulin Athyrotic: <0.1 ng/mL
• Thyroglobulin Intact Thyroid Standard Range 2.8-40.9 ng/mL

LC/MS/MS (Chromatography/Mass Spectrometry) method:

• Thyroglobulin Athyrotic: <0.4 ng/mL

References

Belin, Ruth M et al. “Smoke exposure is associated with a lower prevalence of serum thyroid autoantibodies and thyrotropin concentration elevation and a higher prevalence of mild thyrotropin concentration suppression in the third National Health and Nutrition Examination Survey (NHANES III).” The Journal of clinical endocrinology and metabolism vol. 89,12 (2004): 6077-86. doi:10.1210/jc.2004-0431

Bertelsen, J B, and L Hegedüs. “Cigarette smoking and the thyroid.” Thyroid : official journal of the American Thyroid Association vol. 4,3 (1994): 327-31. doi:10.1089/thy.1994.4.327

Cahoon, Elizabeth K et al. “Factors associated with serum thyroglobulin levels in a population living in Belarus.” Clinical endocrinology vol. 79,1 (2013): 120-7. doi:10.1111/cen.12107

Chanoine, J P et al. “Selenium decreases thyroglobulin concentrations but does not affect the increased thyroxine-to-triiodothyronine ratio in children with congenital hypothyroidism.” The Journal of clinical endocrinology and metabolism vol. 86,3 (2001): 1160-3. doi:10.1210/jcem.86.3.7312

Giovanella, Luca et al. “Serum thyroglobulin reference values according to NACB criteria in healthy subjects with normal thyroid ultrasound.” Clinical chemistry and laboratory medicine vol. 50,5 891-3. 26 Jan. 2012, doi:10.1515/cclm.2011.756

Indrasena, Buddhike Sri Harsha. “Use of thyroglobulin as a tumour marker.” World journal of biological chemistry vol. 8,1 (2017): 81-85. doi:10.4331/wjbc.v8.i1.81

Ma, Zheng Feei, and Sheila A Skeaff. “Thyroglobulin as a biomarker of iodine deficiency: a review.” Thyroid : official journal of the American Thyroid Association vol. 24,8 (2014): 1195-209. doi:10.1089/thy.2014.0052

Ovadia, Yaniv S et al. “Elevated Serum Thyroglobulin and Low Iodine Intake Are Associated with Nontoxic Nodular Goiter among Adults Living near the Eastern Mediterranean Coast.” Journal of thyroid research vol. 2014 (2014): 913672. doi:10.1155/2014/913672

Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 15th ed., Mosby, 2021.